Tag Archives: Hypertension

VITAMINs K2+D3 – VITAMIN DUO OF THE NEXT DECADE

update 16 May 2016.   to our health: neil.burman@gmail.com

HIGH TO MASSIVE DOSE VITAMIN D3 IMPORTANCE – TEN TIMES MORE THAN MAXIMUM SUNLIGHT CAN PROVIDE – IN REVERSING  COMMON VIT D DEFICIENCY/RESISTANCE FOUND IN ALL MAJOR DISEASE eg ALL  INFECTIONS, INSOMNIA, MULTIPLE SCLEROSIS MS,  Myasthenia Gravis, SLE, RA, PARKINSON’S, DEPRESSION, VASCULAR DISEASE, CANCER, VITILLIGO, PSORIASIS,  PERIPHERAL NEUROPATHIES, MENTAL ILLNESS.

  introduction:     Cape Town is the world epicenter of epidemics (of poverty – malnutrition- HIV- HAART- TB –Diabetes, asthma-COPD,  and vitamin D  and iodine deficiency). And we  are seeing neuroarthropathy with a vengeance in our township clinics, where a majority of such diabesity or/and HIV patients  admit if questioned to chronic burning cramping legs  and sore muscles/joints if not also consequent insomnia, falls and leg ulcers.

Poor ill patients  seem to  accept it- neuroarthropathy-  as a way of life since it  usually has no visible signs (for anyone to see) till late– poor circulation, ulcers, falls,  arthritis- , and  malnourished diabesity patients  have bigger worries with uncontrolled diabetes and often uncontrolled hypertension despite even insulin; and the HIV+-Tuberculosis patients  have the multiple toxic burdens of antiretroviral and antituberculous therapy.

Because the burden of these diseases as well as stress from corruption and violence  here  is amongst the highest in a major city in the world, affecting especially the poorest and most illiterate labourers, state clinics rarely have budgets to cover the necessary vitamin and mineral supplements the poor  also need on their poverty fast food diet.

Our patients  accept that in return for life extension by designer antimicrobials and antidiabetic/ antihypertensives, all they will get for pain relief  is the combination of physiotherapy, and  designer synthetic palliative drugs- paracetamol, ibrufen /diclofenac, tramadol, amitryptiline, and if lucky some ung meth sal . These factory-synthesised drugs  give little relief,  and no improvement in prognosis since they do not address the proximate causes of the neuroarthropathy,  associated depression and  work incapacity (and later strokes, arthritis, dementia, ulcers, gangrene, chronic lung/heart/ liver/ kidney/visual disease)- respective causes including stress,  infective, drug-induced, tissue glycogenation, the misguided fast-food high carbohydrate-low fat diet  obesity; and manual labour/multiple trauma  wear and tear, and nutritional deficiency including much-needed marine and saturated fats, vitamins and minerals..

The pioneer  work discussed below in Pakistan(Salahuddin ea, Basit ea), Italy (Cipriani ea) and Brazil (Coimbra ea) in using respectively Vit D3 ~700 000iu loading dose and chronically up to 1000iu /kg/day ie average 70 000iu/day, up to 120000iu per day to reverse deadly acute and chronic disease,  is comparable in its simplicity safety and low cost to :

*Semmelweis’ revolutionary discovery  Vienna in the mid 19thC  of hand disinfection to decimate childbirth sepsis deaths; and

*Pauling’s landmark lifesaving escalation of Vit C dose to a gm  per kg per day for all severe disease; and

*the parallel discovery in UK and USA of the crucial role of not just the RDA preventative microdose but also the pharmacological anti-disease benefits of 10 to 100times bigger doses of all the vitamins B complex 1 to 12.

Cipriani ea 2010 seems to be the first report on Pubmed of deliberate oral dosing with  megadose     600 000iu vit D3 ie 10 000iu/kg, albeit only in health to assess bloodlevel response and safety. Since then, as we previously noted, 2 million unit single overdose in nonagenarians in Netherlands  has been shown to do no harm – ie about 40 000iu/kg. .

And as the Australians and others report below, there is no hint of vigorous vitamin or mineral  supplements being stigmatized as performance enhancing for eg sport –  despite vitamin D3 having the distinction of being truly an anabolic ie performance-enhancing (seco)steroid .

There is no point in giving vitamin D by injection (except in those in ICU on prolonged nil per mouth) since it is so well absorbed provided given with fat eg in fishoil/coconut/DMSO oil. And obviously the higher the dose given, the more important to avoid more than a traditional multisupplement pill a day  with low calcium and vitamin A retinol; combined with a low calcium diet (ie low dairy low peanut) ; and supplementing plenty fresh green produce [providing magnesia a few hundred mgs a day, and vitamin K2 perhaps 35mcg/d].

Dr  Mike Holick Prof of Medicine at Boston University interviewed by Dr Joe Mercola Dec 2015 details  the  rationale underpinning the (eg Coimbra) massive vit D3 dose regime for severe immune disease, “as opposed to  plenty of sensible sun exposure for general good health and lower deathrate from all diseases and infections.                 Most melanoma occurs on the least sunexposed skin, with lower melanoma and all other deaths with high sun exposure. Dark days promote melatonin and thus daytime sleepiness and depression- which bright light in the morning for an hour reverses, and elevates b-endorphan, which has many times the painkilling effect of morphines ie opioids, and antidepressants. Vitamin D deficiency more than doubles the risk of all diseases; even 2000iu vit D3 a day in the 1st yr of life in Finland halved the risk of type 1 diabetes– with loss of protection if vit D dose dropped to 400iu/day. Vitamin D/ sunlight reverse leukemic cells. But maximum sunlight exposure nearer the tropics still only elevates 25OHvit D level to a maximum of about 50ng/ml- whereas increasing evidence proves that it may take more than 10 times that bloodlevel to prevent and treat deadly diseases- depending on your genetic vitamin D receptors.

 Even 1000iu/d vit D with bld level about 30ng/ml halves risk of many cancers, with doubling benefit as 25OHvit D level is doubled serially  eg by 10 000iu/d or 50 000iu/d. The kidneys however limit production of the hypercalcemic 1,25vit D, thus avoiding hypercalcemia provided calcium intake is not supplemented by calcium pills, nuts. vit A  etc. The higher the vit D level above 30ng/ml (up to >? 500ng/ml), the more  of our 2000 enzyme systems are activated  to fight all disease without hypercalcemic risks. Hunter gatherers had levels twice as high as dressed housed people today, around 50ng/ml, with increasing anticancer and antiinfection/antiautoimmune benefit from vit D up to safe levels eg 100ng/ml and higher. .”

At Thisisms.com this is multiple sclerosis  March 2016 seems to be the latest from neurologist  Dr Cicero Coimbra  via grassroots health. He stresses that to cure degenerative/ autoimmune disease eg  MS, Parkinson’s, SLE, RA, vitiligo ie to overcome genetic Vit D resistance may require vit  D titration up to 1000iu/kg/d ie up to even 40000iu/d to 200000iu/d,
And 25OHvitD blood level to 1000ng  and even 4000ng / ml for a few years to produce cure, before reducing to maintenance vit D3  eg 100iu/kg/day ie ~ 50000iu/wk.
Hypercalcemia and thus calcinosis  is avoided provided PTH level is maintained in the low normal range, not suppressed. Optimal support includes low calcium and  high water diet and  Vit B2, magnes selenium zinc phosphor  supps.

      COST IMPLICATION:

The spectrum of vitamin D3 adult dose thus extends from the

traditional prevention RDA 10iu/kg/ ie~700iu/d against rickets (infants start with 1000iu/d or 25000iu ie ½ scoop/month of standardized vit D3  100iu/mg powder)

to  vigorous 100iu/kg/day (ie 50 000iu scoop /wk ) for common disease prevention/treatment (toddlers 2000iu/d/ ½ scoop/fortnight));

 to  massive  1000iu/kg/day eg 60 000iu/dy for severe autoimmune/immunodeficiency diseases – with mandatory monitoring of levels of calcium, creatinine, 25OHvitD3 and now PTH levels;

to mega 10 000iu/kg eg 650 000iu as a loading dose for eg TB or meningitis or severe trauma—which dose may maintain  25OHvit D3 blood levels in a “sufficiency” range above ~40ng/ml for a month or two, so obviously requires appropriate maintenance dosing.

Imported vitamin D3 100cwt concentrate powder (100iu/mg) per kg from an importing pharmacist costs about R500/kg ie R0.50/100 000iu- far lower than the cost of the highrisk plant xenocalciferol vitamin D2. Thus to the State (excluding packaging and dispensing cost) , the wholesale cost of vit D3 is about R0.15 per 50 000iu per week for maintenance dose; or for 50 000iu/day R10( US $0.6)/month ie retail abt R60pm ie US$5  for megadose therapy; compared to the quoted retail US$20/month in Brazil. .

     THE NEUROPATHY OF DIABETES, DRUGS/TOXINS, POST-VIRAL,TRAUMA,  SPONDYLOSIS, DEMENTIA:

PERIPHERAL NEUROPATHY:  Already in 2006 Oh-Park ,Sheehan .ea,  Lancet. Albert Einstein College of Medicine, New York wrote about AIDS-ARV neuropathy Charcot neuroarthropathy in the era of HAART.

Young, Dancho ea Tucson, Arizona, wrote 2012,   ” Charcot arthropathy is a devastating joint condition that affects persons with neuropathy. With HIV/AIDS treatments prolonging the lives of these persons, it is likely that long-term sequelae of the disease will become more evident in the near future. Patients with this disease frequently develop peripheral neuropathy. A high index of suspicion must be raised in any patient with peripheral neuropathy of any cause and a red, hot, swollen, painful foot for Charcot neuroarthropathy to give these patients proper treatment to help prevent the devastating effects of Charcot neuropathy with its potential consequences including foot ulceration and amputation. We know only too well the same applies to diabesity, as it did in the days of heavy smoking.”
In 2013 Zubair ea in India showed that diabetics with foot ulcers had vitamin D levels 1/4 of that of matched diabetics without foot ulcers; and “factors which predict the risk of developing ulcer independent of 25(OH)D status were A1c (>6.9%) [OR 4.3), neuropathy [OR 6.9retinopathy [OR 3.3;  nephropathy [OR 3.1) and smoking [OR 4.5]. It is not clear whether the suppression of delayed wound healing seen during 25(OH)D deficiency is a secondary effect or is a direct action of vitamin D on certain components of the immune system.”  

Tiwari, Singh, Swain  ea at Hindu Universities Uttar Pradesh,India have shown elegantly in                          

    *2012 Tiwari ea   Vascular calcification in diabetic foot and its association with calcium homeostasis.      Vascular calcification (VC), long thought to result from passive degeneration, involves a complex process of biomineralization, frequently observed in diabetes and an indicator of diabetic peripheral vascular disease.. ..In  74 patients with diabetic foot ulcer,   Vascular calcification was present in 42% of patients. Significant difference in vitamin D, HbA1C, and eGFR  levels was observed in VC +ve compared to VC -ve.  Severe vitamin D deficiency was more common in VC +ve (51%) compared to in VC -ve (18%). Sub-group analysis showed that the risk of VC was significantly higher (RR = 2.4, P < 0.05) in patients with vitamin D < 10 ng/ml compared to others. .and        

     * Br J Nutr. 2013. Tiwari  ea  Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection.   In Diabetic Patients with and without  infection (n289), 25(OH)D (nmol/l) was significantly lower (16) v. 20ng/ml  P < 0·001) in cases than in controls. Risk of severe vitamin D deficiency (25(OH)D < 10ng/ml) was significantly higher in cases than in controls (OR 4·0, P < 0·0001). Age, duration of diabetes and HbA1c were significantly higher in cases than in controls and therefore adjusted to nullify the effect of these variables, if any, on study outcome. The study concluded that vitamin D deficiency was more prevalent and severe in patients with diabetic foot infection. ;  and the need for vitamin D supplementation in such patients for a better clinical outcome

*.in  Br J Nutr.. 2014 Tiwari ea  show Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection  . Vitamin D is a potent immunomodulator and  a common deficiency  in different population groups including patients with diabetic foot infection.   in 112 diabetic foot infection cases and 109 diabetic controls , cases had significantly higher concentrations of IL-6 (P≤ 0.001), IL-1β and TNF-α (P≤ 0.006) than controls. Risk of severe vitamin D deficiency (25(OH)D <10ng/ml) was significantly higher in cases than in controls (OR 4·0, P < 0·0001). A significant negative correlation was also observed between 25-hydroxyvitamin D concentration and circulating concentrations of IL-1β (r -0.323; P≤ 0.001) and  IL-6 but not between 25-hydroxyvitamin D and TNF-α and IFN-γ concentrations.

 

This year  2016     Wukich , Sadoskas  ea. University of Pittsburgh & Georgetown USA  in Diabetes Metab Res Rev.  show that (Charcot) neuroarthropathy (CN) of the ankle and hindfoot  is challenging to treat surgically or nonsurgically. Deformities associated with ankle/hindfoot CN are often multiplanar, resulting in  malalignment; and  shortening of the limb often occurs from collapse of the distal tibia, and ankle, with  significant alterations in the biomechanics of the foot. eg predisposing the patient to lateral foot ulceration. Collapse of the talus, secondary to avascular necrosis or neuropathic fracture, further accentuates these deformities and contributes to a limb-length inequality   CONCLUSION:  Surgical reconstruction of ankle and hindfoot CN is associated with a high rate of infectious and noninfectious complications. Preoperative measures that can improve outcomes include assessment of vascular status, optimization of glycemic control, correction of vitamin D deficiency and cessation of tobacco use. 

Now 2016 Basit A,  Malik RA5 ea in  Universities Karachi Pakistan & Manchester UK ,  show that A single intramuscular dose of 600000IU vitamin D in  143 participants with predominantly type 2 diabetes, aged ~ 52.3years, with high Douleur Neuropathique 4 (DN4) score  by  20weeks gave significant increase in 25(OH)D (from 31.7 to 46.2±10.2ng/mL, p<0.0001) and  significant  reduction (p<0.0001)  in positive symptoms on the DN4 , and total pain score (p<0.0001, The Basit – Malik Pakistan-Manchester paper showing great efficacy of 600 000iu vit D3 load dose in peripheral neuropathy diabetics matches the huge 40% improvement benefit of similar loading and monthly vit D3 dose against severe PTB shown by Salahuddin ea in Pakistan in 2013 http://www.ncbi.nlm.nih.gov/pubmed/23331510 that we have previously analyzed in this column

ie  apart from smoking; the very low vitamin D levels common in most but especially ill people  associate   with about 5 fold  risks of uncontrolled diabetes, infections,  retinopathy , progressive leg ulcers, peripheral neuropathy  and arthritis- Charcot arthroneuropathy- -and thus  gangrene and amputation; and vigorous safe (supraphysiological) vit D boost reverses the risks. .

 

And a reminder that a 2015 study in Cape town from Coussens ea Universities in W Cape and Penn State confirm what we see daily in practice, that vitamin D deficiency is endemic  in our population

 

while as we have pointed out repeatedly, the State here continues to dispense the inferior vitamin D2 (as the fraudulently labeled “strong calciferol”, not disclosing that it is ergocalciferol  D2) despite this plant xenohormone vit D2 having been rejected by world authorities in favour of the much cheaper and effective  human D3 cholecalciferol.

 

 

       And now 2016 Cadegiani , Brasilia, Brazil another  landmark massive-vit D dose report ;  Remission of Severe Myasthenia Gravis After Massive-Dose Vitamin D Treatment.Vitamin D has been shown to be related to autoimmune diseases, such as multiple sclerosis and psoriasis. Correlations have been reported between vitamin D levels and prevalence and severity of other autoimmune disorders, and also between vitamin D therapy and disease improvement and remission. This reports a patient with severe and refractory myasthenia gravis (MG) who followed a massive-dose treatment (80,000 to 120,000 IU/day) promoted by a medical center in Brazil  (Coimbra ea) and she had her first complete remission after this type of treatment  for at least 18 months (ie at least 50 million iu) with increased vitamin D serum levels (400 to 700 ng/mL) and major fall in her AChR antibodies – but acute relapse when vit D was inadvertently stopped and her vit D level halved; with again recovery when megadose vit D was resumed  CONCLUSIONS: This case may reinforce the reported correlation between vitamin D level and disease severity and introduces a possible new use for vitamin D as a potential target for treating autoimmune diseases. We recommend large, double-blind, placebo-controlled, randomized studies using high-dose vitamin D treatment for refractory autoimmune diseases to reliably assess this pharmacotherapy target for these diseases

 

     The above case concurs with previous reported massive dose daily vitamin D3: Finamor , Coimbra ea , Universities of Brazil  2013 A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Autoimmunity has been associated with vitamin D deficiency and resistance, with gene polymorphisms related to vitamin D metabolism frequently described. High doses of vitamin D3 may conceivably compensate for inherited resistance to its biological effects. Nine patients with psoriasis and 16 patients with vitiligo received vitamin D3 35,000 IU once daily for six months ie ~7million iu  in association with a low-calcium diet (avoiding dairy products and calcium-enriched foods like oat, rice or soya “milk”) and hydration (minimum 2.5 L daily).. After treatment 25(OH)D3 levels significantly increased (from ~15 to 106-132ng/mL. PTH and 25(OH)D3 serum concentrations correlated inversely. The PASI score significantly improved in all nine patients with psoriasis. Fourteen of 16 patients with vitiligo had 25-75% repigmentation. Serum urea, creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range. High-dose vitamin D3 therapy may be effective and safe for vitiligo and psoriasis patients.

 

 

     neurologist Prof Dr Cicero Coimbra from Univ Sao Paulo  presents their results since 2002 in over 4000 pts ( 1000 patients each with multiple sclerosis and Parkinson’s diseases), who have been well controlled without other therapies,  provided the dose is high enough- 10 000iu/d up to about 1000iu/kg/d eg >70 000iu/d for the obese, on a low calcium ie low dairy/peanuts diet, high fluid intake and high exercise, to normalize blood calcium,  and titrate  PTH level to  the low normal range. Dr Cicero Coimbra discusses  high dose vitamin D toxicity: https://www.youtube.com/watch?v=Vxwk-YPrx7o&feature=youtu.be. PTH level should not be completely suppressed. In their clinic ( of 7 doctors)  for Autoimmune chronic diseases incl MS, RA, SLE, psoriasis, vitiligo, type 1 diabetes ,  they have treated over 4500 pts on this high quality vit D3 high fluid  low calcium diet  protocol, with only 14 cases of reversible vitamin D toxicosis (hypercalcemia) so far detected ie 0.3%. Babies of mothers thus treated in pregnancy  have high psychomotor development. (Vitamin C supplement should not be concurrently excessive to avoid oxalosis). They define success as being disease-free or non-progressive old fixed disabilities- 95% reach full cure. There vit D3 therapy  costs only ~US $20/mo, to optimize the immune system against both infections and autoimmune disease let alone cancer. Optimal dose of vit D3 replacement becomes at least 10 000iu/day for adults especially with autoimmune diseases  due to common vitamin D resistance. Ideally testing baseline blood and urine at baseline and after a few months on at least 10 000iu/d.

 

 

     In Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency:. 2010. Cipriani ,Minisola ea .University of Rome  Italy tested    48 young subjects with vitamin D deficiency with a single oral dose of 600,000 IU of cholecalciferol. The 25(OH)D level was ~15.8ng/ml at baseline and became ~77ng/ml at 3 d (P < 0.001) and ~62 ng/ml at 30 d (P < 0.001). The trends were maintained in a subgroup followed up to 90 d (P < 0.001). Mean serum Ca and P significantly increased compared to baseline, whereas serum Mg decreased at 3 d. CONCLUSIONS: A single oral dose of 600,000 IU of cholecalciferol rapidly enhances 25(OH)D and reduces PTH in young people with vitamin D deficiency.

 

       Looking at some new alarmist myth refs about vit D3 overdose :

Moderate  ie physiological increase in just vitamin D levels and intake  (from average diet and sunshine and a traditional supplement) within the average population bloodlevel range understandably has modest  benefit- reversing at least rickets-  in an  indoor living clothed population, even  1st world middleaged:  from Wisconsin Univ, Karen Hansen ea’s recent RCT – JAMA 2015- Treatment of Vitamin D Insufficiency in Postmenopausal Women confirmed this, showing little practical benefit shortterm (ie over 12mo) between placebo, and supplemented vit D3  5600iu/wk and 25000 iu a week, (~3600iu/d);  the highest dose perhaps doubling the baseline 20ng/ml  25OH vit D level. ie into the low “adequate” range average around 40ng/ml.

Be aware again that  the same university’s group published in 2014   An Evaluation of High-Dose Vitamin D 2  for Rheumatoid Arthritis Karen Hansen ea that vit D2 ~100 00iu/month  for a year actually worsens patients and lowers vit D3 levels  , so there is no longer excuse for using vitamin D2 supplement when it blocks D3 receptors and lowers blood vit D3.

The inferiority of vit D2 was confirmed in eg    Clinical Trial of Vitamin D2 vs D3 Supplementation in Critically Ill Pediatric Burn Patients.  Gottschlich, Kagan U Cincinnati Ohio 201550  patients  aged 1 to 18yrs with burns  were enrolled. All participants received multivitamin supplementation ,  plus , 100 IU/kg D2, D3, or placebo daily  RESULTS: There were no significant differences in serum vitamin D levels between groups, but >10% of patients had low 25OHD  at discharge, and %deficiency worsened by the 1-year follow up for the placebo (75%), D2 (56%), and D3 (25%) groups. There were no statistical differences in clinical outcomes between treatment groups, although vitamin D supplementation demonstrated clinically relevant decreases in exogenous insulin requirements, sepsis, and scar formationThe high incidence of low serum 25OHvit D levels 1 year following serious thermal injury indicates prolonged compromise. Continued treatment with vitamin D3 beyond the acute phase postburn is recommended to counteract the trajectory of abnormal serum levels and associated morbidity. 

The perception seems to be that up to 40 000iu vit D3 a day, a bld level below abt 150-350ng/ml  is safe, ie unsafe above that. The evidence for such ceiling ie  higher dose harm in fact is lacking since as we have previously discussed here,  healthy people have taken up to 150 000iu a day for decades without evidence of harm…  provided they took adequate fluids, and did not take supplements of calcium, or also take high  vitamin A which notoriously causes acute hypercalcemic toxicity, or have rising calcium levels . .

But note that vit K2 improves absorption of vit D3 CHOLECALCIFEROL , and vit K2 and magnesia improve benefit of vit D3,while protecting against overdose effects ie calcification, stones  and confusion.  Problem in many  toxicity reports is that they used either vit D2 ergocalcif (WHICH BLOCKS THE NEEDED D3) , or used accidental massive overdose (millions of units vit D ) daily for months- or massive INJECTIONS) or combined vit D WITH CALCIUM REPLACEMENT AND/ OR EXCESSIVE VITAMIN  A  – which combinations are  dangerous;  we need magnesium (not calcium  or high vitamin A supplements).

    Vitamin D3: What’s the Latest? recent 2015 reviews from  Univ California and CommonHealth contrast the Instit Medicine IOM (Big-Pharma-sponsored)  conservative target of  vit D3 800 to max 4000iu/d with much evidence that safe optimal D3 dose may be up to 10 000 to 50 000iu/d, and up to  1 000 000iu as an acute eg antiinfection  loading dose; with risk of toxicity only if blood level exceeds 150-500ng/ml. the evidence-based IOM recommendation of optimal blood level 20-40ng/ml, up to 2000iu a day promoted by conservatives like Prof JoAnn Manson, contrasts with the more proactive view of eg Prof Michael Hollick and the Vitamin D Council promoting double that dose as supplements, safely up to 10 000iu/day.

 

   SO  I continue to take vit D3 ~70 000iu/wk ie ~10 000iu/d,  with vit K2 supp ~700mcg a wk ie 100mcg/dy and a balanced multisupplement incl. magnesia in addition to a multisupplement A-Z, and fish oil and Lugols iodine 15% 2 drops a day; with if I do get a “flu” attack during bad weather, prompt abolition by a few antibiotic doses of topup Lugols iodine 15% a few tsp (ie ~1000mgs iodine),  and vitamin D3 eg 300 000iu, and vitamin C a few tsp orally and by sniffing. .

The problem with many adverse effect reports of vit D3 overdose eg the Dominican Republic Soladek  2011 report Lowe ea below, and Prof Heaney’s response,  is that they failed to even consider the massive associated  overdose of the far more hypercalcemic vitamin A let alone calcium supp reported by most  patients. It becomes apparent that NO calcium supplement should be encouraged on a prudent diet; but instead supplements of  Vit D3, magnesia, vits K2 and C, CoQ10, and fish oil ; in addition to a balanced (A to Z) RDA-based multisupplement for seniors  like eg Solal’s,  Vital’s Multitime, Centrum etc.. with a low calcium diet if massive dose vitamin D3 is indicated as in autoimmune diseases (Coimbra ea).

Ndb

APPENDIX: RECENT REFS:
VITAMIN D ANABOLIC STEROID ABUSE IN SPORT?

the Australian Govt  Supplement Overview   has an intriguing report on vit D in sports, with no hint of vit D supplement being a steroid abuse. .http://www.ausport.gov.au/data/assets/pdf_file/0003/594174/CORP_33413_SSF_Vitamin_D_FS.pdf        Vitamin D is classified as a fat soluble vitamin which acts functionally as a steroid hormones. There are 2 different isoforms of Vitamin D: D3 (cholecalciferol) which is the important isomer formed in human   skin and D2 (ergocalciferol) which is the plant-derived ie xeno-equivalent. D2 was the first isoform to be characterised   and was first used in Vitamin D supplements and for food fortification. D3 is now considered preferable. D3 is   biologically inert until converted in the liver to 25(OH)D and to 1,25(OH)D in the kidney.  Vitamin D plays an important role in calcium and phosphorous homeostasis (bone health),but more so in  gene expression and cell growth. The recent recognition of Vitamin D receptors in most body tissues indicates a role for Vitamin D in  many aspects of health and function. Vitamin D is now known to be important for optimal muscle function.

         The principal source of circulating vitamin D comes from exposure to ultraviolet B (UVB) radiation from sunlight.   In 2010, the Institute of Medicine issued new Dietary Reference Intakes for Vitamin D, assuming no sunlight exposure: this included a Recommended Dietary Intake of 600 IU/d and an Upper Level intake of 4000 IU/d  (www.iom.edu/vitamind). BUT no evidence has ever been published to support this ceiling intake.

Whereas Vitamin D deficiency can lead to several health issues including increased risk of bone injuries, chronic musculoskeletal pain and viral respiratory tract infections. There is also emerging evidence that supplementing Vitamin D in athletes with sub-optimal Vitamin D levels may   have beneficial effects on athletic performance in particular strength, power, reaction time and balance.

         There is no universally accepted definition of vitamin D deficiency however, the following definitions based on  serum levels of 25(OH) Vitamin D are often cited:

Vitamin D deficiency: serum levels < 20 ng/ml (50 nmol/L);  Vit D insufficiency: serum levels < 30 ng/ml

Vit  D sufficiency: serum levels > 30 ng/ml    Ideal Vit D range*: 30-50ng/ml 

Toxicity: > 150ng/ml, when combined with raised serum calcium

(*Higher status may be preferred for athletes to allow a greater safety margin and to optimize performance;   some agencies working with elite athletes often set their own thresholds for desired Vitamin D concentrations)

Ie they quote no evidence for the 25OH vit D ceiling of 50ng/ml.

 

Confirmed in

  Owens DJ1, Close GL ea .  UK Universities  . 2015..A systems-based investigation into vitamin D and skeletal muscle repair, regeneration, and hypertrophy. Skeletal muscle is a direct target for  vitamin D. Observational studies suggest that low 25[OH]D correlates with functional recovery of skeletal muscle following eccentric contractions in humans and crush injury in rats. However, a definitive association is yet to be established. To address this gap in knowledge in relation to damage repair, a randomised, placebo-controlled trial was performed in 20 males with insufficient concentrations of serum 25(OH)D (~18ng/ml). Prior to and following 6 wk of supplemental vitamin D3 (4,000 IU/day) or placebo (50 mg of cellulose), participants performed 20 × 10 damaging eccentric contractions of the knee extensors.  Supplemental vitamin D3 increased serum 25(OH)D and improved recovery of peak torque at 48 h and 7 days postexercise. Together, these preliminary data are the first to characterize a role for vitamin D in human skeletal muscle regeneration and suggest that maintaining serum 25(OH)D may be beneficial for enhancing reparative processes and potentially for facilitating subsequent hypertrophy.

 

2016 Is there an optimal vitamin D status for immunity in athletes and military personnel?  He CS1, Gleeson M ea .Vitamin D is mainly obtained through sunlight ultraviolet-B (UVB) exposure of the skin, with a small amount typically coming from the diet.It is now clear that vitamin D has important roles beyond its well-known effects on calcium and bone homeostasis. Immune cells express the vitamin D receptor, including antigen presenting cells, T cells and B cells, and these cells are all capable of synthesizing the biologically active vitamin D metabolite, 1, 25 hydroxy vitamin D.There has been growing interest in the benefits of supplementing vitamin D as studies report vitamin D insufficiency (circulating 25(OH)D < 50 nmol/L) in more than half of all athletes and military personnel tested during the winter, when skin sunlight UVB is negligible. The overwhelming evidence supports avoiding vitamin D deficiency (25(OH)D< 30 nmol/L)to maintain immunity and prevent upper respiratory illness (URI) in athletes and military personnel.Recent evidence supports an optimal circulating 25(OH)D of 75 nmol/L to prevent URI and enhance innate immunity and mucosal immunity and bring about anti-inflammatory actions through the induction of regulatory T cells and the inhibition of pro-inflammatory cytokine production. We provide practical recommendations for how vitamin D sufficiency can be achieved in most individuals by safe sunlight exposure in the summer and daily 1, 000 IU vitamin D3 supplementation in the winter.

 

Sarris J1, Ng CH1. Ea, Universities  of Melbourne, & Deakin, Australia;  &  Harvard Boston; 2016  show in   Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. http://www.ncbi.nlm.nih.gov/pubmed/27113121  Adjunctive  standardized pharmaceutical-grade nutrients, known as nutraceuticals, has the potential to modulate several  neurochemical pathways implicated in depression. A systematic search up to 2015 for clinical trials using adjunctive nutrients for depression    RESULTS: Primarily positive results were found for studies testing S-adenosylmethionine (SAMe), methylfolate, omega-3 (primarily EPA or ethyl-EPA), and vitamin D,.  Mixed results were found for zinc, folic acid, vitamin C, and tryptophan. . No major adverse effects were noted in the studies  adjunctive omega-3 versus placebo revealed a significant and moderate to strong effect in favor of omega-3. CONCLUSIONS: Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.

Raina AH1, Bhat FA1 ea ., India.. 2016 Association of Low Levels of Vitamin D with Chronic Stable Angina: A Prospective Case-Control Study.  http://www.ncbi.nlm.nih.gov/pubmed/27114971  Coronary artery disease (CAD) is a major cause of death and disability in developed countries. Chronic stable angina is the initial manifestation of CAD in approximately 50% of the patients. Recent evidence suggests that vitamin D is crucial for cardiovascular health. The prevalence of vitamin D deficiency in our region is 83%. METHODS: a prospective case-control study in  100 cases of chronic stable angina compared controls. Vitamin D deficiency was defined as <20 ng/mL, vitamin D insufficiency as 20-30 ng/mL and normal vitamin D level as 31-150 ng/mL.RESULTS: The prevalence of vitamin D deficiency among cases and controls was 75% and 10%, respectively. 13% had normal vitamin D levels (31-150 ng/mL). None had a toxic level of vitamin D. Among the controls, 10% were vitamin D-deficient, 57% had normal vitamin D levels. The mean vitamin level among cases and controls was 15.53 ng/mL and 40.95 ng/mL, respectively, statistically significant (P ≤ 0.0001). Among the cases, we found that an increasing age was inversely related to vitamin D levels (P = 0.027). Low levels may be an independent, potentially modifiable cardiovascular risk factor.

Jetty , Glueck   Kumar  ea . Jewish Hospital Cincinnati, Ohio, USA  2016  show 12mo Safety of 50,000-100,000 Units of Vitamin D3/Week in Hypercholesterolemic  Vitamin D-Deficient,   Patients with Reversible Statin Intolerance. : http://www.ncbi.nlm.nih.gov/pubmed/27114973   Such Vitamin D3 therapy (was safe and effective when given for 12 months to reverse statin intolerance in patients with vitamin D deficiency. Serum vitamin D rarely exceeded 100 ng/mL, never reached toxic levels, and there were no significant change in serum calcium or eGFR

https://riordanclinic.org/2013/10/vitamins-d3-and-k2-the-dynamic-duo/ As we explore the healing power of higher doses of vitamin D3 at the Riordan Clinic, we have found it prudent to partner the safety and effectiveness of this dynamic duo. For every 5,000–10,000 units of D3 being recommended and tested for, we are recommending 100 mcg of K2 mk7 to be sure and prevent the inappropriate calcification that higher doses of D3 alone could cause.

http://www.amazon.com/MIRACULOUS-RESULTS-EXTREMELY-SUNSHINE-EXPERIMENT-ebook/dp/B005FCKN2S#reader_B005FCKN2S     is a recent book by Jeff T Bowles .

 Newsletter: Gary Null and vitamin D toxicity    2010 by John Cannell, MD http://www.vitamindcouncil.org/newsletter/newsletter-gary-null-and-vitamin-d-toxicity/     “Warning: If you intend to take massive doses of vitamin D based on this newsletter, which I highly recommend you do not, read the entire newsletter. In addition, accurate determination of side effects of massive doses of vitamin D was not available in the early 1930s, nor was accurate determination of the true amount in each pill possible.    Is 2,000,000 IU/day of vitamin D toxic?   Ask Gary Null, alternative medicine guru and entrepreneur. He took his own supplement, Ultimate Power Meal, for a month and became extremely ill; one batch of Power Meal apparently contained 1,000 times more vitamin D than it should. That is, it contained 2,000,000 IU of vitamin D3 per serving instead of 2,000 IU per serving. Mr. Null became sicker and sicker as he gulped it down.

After suing his own supplier for permanent physical damage, Mr. Null then reported it took 3 months to get the extra vitamin D out of his system and that he is now alive and well. If Mr. Null took it for the full month that he claims, and if his Power Meal contained 2,000,000 IU per dose, Mr. Null consumed 60,000,000 IU in one month. Could he really be fine now with no lasting injuries?  In an attempt to answer that question, I went back to the 1930s and 40s.  Massive doses in the 1930s  The earliest references I could find to enormous doses of vitamin D were in the 1930s. In 1935, Drs. Dreyer and Reed, of the University of Illinois School of Medicine, published their observations on 700 patients treated with “massive” doses of vitamin D for up to two years.1  ….” read on..http://www.vitamindcouncil.org/newsletter/newsletter-gary-null-and-vitamin-d-toxicity/ http://www.livescience.com/50765-vitamin-d-supplements-toxicity.html

Vitamin D Overdose   Dr. Liji Thomas, MD  2016  http://www.news-medical.net/health/Vitamin-D-Overdose.aspx   vitamin D toxicity can occur from high intakes of supplements containing vitamin D, but not from dietary intake. Prolonged sun exposure also does not result in vitamin D toxicity because the previtamin D3 is degraded as the skin heats up, and also because of the formation of various other non-functional forms of vitamin D from the thermally activated compound.   Long term intakes of vitamin D above the upper limit recommended causes symptoms of toxicity. However, the intakes must be higher than about 40,000 IU/day, or the serum level of 25-hydroxy above 500-600 ng/mL, and the patient is usually also taking excessive amounts of calcium as well.

Dietary Supplement–Induced Vitamin D Intoxication  Klontz KC, Acheson DW.  To the Editor 2004:    Vitamin D intoxication that is associated with the consumption of dietary supplements is reported rarely. In 2004, the Food and Drug Administration (FDA) learned of the following case. A 58-year-old woman with diabetes mellitus and rheumatoid arthritis began taking a dietary supplement called Solutions IE Ageless Formula II on January 12, 2004. Fatigue, constipation, back pain, forgetfulness, nausea, and vomiting soon developed. On March 15, 2004, she was hospitalized because her speech was slurred, and a blood glucose reading taken at home was 30 mg per deciliter. On admission, her serum levels were as follows: calcium, more than 3.75 mmol per liter; 25-hydroxyvitamin D, 460ng/ml (normal range, 9-5);; parathyroid hormone, 12 ng per liter (normal range, 10 to 65); and creatinine, 265 μmol per liter.   The patient was treated with intravenous normal saline, furosemide, and pamidronate. On March 19, 2004, while still hospitalized, she was informed by the product distributor of an error in product formulation such that 188,640 IU of vitamin D3/d  had been added to the daily serving size of six capsules instead of the intended 400 IU. IE SHE HAD TAKEN ~12.2MILLION IU OF VIT D3 IN 2 MONTHS. At discharge on March 24, the patient’s serum levels were as follows: calcium, 2.60 mmol per liter; blood urea nitrogen, 10.0 mmol per liter; and creatinine, 221 μmol per liter. The patient died from a cause unknown to us on January 8, 2005.   Laboratory analysis of the product by the FDA, obtained from one of two lots reportedly overfortified with vitamin D3, revealed 186,906 IU of vitamin D3 in each serving size of six capsules, indicating that the patient had consumed roughly 90 times the recommended safe upper limit of 2000 IU per day. Long-term daily vitamin D consumption of more than 40,000 IU (1000 μg) is needed to cause hypercalcemia in healthy persons.2     In March 2004, the product distributor announced that during the previous month it had received three complaints from customers who had been hospitalized for hypercalcemia and vitamin D toxicity

2011 Vitamin D toxicity due to a commonly available “over the counter” remedy from the Dominican Republic. Lowe H1, Bilezikian JP. ea  Columbia Univ, NY.. http://press.endocrine.org/doi/10.1210/jc.2010-1999?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&   Hypercalcemia in ambulatory patients is occasionally caused by vitamin D toxicity. We report nine patients presenting to Columbia University Medical Center with hypercalcemia due to a supplement from the Dominican Republic containing massive amounts of vitamin D. All reported recently taking Soladek readily available in the Dominican Republic and in Upper Manhattan. serum calcium values before the ingestion of Soladek were not elevated  According to the manufacturer’s label, each 5-ml vial of Soladek contains vitamin D3 (600,000 IU), vitamin A (120,000 IU), and vitamin E (5 mg). Laboratory analysis by HPLC revealed that the supplement actually contained vitamin D(3) (864,000 IU) and vitamin A (predominantly retinyl palmitate 123,500 IU) per vial.IE 864000 IU VIT D /day FOR UNKNOWN DURATION. a similar case was reported earlier  http://www.thecamreport.com/2009/11/soladek-toxicity-in-a-60-year-old-woman/

Comments by Prof Robert P. Heany    Creighton University, Omaha, Nebraska  on Lowe et al:   Hypercalcemia in vitamin D intoxication JCEM   http://press.endocrine.org/e-letters/10.1210/jc.2010-1999        The report by Lowe et al. on vitamin D intoxication from an OTC supplement (1) is instructive and useful. I comment on the authors’  suggested mechanism of hypercalcemia in such cases. The authors propose that the elevated concentration of serum 25- hydroxy-vitamin D [25(OH)D] is the responsible agent, through loose binding to the vitamin D receptor. While my colleagues and I have shown that 25(OH)D can improve calcium absorption (2), I believe there is a simpler explanation for hypercalcemia in vitamin D intoxication, particularly as the reported values of 25(OH)D were not uniformly high in these nine cases. [In fact the patient with the highest serum calcium had actually the lowest value for 25(OH)D.] Instead, as Vieth suggested several years ago in a paper actually referenced by Lowe et al. (3), elevation of free circulating 1,25(OH)2D (calcitriol) is the most parsimonious explanation. This level is not commonly measured, and was not reported in the cases described by Lowe et al. Vieth has estimated the binding capacity of the D-binding protein (DBP) at approximately 4700 nmol/liter, and it is generally recognized that fewer than 5% of its binding sites are occupied at typical cholecalciferol inputs. However, in the face of huge cholecalciferol doses, as in the nine cases described here, it can easily be calculated that most or all of the binding sites on the DBP would be occupied by cholecalciferol itself as well as by 25(OH)D and 24,25(OH)2D, all of which are bound to the DBP more avidly than is calcitriol. Lowe et al. did not measure serum cholecalciferol, but it is virtually certain that its concentration would have been elevated, if for no other reason than that the capacity of the hepatic 25-hydroxylase is limited, and serum cholecalciferol concentration rises steeply for cholecalciferol inputs in excess of the saturation level of the 25-hydroxylase [which typically occurs at serum cholecalciferol levels of about 10 nmol/L and serum 25(OH)D of about 80 nmol/liter (4)].Even if all of the binding sites of the DBP were not continuously occupied by less polar metabolites, high occupancy would shift the equilibrium between the free and the bound calcitriol, so that free calcitriol concentration would likely have been substantially above normal values continuously. The authors speculate as to the origin of the elevated total calcitriol concentrations, given the down-regulation of the renal 1-á- hydroxylase in such cases. 

 

     2016.Deficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study. Lupton JR1Michos  ea .  Cross-sectional studies have found an association between deficiencies in serum vitamin D, as measured by 25-hydroxyvitamin D (25[OH]D), and an atherogenic lipid profile. These studies have focused on a limited panel of lipid values including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).OBJECTIVE: Our study examines the relationship between serum 25(OH)D and an extended lipid panel (Vertical Auto Profile) while controlling for age, gender, glycemic status, and kidney function.METHODS: We used the Very Large Database of Lipids, which includes US adults clinically referred for analysis of their lipid profile from 2009 to 2011. Our study focused on 20,360 subjects who had data for lipids, 25(OH)D, age, gender, hemoglobin A1c, insulin, creatinine, and blood urea nitrogen. Subjects were split into groups based on serum 25(OH)D: deficient (<20 ng/mL), intermediate (≥20-30 ng/mL), and optimal (≥30 ng/mL). The deficient group was compared to the optimal group using multivariable linear regression.RESULTS: In multivariable-adjusted linear regression, deficient serum 25(OH)D was associated with significantly lower serum HDL-C (-5.1%) and higher total cholesterol (+9.4%), non-HDL-C (+15.4%), directly measured LDL-C (+13.5%), intermediate-density lipoprotein cholesterol (+23.7%), very low-density lipoprotein cholesterol (+19.0%), remnant lipoprotein cholesterol (+18.4%), and TG (+26.4%) when compared with the optimal group.CONCLUSION:  Deficient serum 25(OH)D is associated with significantly lower HDL-C and higher directly measured LDL-C, intermediate-density lipoprotein cholesterol, very low-density lipoproteins cholesterol, remnant lipoprotein cholesterol, and TG

 

  1. Low-Level VitaminD Is strongly Associated with Atrial Fibrillation in Patients with Chronic Heart Failure.Belen E1, , Cetin M2ea. Atrial fibrillation (AF) freuently accompanies heart failure (HF), and causes exacerbation of symptoms and treatment failure in such patients. Vitamin D was recently suggested to be an important mediator of cardiovascular disease, including HF.OBJECTIVES: The aim of this study was to evaluate the relationship between vitamin D deficiency and AF in patients with chronic HF. METHODS: The study included 180 chronic HF patients that were divided into 2 groups based on having sinus rhythm [AF (-) group] or chronic AF [AF (+) group]. Vitamin D status was assessed via measurement of the serum 25-hydroxyvitamin D (25[OH]D) concentration.RESULTS: Mean age of the patients was 66 ± 8.7 years and 53.9% were male. There weren’t any significant differences in age, gender, body mass index, etiology or chronic HF stage between the 2 groups. The vitamin D level in the AF (+) group was significantly lower than in the AF (-) group (11.05 ng/mL vs. 20 ng/mL, p < 0.001) The left atrium to body surface area ratio (LA/BSA) was significantly higher in the AF (+) group (45.03 mm/m2 vs. 42.05 mm/m2, p < 0.01). Independent predictors (based on multiple regression) of AF were vitamin D level (OR = 0.854, 95% CI: 0.805-0.907, p < 0.001) and LA/BSA ratio (OR = 1.077, 95% CI: 1.003-1.156, p < 0.05). The optimal vitamin D cut-off value for the prediction of AF was 16.50 ng/mL, with a sensitivity of 76.0% and specificity of 65.5% (AUC = 0.75, 95% CI: 0.67-0.82).

 

Vitam Horm. 2016;100:255-71. doi: 10.1016/bs.vh.2015.10.001. Epub 2015 Nov 30. Molecular Approaches for Optimizing Vitamin D Supplementation.   Carlberg C1.Vitamin D can be synthesized endogenously within UV-B exposed human skin. However, avoidance of sufficient sun exposure via predominant indoor activities, textile coverage, dark skin at higher latitude, and seasonal variations makes the intake of vitamin D fortified food or direct vitamin D supplementation necessary. Vitamin D has via its biologically most active metabolite 1α,25-dihydroxyvitamin D and the transcription factor vitamin D receptor a direct effect on the epigenome and transcriptome of many human tissues and cell types. Different interpretation of results from observational studies with vitamin D led to some dispute in the field on the desired optimal vitamin D level and the recommended daily supplementation. This chapter will provide background on the epigenome- and transcriptome-wide functions of vitamin D and will outline how this insight may be used for determining of the optimal vitamin D status of human individuals. These reflections will lead to the concept of a personal vitamin D index that may be a better guideline for an optimized vitamin D supplementation than population-based recommendations.

 

  1. Comparative efficacy of vitamin D status in reducing the risk of bladder cancer: A systematic review and network meta-analysis.Zhao, , Huang J3. The optimal concentration of individual vitamin D intake for preventing bladder cancer has not, to our knowledge, been defined. To evaluate the comparative efficacy of different serum 25-hydroxyvitamin D concentrations in preventing bladder cancer, we conducted a systematic search of the literature published up to April 2015.METHODS: We applied a pairwise meta-analysis to estimate direct evidence from intervention-control studies and a network meta-analysis within a Bayesian framework to combine direct and indirect evidence. Moreover, a dose-response curve was utilized to predict the optimal median serum 25-hydroxyvitamin D concentration based on the odds ratio (OR) for each quintile concentration.: Seven studies of a total of 90757 participants, including 2509 bladder cancer patients, were included. Two prospective cohort studies with 57 591 participants and 494 bladder cancer patients, and five case-control studies with 33 166 participants and 2264 bladder cancer patients. From the network meta-analysis, we observed that sufficient serum 25-hydroxyvitamin D concentrations (>75 nmol/L) were superior to all other 25-hydroxyvitamin D concentrations in decreasing the risk of bladder cancer: OR = 0.68 and 95% credible interval (CrI) 0.52 to 0.87 compared with severely deficient concentrations (<25 nmol/L); OR = 0.65 and 95% CrI 0.49 to 0.86 compared with moderately deficient concentrations (25-37.5 nmol/L); OR = 0.61 and 95% CrI 0.47 to 0.80 compared with slightly deficient concentrations (37.5-50 nmol/L); and OR = 0.65 and 95% CrI 0.48 to 0.85 compared with insufficient concentrations (50-75 nmol/L). In addition, we noted a roughly inverse correlation between bladder cancer risk and 25-hydroxyvitamin D concentrations (R(2) = 0.98, P = 0.007).CONCLUSIONS:   Ensuring sufficient serum 25-hydroxyvitamin D concentrations might play an important role in decreasing the risk of bladder cancer. The serum 25-hydroxyvitamin D concentration ≥30ng/ml  was associated with a 60% lower risk of bladder cancer incidence.

the Ides of March 2016:  Where have we been the past 5 years in ignoring the crucial role of K2 supplement  with vit D3? against cancer, fractures, infections, vascular disease and diabetes , 

      like the crucial role of Lugols iodine + selenium, and magnesium (not calcium), coQ10, and animal, marine and coconut ie saturated fat oil- supplement  for all chronic disease prevention?

     Considering that our western processed food staple diet, and the diet of the poor majority everywhere,  is increasingly deficient especially in these nutrients,  with by profit-motivated industrial design  disease-promoting cholesterol-depletion, refined sugars, transfats, antibiotics, hormones,  and noxious at-any-dose elements from fluorine and aluminium upwards.

 

I see I was  promoting K2 in my emails 4 years ago,  and since 2009, on my Healthspanlife blog  ie in  my lectures  and thus in my healthspanlife blends .

     But  I indeed don’t seem to have published a review of K2 on my blog- till now!
– and there are so many refs out there since the first K2 mention on Pubmed in 1946,
and its first Pubmed  human supplement mention in 2002  Improvement with maternal supplement of vitamin K2  of vitamin K status of breastfeeding infants  (MK40).  Nishiguchi T, Terao T ea.   Semin Thromb Hemost. 2002 : 28533-8.

Unlike the Big Pharma-Disease-Industry- controlled denialists of conservative safe  natural phamacological vitamin therapy  like the   Linus Pauling Institute   and   Wikipedia                 https://en.wikipedia.org/wiki/Vitamin_K2,

the vitamin  K2 Polish scientist Dr Katarzyna Maresz PhD     2015 writes (see abstract below)  Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health.  Maresz K1. International Science and Health Foundation Krakow, Poland    Inadequate calcium intake can lead to decreased bone mineral density, thus  increase the risk of bone fractures. Recent scientific evidence, however, suggests that elevated consumption of calcium supplements may raise the risk for heart disease and can be connected with accelerated deposit of calcium in blood-vessel walls and soft tissues. In contrast, vitamin K2 is associated with the inhibition of arterial calcification and arterial stiffening. Dosing of K2 was supported by a population-based study with 16 000 healthy women aged 49 to 70 years drawn from EPIC’s cohort population. After 8 years ,it showed that a high intake of natural vitamin K2 (ie, not synthetic K2, but not of vitamin K1) was associated with protection against cardiovascular events. For every 10 mcg of dietary vitamin K2 consumed (in the forms of menaquinone 7 (MK-7), menaquinone 8 (MK-8), and menaquinone 9 (MK-9), the risk of coronary heart disease was reduced by 9%. … The researchers found that a daily dose of 180 mcg was enough to improve bone mineral density, bone strength, and cardiovascular health. They also showed that achieving a clinically relevant improvement required at least 2 years of supplementation.
      While vit D3  cholecalciferol soltriol  was the multiprevention megavitamin   of the past decade, and CoQ10 the decade before that, catching up with the protean benefits of increasingly diet- deficient vitamins published (350 000 Pubmed citations) the past century, and of vitamin K since 1936, and K2 since 1946,
vit K2 is the most publicized ie advancing megavit of the current decade:
Adequate intake ie ~45 to ~150mcg/d is crucial with magnesium, boron etc to balance vigorous  vit D3 supplement,
for both bone, immune/cancer, and cardiovascular health.
Thus even just ~55mcg/d K2 supplement HALVES the risk of cardiovascular disease – very important in overweight/stressed/ aging people. 

BUT The authorities quoted have assessed safety and optimal longterm effective doses of vitamin K3 and vitamin D3 IN ISOLATION  for major prevention. However, we know that optimal nutrition is balanced nutrition, not one or two nutrient is superdose with an average fastfood mediocre diet. 

This finally convinces me to add vit K2 ~ 35 to 100mcg/day ie 200 to 700mcg/wk  to my own  vit D3 supplements. at a trivial bulk wholesale cost of  ~10mg/d 1% K2 ie ~R0.1/day or R14 – ( US$1)   bag  per 40 weeks of vit D3 @ 50 000iu vit D3 twice a month.

Like  Mercola 2010  http://articles.mercola.com/sites/articles/archive/2010/08/26/this-could-be-even-bigger-than-the-vitamin-d-discovery.aspx,             Byron Richards already in 2010 wrote a major review promoting K2 multipurpose: http://www.wellnessresources.com/health/articles/vitamin_k2_bones_cardiovascular_health_blood_sugar_control_cancer_prev/

As a recent BBC review   details,    “Vitamin K1 has a relatively short half-life and is rapidly cleared from the blood  by the liver within eight hours. In comparison vitamin K2 has a longer half-life of up to 72 hours, meaning it remains biologically active in the body for longer.   Vitamin K2 is also absorbed better by the body, and is linked to cardiovascular health. It directs calcium to the bones, and prevents it from being deposited where it shouldn’t be, for example arteries and organs, where it can cause harm.

The Kansas Riordan Clinic  promotes the Superhuman Duo  of D3+K:   they point out that ” Because an accurate LD50 for vit D in humans has never been determined (thank God!) most researchers use the LD50 for dogs as an estimate for humans, using a hypothetical human subject weighing  50kg, 110 pounds: in order to reach the LD50 dose, that subject would need to consume over 3,500 of the 50,000 IU D3 caps in a 24 hour period (146 capsules an hour,  total  175million iu) in order to have a 50% chance of dying. By conscientiously using vitamin K2 in conjunction with D3, this issue of “metastatic calcium” is thoroughly avoided.  Finally, like vitamin D3, strong evidence demonstrates vitamin K’s amazing ability to reduce cancer risk. For example, men taking vitamin K2 mk7 (a naturally occurring long acting form of K2) at 45 mcg a day can statistically reduce their risk of prostate cancer by 60%! That is just one of many cancer risks that are reduced significantly by regular K2 ingestion.      As we explore the healing power of higher doses of vitamin D3 at the Riordan Clinic, we have found it prudent to partner the safety and effectiveness of this dynamic duo. For every 5,000–10,000 units of D3 being recommended and tested for, we are recommending 100 mcg of K2 mk7 to be sure and prevent the inappropriate calcification that higher doses of D3 alone could cause.

            For the safety of vigorous dose of vitamin D3, the masses of D3  evidence we assembled by August 2015   is that 2million units as a single oral dose does no harm to nonagenarians, nor has over 100 000iu a day for 28 years ie over a billion  iu  in middle-aged women.  

 In 2015,    Like *Joe Leech                                          and             *Hogne Vik   ,                                                    *Angela Pifer nutritionist notes the essensiality of balancing vit D3 with K2  “Vitamin D3 should never be taken alone. Always take a combination Vitamin D3/ Vitamin K2 liquid emulsion, at night for best absorption. This is because vitamin D3 improves calcium absorption across the GI tract and vitamin K2 is the cofactor needed to transfer calcium into your bones, and not your arteries.   (Eur J Clin Nutr. 2016 Feb 24. doi: 10.1038/ejcn.2016.3. Steady-state vitamin K2 (menaquinone-7) plasma concentrations after intake of dairy products and soft gel capsules.   KnapenVermeer  ea . Maastricht University, Netherlands.   In a previous human intervention study, we observed an improved vitamin K status after 8 weeks of intake of a yogurt  fortified with vitamin K2 (as menaquinone-7, MK-7) and vitamins C and D3, magnesium and polyunsaturated fatty acids. It was hypothesized that the added nutrients contributed to this improvement. Here we report on a study in which we compared the fasting plasma concentrations of MK-7 from (a) yogurt enriched with MK-7, vitamins D3 and C, magnesium, n-3 poly unsaturated fatty acids (n-3 PUFA) and fish oil (yogurt Kplus), (b) yogurt fortified with MK-7 only (yogurt K) and (c) soft gel capsules containing only MK-7, For 42 days in healthy men and postmenopausal women between 45 and 65 years of age daily consumed either yogurt K, yogurt Kplus or capsules.  RESULTS: The increase in plasma MK-7 with the yogurt Kplus product was more pronounced than the increase in MK-7 with the capsules, reflecting vitamin K status improvement. No significant differences in fasting plasma concentrations of various biomarkers between the yogurts were found.   CONCLUSIONS: Dairy matrix and nutrient composition may affect MK-7 delivery and improvement of vitamin K status. Yogurt fortified with MK-7 is a suitable matrix to improve the nutritional status of the fat-soluble vitamins.)

Some recent of the other 5000 K2 refs on Pubmed, apart from the abundant reviews by Garry Gordon, Joe Mercola, Mike Howard, Jeff Dach, Townsend letter, ea  , are

Integr Med (Encinitas). 2015;14; 34-9.  Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health.  Maresz K1. International Science and Health Foundation Krakow, Poland    Inadequate calcium intake can lead to decreased bone mineral density, thus  increase the risk of bone fractures. Supplemental calcium promotes bone mineral density and strength and can prevent osteoporosis. Recent scientific evidence, however, suggests that elevated consumption of calcium supplements may raise the risk for heart disease and can be connected with accelerated deposit of calcium in blood-vessel walls and soft tissues. In contrast, vitamin K2 is associated with the inhibition of arterial calcification and arterial stiffening. An adequate intake of vitamin K2 has been shown to lower the risk of vascular damage because it activates matrix GLA protein (MGP), which inhibits the deposits of calcium on the walls. Vitamin K, particularly as vitamin K2, is nearly nonexistent in junk food, with little being consumed even in a healthy Western diet. Vitamin K deficiency results in inadequate activation of MGP, which greatly impairs the process of calcium removal and increases the risk of calcification of the blood vessels. An increased intake of vitamin K2 could be a means of lowering calcium-associated health risks.    “  Calcium ConcernsIf at least 32 mcg/d of vitamin K2 is present in the diet, then the risks for blood-vessel calcification and heart problems are significantly lowered, the elasticity of the vessel wall is increased. Moreover, the beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women has been seen in clinical trials. If less vitamin K2 is present in the diet, then cardiovascular problems may arise. Dosing of K2 was supported by a population-based study with 16 000 healthy women aged 49 to 70 years drawn from EPIC’s cohort population. After 8 years ,it showed that a high intake of natural vitamin K2 (ie, not synthetic K2, but not of vitamin K1) was associated with protection against cardiovascular events. For every 10 mcg of dietary vitamin K2 consumed (in the forms of menaquinone 7 (MK-7), menaquinone 8 (MK-8), and menaquinone 9 (MK-9), the risk of coronary heart disease was reduced by 9%. A study on 564 postmenopausal women also revealed that intake of vitamin K2 was associated with decreased coronary calcification, whereas intake of vitamin K1 was not.  ”  A recent, double-blind, randomized clinical trial investigated the effects of supplemental MK-7, MenaQ7 (NattoPharma ASA, Hovik, Norway) for a 3-year period in a group of 244 postmenopausal Dutch women. The researchers found that a daily dose of 180 mcg was enough to improve bone mineral density, bone strength, and cardiovascular health. They also showed that achieving a clinically relevant improvement required at least 2 years of supplementation.It showed a significant improvement in cardiovascular health as measured by ultrasound and pulse-wave velocity, which are recognized as standard measurements for cardiovascular health. In that trial, carotid artery distensibility was significantly improved for a 3-year period as compared with that of a placebo group. Also, pulse-wave velocity showed a statistically significantly decrease after 3 years for the vitamin K2 (MK-7) group, but not for the placebo group, demonstrating an increase in the elasticity and reduction in age-related arterial stiffening.” 

*     Nutrients. 2015 Oct ;7;8905-15.  Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial).Vossen, Kroon ea  Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months.  We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.
*            
Ugeskr Laeger. 2015 Aug;177:V12140700. Vitamin K2 influences several diseases]. Hey H1, Brasen CL. Lillebælt, Kabbeltoft, In this paper we discuss the evidence of vitamin K2 deficiency which is a factor in several chronic diseases like diabetes, osteoporosis, cancer, inflammatory and cardiovascular diseases. This deficiency is very common in the mentioned diseases although it is rarely treated by clinicians. Randomized clinical trials have shown that patients witr can benefit from vitamin K2 supplement. Further studies are needed to ascertain the effect of vitamin K2 supplement in patients with diabetes and inflammatory bowel diseases.
*           Oman Med J. 2014;29;172-7. Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review.  El Asmar, Arbid  ea, American University of Beirut, Lebanon. Vascular calcification, a cause of cardiovascular morbidity and mortality, is an actively regulated process involving vitamin K dependent proteins (VKDPs) among others. Vitamin K is an essential micronutrient, present in plants and animal fermented products that plays an important role as a cofactor for the post-translational γ-carboxylation of glutamic acid residues in a number of proteins. These VKDPs require carboxylation to become biologically active, and they have been identified as having an active role in vascular cell migration, angiogenesis and vascular calcification. calcification.
*             Dermatoendocrinol. 2015 Jan;6e968490. Vitamin K: an old vitamin in a new perspective.   Gröber U, Reichrath J, Holick MF, Kisters Essen, Germany.&  Boston, MA USA. The topic of “Vitamin K” is currently booming on the health products market. Current research increasingly indicates that the antihaemorrhagic vitamin has a considerable benefit in the prevention and treatment of bone and vascular disease. Vitamin K1 (phylloquinone) is more abundant in foods but less bioactive than the vitamin K2 menaquinones (especially MK-7, menaquinone-7). Vitamin K compounds undergo oxidation-reduction cycling within the endoplasmic reticulum membrane, donating electrons to activate specific proteins via enzymatic gamma-carboxylation of glutamate groups before being enzymatically reduced. Along with coagulation factors (II, VII, IX, X, and prothrombin), protein C and protein S, osteocalcin (OC), matrix Gla protein (MGP), periostin, Gas6, and other vitamin K-dependent (VKD) proteins support calcium homeostasis, inhibit vessel wall calcification, support endothelial integrity, facilitate bone mineralization, are involved in tissue renewal and cell growth control, and have numerous other effects.

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2016 CHOOSING BREAST SCREENING, BAD DIET/LIFESTYLE ARE OBSESSIVE-COMPULSIVE DISORDERS. SCREENING MAMMOGRAPHY ASSAULT UPDATE : FLOOD OF PROGRESS AGAINST BREAST CANCER/ DISEASE.

neil.burman@gmail.com  Cape Town.                   read this  in concert with:               combating rising-occurrence-of-breast-cancer-in-younger-women;  and

NEXT SURE TOUCH CLINIC CAPETOWN 30 April 2016     For those who (despite clinical reassurance,  and the evidence against screening for silent breast and prostate cancer as recently again published below in a British Journal) ), still want screening breast imaging,   Saturday 30 April 2016  is the next  Sure Touch imaging clinic  by our Breast  Screening  Sister  (and if required, specialist doctor)  for asymptomatic women with well breasts  who despite the futility and risks still desire  screening breast imaging.

Book  at the Natural Wellness  Clinic in Grove Bldg Claremont Cape Town (between ABSA on Grove and Cavendish). ph 021 6831465/ 021 6717415 or 0712025274  office hours to book appointments , or email doctor@healthspanlife.com, or ph Reyhana 0763910463 .  (next Thermography  clinic +- June  tba ).

UPDATE 22 APRIL 2016:     BREAST SCREENING OF WELL WOMEN BY SOUTH AFRICAN  MEDICAL SCHEMES a reminder:

DIAGNOSTIC  xray mammography is an invasive  DIAGNOSTIC  procedure FOR A BREAST LUMP/BLEEDING  that irradiates and crushes  the breasts; and is therefore universally recommended by independent experts and trials  ONLY  for women ( with a breast lump) where cancer needs to  be excluded; and provided as a free service by the state every 10 years, and by medial schemes as a prescribed medical benefit PMB  on demand.

                         BREAST SCREENING IMAGING  IN THE WELL:  as this column   has repeatedly pointed out from international experts’ and local experience, because of the long-known RISKS of xray mammography- which risks balance if not exceed the BENEFITS- the RSA Council for Medical Schemes has just publicized  again   that screening mammography for the above reasons is not a PMB . “ 4. Screening: Current evidence regarding Screening Mammography to reduce mortality of breast cancer is conflicting. Screening xray mammogram is therefore not  prescribed minimum benefit (PMB) level of care. Clinical breast examination is considered PMB level of care. “http://www.medicalschemes.com/files/Circulars/Circular24Of2016.pdf
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          To capture the images (PICTURES)  of findings on clinical breast exam (which remains the worldwide gold standard as to whether xray mammogram is needed), the Natural Wellness Clinic follows  the SA Cancer Association and many authorities worldwide for the past 5 years in offering no-xray no-crushing simple mechanical breast  Sure Touch imaging as part of the clinical exam for those who desire the extra reassurancehttp://www.cansa.org.za/get-screened-early-detection/.

     See the new reviews below of the efficiency of ultrasound (China 2015) over  xray mammography;
and  of Sure Touch  by Prof Cary Kaufman(Univ Washington)  ea at  the 2014 San Antonio Breast Cancer Symposium, which confirms what we tabulated 2 years ago from 11 comparative trials, that in 6 comparative trials, Sure Touch was equal to or better  (sensitivity vs specificity vs accuracy) overall than xray mammography, ultrasound or  clinical exam; clinical exam plus one if not two of the nonxray screenings  greatly improve risk assessment before deciding whether mammography- or lump excision- is warranted. .
UPDATES:
October was breast cancer awareness month. For that, the Radiological Association of RSA recently published on line a lengthy promo for screening mammography http://www.grocotts.co.za/content/newsletter-nycu-october-breast-cancer-awareness-month-22-09-2015  that ignores the tsunami of expert evidence showing that xray mammography actually does more harm than good, and overall doesnt save lives. and at the same time criticizes Sure Touch and thermography as prescreening, while ignoring that they are done by highly trained practitioners eg nurses and radiographers, and have many evidence-based studies supporting their use.
      As this column has pointed out for years, and radiologists and oncologists remain silent about, the USA Government National Cancer Institute and the  UK NHS cancer website continue to point out objectively that the benefits and harms of well-breast screening mammography are finely balanced- without even mentioning the gigantic cost of screening in resources, patient discomfort, and major emotional drain; when in such older western women, below 4% die of breast cancer. Contrary to the blind for-profit  mantra for annual breast-crushing -and irradiating xray mammography from the Radiology Associations, the Cancer Association of South Africa recently continues to promote  SureTouch – non-invasive device for safe breast screening
      In the prestigious Jnl of the Royal Society of Medicine 2015,
in the July issue  two  major international  groups –  Autier ea from France and London and Tabar ea from Sweden, Cambridge, London, Atlanta and Tapei – fiercely contest the spin, the validity of Swedish studies the past decades  that claimed benefit from screening mammography.
 and
     in the September issue of the same leading UK journal, two breast screening experts- from Denmark and London-  again point out the dangers of and lack of benefit from routine xray screening mammography:
         In support of   the comprehensive review of Xray  Mammography screening is harmful and should be abandoned , by Prof Peter C Gøtzsch  Nordic Cochrane Centre, Rigshospitalet, Denmark,

     Prof Michael Baum  University College London, London responded:   “Catch it early, save a life and save a breast’: this misleading mantra of mammography:     The one thing every layperson and politician knows with confidence with regard to breast cancer is that you’ve got to ‘catch it early,’ preferably before you can even feel it.    It may come as a shock to some readers, but I disagree and there’s such a thing as ‘catching it too early’. Like Peter Gøtzsche in the current edition of the JRSM,1 the global breast cancer screening programme has to be considered a ‘failed experiment.’ I also agree that the screening service as now provided should be closed down. I would go on to suggest that all the human and technological resources released by the closure of the National Health Service Breast Screening Service (NHSBSP), be redeployed into more fruitful areas for enhancing women’s health. That aside we have much to learn from the fact that the experiment, set up in good faith, has indeed failed to live up to our expectations. The mantra, ‘Catch it early, save a life and save a breast’, turns out to be a false promise. Screening may have a borderline effect on reducing cause-specific mortality but does not save lives as judged by the outcome measure of all-cause mortality.2 As far as saving breasts is concerned, the opposite is the truth. Populations of women attending for screening have a greater chance of a mastectomy than any control group.2

         The hypothesis being tested in the experiment originated in the last half of the 20th century and was based on the assumption of the log linear kinetics of cancer development with distant dissemination being determined by the size (a poor surrogate for ‘age’) of the cancer. This was considered so self-evident as to have been translated into an ideological expression of faith. Yet, the experiment failed. The national breast screening programmes around the world have provided us with a natural experiment of the greatest historical importance, first, because it failed to deliver and, second, because of the recognition that mammography in asymptomatic women leads to the over-diagnosis of ‘pseudo-cancers’.3

        Cancer was defined by its microscopic appearance about 200 years ago. The 19th century saw the birth of scientific oncology with the discovery and use of the modern microscope. Rudolf Virchow, often called the founder of cellular pathology, provided the scientific basis for the modern pathologic study of cancer.4 As earlier generations had correlated the autopsy findings observed with the unaided eye with the clinical course of cancer 100 years earlier,5 so Virchow correlated the microscopic pathology of the disease. However, the material he was studying came from the autopsy of patients dying from cancer.

       In the mid-19th century, pathological correlations were performed either on cadavers or on living subjects presenting with locally advanced or metastatic disease that almost always were pre-determined to die in the absence of effective therapy. Since then without pause for thought, the microscopic identification of cancer according to these classic criteria has been associated with the assumed prognosis of a fatal disease if left untreated. There is a syllogism at the heart of the diagnosis of cancer and therefore runs like this; people frequently die from malignant disease, under the microscope this malignant disease has many histological features we will call ‘cancer,’ ergo anything that looks like ‘cancer’ under the microscope, will kill you. I would therefore like to restate the argument, that some of these earliest stages of ‘cancer’ if left unperturbed, would not progress to a disease with lethal potential. These pathological entities might have microscopic similarity to true cancers, but these appearances alone are insufficient to predict a life-threatening disease. If we stand back and take a broader look at nature this shouldn’t be surprising.

      Conventional mathematical models of cancer growth are linear or logarithmic, in other words completely predictable at the outset; predicting transition from in-situ phases to early invasive and from early invasive to late invasive over time. Most natural biological mechanisms are non-linear or better described according to chaos theory. The beauty of the tree in full leaf and the symmetry of a sprig of broccoli, reflect their fractal geometry that looks remarkably similar to the appearance of the mammary ducts and lobules under the microscope.6 The rate of growth and the development of the lung along with the fingers and toes in the fetus cannot be described in linear terms. Prolonged latency followed by catastrophe should not be all that surprising.7 We accept the case for prostate cancer, as we know that most elderly men will die with prostate cancer in situ and not  die of prostate cancer. In fact, the UK national PSA screening trial (ProtecT) is predicated on that fact with two a priori outcome measures defined, deaths from prostate cancer versus the number of cancers over-detected and treated unnecessarily.8

      Further support for this contention comes from other sources. For example, there has been an epidemic of bilateral mastectomies in the USA following the uncontrolled proliferation of MRI scans in the routine work-up of women presenting with a single focus of early breast cancer.9,10 The MRI scan is guilty of unveiling not only latent foci of pseudo-cancers outside the index quadrant but also latent foci harboured in the contra-lateral breast. This is heartbreaking when one considers all the work over three decades and all the patient volunteers in trials of breast conservation.11,12 We now know with the utmost confidence that breast-conserving surgery is a safe alternative to more radical surgery, yet that hard won knowledge is brutally ignored when the surgeon is induced to treat the MRI image rather than the patient. Next, it is worth noting that contrary to all common sense predictions, the increased rate of detection of duct carcinoma in situ has led to an increase in the mastectomy rate for the screened population.2,3 Up to 45% of screen detected cases of duct carcinoma in situ end up having mastectomy because of the multi-centricity of the disease.13 Yet, the paradox is that clinically detected multi-centric invasive breast cancer is relatively uncommon.14         In conclusion, therefore, we can state, with a great deal of conviction, that a large proportion (in the order of 50%3) of screen detected (pre-clinical) foci of breast cancer is not programmed to progress if left unperturbed. This observation is of seismic importance and could set the agenda for breast cancer research for the next decade. If we choose to ignore these observations, because they fail to support our ideological belief system, then we will have missed an opportunity of a lifetime and that would be unforgivable.

The superiority of even ultrasound screening over xray mammography has been shown in women with dense breasts (like most today in our obese society) in  Br J Cancer. 2015 ; 112: 998–1004. A multi-centre randomised trial comparing ultrasound vs mammography for screening breast cancer in high-risk Chinese women Shen ea,  Chinese women tend to have small and dense breasts and ultrasound is a common method for breast cancer screening in China. However, its efficacy and cost comparing with mammography has not been evaluated in randomised trials.   Methods: At 14  centres across China during 2008–2010, 13 339 high-risk women aged 30–65 years were randomised to be screened by mammography alone, ultrasound alone, or by both methods at enrolment and 1-year follow-up.   Results:  Among the 30 cancers (of which 15 were stage 0/I) detected, 5 (0.72/1000) were in the mammography group, 11 (1.51/1000) in the ultrasound group, and 14 (2.02/1000) in the combined group (P=0.12). In the combined group, ultrasound detected all the 14 cancers, whereas mammography detected 8, making ultrasound more sensitive (100 vs 57.1%, P=0.04) with a better diagnostic accuracy (0.999 vs 0.766, P=0.01). There was no difference between mammography and ultrasound in specificity (100 vs 99.9%, P=0.51) and positive predictive value (72.7 vs 70.0% P=0.87). To detect one cancer, the costs of ultrasound, mammography, and combined modality were $7876, $45 253, and $21 599, respectively.

      update:         28 July 2015 Mammography’s $4-Billion Problem   Millions of women receive false-positive results annually, and 20,000 are overtreated.  by Shannon Firth             WASHINGTON — For too many women, breast cancer screening does more harm than good, a researcher said here.     Thermography is a non-invasive imaging procedure which uses a heat-sensitive camera to capture an image of the human body. Since we are pretty much symmetrical beings, seeing one breast significantly warmer than the other would be a red flag, suggesting the presence of a heat-generating lesion. The lesion could be an abscess, or increased blood vessels feeding an early tumor, or simply a recent hematoma from injury. In any case, no radiation is used to obtain the image, there is no compression of the breast, and the study can be repeated frequently with no risk of inducing neoplastic transformation. Studies show that thermography can diagnose significant inflammatory disease up to several years before a mammogram shows calcification. Insurance does not pay for this test. Thermography does not diagnose cancer. Nor does mammography. At least thermography is helpful and does no harm. And if a mass is palpated, then excisional biopsy is indicated no matter what the tests show. Common sense needs to prevail.

July 06, 2015  Mammograms Again Found to Have No Impact on Mortality   JAMA Intern Med.  .  Breast Cancer Screening, Incidence, and Mortality Across US Counties   Harding, Pompei; Burmistrov, Welch, Abebe, Wilson,     Harvard University, Cambridge, Massachusetts   Importance  Screening mammography rates vary considerably by location in the United States, providing a natural opportunity to investigate the associations of screening with breast cancer incidence and mortality, which are subjects of debate.   Objective  To examine the associations between rates of modern screening mammography and the incidence of breast cancer, mortality from breast cancer, and tumor size.  Design, Setting, and Participants  An ecological study of 16 million women 40 years or older who resided in 547 counties reporting to the Surveillance, Epidemiology, and End Results cancer registries during the year 2000. Of these women, 53 207 were diagnosed with breast cancer that year and followed up for the next 10 years. The study covered the period January 1, 2000, to December 31, 2010, and the analysis was performed between April 2013 and March 2015.   Exposures  Extent of screening in each county, assessed as the percentage of included women who received a screening mammogram in the prior 2 years.   Main Outcomes and Measures  Breast cancer incidence in 2000 and incidence-based breast cancer mortality during the 10-year follow-up. Incidence and mortality were calculated for each county and age adjusted to the US population.Results  Across US counties, there was a positive correlation between the extent of screening and breast cancer incidence (weighted r = 0.54; P < .001) but not with breast cancer mortality (weighted r = 0.00; P  = .98). An absolute increase of 10 percentage points in the extent of screening was accompanied by 16% more breast cancer diagnoses (relative rate [RR], 1.16; 95% CI, 1.13-1.19) but no significant change in breast cancer deaths (RR, 1.01; 95% CI, 0.96-1.06). In an analysis stratified by tumor size, we found that more screening was strongly associated with an increased incidence of small breast cancers (≤2 cm) but not with a decreased incidence of larger breast cancers (>2 cm). An increase of 10 percentage points in screening was associated with a 25% increase in the incidence of small breast cancers (RR, 1.25; 95% CI, 1.18-1.32) and a 7% increase in the incidence of larger breast cancers (RR, 1.07; 95% CI, 1.02-1.12).   Conclusions and Relevance  When analyzed at the county level, the clearest result of mammography screening is the diagnosis of additional small cancers. Furthermore, there is no concomitant decline in the detection of larger cancers, which might explain the absence of any significant difference in the overall rate of death from the disease. Together, these findings suggest widespread overdiagnosis.

            Unlike irradiation and crushing by mammography, Sure Touch  physical (pressure transducer) scanning on its own combined with usual clinical exam  is similar to ultrasound in scope and feel, but better –  in comparative trials is  like if not better than mammography  in sensitivity and specificity, but without the significant harms of crushing and  xray irradiating mammography. ( Only tissue biopsy can confirm or exclude  potentially threatening cancer (or pick up-  over-diagnose- pre-cancers -many of which are best left unknown in eg breast, prostate, colon, will never cause cancer disease in lifetime).
 As Prof Peter Gotzsche says, WELL people with a silent ie tiny internal  cancer – whether in situ eg DCIS, or localized,  DO NOT HAVE DISEASE; ie such silent lumps vanishingly rarely   cause illhealth.
see latest warnings at    Too Much Medicine   Alexandra Barrett Univ Sydney, Australia:    Overdiagnosis in mammography screening: a 45 year journey from shadowy idea to acknowledged reality: note the  graph about overdiagnosis, that as with screening for silent prostate cancer, the rate of advanced cancer hasnt increased with invasive screening, DESPITE the ~40% futile  increase in (early) breast cancer diagnosis by crushing, biopsy , irradiation and surgery. Not saving lives , but perhaps earlier death by screening terrorizing, , burning, cutting and poisoning. .

Figure1

2 March 2015: this update says it al about the futility and risks of breast cancer mammography screening:

Breast Cancer Screening: Benefits and Harms:  Jill Jin, MD, MPH

For More Information: Centers for Disease Control and Prevention

Image not available.

Breast cancer is the second most common cancer among women in the United States.

BENEFITS OF SCREENING    Screening for breast cancer means looking for signs of breast cancer in all women, even if they have no symptoms. The goal of screening is to catch cancers early. Early-stage cancers are easier to treat than later-stage cancers, and the chance of survival is higher. Routine screening for breast cancer lowers one’s risk of dying of breast cancer.

Screening for breast cancer is done by mammography. A mammogram is a special series of x-rays taken of the breast. A doctor looks for any abnormal signs or patterns on the mammogram that might be breast cancer. These signs usually show up on the mammogram before any lump can be felt in the breast. If there is anything unusual on the mammogram, more tests have to be done. These tests can include another mammogram, an ultrasound, or a biopsy. Studies have shown that women who have routine mammograms have 10% to 25% less chance of dying of breast cancer than women who do not have mammograms.

CURRENT US SCREENING GUIDELINESIn the United States, the US Preventive Services Task Force recommends that women aged 50 to 74 years get a screening mammogram every 2 years. For women younger than 50 years, some women may choose to be screened, but not all women need to be. This depends on several factors, as discussed below.
      POSSIBLE HARMS OF SCREENINGMammograms are not perfect tests. Some cancers are missed by a mammogram. On the other hand, sometimes mammograms find things that look like cancer but turn out not to be cancer. This is called a false-positive result. False-positive mammogram results lead to more testing, which is time consuming and can cause unnecessary anxiety. On average, among all 50-year-old women who start breast cancer screening, more than half will have a false-positive mammogram result over the next 10 years

Another possible harm of screening is overdiagnosis. This means finding something on a mammogram that is breast cancer or has a chance of becoming breast cancer, but is such a low-risk type of tumor that it would never have caused any health problems if left alone. Instead, because it was found on mammogram, standard cancer treatment, such as surgery and radiation therapy, is recommended. In cases of overdiagnosis, these treatments are unnecessary and costly and can have both physical and psychological side effects. It is difficult to know exactly how often overdiagnosis happens, but some studies estimate that 1 in 5 breast cancers found on mammograms are overdiagnosed and lead to unnecessary treatment.

   BALANCING BENEFITS AND HARMS  The pros and cons of breast cancer screening are different for every woman. Age is an important factor. Even though the general recommendation is to start screening at 50 years of age, for women at higher risk (such as those who have breast cancer in their family), it may be a good idea to start screening at a younger age. Each woman also has different personal values, especially toward the idea of unnecessary medical tests and treatments.      

Why I’m Opting out of MammographyChristie AschwandenJAMA Intern Med.    at  a routine appointment a few days after my 40th birthday, my gynecologist gave me a prescription for a mammogram. There was no discussion, no explanation. Just a slip of paper, handed to me without a word as I left the examination room. When I asked the doctor what she’d just given me, she told me it was an order for a mammogram. I could call the number to schedule an appointment.    “Wait—why should I get a mammogram?” I asked.                                                    “Because it could save your life.” Her voice conveyed a note of impatience…  read on..

 24 Jan 2015        early diagnosis ( by screening the well), and treatment of pre-cancer of eg breast and prostate is increasingly discredited as dangerous, especially for women at ~10years younger prime-of life ( and much higher risk than men)  due to menopause. .

           so just how safe can it be- for cancer spread, and misdiagnosis- when needle biopsy is done on a silent 7mm incidentally palpated lump, and the surgeon sticks a needle in (blind)  and stirs up the lump before biopsy.  What does stage 1A at the excision 2 months later mean then?
            BACKGROUND .  we have oft reported below that the mammoth ATLAS trial showed that  after diagnosis of preclinical “cancer” at around 50years (by screening mammography, biopsy, mostly mastectomy or DHRT, then annual screening mammo on tamoxifen for 5 to 10 years),  15  years after diagnosis, of the hundreds of women who had by then died +-70-yrs old of diverse causes, only 14% had had clinical cancer recurrence but 45% had silent breast cancer present at autopsy.
       This is the same cancer  rate found in random adults killed in accidents. SO WHAT  MAMMOGRAPHY SCREENING OF WELL BREASTS ACHIEVED EXCEPT COUNTLESS IRRADIATION, SURGERIES AND THUS STRESS?
        Now the IBIS-1 trial shows that   Between 1992 and 2001, 7154 eligible women aged 35 to 70 years were randomized to 5 years of tamoxifen 20 mg/day or placebo. All women were deemed to be at increased risk for breast cancer based on predefined family history or benign breast disease criteria. In this  20-year follow-up report, the cumulative incidence of breast cancer (defined as invasive breast cancer or DCIS) was reduced ~47% from   12.3% with placebo to 7.8% with tamoxifen  (P < .001). Reductions were seen in the risk for developing ER-positive breast cancer (HR, 0.66) and DCIS (HR, 0.65) but not ER-negative breast cancer (HR, 1.05). BUT There was no significant difference in breast cancer–specific or overall mortality. –and  in IBIS1, tamoxifen increased uterine cancer rate from 20 on placebo to 29 on tamoxifen, of whom 5 women in the tamoxifen group died from endometrial cancer compared with none in the placebo group (P = .06).
and in the Asian-  Taiwan population-based cohort study to assess whether tamoxifen treatment is associated with an increased incidence of diabetes. in  22 257 breast cancer patients diagnosed between 1 January 2000 and 31 December 2004,     15 210 cases received tamoxifen treatment and 7047 did not. Four subjects without breast cancer were frequency-matched by age and index year as the control group.  Breast cancer patients exhibited a 14% higher rate of developing diabetes (adjusted HR=1.14, 95% CI=1.08–1.20) compared with non-breast cancer controls, but the significant difference was limited to tamoxifen users. In addition, tamoxifen users exhibited a 31% significantly increased risk of diabetes compared with non-tamoxifen users among women diagnosed with breast cancer (adjusted HR=1.31, 95% CI=1.19–1.45). Stratification by age groups indicated that both younger and older women diagnosed with breast cancer exhibited a significantly higher risk of diabetes than the normal control subjects did, and tamoxifen users consistently exhibited a significantly higher diabetes risk than non-tamoxifen users or normal control subjects did, regardless of age. Both recent and remote uses of tamoxifen were associated with an increased likelihood of diabetes.

And Tamoxifen prevention lessens future breast cancer, but both tamoxifen and the enormous burden of mass screening do not save lives, create vast numbers of patients. so early diagnosis and treatment  of preclinical breast cancer- overdiagnosis- does not save lives, in fact seriously increases non-breastcancer  mortality including by increasing diabetes, melanoma, deepvein thrombosis, uterine carcinoma, depression-stress-related vascular disease, etc..
22 January 2015

Commentary: Prof Peter  Gøtzsche  Nordic Cochrane, Denmark. Int. J. Epidemiol. Jan 2015: SCREENING- A SEDUCTIVE PARADIGM THAT HAS GENERALLY FAILED US: Screening healthy people has face value and great public and political appeal. It looks so simple, and yet screening is fraught with difficulties. These start already with the terminology, and common slogans like, ‘Catch the disease early, before it has produced any symptoms!’ are misleading on two counts.

First, disease means lack of ease, which is not what we understand by being healthy; but people who work with screening tend to forget that they deal with healthy people. For example, women being invited to mammography screening are often called patients in scientific articles.            The second error is the assumption that the disease is caught early. That is rarely the case, and breast cancer is again a good example. If we assume that the growth rate for a particular cancer is constant, then the women have harboured the cancer for 21 years on average before it is large enough to be detected by mammography screening.1 Finding precursors to cancer is of course an entirely different matter.

A third problem with screening is that it always causes harm. Sometimes it also leads to benefits, and sometimes the benefits are sufficiently large to outweigh the harms. The main focus in screening trials should therefore be to quantify the harms, but this has rarely been the case, if ever. Screening trials focus on disease-specific mortality, which may seem natural, but it is the wrong outcome. Screening leads to overdiagnosis, and interventions that are beneficial for real patients can be lethal for healthy overdiagnosed people. Radiotherapy of overdiagnosed women may kill at least as many as those who are spared dying from breast cancer by attending breast screening.2

Total mortality should therefore be the primary outcome in screening trials of mortality, and Saquib et al. report a systematic review in this issue of the journal that aimed at clarifying whether screening lowers total mortality for diseases that carry a high disease-specific mortality.3 They focused on cancer, cardiovascular diseases, type 2 diabetes and chronic obstructive pulmonary disease. They did not find any screening trials for hypertension or chronic obstructive pulmonary disease. Disease-specific mortality was reduced with ultrasound for abdominal aortic aneurysm in men, mammography for breast cancer and faecal occult blood test and flexible sigmoidoscopy for colorectal cancer, but the risk ratio point estimates for all-cause mortality were all very close to 1.00 (range 0.98–1.03).

Screening proponents often say that disease-specific mortality is the right outcome, arguing that in order to show an effect on total mortality, trials would become unrealistically large. I believe this argument is invalid, for both scientific and ethical reasons. We do randomized trials in order to avoid bias, and our primary outcome should therefore not be a biased one. Drug interventions are usually more common in a screened group, and they tend to increase mortality for a variety of non-disease related reasons.4

From an ethical perspective, it is problematic to screen the whole population in a certain age group without knowing whether this makes people live longer, while knowing almost certainly that it makes people less happy. It took 50 years after the first randomized trial of mammography started before we knew what the psychological consequences are of the many false-positive findings.5 A specially designed questionnaire was developed using focus groups and women who had attended screening were followed up for 3 years. Even after so long a time, those who had experienced a false-positive diagnosis had an anxiety level (and other psychological problems) that fell between that for women with breast cancer and women who had always been told they did not have cancer. This study showed for the first time that the psychological harms of breast screening are substantial and long-lasting, and they affect a huge number of healthy women, as the cumulative risk of a false-positive result after 10 mammograms ranges from about 20% to 60%.6 Added to this comes the psychological harm inflicted on all the overdiagnosed women who do not know that they are overdiagnosed but think that they suffer from a fatal disease. It is therefore pretty clear that any utility analysis that takes the psychological harms of breast screening into account will come out negative, as was recently reported by the Swiss Medical Board.7

It is worth noting that when screening does not work, it might be because beneficial effects are outweighed by harmful ones. Diabetes drugs, for example, are approved on the basis of their glucose-lowering effect without knowing what they do to patients. And the only large trial of tolbutamide ever performed was stopped prematurely because the drug increased cardiovascular mortality.4 Rosiglitazone was once the most-sold diabetes drug in the world, but it was taken off the market in Europe in 2010 as it causes myocardial infarction and cardiovascular death; and pioglitazone has been linked to heart failure and bladder cancer.4

Screening is popular, but we need to be much more careful in the future when we contemplate approaching healthy people with our screening tests, and should demand much stronger evidence than when we treat patients.”

Stanford University Saquib ea.Int J Epidemiol. 2015 Jan.  Screening for disease doesnt  save lives in asymptomatic adults? Systematic review of meta-analyses and randomized trials. Several popular screening tests, such as mammography and prostate-specific antigen, have met with wide controversy and/or have lost their endorsement recently. We systematically evaluated evidence from randomized controlled trials (RCTs) as to whether screening decreases mortality from diseases where death is a common outcome.We selected 19 diseases (39 tests) out of 50 diseases/disorders for which USPSTF provides screening evaluation. Screening is recommended for 6 diseases (12 tests) out of the 19. Among the results of the meta-analyses, reductions where the 95% confidence intervals (CIs) excluded the null occurred for NO DISEASES FOR ALL-CAUSE  mortality estimates .  Among individual RCTs, reductions in disease-specific and all-cause mortality where the 95% CIs excluded the null occurred in 30% and 11% of the estimates, respectively.  CONCLUSIONS:Among currently available screening tests for diseases where death is a common outcome, reductions in disease-specific mortality are uncommon and reductions in all-cause mortality are very rare or non-existent.
 Thus the  $trillion  screening mammo war   by the Disease Industry  on healthy breasts to create and find as much silent precancer as possible to profiteer burn and cut hots up. Its about ethics- that women are made anxious about the necessity (usually none)  for screening  and the harms understated:  Germany  (like Switzerland,  Scandinavia, Canada and USA)  also has grave doubts.
Mammo skeptics make new bid to stop U.K. breast screening trial   Frances Rylands-Monk, AuntMinnieEurope.com staff writer
with some good Forum comments that follow:

September 16, 2014 A U.K. clinical trial examining whether mammography screening should be offered to a broader range of women must be halted due to ethical and medical concerns, according to a letter published in BMJ by a group of longtime opponents to breast screening. But not everyone agrees, and the controversy looks set to continue.    In a strongly worded letter published (BMJ) on 16 September,  a group led by Dr. Susan Bewley raised concerns about the U.K. age-extension trial, which is examining whether the age range for screening should be extended to both younger and older women. They challenge the design of the trial as well as the qualifications of its chief investigator, calling the study an “out of control trial with ineffective oversight.”“Our concerns relate to the science and ethics of this trial. Women should always be told the full facts — here they are unwittingly participating in a research trial without fully realizing that the harm/benefit ratio is uncertain,” Bewley said. “There is no overall mortality benefit from breast screening at any age if you look at the Nordic Cochrane review — only a reduction in breast cancer mortality.”

update 9 November 2014  WOMEN WITH HIGHEST BLOOD VITAMIN D  HAVE 90% LOWER RISK OF BREAST CANCER : PLoS One. 2013; 8(1): e49312.  Evidence from a Chinese Population Based Case-Control Study and Meta-Analysis of the Observational Studies   Peizhan Chen,Hui Wang ea; Chinese Academy of Sciences,  Shanghai,  China
NATIONAL CANCER INSTITUTE:   Table 3. Estimated Benefits and Harms of Mammography Screening for 10,000 Women Who Undergo Annual Screening Mammography Over a 10-Year Period:
Age, y No. of Breast Cancer Deaths Averted With Mammography Screening Over Next 15 y No. (95% CI) With ≥1 False-Positive Result During the 10 yc  No. (95% CI) With ≥1 False Positive Resulting in a Biopsy During the 10 yc  No. of Breast Cancers or DCIS Diagnosed During the 10 y That Would Never Become Clinically Important (Overdiagnosis)d 
40 1–16 6,130 (5,940–6,310) 700 (610–780) ?–104e
50 3–32 6,130 (5,800–6,470) 940 (740–1,150) 30–137
60 5–49 4,970 (4,780–5,150) 980 (840–1,130) 64–194

         Invisible Risks, Emotional Choices — Mammography and Medical Decision Making   Lisa Rosenbaum, M.D. cardiologist & journalist    N Engl J Med  October 16, 2014:       in 1993, frightened New York City parents agitated for asbestos removal from schools. As often occurs, public fear trumped expert risk assessment; the parents’ demands were met, the victory was celebrated, but then the celebration crashed. It turned out that removing the asbestos would mean closing the schools for weeks, disrupting parents’ lives. “As the costs of the removal came on-screen,” writes behavioral economist Cass Sunstein, “parents thought much more like experts, and the risks of asbestos seemed tolerable: Statistically small, and on balance worth incurring.”1

It is partly because our perceptions of risk are so influenced by our changeable emotions that we turn to experts to perform cost–benefit analyses. From environmental regulations to nuclear energy, such expert assessments inform policies meant to improve public health and welfare. We would not ask airline passengers to create standards for aviation safety or car owners to optimize fuel-emission standards, and in medicine, too, we still depend on expert-generated guidelines. Increasingly, however, in this era of patient-centered care and shared decision making, those guidelines emphasize the role that patient preference should play in the weighing of risk and benefit for any given evidence-based recommendation. This approach, with virtue on its side, is driven by the aspiration that we can, with the proper tools, empower patients to think like experts. But can we?

Many medical decisions involve considerable uncertainty and complex tradeoffs, but none seem to highlight the tension between emotions and risk assessment more than mammography screening. Although the U.S. Preventive Services Task Force (USPSTF) recommended in 2009 that women under 50 years of age not undergo routine mammography screening, and that those between 50 and 75 years of age be screened less frequently, screening rates have apparently held steady or perhaps even increased. There are many possible reasons for this trend: physicians’ habits, conflicting guidelines, medicolegal concerns, radiologists’ preference for the status quo, and the mandating of screening coverage for women of all ages in the Affordable Care Act. But I suspect that the trends also reflect the powerful role that emotions play in both reinforcing women’s commitment to screening and the challenge of communicating the potential harms of mammography.

Consider a discussion with a 45-year-old woman with no family history of breast cancer about the most likely harm of screening: a false positive result. Maybe you say, “For someone like you, there is around a 50% chance that if you have regular screening over the next 10 years, you will have a false positive result. That could lead to repeat testing, potentially including a biopsy, and lots of worry and anxiety.”2 But though doctors striving to reduce unnecessary testing tend to emphasize the psychological stress involved, this possibility does not seem to loom large for women facing this decision.

Perhaps these results reflect the likelihood that, when facing tough tradeoffs, we anticipate and try to avoid regret, rather than anxiety. Despite the demonstrable harms on the population level, cancer screening rarely begets regret for the individual. As Ransohoff and colleagues have written about the persistence of prostate-cancer screening, “the screening process is one without negative feedback. A negative test provides reassurance. A positive one is accompanied by gratitude that disease was caught early. And a false positive test, regardless of the distress it may cause, is nevertheless followed by relief that no cancer was ultimately found.”5 So women who have had false positive mammograms may spend the rest of their lives worrying that they are at heightened risk for breast cancer. But they are not left with regret about having had the test in the first place.

What about the risk of overdiagnosis — being diagnosed with and treated for a tumor that would never have become clinically significant? The potential toxic effects of treatments, ranging from chemotherapy and radiation to lumpectomy and mastectomy, make overdiagnosis the greatest potential harm of mammography screening. Though overdiagnosis has been notoriously difficult to quantify, a recent analysis of data on mammography screening over the past 30 years suggests that of all breast cancers diagnosed, 22 to 31% are overdiagnosed.6 Nevertheless, there are few risks of this magnitude that are more “off-screen” than overdiagnosis.

The first challenge in conveying this risk to women is that many are simply unaware that overdiagnosis occurs. One survey showed that only 7% of women believed that there could be tumors that grow so slowly that an affected woman would need no treatment; another study showed that women found the concept confusing even after a brief educational intervention. After being educated, women thought the information should be considered in decision making, but most believed it would not affect their own intent to be screened.3,7

This disconnect between awareness and intent speaks to the fundamental challenge of conveying the potential harms of mammography screening. That is: we do not think risk; we feel it. As research on risk perception has shown, we are often guided by intuition and affect.8 For example, when our general impressions of a technology are positive, we tend to assume that its benefits are high and its risks are low. We estimate our personal risks of disease not on the basis of algorithms and risk calculators, but rather according to how similar we are, in ways we can observe, to people we know who have the disease. And when we fear something, we are far more sensitive to the mere possibility of its occurrence than its actual probability.

That may be why overdiagnosis does not resonate emotionally. We do not see women walking around with “an overdiagnosis.” Instead, we see breast-cancer survivors. We do not hear people complaining about having endured radiation, chemotherapy, and a lumpectomy. What we hear instead is, “Thank goodness I had a mammogram and caught it early.” Our relatives do not eye us critically when we get a mammogram that reveals a nascent tumor. But people shake their heads and say, “I wish she had taken better care of herself,” when we are diagnosed after not having been screened. Thus, we can be educated about overdiagnosis. We can refine our estimates about its likelihood and incorporate them into our recommendations, as the USPSTF did in 2009. But it is hard to summon fear of a risk that remains invisible.

So how do we balance the goal of engaging women in decision making with the reality that emotions play a powerful role in shaping our understanding of benefit and risk? Some experts emphasize the need to address sources of misperception that inform beliefs far outside clinical encounters. Researchers at Dartmouth, for example, have described the misleading nature of various screening-advocacy campaigns. One advertisement by the Komen Foundation, for instance, features a photo of a beautiful young woman, with a caption reading, “The 5-year survival rate for breast cancer when caught early is 98%. When it’s not? 23%.”9 Though 5-year survival rates, because of lead-time bias and overdiagnosis, do not actually tell you whether the test saves lives, the visceral appeal of “catching something early” easily eclipses the difficult mental calculations one must undertake to figure out why early detection does not necessarily mean living longer.

The problem is that once impressions have formed, whatever their source, educational efforts to address misperceptions often fail and can even backfire. In a recent randomized trial evaluating approaches to vaccine education, for example, researchers found that, among parents least likely to vaccinate their children, exposure to information emphasizing that there is no link between vaccines and autism mitigated misperceptions but nevertheless further reduced their intention to vaccinate.10 Indeed, the fact that sound scientific information that challenges beliefs can simply intensify those beliefs has been recognized by cognitive psychologists for decades. What was more disappointing in this study was that more creative attempts to engage parents emotionally, such as using images or narratives of children dying of measles, not only failed to increase vaccination intent but also cemented some parents’ conviction that there is a link between vaccines and autism.

If there is tension between belief and sound medical information regarding vaccines, for which the benefits so clearly outweigh the risks, the tension is only heightened for decisions with more complex tradeoffs. The vaccine study thus raises two key challenges for the profession.

The first is empirical. As the locus of decision making shifts toward the patient, this study reminds us how little we know about how beliefs inform interpretation of medical evidence — or about how to negotiate those beliefs in pursuit of better health. Closing this empirical gap is daunting. Not only does each person have his or her own belief system, but the particular beliefs that are relevant for a decision regarding, say, elective percutaneous coronary intervention or palliative chemotherapy may be quite different from those relevant to childhood vaccination or mammography screening. Moreover, even though it is more practical and financially feasible to conduct a study that looks at how interventions affect knowledge and intent, what we really need are long-term studies of how new approaches to sharing information affect downstream behaviors and outcomes.

Which brings us to the second challenge, more ethical than empirical: How do we balance the need to honor preferences and values with the imperative to translate our evidence base into better population health? Our current default, particularly since medical recommendations are increasingly debated publicly, is to emphasize that decisions are “personal.” After the 2009 guidelines were published, the Obama administration and many physician leaders were all over the news reminding us of the importance of personal preferences. But even as more data accrue, including a recent review suggesting that the harms of mammography are greater than we once thought and the benefits fewer,11 the message we hear is not “Let’s do fewer mammograms.” Rather, it is “Let’s honor patients’ preferences.”

Though we certainly need to be sensitive to patients’ values, it is often hard to distinguish values from an emotional understanding of risk. Consider the decision to initiate statin therapy for primary prevention of cardiovascular disease. One patient, an avid tennis player, may recognize the potential for improved cardiovascular health but feel that the prospect of myalgias simply outweighs any potential benefit. That is a preference. Another patient hates drug companies and therefore believes that statins must lack cardiovascular benefit and be highly likely to cause myalgias and liver disease. That is an emotional understanding of risk. Both patients arrive at the same choice, but should we really celebrate them as equally informed decisions?

The tangled nature of emotions and values is particularly relevant to mammography screening, as evidenced in qualitative research done since the 2009 guidelines were released. One study explored the beliefs and attitudes of an ethnically diverse sample of women in their 40s. Though many were unaware of the guidelines, the researchers found that educating them about the new recommendations strengthened rather than diminished their commitment to screening. Women also expressed fears that the guidelines were an attempt by insurers to save money and keep them from getting the care they needed. Many women, expressing their abiding conviction that mammograms save lives, said they would have “no use” for a decision aid and viewed the weighing of benefits and harms as “irrelevant.” In fact, many said they wanted to be screened more than once a year and beginning before the age of 40 years. Finally, many believed that it was unjust that laywomen had been left out of the guideline-development process and the weighing of potential benefits and harms that it entailed.12

Such responses echo a broader debate among leading scholars of risk perception about whom we should rely on to evaluate risk. Some, such as Sunstein,1 recognizing our general difficulties in thinking about probabilities, argue that this task ought to be left to experts who can create policies to maximize public welfare. But the psychologist Paul Slovic has argued that the very concept of risk is subjective. Whereas experts tend to conceive of risk as “synonymous with expected annual mortality,” Slovic reminds us that riskiness means more to people than mortality rates.13

Undoubtedly, the recognition of the affective nature of risk perception is critical to the physician’s role in helping patients live longer, higher-quality lives. But even if we can, in some general way, address misleading statistics that drive inflated perceptions of the benefits of mammography, what do we do about the 38-year-old woman who insists on annual screening because she just lost her best friend to breast cancer? Or the 43-year-old with fibrocystic breasts who last year had a false positive mammogram and is now convinced her risk is even higher? Is there some hierarchy of emotional reasoning dictating that certain causes of heightened fears are more acceptable than others? Or because we know it is often impossible to tease out sources of belief, much less rank them, is a better approach the more paternalistic one: definitive guidelines on which physicians base their recommendations, with less emphasis on the role that patient preference ought to play?

One of the hallmarks of heuristic reasoning, as emphasized by Daniel Kahneman,14 is that faced with a hard question, we answer an easier one instead. In some sense, then, as a profession, we have fallen into a collective heuristic trap. Rather than confront these thorny ethical questions head on, we have answered an easier question: Should we respect patients’ values and preferences? The right answer will always be yes. The much harder question is how to balance that respect with our professional responsibility to use our expertise to translate clinical science into better population health.

Defaulting to patient preference in the face of uncertainty has become the moral high ground. But it is as much our job to figure out how to best help our patients lead healthier lives as it is to honor their preferences. No matter how well we can define the tradeoffs of a medical decision, the threshold at which we decide that benefits outweigh harms is as subjective as individual patients’ perceptions of those tradeoffs. But this recognition does not stop us from making rigorous attempts to quantify the tradeoffs, any more than it should stop us from trying to better understand how our patients’ feelings and beliefs inform their understanding of those numbers, consequent behaviors, and health outcomes. As Slovic has emphasized, experts’ efforts to communicate risk will fail in the absence of a structured two-way process. “Each side, expert and public, has something valid to contribute,” he notes. “Each side must respect the insights and intelligence of the other.”13                                   

update 21 Oct 2014 Dr Garry Gordon writes :

  “Hello ,  What are you doing to detox your patients on a daily basis? We live in a crazy world where  nutritional supplements with little or no clear risks to consumers are seized/ restricted, but Authorities drag feet  on stopping the use of a proven toxin like BP-A found as a coating inside of most canned goods.  Please understand that Randy Jirtle at Duke has shown that BP-A made healthy brown Agouti mice become obese, yellow and diabetic!  That effect led to an epigenetic change, which will persist for generations and was shown to be an epigenetic change in methylation.Plan to protect yourself with lots of methylation support. I take my Beyond B12 sublingual product that provides Methyl Folate and Methyl B12. Please know virtually everyone tests positive for BP-A in urine much of the time, as we have great difficulty in avoiding this poison in our daily living. Yet authorities  ignores the dangers although they finally are doing something to protect babies a little.How can anyone practice effective medicine today and ignore the toxin burden we all carry. Remember when I got out of training in 1958 normal sperm count was 140 million; today few have 40 million. I detox daily with my “Power Drink” and PEMF and I definitely show real benefits even at age 79.“BPA has been linked to possible health problems of the brain, breast and prostate. In 2008, the environmental group Natural Resources Defense Council asked the FDA to ban use of the chemical because of what it termed “serious adverse health effects.”In 2011, the American Medical Association deemed BPA an “endocrine-disrupting agent” and urged that “BPA-containing products with the potential for human exposure be clearly identified.” The FDA said it continues to evaluate the safety of BPA-containing products.”http://online.wsj.com/article/SB10001424127887323740804578600113164806902.html?mod=djemHL_t

Wassertheil-Smoller S ea .   Albert Einstein College of Medicine, NY, write in Breast Cancer Res Treat. 2013 Oct;141(3):495-505.  Multivitamin and mineral use and breast cancer mortality in older women with invasive breast cancer in the women’s health initiative..  “Multivitamin use is common in the United States. It is not known whether multivitamins with minerals supplements (MVM) used by women already diagnosed with invasive breast cancer would affect their breast cancer mortality risk.   a prospective cohort study  of 7,728 women aged 50-79 at enrollment in the women’s health initiative (WHI) in 40 clinical sites across the United States diagnosed with incident invasive breast cancer during WHI and followed for a mean of 7.1 years after breast cancer diagnosis, showed :” At baseline, 37.8 % of women reported MVM use. After mean post-diagnosis follow-up of 7.1 ± 4.1 (SD) years, there were 518 (6.7 %) deaths from breast cancer. In adjusted analyses, breast cancer mortality was 30 % lower in MVM users as compared to non-users (HR = 0.70; 95 % CI 0.55, 0.91). This association was highly robust and persisted after multiple adjustments for potential confounding variables and in propensity score matched analysis (HR = 0.76; 95 % CI 0.60-0.96). Postmenopausal women with invasive breast cancer using MVM had lower breast cancer mortality than non-users. The results suggest a possible role for daily MVM use in attenuating breast cancer mortality in women with invasive breast cancer but the findings require confirmation.

Tying up Garry Gordon’s two themes above  is obviously the fact that , as in eg the USA ARED (Centrum) trial, the Lemon-Rollo McMaster supermouse trials and the Scottish Highlands,  and China supplement trials, multisupplements are longterm (especially with vigorous levels of vitamins C and D and magnesium) both antioxidant, insulin sensitizing, methylating, Nitric-oxide promoting and (heavy metal) detoxicants- ie promote healthspan and suppress degenerative diseases and infection. . .

 UPDATE 18 OCT 2014: more arguments against screening mammography from UK and Canada:Curr Oncol. Oct 2014; 21(5): 210–214.  Reflections on screening mammography and the early detection of breast cancer.  A Countercurrents Seriesa    S.A. Narod, MD  *Women’s College Research Institute, Women’s College Hospital, Toronto, ON.A little learning is a dangerous thing.— Alexander Pope, An Essay on CriticismIn the stormy aftermath of the recent publication of results from the 25-year Canadian National Breast Screening Study (nbss)1, various opinions questioning the validity of the study’s results have been expressed27. I was a latecomer to the study. In 2005, I was charged with oversight of the final record linkage and the statistical analysis and interpretation of the final data set. Dr. Anthony Miller has been my mentor since 1987. Our first joint paper, on screening for cervical cancer, was published in 19918. I chose not to respond to individual criticisms, but instead to collect my thoughts and to try to explain why the study authors saw no benefit from screening.Most of the criticism from the radiology community focuses on issues of study design (which they claim was inadequate) and on the quality of the mammography (which they also claim was inadequate). Cancer survivors bolster those criticisms with testimonials and appeals to common sense. Supporters of the study are drawn from the public health community, and they tend to focus on overdiagnosis and health economics.The report at issue is not the first emerging from the nbss. Earlier reports9,10 were criticized for not having allowed adequate follow-up time. But the 25-year results resemble the early results, and the authors are no longer criticized for premature disclosure. None of the first-generation critics have acknowledged the consistency; instead, they look elsewhere and point out other weaknesses. They claim that high-risk women were assigned to the mammography arm in violation of the principle of randomization. In his bestseller The Emperor of All Maladies, Siddhartha Mukherjee says, as a matter of fact, that high-risk women were assigned surreptitiously to the mammography arm, which explains the lack of observed benefit11.The most recent nbss report1 tallied the breast cancers that occurred in each of the two study arms after the screening period ended (that is, between years 6 and 25), counting 2584 cancers in the screening arm and 2609 cancers in the control arm. If the screening arm had been enriched for women at “high risk,” that enrichment must have been performed in a peculiar fashion, using only risk factors that have a transient effect. Perhaps Dr. Mukherjee would care to explain what those factors were. It follows that the excess of cancers seen in the screening period (years 1–5: 666 vs. 524) was a result of early diagnosis and not from stacking the deck.In any case, compelling evidence against the criticism of assignment of high-risk women to the screening arm is provided in the most recent analysis1, and that criticism is no longer raised (although no one has retracted or apologized). Instead, critics now insist that many women with palpable lesions were sent directly to the screening arm by duplicitous research assistants. There is no reason to believe that such actions (which would involve a national conspiracy of dozens of coordinators who spoke two official languages) were taken, but even if they had been, the study and its conclusions would not necessarily be invalidated. Even if all the women with prevalent cancers had been shunted to the screening arm, the situation could still be remedied by ignoring all cancers found at the first screening round (prevalent cancers) and focusing instead on the incident cancers. Such a strategy is not uncommon in screening studies. In the nbss, no woman had the opportunity to “cross the floor” from one study arm to the other after initial assignment. Therefore, if we exclude all prevalent cases from the analysis and focus on women with no cancer at study entry, we can re-evaluate the benefit of mammography thereafter. The hazard ratio for death from breast cancers detected in screening rounds 2–5 was 0.90 (95% confidence interval: 0.69 to 1.16;p = 0.40).But what about crossover? It is claimed that a certain proportion of the women in the control arm—perhaps as high as 20%—opted for screening off-study, in particular after the screening period was over. That crossover will, some say, eclipse a benefit of screening that might otherwise have ensued. That is, the benefit of mammography (which might well have been substantial) was nullified by a subcohort of independently-minded women who went for mammography at the end of the 5 years. That speculation is fanciful, but if true, should be welcomed, because it can now be said to a patient who, at age 40, requests a mammogram, that there is no hurry; she can come back in 5 years for a mammogram and achieve the same net benefit. And when she comes back at age 45, she can be reprieved again until age 50.Crossover is a form of contamination that results in misclassification of the exposed and unexposed groups. In a trial, it will tend to bias the result toward the null. The best way to avoid misclassification is to randomize the patients after they agree to participate—as the nbss did. In contrast, in the Swedish two-county trial (discussed in more detail a little later in this article), the subjects were randomized by intention-to-treat—that is, by whether they received or did not receive an invitation to mammography1215. Of the 78,085 women in Sweden who were offered screening, 69,645 accepted and 8440 declined. In effect, then, 8440 women in the Swedish study were de facto misclassified (versus an undisclosed number of hypothetical crossers-over in the Canadian study). The proponents of the Swedish study do not see that misclassification as a shortcoming, but instead use it to buoy their argument in favour of screening. They say that if everybody invited for screening came for screening, then the protective effect would have been more profound. In the Swedish study, all women in the control group were offered a screening test after the screening period ended (a reasonable thing to do); but those authors were not criticized for “contaminating” their study.

The second issue raised concerns the quality of the mammography. After all, the nbss tests were completed 30 years ago using 30-year-old technology. I still wonder how things might have been done differently. Mammography screening identified 212 women with breast cancer who would otherwise have been missed. They had cancers that were, on average, 1.4 cm in size, with 67% being node-negative. The survival of those women was very good. At the end of the study period, 170 women with a nonpalpable mammography-detected breast cancer were alive or had died of other causes. How many of those lives did screening save? Fifty? Twenty-five? Ten? Unfortunately, all we can say is that the number was too few to be noticed. If a significant number of those 170 lives had, in fact, been saved, surely the difference between study arms would have been noticeable. Breast cancer deaths numbered 180 in the mammography group and 171 in the control group. Perhaps some of the survivors believe that their lives were saved. They might perhaps have written a letter to the editor of their local newspaper extolling the virtues of mammography. But 42 women with a nonpalpable mammography-detected cancer died (none of whom has written a letter to the editor).

I am also among the authors of several publications on the benefits of screening by magnetic resonance imaging (mri) in high-risk women1618. Those studies were greeted as successes, given that they demonstrated how, with the use of mri, breast cancers could be downstaged. Those studies were accepted by the radiology community as being supportive of screening. Whether mri reduces mortality has not yet been shown. I cannot predict whether  mri screening will be effective in reducing mortality 10 years down the line, but I fully expect that if a mortality benefit fails to materialize, the studies will be criticized for using 30-year-old equipment and a poor study design.

Much of the criticism of the nbss has come from Drs. Daniel Kopans and László Tabár, and fellow travellers such as Siddhartha Mukherjee and Patrick Borgen27,11. They use the Swedish two-county trial as evidence of a good study that supports the use of mammography and quote a 30% reduction in mortality. Naturally, they do not criticize their canonical study, but it is time to take a closer look.

In the nbss, women were randomized on an individual basis after they had attended the study centre. The result was two groups of equal size and 100% compliance with the first screen. In Sweden, the two counties were divided into 19 geographic strata that were then divided into either 2 blocks (Östergötland) or 3 blocks (Kopparberg). The resulting 45 blocks were randomized, and women in more than half the blocks were sent a letter of invitation to screening. Of the 59% of women who received an invitation, 89% came for the first screen and 83% came for the second screen14.

The Canadian women were offered 5 mammograms 1 year apart. The Swedish women were offered mammograms every 2 years (ages 40–49) or every 3 years (ages 50–74) for up to 8 years. They underwent fewer screens (Table i). The cancers detected by mammography in Canada were similar in size to those detected in Sweden (Table i), but the size of the cancers occurring in the control group were very different. Those comparisons suggest that physical examinations or breast cancer awareness (or both) were important contributors to the size of cancers detected in Canada. A diminution of cancer mortality would not be expected to be associated with a 0.2 cm mean difference in tumour size, but might be expected with a net reduction of 0.7 cm in size19. Of the cancers detected in the screening arm of the Canadian trial, 68% were palpable. That fact has been a source of criticism. But a physical examination was not conducted as part of the screening protocol in Sweden, and the comparable number of palpable tumours was not given. Therefore, given the much longer mean time between screening visits in Sweden, and the high proportion of women in the screening arm that were never screened, I estimate that between 70% and 80% of the cancers in the mammography arm in Sweden would have been palpable and could have been detected by physical examination—had it been done. The fact that the relevant number is not given is a critical lapse. Suppose, for the sake of argument, that 100% of the cancers detected in the screening arm in Sweden were in fact palpable (not a gross exaggeration). What then would be the point of mammographic screening? And if that number (the palpable fraction) is not available, how can the results be judged? Neither the Swedish nor the Canadian trial can exclude the possibility that the benefit from invitation to mammography might have been restricted to women with palpable cancers.

A comparison of key parameters in the Canadian National Breast Screening Study (nbss) and the Swedish two-county trial

The Canadian study reports the number of cancers detected in the follow-up period after the end of the screening period and the number of subsequent deaths from breast cancer. From year 6 to year 25, 2584 incident cancers occurred in the screening group, resulting in 298 deaths (11.5%), and 2609 incident cancers occurred in the control group, resulting in 321 deaths (12.3%). Those data are important because they confirm that, in the absence of screening, the cancer incidence and mortality are equal in the study groups. Where are the comparable numbers for the Swedish study? Again, they are not given. But in looking at the extraordinary Figure 1 from the most recent report of the Swedish study12, the mortality curves are seen to continue to separate at 25 to 29 years after the initiation of screening, and long since screening had stopped.

Tabár and colleagues ask readers to believe that the benefits of mammography are everlasting (or at least for 20 years beyond the end of screening). They make that claim despite having no surety about whether the deaths from breast cancer in years 25–29 were the result of cancers diagnosed during the screening period or diagnosed after screening had stopped. They claim that most of the deaths from breast cancers diagnosed in the control arm occurred more than 10 years after diagnosis. Thus, the reader is asked to accept that a mean of 2.3 mammograms obtained in year 1–7 are more likely than a baseline imbalance in breast cancer risk to lead to a reduction in breast cancer mortality of 30% in years 25–29!

The incidence and mortality rates corresponding to cancers that were diagnosed after the screening trial was stopped are unavailable. Seeing the survival curves corresponding to cases detected in the screened and unscreened cohorts would be interesting. In the nbss, most cancer deaths occurred, as expected, within 10 years from diagnosis1. When the nbss was challenged as to having achieved an even balance in the study groups, the authors provided the relevant data. The Swedish authors should do the same. Patrick Borgen has stated that the  nbss is the “worst clinical trial ever done”5—an extraordinary statement. Either he has devoted his life to poring over medical tracts with the zeal of a Talmudic scholar, or he is speaking nonsense. But refuting his claim is easy: it takes merely the time required to read the Swedish papers.

Once the facts are accepted (that screening mammography fails to do what it was intended to do, and that overdiagnosis is real and substantial), then the most interesting questions can begin to be addressed. Did the nbss  fail because mammography is not a sufficiently sensitive imaging technique? Or has the screening community been working under false premises?

Consider sensitivity. Proponents of mammography say that the technique is currently better than it was in the 1980s, largely because it is more sensitive. (Specificity is also important, but is not at issue here.) They argue that “the more sensitive, the better.” The earlier a cancer can be identified and managed, the better. The smaller, the better. But those contentions generate an interesting paradox. Consider a woman with a small early-stage breast cancer. The recommendation is that this woman be followed with annual bilateral mammography for 5 or more years to identify recurrences and contralateral cancers20. That recommendation is based on the knowledge that the risk of contralateral cancer is between 0.5% and 0.8% annually21 and that a diagnosis of contralateral cancer is associated with an increase in mortality from breast cancer22. (It has not been shown that screening for contralateral cancer reduces mortality.) But mri is a much more sensitive screening tool than mammography, and by using mri in that setting, a small contralateral breast cancer can be identified in 4% of women with newly-diagnosed breast cancer23. And yet routine mri of the contralateral breast is not recommended, because it has not been shown to improve survival. Instead, the recommendation for follow-up with annual mammography continues. The paradox is this: If 8 years’ worth of incident breast cancers can be identified in one shot, why bother to pick them up in dribs and drabs? The mri-detected occult lesions are understood not to be clinically meaningful because they do not adversely affect mortality (overdiagnosis); however, if a similar lesion were to be found as a primary cancer in the ipsilateral breast, the radiologists insist that it is clinically meaningful. Once the paradigm that an increase in sensitivity increases overdiagnosis is accepted (that is, not all lesions are clinically meaningful), then it is the responsibility of clinicians to try to determine the ideal level of sensitivity.

The nbss has been berated for working with 30-year-old machinery, but I think that the greater problem is that clinicians are still working under 30-year-old assumptions. How much is really known about the relationship between size and survival? How confident is our community about early detection? It is universally accepted that tumour size and survival are inversely related for women diagnosed with palpable breast cancer24. That understanding is the rationale for early detection by mammography or other means. But it does not logically follow that a decrease in tumour size will necessarily lead to a decrease in mortality.

Consider two analogous situations. First, among women with breast cancer who experience a local recurrence, the strongest predictor of death is a short time from diagnosis to local recurrence25. However, that finding does not imply that a further shortening of the time from diagnosis to recurrence through intensive imaging would worsen survival. Second, studies of children with neuroblastoma noted that the children diagnosed in the first year of life experienced much better survival than those diagnosed thereafter26. That observation encouraged physicians to consider that screening for neuroblastoma by measuring urinary metabolites would increase the proportion of children diagnosed in the first year and thereby reduce mortality. The resulting clinical trial unfortunately found no benefit27. Neuroblastoma with a favorable prognosis is detectable by screening, but those cases are associated with a very high rate of spontaneous regression or maturation of the neuroblastoma into benign ganglioneuroma. Very few cases of neuroblastoma detected by screening have unfavourable biologic features such as N-Myc amplification28.

The relationship between breast cancer size and survival is not fixed, and the slope of the curve that defines the relationship varies according to the stage and pathologic features of the breast cancer24. The strongest relationship is seen with large cancers and node-positive cancers29. The relationship is attenuated among women with triple-negative cancers, with her2 (human epidermal growth factor receptor 2)–positive cancers, and with BRCA1-positive cancers19,30. Size does not predict mortality well for women with nonpalpable cancers29. Is it possible that there are additional categories wherein the size–survival relationship does not hold, and that eventually every woman with breast cancer will be able to be assigned to one of those categories? If more specific categorization were to be possible, then there would be no expectation of benefit from early detection—through mammography or any other means. In statistical terms, the question is “Are there variables n1, n2, n3, … nx, such that, after adjusting for n1, n2, n3, … nx in a follow-up study, size is no longer predictive of survival?” For example, in a study of 5423 women with cancers of less than 2.0 cm, tumour size was not predictive of survival after adjustment for grade, hormone receptor status, and her2 expression30. Those data suggest that, as the mean size of breast cancers in a population diminishes, further reductions in size can achieve only marginally less benefit. The lesson of mammography should be used to rethink the fundamentals of breast cancer and its natural history so that planning can commence for the experiments and clinical studies that will lead to better outcomes in the future.

 

Curr Oncol. Oct 2014; 21(5): 215–216.  re: Reflections on screening mammography and the early detection of breast cancer   Baum, MD ChM* *Professor Emeritus of Surgery &  Medical Humanities, University College, London, U.K.

I welcome this opportunity to comment on the piece by Dr. Steven Narod in this issue of Current Oncology. His commentary systematically responds to, and rebuts, the near-hysterical reactions to the recent publication of the 25-year follow-up results of the Canadian National Breast Cancer Screening Study1. I admire his restraint in the face of criticisms that go way beyond the boundaries of polite scientific disputation.

Much of the criticism the authors of the trial have faced goes so far as to accuse them of being guilty of scientific misconduct and fraud. Those charges are libellous, but I’m sure that Narod et al. are wise enough not to resolve their differences in a court of law, but simply to open their books to scientific scrutiny, in a way that fair-minded clinicians can judge who are the real culprits. Narod has achieved precisely that end in his timely and measured response. My only criticism is minor … in that he doesn’t go far enough. For example, it could easily be pointed out that the results of the National Breast Cancer Screening Study sit comfortably within the confidence intervals of a Cochrane Collaboration overview of the screening trials, with no hint of heterogeneity2. If anything, the trial in that overview that is closest to being an outlier is the Swedish two-county trial, whose authors are the shrillest of all the critics3.

The debate is so polarized that, leaving aside possible conflicts of interest, the only assumption that can be made is that the clash is one of ideology rather than scientific discourse. In other words, the true believers in the screening dogma will never be persuaded of the error of their ways by data alone, and so when facts don’t fit their prejudice, they resort to ad hominem attacks.

I was one of those who established the first screening centre in London and South East England in 1988, but as an open-minded clinical scientist, I allowed the emerging new data to change my mind. With all due modesty, that is what is called an expression of scientific integrity. Of course, as Narod points out, the prolonged and futile debate merely inhibits real progress on the subject. The importance of breast screening programs lies not in their success, but in their failure. As Huxley put it, “The tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.”

The national breast screening programs around the world have provided us with a natural experiment of the greatest historical importance, not because of their success in reducing breast cancer mortality, but because of the observations that have emerged concerning overdiagnosis of the disease4,5. About two hundred years ago, cancer was defined by its microscopic appearance. With the discovery and use of the modern microscope, the nineteenth century saw the birth of scientific oncology. Rudolf Virchow, often called the founder of cellular pathology, provided the scientific basis for the modern pathologic study of cancer6. As earlier generations had correlated autopsy findings observed with the unaided eye with the clinical course of cancer one hundred years earlier7, so Virchow correlated the microscopic pathology of the disease. However, the material he was studying came from the autopsies of patients dying from cancer. In the mid-nineteenth century, pathology correlations were performed either on cadavers or on living subjects presenting with locally advanced or metastatic disease who were almost always predetermined to die in the absence of effective therapy. Since then, and without pause for thought, the microscopic identification of cancer according to those classical criteria has been associated with the assumed prognosis of fatal disease in the absence of treatment.

A syllogism at the heart of the diagnosis of cancer therefore runs like this: People frequently die from malignant disease. Under the microscope, this malignant disease has many histologic features that we will call “cancer.” Ergo, anything that looks like “cancer” under the microscope will kill you. The screening debacle therefore suggests that some of the earliest stages of “cancer,” if left unperturbed, will not progress to a disease with lethal potential. Those pathologic entities might have microscopic similarity to true cancers, but their appearances alone are insufficient to predict a life-threatening disease.

Conventional mathematical models of cancer growth are linear or logarithmic—in other words, completely predictable at the outset. They predict transition from in situ phases to early invasive, and from early invasive to late invasive over time. Most natural biologic mechanisms are nonlinear or are better described by chaos theory8. Prolonged latency followed by catastrophe should not be all that surprising. We accept the case for prostate cancer, because we know that most elderly men will die with prostate cancer in situ and not of prostate cancer. In fact, the United Kingdom’s national prostate-specific antigen screening trial (protect) is predicated on that fact, with two a priori outcome measures defined: deaths from prostate cancer, and the number of cancers over-detected and treated unnecessarily9.

Next, it is worth noting that, contrary to all common-sense predictions, the increased detection rate of ductal carcinoma in situ has led to an increase in the mastectomy rate for the screened population4,5. Up to 45% of women with a screen-detected case of ductal carcinoma in situ end up undergoing mastectomy because of the multicentricity of the disease10. And yet the paradox is that clinically detected multicentric invasive breast cancer is relatively uncommon11. Surely that is proof enough that at least half the foci of ductal carcinoma in situ will regress if left alone; of course, determining which half remains the problem.

In conclusion, then, it can be stated with a great deal of conviction that a large proportion (on the order of 50%) of screen-detected (preclinical) foci of breast cancer are not programmed to progress if left unperturbed. That observation is of seismic importance and could set the agenda for breast cancer research into the next decade. The choice to ignore those observations, either because they do not support personal prejudice or because of some sleazy political agenda, will result in our community missing an opportunity of a life-time—and that would be unforgivable.

Narod is to be congratulated for his systematic and robust rebuttal of the unjustified attempts to destroy the credibility of the Canadian trial by a small group of vociferous critics who provide a background noise so loud that it nearly drowns out the true signal of the 25-year experiment of population screening for breast cancer.

“There’s non so blind as those that will not see.”— Jonathan Swift, Polite Conversation

Curr Oncol. Oct 2014; 21: 205–207. Screening mammography: the turning of the tide?  W.D. Foulkes, MBBS PhD McGill University, Montreal, Quebec     This issue of Current Oncology features a Counter-currents article by Dr. Steven Narod, “Reflections on screening mammography and the early detection of breast cancer”1, that is accompanied by a commentary from Professor Michael Baum2 supporting Narod’s thesis. Indeed, in Baum’s view, Narod’s only error was not to push home the point that the Canadian National Breast Cancer Screening Study (nbss) is not an outlier among mammography screening studies. He commends Narod for a measured response to the widespread criticism that followed publication of the 25-year follow-up results of the by now notorious nbss.

It seems as if almost everyone has an opinion on screening mammography. Everyone is entitled to an opinion, of course; but discussions about mammographic screening tend to take on a special, almost unique, quality—which perhaps speaks to the investments (financial, psychological, and career) made by many of the protagonists, which Professor Baum fleetingly mentions as potential conflicts of interest in his editorial. Baum prefers to see the ongoing debate—if that is what it is—as a clash of ideologies. But what are these ideologies that are so opposed?

Essentially, Baum’s argument is that the proponents of screening are not really scientists, in the sense that they do not accept refutation of data by data. He could be right, but I think the more parsimonious and psychologically more plausible explanation is that the aforementioned investments are simply too great: the stakes are too high. That the stakes are high is, in my view, very clear. Breast cancer is a common disease, and if population-based screening mammography is shown to have failed and is therefore no longer offered, billions of dollars would be saved every year in the United States alone3.

Narod contrasts the results of two large trials of mammography (one carried out in Sweden, the two-county study) with the nbss data. Having read these carefully laid out arguments, I think that most disinterested, but informed, readers will accept that many of the legion of criticisms that have been placed at the door of the nbss simply do not hold up to scrutiny. But mud sticks, and so many observers who do not like the results of the nbss point again and again to the same “flaws.”

One of Narod’s most telling points is that the survival curves for the two arms of the Swedish trial continue to remain separate up to 29 years after the trial was started. That observation is not consistent with any known effect of mammographic screening. It is much more likely that the populations were simply different to start with.

Further discussion of the pros and cons of these two trials is now fairly pointless. There are not much new data to be had, and I can’t see Drs. Kopans and Tabár, on reading Narod’s article, deciding that perhaps the benefits of mammography have, after all, been overestimated. Without new data, we can’t resolve this critical issue. So perhaps we need to stop the current process and actually do some new research to gather the required data.

A recent Perspective article in the New England Journal of Medicine4 noted the presence of a deep chasm separating women’s views of the likely benefit of mammographic screening and the actual data available. The nongovernmental Swiss Medical Board subsequently determined that women could not make informed decisions about screening without access to more nuanced information. Moreover, the Board felt that the benefits of mammographic screening were likely to be so small that no new screening programs should be introduced and existing programs should be allowed to run down. Their decision caused the expected uproar, but it is interesting to note that the results of a reader poll after a Clinical Decisions article 2 years earlier in the New England Journal of Medicine5 showed that a clear majority did not think that screening mammography should be started at age 40. Those results are contrary to the recommendation of many breast cancer organizations. But on the basis of these newer findings, it seems to me that the tide has turned, insofar as there are now enough interested parties prepared to question the benefits of mammography.

One of the points that Narod makes bears some discussion: He sees the problem not in terms of 30-year-old mammography machines in nbss study, but in 30-year-old thinking about the biology of breast cancer on the part of those who support screening. Logically, it can be seen that, as breast cancers enlarge, the number of cancer cells within them increases, which can provide opportunities for more malignant clones to emerge. Earlier detection will thus prevent those emerging clones from worsening outcomes. This quasi-Halstedian view, that a breast cancer makes a stately progression through biologically distinct and distinguishable stages and that the grade worsens as the tumour enlarges (assumptions that are at the heart of the original explanation of how mammography “works”6), are no longer part of mainstream thinking about breast cancer biology. Even ductal carcinoma in situ seems to possess many of the molecular changes found in invasive breast cancers, albeit at lower frequencies7,8. It seems as if the “die is cast” fairly early in the life of a breast cancer9. Intrinsic subtypes hold true as cancers grow and metastasize10, and the sojourn time varies from subtype to subtype11. Some breast cancers regress12. Others grow very rapidly13. These are not ideal biologic circumstances for the success of an “across the board” screening program. That conclusion is even borne out by a careful examination of the two-county study data14. The one group for whom screening mammography would be hoped to work—women between 40 and 49 years of age with a grade iii breast cancer (a group likely to contribute disproportionately to the observed mortality from breast cancer)—does not seem to achieve any mortality savings (see Figure 20 in Tabár et al.14). Survival at 16 years from randomization was identical in the invited and screened groups (relative risk: 0.95; 95% confidence interval: 0.55 to 1.64). One wonders if, in fact, the shoe is on the other foot. What has been learned about interpreting screening data from the current understanding of the natural history of breast cancer?

On the other side of the ledger, overdiagnosis has emerged in the past several years as a major issue in breast cancer screening. Quantifying the benefits and harms of mammography make for sobering reading by disinterested parties. If one starts with a sample of 1000 U.S. women 50 years of age, and if those women are screened annually for a decade, fewer than 4 women will avoid a breast cancer death; 3–14 women will suffer the consequences of over-diagnosis; and many hundreds will have at least 1 false alarm15. Work by Welch and Frankel suggests that women would think differently about mammographic screening for breast cancer if they were made aware of those figures at time of invitation for screening. Using best estimates, only 1 woman in 4 who develop a screen-detected breast cancer will avoid a breast cancer death16. The other 3 will do just as well, or just as poorly, without screening—or, of more concern, will have been diagnosed with a cancer that was not destined to ever present clinically. In the observational Norwegian study, only one third of the reduction in deaths from breast cancer could be attributed to mammographic screening per se17. Most women with a screen-detected breast cancer are therefore either diagnosed early (but with no effect on outcome) or are overdiagnosed.

We have been here before. Maureen Roberts, director of the Edinburgh breast screening project, died of breast cancer in 1989. While hopeful that mammographic screening would benefit women, she concluded from an analysis of the Edinburgh trial results that it did not. Before she died, she wrote “Breast screening: time for a rethink?” for the British Medical Journal18, concluding, “I feel sad to be writing this; sad because naturally after so many years I am sorry that breast screening may not be of benefit. I am also sad to seem to be critical of the many dear and valued colleagues I’ve worked with over the years, particularly those who have made such a magnificent contribution to the care and welfare of women with breast cancer. But they will recognise that I am telling the truth.”

It is time to work toward a trial of screening mammography that will incorporate variable thresholds, molecular markers, genetic testing, and psychological and physical measures of the effect of overdiagnosis. One of the two authors of the New England Journal of Medicine Perspective article discussed earlier, an ethics representative on the Swiss Medical Board, has argued that there is a moral requirement for a randomized controlled trial of mammography19 based on Welch’s idea of differing detection thresholds. I believe that women will be interested in such a study. But because almost every major U.S. medical organization focusing on breast cancer prevention, diagnosis, or treatment has stated that women should begin undergoing mammography annually from the age of 40 years, will any agency have the courage to fund it?

 
October 07, 2014  Dr. Joe Mercola DC  does a nice review of recent critiques  in   Why So Many Mixed Messages on Mammogram Benefits?
Earlier this year, one of the largest and longest studies of mammography to date — involving 90,000 women followed for 25 years — found that mammograms have no impact on breast cancer mortality. The Canadian Breast Screening Trial ll Miller ea 
Over the course of the study, the death rate from breast cancer was virtually identical between those who received an annual mammogram and those who did not, while 22 percent of screen-detected invasive breast cancers were over-diagnosed, leading to unnecessary treatment. The researchers concluded “the data suggest that the value of mammography screening should be reassessed.”2
A Cochrane Collaboration review also found no evidence that mammography screening has an effect on overall mortality, which, taken together, seriously calls into question whether mammography screening really benefits women.3
Public health agencies, however, have been slow to update their recommendations. The American Cancer Society recommends annual mammograms for average-risk women starting at the age of 40, while the US Preventive Services Task Force recommends mammograms every other year starting at age 50
The conflicting recommendations send women mixed messages on whether screening is helpful or harmful, yet, earlier this year the Swiss Medical Board made a clear-cut recommendation: no more systematic mammography.  
Why Did the Swiss Medical Board Do Away with Routine Mammograms? 
After a year of reviewing the available evidence and its implications, the Swiss Medical Board, an independent health technology assessment initiative, noted they became “increasingly concerned” about what they were finding. The “evidence” simply did not back up the global consensus of other experts in the field suggesting that mammograms were safe and capable of saving lives.
        On the contrary, mammography appeared to be preventing only one death for every 1,000 women screened, while causing harm to many more. Their thorough review left them no choice but to recommend that no new systematic mammography screening programs be introduced, and that a time limit should be placed on existing programs.  
In their report, made public in February 2014,4 the Swiss Medical Board also advised that the quality of mammography screening should be evaluated and women should be informed, in a “clear and balanced” way, about the benefits and harms of screening.  
Unfortunately, many women are still unaware that the science backing the health benefits of mammograms is sorely lacking. Instead of being told the truth, women are guilt-tripped into thinking that skipping their yearly mammogram is the height of medical irresponsibility. It can be hard to stand your ground against such tactics.  
      When it comes to cancer prevention, however, many doctors are just as confused and manipulated as the average person on the street because of the relentless industry and media propaganda that downplays or ignores research that dramatically contradicts their profit-based agenda.
Five Facts About Mammograms That Every Woman Should Know
Before your next (or first) mammogram, you may be interested to know the following:

1. Mammograms May Offer Less Benefit Than You Think:

In one survey, most women said they believed mammography reduced the risk of breast cancer deaths by at least half and prevented at least 80 deaths per 1,000 women screened.5 In reality, mammography may, at best, offer a relative risk reduction of 20 percent and prevent in absolute terms only onebreast-cancer death per 10,000 women.

2. Mammography May Increase the Risk of Breast Cancer in Women with a BRCA 1/2 Mutation:

Results published in the British Medical Journal (BMJ) show that women carrying a specific gene mutation called BRCA1/2 (which is linked to breast cancer) are particularly vulnerable to radiation-induced cancer.6

Women carrying this mutation who were exposed to diagnostic radiation (which includes mammograms) before the age of 30 were twice as likely to develop breast cancer, compared to those who did not have the mutated gene. They also found that the radiation-induced cancer was dose-responsive, meaning the greater the dose, the higher the risk of cancer developing.

3. False Positives are Common (and Dangerous)

In the US, the risk of having a false-positive test over 10 mammograms is a concerning 58 percent to 77 percent!78 When a woman is told she may have breast cancer, it causes considerable anxiety and psychological distress. Meanwhile, you will be subjected to more testing, such as biopsy or surgery, which carry their own set of risks, unnecessarily.

4. Mammograms May Not Work if You Have Dense Breasts

Up to 50 percent of women have dense breast tissue, which makes mammograms very difficult to decipher. Dense breast tissue and cancer both appear white on an X-ray, making it nearly impossible for a radiologist to detect cancer in these women. It’s like trying to find a snowflake in a blizzard.

Breast density laws have been passed in California, Connecticut, New York, Virginia, and Texas, making it mandatory for radiologists to inform their patients who have dense breast tissue that mammograms are basically useless for them. A law is now being considered at a federal level as well.

5. There are Other Screening Options

There are other screening options, each with their own strengths and weaknesses, and you have a right to utilize those options.  Remember, only a biopsy can confirm cancer.  Screening tools only aid in the process of showing concern.  

Your Waist Size Is Linked to Your Breast Cancer Risk It’s important to remember that getting a mammogram, if you choose to, is not the same as prevention. In order to truly avoid breast cancer, you need to focus your attention on actual prevention and not just early detection, and one way to do this is by maintaining a healthy weight, and, particularly, a healthy waist size.

Researchers analyzed data from 93,000 mostly overweight post-menopausal women. This included data such as their general health, cancer status, and skirt size (which was used as a gauge of waist size). The latter – skirt size – was strongly linked to breast cancer risk.9 As TIME reported:10

An increase in skirt size was the single most predictive measure of breast cancer risk, the study concluded. When women went up a single skirt size over a 10-year span between their mid-20s and mid-60s, they were shown to have a 33% greater risk of developing breast cancer after menopause. Buying two skirt sizes up during that same period was linked to a 77% increased risk.”

Clothing sizes can be quite ambiguous, of course, with a size 8 in one brand equal to another’s size 10. Yet, the premise that increasing waist size might increase cancer risk is sound. Breast cancer is the most common cancer in women, and obese women are thought to be up to 60 percent more likely to develop cancer than those of normal weight.

The reason for this increased risk is because many breast cancers are fueled by estrogen, a hormone produced in your fat tissue. So the more body fat you have, the more estrogen you’re likely to produce. However, excess fat around your mid-section may be particularly dangerous.

Why Your Waist-to-Hip Ratio Matters     If you have a high waist-to-hip ratio, i.e. you carry more fat around your waist than on your hips, you may be at an increased risk for certain chronic conditions. Certain body compositions do tend to increase your risk of chronic disease, and carrying extra inches around your midsection has been repeatedly shown to increase cardiovascular health risks. Your waist size is also a powerful indicator of insulin sensitivity, as studies clearly show that measuring your waist size is one of the most powerful ways to predict your risk for diabetes, and this could also play a role in cancer as well.

To calculate your waist-to-hip ratio, measure the circumference of your hips at the widest part, across your buttocks, and your waist at the smallest circumference of your natural waist, just above your belly button. Then divide your waist measurement by your hip measurement to get the ratio. (The University of Maryland offers an online waist-to-hip ratio calculator11 you can use.) To determine your waist-to-hip ratio, get a tape measure and record your waist and hip circumference. Then divide your waist circumference by your hip circumference. For a more thorough demonstration, please review the video below.

Waist to Hip Ratio Men Women
Ideal 0.8 0.7
Low Risk <0.95 <0.8
Moderate Risk 0.96-0.99 >0.81 – 0.84
High Risk >1.0 >0.85

  The Sugar Connection  Obesity, including abdominal obesity, is driving up rates of breast cancer in many developed countries. And what is driving up rates of obesity? Many factors, actually, but sugar certainly plays a primary role. There is no shortage of research linking excessive sugar consumption with obesity, and the intake of sugar-sweetened beverages appears to have a particularly strong link. It was more than five years ago when UCLA researchers found that adults who drank at least one sugar-sweetened beverage a day are 27 percent more likely to be overweight or obese.12 Even those who only drank soda occasionally had a 15 percent greater risk.

This is far more than simply an issue of consuming “empty calories,” as sugary drinks, soda, and even fresh-squeezed fruit juice contain fructose, which has been identified as one of the primary culprits in the meteoric rise of obesity and related health problems—in large part due to its ability to turn on your “fat switch.” Alarmingly, research presented at the American Heart Association’s Epidemiology and Prevention/Nutrition, Physical Activity and Metabolism 2013 Scientific Sessions suggested sugary beverages are to blame for about 183,000 deaths worldwide each year, including 133,000 diabetes deaths, 44,000 heart disease deaths, and 6,000 cancer deaths.

About 77 percent of food items in US grocery stores contain added sugar. So it’s no wonder that, while the American Heart Association recommends a daily sugar limit of six teaspoons for women and nine for men, the average American consumes more like 22. If health agencies really wanted to make a dent in breast cancer, they would focus on sharing the truth about sugar (and grains), and their role in obesity and cancer. Unfortunately, breast cancer is big business, and mammography is one of its primary profit centers. This is why the industry is fighting tooth and nail to keep it, even if it means ignoring (or downplaying) the truth.

Avoiding Sugar and Other Top Breast Cancer Prevention Tips   I believe the vast majority of all cancers, including breast cancer, could be prevented by strictly applying basic, commonsense healthy lifestyle strategies, such as the ones below. No available screening method, whether mammography or otherwise, is going to lower your risk of breast cancer… but the tips that follow will:

    • Avoid sugar, especially fructose, and processed foods. All forms of sugar are detrimental to your health in general and tend to promote cancer. Refined fructose, however, is clearly one of the most harmful and should be avoided as much as possible. This automatically means avoiding processed foods, as most are loaded with fructose.
    • Optimize your vitamin D levelsVitamin D influences virtually every cell in your body and is one of nature’s most potent cancer fighters. Vitamin D is actually able to enter cancer cells and trigger apoptosis (programmed cell death). If you have cancer, your vitamin D level should probably be between 70 and 100 ng/ml. Vitamin D works synergistically with every cancer treatment I’m aware of, with no adverse effects. Ideally, your levels should reach this point by exposure to the sun or a tanning bed, with oral vitamin D used as a last resort and balanced by other nutrients like vitamin K2 and magnesium.
    • Limit your protein. Newer research has emphasized the importance of the mTOR pathways. When these are active cancer growth is accelerated. One way to quiet this pathway is by limiting your protein to one gram of protein per kilogram of lean body mass, or roughly a bit less than half a gram of protein per every pound of lean body weight. For most people, this ranges between 40 and 70 grams of protein a day, which is typically about 2/3 to half of what they are currently eating. You can eat 25% more if you are exercising or pregnant.
    • Avoid unfermented soy productsUnfermented soy is high in plant estrogens, or phytoestrogens, also known as isoflavones. In some studies, soy appears to work in concert with human estrogen to increase breast cell proliferation, which increases the chances for mutations and drives the phenotype associated with cancer.
    • Improve your insulin and leptin receptor sensitivity. The best way to do this is by avoiding sugar and grains and restricting carbs to mostly fiber vegetables. Also make sure you are exercising, especially with Peak Fitness.
    • Exercise regularly. One of the primary reasons exercise works to lower your cancer risk is because it drives your insulin levels down, and controlling your insulin levels is one of the most powerful ways to reduce your cancer risks. It’s also been suggested that apoptosis (programmed cell death) is triggered by exercise, causing cancer cells to die in the way nature intended. Studies have also found that the number of tumors decrease along with body fat, which may be an additional factor. This is because exercise helps lower your estrogen levels, which explains why exercise appears to be particularly potent against breast cancer.

In addition to exercise, try to limit your sitting time to three hours a day while taking 10,000 daily steps during your non-exercise hours.

  • Maintain a healthy body weight. This will come naturally when you begin eating right and exercising. It’s important to lose excess body fat because fat produces estrogen, creating a vicious self-perpetuating cycle.
  • Drink a pint to a quart of organic green vegetable juice daily. This is a simple way to get more cancer-fighting nutrients into your diet. Please review my juicing instructions for more detailed information.
  • Get plenty of high-quality, animal-based omega-3 fats, such as krill oil. Omega-3 deficiency is a common underlying factor for cancer.
  • Curcumin. This is the main active ingredient in turmeric and in high concentrations can be very useful adjunct in the treatment of cancer. It actually has the most evidence-based literature supporting its use against cancer of any nutrient, including vitamin D.13 For example, it has demonstrated major therapeutic potential in preventing breast cancer metastasis.14 It’s important to know that curcumin is generally not absorbed that well, so I’ve provided several absorption tips here. Newer preparations have also started to emerge, offering better absorption. For best results, you’ll want to use a sustained-release preparation.
  • Avoid drinking alcohol, or at least limit your alcoholic drinks to one per day.
  • Avoid electromagnetic fields as much as possible. Even electric blankets may increase your cancer risk.
  • Avoid synthetic hormone replacement therapy, especially if you have risk factors for breast cancer. Many forms of breast cancer are estrogen-fueled, and according to a study published in the Journal of the National Cancer Institute, breast cancer rates for women dropped in tandem with decreased use of hormone replacement therapy. (There are similar risks for younger women who use oral contraceptives. Birth control pills, which are also comprised of synthetic hormones, have been linked to cervical and breast cancers.) If you are experiencing excessive menopausal symptoms, you may want to consider bioidentical hormone replacement therapy instead, which uses hormones that are molecularly identical to the ones your body produces and do not wreak havoc on your system. This is a much safer alternative.
  • Avoid BPA, phthalates, and other xenoestrogens. These are estrogen-like compounds that have been linked to increased breast cancer risk.
  • Make sure you’re not iodine deficient, as there’s compelling evidence linking iodine deficiency with certain forms of cancer. Dr. David Brownstein, author of the book Iodine: Why You Need It, Why You Can’t Live Without It, is a proponent of iodine for breast cancer. It actually has potent anticancer properties and has been shown to cause cell death in breast and thyroid cancer cells. For more information, I recommend reading Dr. Brownstein’s book. I have been researching iodine for some time ever since I interviewed Dr. Brownstein, as I do believe that the bulk of what he states is spot on. However, I am not at all convinced that his dosage recommendations are correct. I believe they are far too high.
  • Avoid charring your meats. Charcoal or flame-broiled meat is linked with increased breast cancer risk. Acrylamide—a carcinogen created when starchy foods are baked, roasted, or fried—has been found to increase cancer risk as well.
 
 27 Sept 2014   Three  thoughtful  new reviews, from Universities in Australia (Robin Bell),  Kuwait (Yusuf Luqmani) and Cape Town (Tim Noakes),  highlight the deadly ethical  problem of the myth-based zealous profiteering  Disease Industry promotion in the well of cancer screening,  and the high carbs low fat-low cholesterol  diet, and “statin deficiency” – iatrogenic  “OBSESSIVE-COMPULSIVE DISORDERS ” that profiteers cultivate in the guileless.
       It is not coincidence that the Food and Disease Industry insist that the dangerous high carbs low fat diet they have promoted for the past 40 years, and mass cancer screening for the past >20years , are correct- for the simple perverse reason that such lies pay ie Only Disease Pays. This brings us via  Lupton’s question of Ethics vs Science  in the fraught  narrow parenting domain,  to our everywhere dilemma:  Can Health Science , Human,  Animal and plant  Rights Survive the Onslaught of ruthless commerce and politics?

           Breast screening: an obsessive compulsive disorder.  in Cancer Causes Control. 2014 Jul 11.  Prof Yunus Luqmani  a British oncology biochemist,  Kuwait University writes   “Mammographic screening was  founded on the premises that “it  saves lives”, early is better than late,’  which prevails  in several countries but  controversial since its inception. Findings and interpretation of clinical trials data vary considerably, with disagreement on the outcome and value of such  procedure, not just about the benefits but about the potential harms of mass screening. Many are being screened for the benefit of the few. Even this might be acceptable  but  for concern for many  women with screen detected cancers that will potentially not cause them harm, and who are very likely receiving unnecessary treatment. Many  call for complete cessation of indiscriminate screening if not re-assessment of  age  and periodicity . Of great concern is that screening is being vigorously advocated by many healthcare workers, the media, and lay persons alike without proper awareness or appreciation of the consequences. Although some National leaflets  now present a truer picture, there is   distinct lack of transparency to allow women to distinguish perception from reality and to make informed choices. How many would elect to be screened if they knew that for every one woman who is notionally saved by early detection, anywhere from 2 to 10 otherwise healthy women are being turned into breast cancer patients?  

          Screening mammography – early detection or over-diagnosis     Climacteric. 2014 Sep 16:1-7. Epidemiologist  Prof Robin Bell  Monash University,  Australia examines  benefits and harms of organized screening mammography. Most  recent reduction in breast cancer-specific mortality is explained by use of adjuvant therapy rather than screening mammography. Impact of screening mammography in countries where women present with early disease and have access to adjuvant treatment is modest. There is a wide range of estimates for the magnitude of over-diagnosis. All-cause mortality (rather than breast cancer-specific mortality) should be used when assessing impact of screening as otherwise the harm of cancer treatment in those  over-diagnosed will be missed. Conclusions The benefits and harms of screening mammography are finely balanced. The impact of screening mammography is at best neutral but may result in overall harm. Women should be informed of the issue of over-diagnosis. It is time to review whether organized mammographic screening programs should continue.  
        AND ON DIET:             It is common cause that humans consume their energy requirements from what they can get- and since animal protein is the most costly,  and excess harmful, this means from carbs or fat, of which natural  animal/ dairy/ nut  fat is the most satisfying. So while keeping energy output and adequate animal protein intake  stable, needed energy intake comes from balance of fat and carbs.
       A  major bone of contention locally is the merits of the Banting diet –  in his words,  ‘four meals per day, consisting of meat, greens, fruits, and dry wine’- before the age of mass refined and chemically-and genetically-polluted food and maize-fed livestock.
        Cereals-carbohydrates in his time 160 years ago were thus largely replaced by fresh meat fats and fresh produce. Considering he was born in 1796, his life of  82 years was   almost double the then average lifespan despite his having been severely obese until he found his optimal diet advised by Dr William Harvey based on Professor Claude Bernard’s work on diabetes.
        But Banting was a businessman  of the pre-automobile  era:  unlike labourers, you walked, or you saddled up- without tarmac, coaches were slow. With modern understanding of the importance of avoiding the sedentary lifestyle and overload of both alcohol, salt, refined carbohydrates, protein, and synthetic ie transfats (margarine) , the Banting diet has adapted in modern times  to be optimal for many people for both energizing and keeping slim and well – with its accent on minimal refined/ processed carbs including concentrated cereals,  pure starches, cooked fatty pastries, and commercial fruit juice;
        with high natural fat 50+% as the  ideal brain-muscle-metabolic energy source- from unprocessed meat,  fish, eggs, cream, coconut, butter, cheese;  and modest mixed nuts; matched with copious  greens and other lowstarch rainbow vegetables.
     The futility of low fat (ie high carbs) diet was borne out in the biggest and costliest   -$billion – trial ever- the Women’s Health Initiative  WHI, published in 2006 (Rossouw ea)  and for cancer,  this week (Thomson ea)“Randomized controlled trial of 48,835 postmenopausal women aged 50 to 79 years,  who participated in the WHI Dietary Modification Trial;  randomly assigned to  intervention [40%]) or comparison group  [60%]) in a free-living setting,  enrollment between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years.  Intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group received diet-related education materials.    “Dietary advice to reduce fat for cancer and cardiovascular disease, stroke or coronary heart disease   prevention after menopause  was not supported in the  WHI.   The diet had no effects on incidence of CHD , stroke ,  or CVD. In fact  Women with higher baseline fat intake (quartile) had breast cancer risk only  HR-0.76; 0.62, 0.92 during intervention). Thus the highest  fat intake lowered breast cancer risk by 24%There were no intervention effects   ie no benefits of low fat diet on invasive breast 1.08  or colorectal cancer, other cancers, cancer-specific or overall mortality.
 
        and  the WHI (Shikany ea 2006 and 2011further showed direct association of  higher Dietary carbs (glycemic load GL  glycemic index)   and risk of breast cancer and cardiovascular disease risk factors .There was a trend toward significance for the positive association between GL and in situ cancers (1.40, 0.94-2.13; P = 0.07).   GL inversely associated with high-density lipoprotein HDL  cholesterol (P for trend = 0.004) and positively with triglycerides,  total cholesterol (P = 0.018) and low-density lipoprotein cholesterol.
            Professor Tim Noakes  Cape Town keeps on pointing out the lack of science in the perverse western (Ancell Keys)   paradigm of high carbs low fat processed diet (as in the WHI) , with  futile overreliance on  synthetic drugs eg statins,  and appliances, surgery  to reverse the consequent epidemic degenerative diseases- and keep the medical disease industry profitable. .

This brings us to the cutting edge of modernity: Can  Ethics Survive the Onslaught of Science ? (Prof Michael Lupton, Bond University, Australia  2013)?  Can health science  survive the onslaught of perverse incentives, profiteering- the Semmelweis Reflex that denies what is cheap, natural and best?
24 Sept 2014  update after the Angela Jolie hype: This month’s JAMA say it all: the less breast  surgery the better:
Use of and Mortality After Bilateral Mastectomy Compared With Other Surgical Treatments for Breast Cancer in California, 1998-2011. Kurian &  Gomez    Stanford Univ.  JAMA. 2014;312:902-914.                Bilateral mastectomy is increasingly used to treat unilateral breast cancer. Because it may have medical and psychosocial complications, a better understanding of its use and outcomes is essential to optimizing cancer care. Conclusions and Relevance  Use of bilateral mastectomy increased significantly throughout California from 1998 through 2011 and with median follow-up of 89 months  was not associated with lower mortality than that achieved with breast-conserving surgery plus radiation. Unilateral mastectomy was associated with higher mortality than were the other 2 surgical options.
Contralateral Prophylactic Mastectomy   Is It a Reasonable Option?         Editorial|Sept 3, 2014     Lisa Newman, Univ Michigan,   JAMA. 2014;312:895-897 The professional oncology community has worked diligently to generate data that facilitate surgical planning and the decision-making process for patients with newly diagnosed breast cancer. Several lines of evidence support the importance of prioritizing treatment of the known cancer over and above consideration of a risk-reducing mastectomy for the unaffected breast (contralateral prophylactic mastectomy [CPM]). For example, the equivalent overall survival for breast-conserving surgery (BCS) and mastectomy makes CPM an unnecessary option for women who are eligible for lumpectomy and desire breast preservation. Incidence of metachronous contralateral breast cancer (ie, contralateral cancer detected several months after initial breast cancer diagnosis) is relatively low, at 0.25% to 1% per year,1,2 and these cancers are usually detected at early, highly curable stages. Synchronous occult contralateral breast cancer is uncommon, as documented by studies revealing incidental cancer in only 1% to 3% of CPM specimens.3,4 Survival is comparable for patients with unilateral vs metachronous bilateral breast cancer5,6 and typically is associated with the stage of first cancer, consistent with the concept that the initially presenting tumor has a lead-time advantage in establishing distant organ micrometastases.
The corollary is obvious:    Less Informed Women With High Anxiety Are More Likely to Choose Bilateral Mastectomy for Breast Cancer  San Francisco Cancer Symposium  PracticeUpdate Editorial Team, 2014 Sept   Women with higher anxiety levels and less knowledge about breast cancer recurrence and survival are more likely to choose bilateral mastectomy ,    Katharine Yao, MD, of  University of Chicago  stated, “There is so much information about breast cancer that it’s easy for patients to get overwhelmed. As doctors, we have to be aware of each patient’s knowledge level and the concerns and worries he or she has. We need to do a better job of educating patients that the risk of developing contralateral breast cancer is actually low and that breast cancer can come back in other parts of the body no matter what type of surgery they have.”    Overall, 59% of patients chose lumpectomy, 32% unilateral mastectomy, and 9% CPM. Eighty-three (58%) considered CPM, and 12 (21%) of this latter group chose CPM contralateral prophylactic mastectomy.
 
11 August 2014  The current SA Menopause Society newsletter says:

Benefits of mammography

“the benefits of screening mammography are modest at best” (Elmore & Harris BMJ 2014;348:g3824). This is the conclusion after the latest research to come out of Norway where the introduction of screening has been gradually introduced over the last 2 decades (Weedon-Fekjaer et al BMJ 2014;348:g3701).The Norwegian authorities invited women between 50 and 70 years old to attend for screening every second year and looked at before and after death rates from breast cancer. They found RELATIVE risk reduction of 28% in those invited compared with those not invited to be screened. Without knowing the ACTUAL risk reduction or the harms of screening this sounds like a “good deal”. However it is an observational study not a randomised trial and therefore susceptible to various biases.For women to make up their own minds about screening, actual figures of benefits and harms need to be given because without accuracy perceived dangers and benefits are very far from reality. For example in the US or UK asking women about their estimates of breast cancer deaths – taking 1000 women aged 50 and following them for 20 years – gave the following results:

Of 1000, number
alive after 20 years
Deaths from
breast cancer
Deaths from
other causes
Women’s estimates
without screening
801 160 39
with screening 881 80 39
In reality
without screening
956 5 39
with screening 956-7 4 39-40

Women believe that breast cancer is a far greater threat than it really is. They also believe that screening halves such risk.

If actual death reductions from breast cancer are taken into account, screening benefits are modest at best and if all cause deaths are taken into account the benefits all but disappear.

20 July 2014 Two new papers from Scandinavia highlight the harms of screening mammography.:

Clin Adv Hematol Oncol. 2014 June;12:407-11    Screening mammography:   do the benefits always outweigh the harms?  Brodersen J, Jørgensen KJ, Brawley OW.

APMIS. 2014 May 26. doi: 10.1111/apm.12278.
Overdiagnosis: How cancer screening can turn indolent pathology into illness.    Brodersen J1, Schwartz LM, Woloshin S. The shift from illness to disease has had a profound impact on modern medicine – particularly in the realm of cancer screening. In screening, it is not patients with illness who seek help from the healthcare system; it is asymptomatic healthy individuals who are invited into the healthcare system to be examined for pathology. The underlying assumption of screening is that abnormalities and pathology always progress. If this were true, it would always make sense to look for disease even when people feel well. The million (or more accurately multi-billion) dollar question is whether the fundamental assumption that disease invariably leads to illness is valid. This is the question that the present paper will try to explore and answer.
The current Wiki article on Cancer Screening    firmly denies benefit for screening for silent prostate cancer;  and for xray screening mammography it  firmly questions  the benefit in lives saved versus the harms of screening.  The balance for screening mammogram is summed up by Wiki : “The phenomenon of finding pre-invasive malignancy or nonmalignant benign disease is commonplace in all forms of cancer screening, including pap smears for cervical cancer, fecal occult blood testing for colon cancer, and prostate-specific antigen testing for prostate cancer. All of these tests have the potential to detect asymptomatic cancers, and all of them have a high rate of false positives and lead to invasive procedures that are unlikely to benefit the patient.”
                Reality  remains that, in average  lean  well adults ie without obvious risks , the only screening justified is regular noninvasive SELF- EXAMINATION of breast, skin, testes, electronic bloodpressure; and professional optometric, dental,  skin and bloodpressure screening and, if suspicious, urine multistix exam.  By contrast, regular xray (chest or  mammogram- cumulative radiation risk) and pelvic  internal exams are highly invasive, thus indicated only for symptomatic or familial-risk cases. .
PEER (perverse) PRESSURE, Beliefs, perceptions, indoctrination –  by peer bodies, Corporates like Hospitals and Big Pharma, Regulators,  Accredition Bodies and dangled incentives – which obviously have commercial group vested self-interests  –  die hard:                                     Prev Med. 2014 Jul 16.Miller JW1,  Goff BA ea .  CDC & Washington State University, USA,   studied Physicians’ Beliefs about Effectiveness of Cancer Screening Tests: National Survey of Family Physicians, General Internists, and Obstetrician-Gynecologists(excluding breast radiologists, pathologists,  and oncologist/surgeons). RESULTS: of   1574 respondents-   62% response rate- the majority agreed with the effectiveness of: mammography aged 50-69 years, Pap tests  aged 21-65 years, and colonoscopy for aged ≥50 years.  Physicians typically listed their respective specialty organizations as a top influence for screening  recommendations.  CONCLUSIONS: There were several substantial inconsistencies between physician beliefs in the effectiveness of cancer screening tests and the actual evidence of these tests’ effectiveness which can lead both to underuse and overuse of cancer screening tests.
This outcome obviously damns professional bodies in respect at least of the evidence discouraging  screening mammography of well breasts.
   Its as Soren Kierkegaard wrote 150 years ago about religious conviction- the difficulty of following ethical theistic belief against the majority tide of convenience and venality;
  and Steven Jay Gould’s Non-Overlapping Magisteria of Science and Religion- for some (but not all), the difficulty of reconciling apparent scientific medical evidence (is it ever immutable? ) with belief, dogma- whether from mythical (is it always?)  religious belief, or simply vested interest.
       As we were taught 50 years ago, if new medical discoveries stand the test of time – they often dont-  it takes a generation for  the majority to accept, apply them. Almost two generations of women have now been martyred by repetitive screening xray mammography. Must it take yet another generation before such barbaric screening is abandoned? As Winwood Reade  and AC Grayling philosophized, countless millions have suffered genocide, holocaust in the post-Greko-Roman “enlightened”  two  millennia for vested interests in the guise of religious let alone medical dogma  .
14 July 2014:  BASTILLE DAY CLARION CALL FOR TRUTH TO PROTECT WOMEN:      Screening mammography & Bambi  This column reported these issues a few months ago (see Dr Gerd Gigerenzer PhD  below in May, and April 16, 2014  from the Swiss Medical Board: Abolishing Mammography Screening Programs? ), but they are worth repeating from Groote Schuur Hospital.  A professor of Obstets and Gyne there writes in the current South African Menopause Matters  news email (“an  editorial opinion that does not necessarily represent the views of  SAMS”) :
(the answer to his question: Whatever happened to Evidence-Based medicine? is quite simple: if  it doesnt pay, then evade, deny and mock the evidence, or better, shoot the messenger who dares blow the whistle on  inconvenient truth. )

The Professor writes: “Screening mammography is an emotive subject. Correctly so, because if it did clearly have more benefits than harms then it should be advocated, promoted and sold as an intervention in every woman’s interest.

      Regrettably screening mammography does not clearly have more benefits than harms and given that it is an unpleasant and costly process it should not be promoted. Both the protagonists and the antagonists claim ample facts supporting their arguments while finding fault with the others’ data. One of the latest trial outcomes from Canada (Miller et al BMJ 2014;348:g366) reports on a large group of women (nearly 90 000) who were randomised to mammography annually for 5 years or annual physical breast examination. This took place in the 1980s and the women were in their 50s and were followed up for 25 years.

Diagnoses of breast cancer and deaths from the disease were collected from national databases, as were all-cause mortality figures. The researchers showed that during the 5 years of mammography (or not) more women were diagnosed with breast cancer in the mammography arm (and treated) but the deaths were not significantly different in the two groups. Similarly over the entire study period there were more cancers diagnosed in the mammography arm but the number of deaths were similar, with the conclusion that mammography was not superior to annual examinations and resulted in overdiagnoses.

This is essentially a negative outcome if “deaths avoided” or “lives saved” are taken as the end points. Maybe modern screening techniques work better but also maybe better treatments have reduced mortality rates. The most recent Cochrane Review suggests that if 1000 women aged 50 were screened for 10 years then 4 women would die from breast cancer. Without screening 5 would die.

If the group’s deaths from any cancer are counted then the results are 21 per 1000 with or without mammography. So does mammography screening save lives? The supposed benefit?

If the harms are tallied for the same 1000 women then 100 in the mammography arm would have a false positive-evaluation and 5 would have an unnecessary partial or complete breast removal (Gøtzche et al Cochrane Reviews 2013;6:CD001877). The financial and convenience costs are not commented on.

Yet screening mammography is treated like a religion. Any suggestion to curtail its promotion is seen as “unfair to women” or not doing “the right thing”. A bit like Bambi bashing. How can something so obviously right be challenged?

Nowhere are the facts more disguised than in breast cancer screening pamphlets (Gigerenzer BMJ 2014;348:g2636). The data are presented without numbers ”Most doctors feel that early detection tests for breast cancer save thousands of lives each year” or as relative risk reduction with the difference between 4 and 5 deaths per 1000 being a “20% reduction in deaths”. A final fallacy of the leaflets is extrapolating ahead where 1 life saved over a decade means 2.5 lives over 25 years which is not supported by the data.

No wonder 98% of women in France, Germany and the Netherlands overestimate the benefit of screening by a factor of 10, 100 or more, or do not know. They get much of their information from leaflets – put out by people whose likelihoods depend on screening – which are blatantly misleading. Advertising of medicines is not allowed to make claims that cannot be backed up by evidence, so why can screening pamphlets?

These semi-facts promote beliefs that screening prevents or reduces the risk of breast cancer and saves many lives through the early detection of aggressive tumours. These beliefs are not valid according to an independent Swiss group reporting in a lead article in NEJM (Biller-Andorno & Jüni 2014;370:1965-7) which states that public health programmes that do not produce more benefits than harms are hard to justify ethically – like mammography screening.

Their report caused an uproar because it challenges a tightly held myth – like the existence of Bambi.    What has happened to evidence-based medicine?

Menopause Matters is a monthly review of matters menopausal that have recently appeared in the journals. It is produced for the South African Menopause Society by Athol Kent and the summaries concentrate on clinical issues although some underlying patho-physiology will be included to ensure a scientific basis for the work. It does not necessarily reflect the views of SAMS or its managementf
15 June 2014 this month:  SMALL BENEFITS, SUBSTANTIAL HARMS WITH MAMMOGRAPHY SCREENING  is a trenchant review by Prof Cornelia Baines breast clinician from Canada on why xray screening mammography does well breasts and women far more harm than good.                Prof Stephen  Duffy statistician at UCL argues the reverse.

DIET RISKS FOR BREAST CANCER:

already 30 years ago Seely and Horrobinin Diet and breast cancer: possible connection with sugar consumption hypothesized: younger and older women (possibly pre- and post-menopausal women) differ with respect to such correlations. In older women a strong correlation was found between breast cancer mortality and sugar consumption (correlation coefficient = 0.9).. In younger women the correlation with diet is weak. A possible connecting link between sugar consumption and breast cancer is insulin. This is an absolute requirement for the proliferation of normal mammary tissue and experimental mammary tumours may regress in its absence. Insulin secretion occurs in response to blood glucose level and could be excessive if the regulatory mechanism is overtaxed by large sugar intake. The same mechanism might account for the increased risk of mammary cancer in diabetics.
  A  major Nurses’ Health decades-long Study  review from Harvard shows no relationship between fat intake and breast cancer.
By contrast, studies from  Mexican  2004,  Canada 2005, Italy 2006 , and New York  2009 confirm direct association between sugar intake and breast cancer. . Only a study from Denmark 2005  shows no relationship.
Hence the HighFat LowCarbs (William Banting 1863) diet is now established by the rigorous scientific references of the past 150 years  assembled by science writer Gary Taubes in The Diet Delusion ,  and advised to all  for prevention and management of obesity and all other common major diseases including breast and all cancers.
      As investigative journalists write recently, like Taubes and rational scientists the past 50years,  the major cause of all common chronic degenerative disease including cancer and immunoincompetence is not fat but refined carbs – the root cause of the SACCHARINE DISEASES  that Cleave, Campbell, Burkitt reported occurring in pastoral tribes converting to the western commercialized diet of sugar, refined cereals and rice .                   They note that in the Mouse Cancer Study in cancer-prone mice, 2011,  which claimed that high (fat)cholesterol intake promotes breast cancer, the control mice  (not major carnivores but omnivores) were fed a balanced natural chow with 4.5% fat, 23% protein, and 50% carbohydrate, whereas the test mice were fed a totally synthetic chow meant to represent a western human  cholesterolemic  diet: 20% fat, 17% protein, and 48% carbohydrate. So in fact the high risk factor for cancer and all disease was not the higher fat intake (20%  as dairy fat) vs 4.5%- from fish meal and soy/cereals) but the 48% carbs (2/3  sucrose, 15% (malto)dextrins -which absorb as rapidly as glucose) intake and 19% casein (a major health problem)   in the test chow. They failed to include a control group on what is natural mouse diet ie free of refined carbs and milk :  “RSPCA 2014:   Wild mice – opportunistic omnivores- will eat a wide variety of seeds, grains, and other plant material as well as invertebrates, small vertebrates and carrion”. Thus plenty of natural seed/grain fats and mixed protein and plant carbs,  zero sugar or refined carbs- ie the Banting diet. ..
A new 18year observational  followup  study from Swedenlast year in 62000 people assessed total energy intake – carbohydrate  from median 61 to 39% , protein 11 to 19% , and  fat 27 to 42% . LCHP scores were positively related to intake of animal protein, but negatively related to plant protein. For carbohydrate and fat, associations were consistent in sucrose and whole grain and saturated and unsaturated fat, respectively. Across the range of macronutrients, there was no clear significant trend for particular cancers. This is not surprising as the intake of carbs range d from 40 to 60% and fat from 27 to 42%. Thus no cohort was on a highfat low carbs ketogenic diet as Banting, Noakes  et al find successful. . the lowest % carbs group at best had similar fat % intake ie there was no low-carbs cohort taking below 30% carbs..There is a vast difference in calorie intake  between their “optimal’  LCHP 42:40 fat:carbs ie 1:1  , versus the  true ketogenic HifatLowcarbs diet of eg 50:<30 fat:carbs ie >1.66:1.
       Allowing up to 20% protein in total energy intake, fat may need to  be  close to 50% energy and carbs below 30%, thus ensuring ketogenesis to shed excess fat and avoid depositing more glycogen and adiposity ; so eg for a 2000kcal/day  diet, thats  up to 100gms protein 400kcal mostly from flesh and nuts; carbs below 150gms 600kcal (in nuts and  rainbow vegs) , and fat up to 1000 kcal ie 110gms from cream (not milk), nuts, avo, eggs, butter, cheese and fatty flesh. .

It is no wonder the public is confused.

The truth of more than four decades worth of research is now very clear: the potential benefit of mammography screening is small and the harms are substantial at all ages, but especially so for women in their 40s.

The bottom line is that mammography screening, implemented to reduce breast cancer deaths due to earlier detection of breast cancer, has been eclipsed by therapy and increased awareness.

– See more at: http://umanitoba.ca/outreach/evidencenetwork/archives/4490#sthash.rf9YcMYp.dpuf

It is no wonder the public is confused.

The truth of more than four decades worth of research is now very clear: the potential benefit of mammography screening is small and the harms are substantial at all ages, but especially so for women in their 40s.

The bottom line is that mammography screening, implemented to reduce breast cancer deaths due to earlier detection of breast cancer, has been eclipsed by therapy and increased awareness.

– See more at: http://umanitoba.ca/outreach/evidencenetwork/archives/4490#sthash.rf9YcMYp.dp

VITAMIN INTAKE AND BREAST CANCER:

VITAMIN C  each 100mg/day increment reduces allcause mortality by 27%, and breast cancer mortality by 22%:   a metaanalysis by the Karolinska- Harris ea   last month found 10 trials of vitamin C use and intake  in breast cancer, included 17,696 breast cancer cases, 2791 total deaths, and 1558 breast cancer-specific deaths. The summary RR (95% CI) for post-diagnosis vitamin C supplement use was 0.81 (95% CI 0.72-0.91) for total mortality and 0.85 (95% CI 0.74-0.99) for breast cancer-specific mortality. The summary RR for a 100mg per day increase in dietary vitamin C intake was 0.73 (95% CI 0.59-0.89) for total mortality and 0.78 (95% CI 0.64-0.94) for breast cancer-specific mortality- ie 25% lower mortality for every 100mg higher daily vit C intake..

VITAMIN D AND BREAST CANCER:
20 years  ago Newmark from Sloan Kettering NY wrote :  High dietary fat increases mammary epithelial cell proliferation, particularly the “hormonally driven” hyperproliferation during breast growth and development in young animals. Increased dietary calcium (and probably vitamin D) lessens the increase of proliferation induced by high fat. These data, although limited, suggest that the maximum effect of diet (high fat increase, as well as calcium and vitamin D modulation) on eventual breast cancer may be during puberty, and adolescence, when the mammary gland is actively growing and developing. (3) An inverse epidemiological correlation exists between sunlight availability as a source of vitamin D and the risk of breast cancer in the U.S. and Canada. (4) Current vitamin D and calcium dietary intake in the U.S. is far below the RDA in all female age groups, particularly for the elderly. (5) Reduction of breast cancer risk, and simultaneously osteoporosis, might be achieved by increasing dietary intake of calcium and vitamin D to RDA levels. This may be particularly applicable to females during puberty and adolescence.
      20 years later we now still find:Vitamin D and Cancer: The promise not yet fulfilled(California) ; and is there a link (France)?

BUT The Vitamin D Council    sums up the study evidence eg in a major Brit J Cancer metaanalysis last month of 30 prospective studies in 32000 BRCA  patients, and a Chinese study a year ago,   show  that  those with highest  vitamin D levels have 50-90% lower risk of  breast cancer risk, and mortality, and the chance of breast cancer spreading.  so far all they can recommend is that  vitamin D dose should for a robust adult not exceed        10 000iu/day, or pro rata at longer intervals eg 150 000iu a fortnight.  Compared to those with the lowest quartile of plasma 25(OH)D level, women with highest quartile 25(OH)D level showed a significant decreased breast cancer risk (Q4 vs.Q1: OR = 0.10, 95% CI = 0.06–0.15) and every 1 ng/ml increment of plasma 25(OH)D level led to a 16% lower odds of breast cancer.

         It is likely that- given the limits on vitamin C intake due to diarrhoea, and cost, and bloating-  increments in vit D3 intake above the current mediocre 400iu/d norm- up to the generally well-tolerated 10 000iu/day, with supplement of vitamin K2-  will give even better benefit against breast cancer than vitamin C.     
                                                                                                                               
20 May 2014 BREASTS TO KILL: KILLER BRAS
          For the past 4 years, Sure Touch examiners  have observed that many women who wear underwired bras have a string of pearl – fibrous lumps- where the bra wire cuts into them inferiorly; and sometimes radially under the ‘ spokes’ of the bra cups.  We have not yet detected a cancer in such symmetrical  lumpiness, which we find diminishes with change to a soft bra and healing massage with Lugols iodine, coconut oil and DMSO.
          This bra risk   was postulated  in  the book  Dressed To Kill: The Link Between Breast Cancer and Bras(1995, 2005), (NaturalNews).     
Dr Joe Mercola muses: ” Would you believe that two of the nation’s most prominent cancer organizations are completely disinterested in a common wardrobe practice that studies suggest could be a leading cause of breast cancer in women? Wearing bras, says the book  ,appears to be a common trigger of this harrowing disease, yet the American Cancer Society (ACS) and the Susan G. Komen Foundation continue to deny any link between the two.
            ” Authors Sydney Ross Singer and Soma Grismaijer, husband and wife medical anthropologists, have conducted extensive research into the link between bras and breast cancer. They are convinced that the lymphatic constriction imposed by wearing bras prevents women’s bodies from effectively clearing out toxins and other waste, leading to an accumulation of these cancer-causing substances. Bras can also cut off circulatory flow within the body, leading to other health problems.
              “[B]ecause lymphatic vessels are very thin, they are extremely sensitive to pressure and are easily compressed,” the Singers are quoted as saying, noting that the perpetual use of bras over the course of several decades can eventually lead to cancer. “Less oxygen and fewer nutrients are delivered to the cells, while waste products are not flushed away.”
             These are powerful claims, and science seems to back them. Based on an analysis comparing women who wear bras to those who don’t, breast cancer risk was found to be significantly higher among women in the former group. At the same time, women who do not wear bras have about the same risk of developing breast cancer as the average man does, which is not very high.
               Beginning in 1991, the Singers initiated a 30-month “Bra and Breast Cancer” study that evaluated roughly 4,000 women from five major U.S. cities. All the women were Caucasian and came from mostly middle-income homes, ranging in age from 30 to 79. About half of them had previously been diagnosed with breast cancer.After determining the bra-wearing habits of all the women, the Singers determined that wearing a bra increases a woman’s risk of developing breast cancer by double. Shockingly, wearing a bra to sleep at night is even worse, with three out of four, or 75 percent, of women who engage in this practice regularly developing the condition.
                 “Women who want to avoid breast cancer should wear a bra for the shortest period of time possible — certainly for less than 12 hours daily,” said Sydney Singer, as quoted by HealingCancerNaturally.com.     One would think that such information would be pertinent to Komen and other cancer organizations, which are purportedly raising money to find a cure. But the Singers and others have never been able to get their attention, with both Komen and the ACS denying any link between bras and breast cancer.So the Singers are calling on women everywhere to not only boycott supporting these organizations, but also to send over their bras whenever they are asked for money. Awareness about the potential dangers of wearing bras should at least be acknowledged by these groups that claim to support cancer awareness, and yet the response of ACS and Komen on the issue has been less than acceptable.
           “Because of this unscientific stonewalling of this information,” Singer wrote, “over the past 20 years 2,000,000 women in the US alone have gotten breast cancer who may have prevented it by simply loosening their bra and wearing it less time each day.”
             To learn more about Dressed To Kill, visit:
http://www.killerculture.com.
19  May 2014 update:  Dr Gerd Gigerenzer PhD, professor at a number of top USA and German institutions and expert in uncertainty, heuristic problem-solving, writes: This One Graphic Will Change the Way You Look at Breast Cancer Screening:The most trenchant reasoning against screening xray mammography this year is in  Time Magazine 1 May 2014;  which he argues definitely applies to screening mammography: he details four tricks used by zealous proponents of screening mammography to infamously  persuade gullible women why ““If you haven’t had a mammogram, you need more than your breasts examined.”  These tricks are as follows, but are debunked  by the absolute facts in his Fact Box below. He says:

“First, look at the benefit. Out of every thousand women aged 50 and older, five without screening died from breast cancer, compared to four in the screening group. This is an absolute reduction of 1 in 1,000. In fact, it might even be an optimistic estimate because the Canadian follow-up study of women for 25 years after these trials found no reduction at all. But the exact number is not my point here. What I want to explain is how women are being misled.

Trick #1: State that screening reduces breast cancer mortality by 20% or more, because it sounds more impressive than explaining that the absolute risk reduction is 1 in 1,000.   This trick has been used for years in pamphlets. You might think, well, it’s not much, but at least one life is saved. But even that is not true. The number of deaths from all cancers, breast cancer included, is the same in both groups, as seen in line two of the fact box.            And that leads us to                                                                                                                             trick #2: Don’t mention that mammography screening doesn’t reduce the chance of dying from cancer. Talk only about the reduction in dying from breast cancer.      Often, and particularly if a person had multiple cancers, the exact cause of death is unclear. For this reason, total cancer mortality is the more reliable information when you look at it in terms of the larger goal: saving lives. In plain words, there is no evidence to date that routine mammography screening saves lives.             Now let’s look at the harms.

Trick #3: Don’t tell women about unnecessary surgery, biopsies and other harms from overtreatment. If you are asked, play these down.            The first way a mammogram can harm women is if it comes back with a false positive, leading to invasive and unnecessary biopsies. This isn’t the rare fluke most people seem to think it is. This happens to about a hundred out of every thousand women who participated in screening. Legions of women have suffered from this procedure and the related anxieties. After false alarms, many worried for months, developing sleeping problems and affecting relationships with family and friends.

Second, not all breast cancers are life-threatening. Women who have a nonprogressive or slowly growing form that they would never have noticed during their lifetime often undergo lumpectomy, mastectomy, toxic chemotherapy or other interventions that have no benefit for them and that are often accompanied with damaging side-effects. This happened to about five women out of a thousand who participated in screening.

The final trick #4    Tell women about increased survival. For instance, “If you participate in screening and breast cancer is detected, your survival rate is 98%.” Don’t mention mortality.

1 May 2014 update:  Dr Iona Heath FRCP, past president of the New Zealand Royal College of GPs ,  says in March that  Breast cancer mammography screening causes more harm than good.  Dr Kurt Kroenke from Univ Indiana two weeks ago  wrote That most screening test results will be normal or negative is commonplace, but the reality that abnormal results are frequently false-positive is not always well appreciated, nor is it fully conveyed to patients. How does a patient feel after a false-positive test result? Tosteson and colleagues1 concluded from their longitudinal study that “false-positive mammograms are associated with a measurable, small, and transient effect on personal anxiety.” However, a closer look at all the outcomes assessed in this well-done study reveal some adverse consequences that, although not serious, may nonetheless be meaningful.
          Given the harms of  screening, the Spanish consortium sum it up nicely last February:  Optimal (mammography)  screening is characterized by quinquennial or triennial periodicities for the low or moderate risk-groups and annual periodicity for the high-risk group.   This last group  is in reality tiny.                                                                                                                                                                    
        As this ongoing Woman’s Care column  stresses, very few well women at any age justify screening mammography, or any screening beyond thorough annual review and bloodpressure  and breast exam check. Only if the annual checkup, with  the examining clinician’s concern about clinical breast feel, or the woman’s  breast symptoms (which in fact rarely originate in the breast and are mostly easily resolved) raise suspicions, may some sort of  no-xray breast imaging be justified- soft SureTouch or ultrasound, or no-touch thermography .  No woman without an obvious  growing solitary breast lump or nipple bleeding/ discharge warrants the harms of initial xray screening mammogram.
                                                                                                                                                                        Unlike Bone Density  Screening available on request,  Sure Touch Breast screening is not charged for since it is part of a proper professional clinical consultation- which can be booked for any regular workday. It is the expert clinical consultation, and any necessary advised evidence-based   natural breast supplements and other changes for prevention, that are billed- obviously at viable market rates, but reduced on justified request based on usual means test.
Breast imaging on its own, without expert clinical assessment and advice , is hazardous because it may cause unwarranted concern and lead to the fearsome  and costly invasive cascade; and because breast imaging without thorough risk factor assessment including expert clinical exam may miss disease that justifies further steps if not immediate resolution.
                                                                                                                                                                HOW TO AVOID UNSETTLING, HARMING WOMEN?  As applies to unjustified mass prostate screening of well men, two new relevant publications below this month highlight the widening gap around MASS BREAST MAMMOGRAPHY SCREENING, between realist  holists- independent  Swiss reviewers  looking at the welfare of women and the real cost-benefits  of  breast screening till now – versus the burn & cut-at-any-cost  screening-industry Dutch career  radiologists’ and cancer experts’vested-interest view looking solely at breast cancer deaths 2004-5, like most for-profit breast -career specialists   targeting every last well breast from 40years upwards.
The latest Cochrane metanalysis  2013 “found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death.”
                                                                                                                                                                       Boston San Francisco- Illinois and Spanish- Catalonia–  universities’  reviewers recently make a less in-your-face case  against universal mass mammography screening,  rather selective screening frequency based on individualized risk factors and  potential harms.. But they dont refer to equally effective non-xray imaging techniques; or the fact that no imaging techniques except tissue histology can confirm or exclude cancer. .
                                                                                                                                                                against: DO NO HARM:  April 16, 2014 / NEJM  Perspective   from the Swiss Medical Board: Abolishing Mammography Screening Programs?          Nikola Biller-Andorno, and Peter Jüni, http://www.nejm.org/doi/full/10.1056/NEJMp1401875?query=TOCIn January 2013, the Health Ministers of the Swiss Cantons, the Swiss Medical Association, and the Swiss Academy of Medical Sciences mandated the Swiss Medical Board (a medical ethicist,  a clinical epidemiologist, a clinical pharmacologist, an oncologic surgeon, a nurse scientist, a lawyer, and a health economist), an independent health technology assessment initiative,  to prepare a review of mammography screening.We were aware of the controversies that have surrounded mammography screening for the past 10 to 15 years. When we reviewed the available evidence and contemplated its implications in detail, however, we became increasingly concerned.
          First, we noticed that the ongoing debate was based on a series of reanalyses of the same, predominantly outdated trials. The first trial started 50 years ago in New York City and the last  in 1991 in the United Kingdom.1 None of these trials were initiated in the era of modern breast-cancer treatment, which has dramatically improved the prognosis of women with breast cancer. Could the modest benefit of mammography screening in terms of breast-cancer mortality that was shown in trials initiated between 1963 and 1991 still be detected in a trial conducted today?
                                                                                                                                                                      
             Second, we were struck by how nonobvious it was that the benefits of mammography screening outweighed the harms. The relative risk reduction of approximately 20% in breast-cancer mortality associated with mammography that is currently described by most expert panels2 came at the price of a considerable diagnostic cascade, with repeat mammography, subsequent biopsies, and overdiagnosis of breast cancers — cancers that would never have become clinically apparent. The recently published extended follow-up of the Canadian National Breast Screening Study is likely to provide reliable estimates of the extent of overdiagnosis. After 25 years of follow-up, it found that 106 of 484 screen-detected cancers (21.9%) were overdiagnosed.3 This means that 106 of the 44,925 healthy women in the screening group were diagnosed with and treated for breast cancer unnecessarily, which resulted in needless surgical interventions, radiotherapy, chemotherapy, or some combination of these therapies.
      In addition, a Cochrane review of 10 trials involving more than 600,000 women showed no evidence of mammography screening benefit  on overall mortality.1 In the best case, the small reduction in breast-cancer deaths was attenuated by deaths from other causes. In the worst case, the reduction was canceled out by deaths caused by coexisting conditions or by the harms of screening and associated overtreatment. Did the available evidence, taken together, indicate that mammography screening indeed benefits women?
                                                                                                                                                                        
      Third, we were disconcerted by the discrepancy between women’s perceptions of the benefits of mammography screening and the benefits to be expected in reality. The figure  Women’s Perceptions of the Effects of Mammography Screening on Breast-Cancer Mortality as Compared with the Actual Effects. shows the numbers of 50-year-old women in the United States expected to be alive, to die from breast cancer, or to die from other causes if they are invited to undergo regular mammography every 2 years over a 10-year period, as compared with women who do not undergo mammography. The numbers in Panel A are derived from a survey about U.S. women’s perceptions,4 in which 717 of 1003 women (71.5%) said they believed that mammography reduced the risk of breast-cancer deaths by at least half, and 723 women (72.1%) thought that at least 80 deaths would be prevented per 1000 women who were invited for screening. The numbers in Panel B reflect the most likely scenarios according to available trials1-3: a relative risk reduction of 20% and prevention of 1 breast-cancer death. The data for Switzerland, reported in the same study, show similarly overly optimistic expectations. How can women make an informed decision if they overestimate the benefit of mammography so grossly?
                                                                                                                                                                        
      The Swiss Medical Board’s report was made public on February 2, 2014 . It acknowledged that systematic mammography screening might prevent about one death attributed to breast cancer for every 1000 women screened, even though there was no evidence to suggest that overall mortality was affected. At the same time, it emphasized the harm — in particular, false positive test results and the risk of overdiagnosis. For every breast-cancer death prevented in U.S. women over a 10-year course of annual screening beginning at 50 years of age, 490 to 670 women are likely to have a false positive mammogram with repeat examination; 70 to 100, an unnecessary biopsy; and 3 to 14, an overdiagnosed breast cancer that would never have become clinically apparent.5 The board therefore recommended that no new systematic mammography screening programs be introduced and that a time limit be placed on existing programs. In addition, it stipulated that the quality of all forms of mammography screening should be evaluated and that clear and balanced information should be provided to women regarding the benefits and harms of screening.
The report caused uproar and was emphatically rejected by a number of Swiss cancer experts and organizations, some of which called the conclusions “unethical.” One of the main arguments used against it was that it contradicted the global consensus of leading experts in the field — a criticism that made us appreciate our unprejudiced perspective resulting from our lack of exposure to past consensus-building efforts by specialists in breast-cancer screening. Another argument was that the report unsettled women, but we wonder how to avoid unsettling women, given the available evidence.
The Swiss Medical Board is nongovernmental, and its recommendations are not legally binding. Therefore, it is unclear whether the report will have any effect on the policies in our country. Although Switzerland is a small country, there are notable differences among regions, with the French- and Italian-speaking cantons being much more in favor of screening programs than the German-speaking cantons — a finding suggesting that cultural factors need to be taken into account. Eleven of the 26 Swiss cantons have systematic mammography screening programs for women 50 years of age or older; two of these programs were introduced only last year. One German-speaking canton, Uri, is reconsidering its decision to start a mammography screening program in light of the board’s recommendations. Participation in existing programs ranges from 30 to 60% — variation that can be partially explained by the coexistence of opportunistic screening offered by physicians in private practice. At least three quarters of all Swiss women 50 years of age or older have had a mammogram at least once in their life. Health insurers are required to cover mammography as part of systematic screening programs or within the framework of diagnostic workups of potential breast disease.
                                                                                                                                                                              

     It is easy to promote mammography screening if the majority of women believe that it prevents or reduces the risk of getting breast cancer and saves many lives through early detection of aggressive tumors.4 We would be in favor of mammography screening if these beliefs were valid. Unfortunately, they are not, and we believe that women need to be told so. From an ethical perspective, a public health program that does not clearly produce more benefits than harms is hard to justify. Providing clear, unbiased information, promoting appropriate care, and preventing overdiagnosis and overtreatment would be a better choice.

from the  Universities of Zurich &  Bern,  Switzerland; and   Harvard Medical School, Boston . Dr. Biller-Andorno is a member of the expert panel of the Swiss Medical Board; Dr. Jüni was a member of the panel until August 30, 2013

                                                                                                                                                                      FOR-SCREENING– FOR CAREER/PROFIT :  do the maximum: 
Breast. 2014 Apr 5.  Breast cancer screening halves the risk of breast cancer death: A case-referent study. Paap E, Verbeek AL,Broeders MJ ea.  Netherlands Breast Screening Centres.   Large-scale epidemiologic studies have consistently demonstrated the effectiveness of mammographic screening programs, however the benefits are still subject to debate. We estimated the effect of the Dutch screening program on breast cancer mortality. In a large multi-region case-referent study, we identified all breast cancer deaths in 2004 and 2005 in women aged 50-75 who had been invited for screening (cases). Cases were individually matched to referents from the population invited to screening. A total of 1233 cases and 2090 referents were included in this study. We found a 58% reduction in breast cancer mortality in screened versus unscreened women (adjusted OR = 0.42, 95% CI 0.33-0.53). Screening, i.e. early detection and treatment, has resulted in a substantial reduction in breast cancer mortality, indicating that the Dutch breast cancer screening program is highly effective.
                                                                                                                                                                 update  23 March 2014: Caroline Huang at the  Ethox Centre at Oxford writes in   Screening mammography: benefits, harms, and evidence-based guidelines in the US and UK:   The Ethox Centre is a multidisciplinary bioethics research centre in the University of Oxford’s Nuffield Department of Population Health.“Authors Bleyer and Welch claim there has been only an 8% reduction in late-stage breast cancer diagnoses (an absolute reduction of 8 cases per 100,000 women), and while mortality has decreased, it appears that most of the benefit has come from better treatment rather than better screening. (For cancer screening to be considered effective, the US National Cancer Institute says that cancer deaths and late-stage cancer diagnoses should decrease, while early-stage cancer diagnoses should increase.[2])
Contrast these findings to another mammography study published the same week in The Lancet, conducted by an independent panel in the UK as a meta-analysis of 11 randomized trials.[3] The panel estimated overdiagnosis of early-stage breast cancers in the UK to be between 11 and 19%. Crucially, though, there appeared to be a 20% mortality benefit from screening alone.What might account for these significantly different estimations of breast cancer screening effectiveness? The most obvious factor is the frequency and age at which average-risk women are offered mammography. In the UK, women ages 50-70 are offered screening every three years through the NHS Breast Cancer Screening Programme. In the US, women ages 40-70 are typically offered screening every one or two years.      
                      Though a 2009 US Preventive Services Task Force (USPSTF) report recommended that average-risk women should receive screening from ages 50-74 every two years,[4] this recommendation has been not been adopted by professional organizations such as the American Cancer Society, the American College of Radiologists, and the National Cancer Institute. In fact, a study published in November in Preventive Medicine showed that there has been no difference in mammograms provided across any age groups in the US since the 2009 USPSTF report was published.[5]These two studies (and many others preceding them) raise plenty of practical questions about diagnostic thresholds, benefits of population screening, limitations of current radiology technologies, and understanding of which cancers do and do not become invasive. But I want to raise a broader question: should there be an ethical imperative compelling different US professional groups that address the same disease or disorder to adopt a common set of evidence-based guidelines?                                                                                                                                                       
          And if there isn’t, then what is the value of having a group like the USPSTF to issue recommendations that may ultimately be ignored by its target audiences?A few reasons for adopting a common set of evidence-based guidelines might be reducing patient and provider confusion, enhancing low-cost access to care, and potentially redistributing funds to further the reach of proven services or improve research. While the National Breast Cancer Screening Programme requires only the NHS to adopt and implement new recommendations, the more fragmented US system means that screening is not organized by a single body and thus involves competing recommendations that could confuse patients trying to make informed choices and providers trying to assist them in doing so. Additionally, because US insurers are increasingly moving towards funding only evidence-based services, having a common set of guidelines would help ensure that providers’ recommended services are covered under patients’ insurance rather than falling into a category of services with questionable benefit that might not be covered. This is perhaps not the optimal ethical consideration to have to make, but it is a necessary component of realistic preventive care. Finally, at the health system level, providing mammograms only to women ages 50-74 might mean that resources currently allocated to mammograms for women ages 40-49 could be put towards more mammograms for women ages 50-74 or other related preventive health services or research.Despite these reasons, however, it would be equally problematic to remove clinical groups’ ability to disagree with recommendations that they believe result from poor statistics or faulty logic. It also does not seem like there is intrinsic opposition to adopting recommendations produced by independent panels or other clinical groups.   
                                                                                                                                                                        The same Preventive Medicine study discussed above references two cases in which recommendations resulted in immediate changes to screening patterns: (1) the National Cancer Institute and American Cancer Society’s 1997 recommendation that mammography be expanded to women ages 40-49 resulted in increased screening, and (2) the USPSTF’s 2008 recommendation against prostate cancer screening in men ages 75 and older resulted in fewer early-stage prostate cancer diagnoses. So the USPSTF has not always been unsuccessful in having its recommendations taken seriously, even in a case where less screening is recommended, and at least one breast cancer screening recommendation has previously had a quick adoption in practice.These cases – as well as the USPSTF 2002 recommendation that originally suggested offering mammography to women ages 40-49 once every 1-2 years, which is reflected in current clinician groups’ guidelines – suggest that the USPSTF’s target audiences aren’t willfully ignoring meta-analyses of available data. Rather, clinicians, advocacy groups, and patients have questioned the methodology behind the 2009 USPSTF recommendation, in a similar fashion to the critiques being raised over the NEJM study.                                                                                
                                                                                                                                                                        
               For example, the American College of Radiology suggested that Bleyer and Welch failed to properly account for an increasing incidence of invasive late-stage breast cancers unrelated to screening uptake.[6] In light of this information, we might reframe the second question to ‘How do we ensure that groups like the USPSTF incorporate the right kind of data into their analyses and recommendations?’ That answer might have to do with rethinking how consultation with relevant clinical and patient advocacy groups is carried out, as well as examining a broader range of data sources. To circle back to the contrast between the NEJM and Lancet findings, it is important to think about how and why the UK’s National Breast Cancer Screening Programme seems to have lower rates of overdiagnosis and greater mortality benefit from screening relative to the US screening system.                                                                                                                                                                                                                                                                             At the very least, these kinds of contradictory non-US outcomes should prompt a re-evaluation of which kinds of evidence we have chosen to evaluate.We might also point to the discourse around prostate-specific antigen (PSA) testing – which has been linked to overdiagnosis of early-stage, non-invasive prostate cancer – as one model for where breast cancer screening recommendations may go. Importantly, while clinical organizations have not reached consensus in whether PSA testing should be recommended as a yearly exam for men over 50,[7] they do agree that a careful discussion of PSA testing’s potential harms and benefits is always appropriate.Indeed, the authors of both the Lancet and NEJM articles conclude with similar thoughts: physicians must initiate conversations about the pros and cons of mammography so that patients can make informed choices. That assertion seems uncontroversial enough to be accepted by the various professional groups involved – so perhaps any common set of guidelines we should expect groups to adopt should relate to the communication of evidence rather than potentially controversial or insufficient evidence itself.”
                                                                                                                                                                      15/3/ 2014 update: Great Mammography Debate :  Dr. Patrick Borgen, Chairman of Surgery at Maimonides Medical Center in Brooklyn, New York, talks about the role of screening mammography, a topic bracketed by strong opinions. It has been a particular focus of discussion at the 31st Annual Miami Breast Cancer Conference, held March 6 through March 9, 2014, in Miami, Florida.

               Commentary  The mammography debate is one of the facets of the Miami Breast Cancer Conference this year.   It seems as though the field of breast cancer has always been controversial, going back half a century, and breast cancer is a disease that, more than most others, is very polarizing. This disease engenders great passion—and great debate, which has been ongoing about the role of screening mammography.

            A few weeks ago, The New York Times covered an article that was published in the British Medical Journal 1 about the Canadian National Breast Screening Study. On the surface, this study failed to show any benefit from mammography. That was the story that the writer, Gina Kolata, picked up and ran with. Ms. Kolata had written about her own experience with breast cancer a number of years ago; her breast cancer had not been picked up on a mammogram, and so she is somewhat biased.

               In short, the Canadian study evaluated mammograms from more than 90,000 women who had very primitive mammograms between 1980 and 1984, and that is really the first problem with this study: the technology and the equipment then was incredibly limited, such that the mammograms only showed 30% of breast cancers; whereas, today, mammography detects 70% to 80% of breast cancers. Thus, taking results generated by technology from 34 years ago and making a conclusion about them in today’s world is a stretch.

One of the fundamental flaws of the Canadian study, besides the dated technology on which the conclusions were based, was that it was not randomized. Nurses, and, in some provinces in Canada, doctors, did a clinical breast exam, and, if they felt a mass or a lump, they preferentially put the patient into the mammography arm. That is what I would have done in their place; if I felt a lump, I would not be willing to send someone home.

By the end of the study, there were more than 100 extra breast cancers in the mammography arm and more breast cancers that had spread to lymph nodes in the mammography arm. And, in fact, the chance of dying of breast cancer was higher in the mammography arm.

All of the authorities with whom I have ever spoken or read who have reviewed this study dismiss it as very flawed. A number of the doctors who were involved with the study resigned their positions in protest. Despite all of that, The New York Times ran an article headlined, “Vast Study Casts Doubts on Value of Mammograms” (February 11, 2014).

Well, it is a vastly flawed study, and, in fact, there are six other, much larger and much better controlled studies, all of which showed a reduction in breast cancer mortality from 20% up to 40% in women who have mammograms—and that is certainly what we observe clinically.

We felt that it was important to really highlight this at the Miami Breast Cancer Conference this year. My guess is that our audience already knows this; but, what we would like to give them is the science about why the Canadian study was flawed so that they can talk to their patients and talk to their colleagues who may not be in the breast cancer field. That is really what I think our mission is for part of this year’s conference.

We think that this is dangerous information. We think that women will unnecessarily lose their lives to breast cancer if they forego mammography, which this study frankly says one should. I have a busy practice in Brooklyn, New York, and, at least once or twice a week, I see someone, without any question, whose life was saved by a mammogram.

I think that we all agree we need something better than mammography. We all agree that mammography can lead to over-diagnosis of breast cancers, and over-diagnosis happens, of course, when we screen for diseases in other areas of the body. We all accept this limitation.

But, for a major media outlet to take a single study that was deeply flawed and not even mention the existence of other studies, even as a point–counterpoint, I think was a bit outrageous!

12 March 2014 this publication on the Huffington Post website  today under screening mammography is as appropriate as when it was published in 2010:

The NBCAM has assured women that “early (mammography) detection results in a cure nearly 100 percent of the time.” More specifically, the NBCAM is directed to claims for reducing the incidence and mortality of breast cancer through early detection by annual mammography starting at age 40. Moreover, mammograms can miss cancers in premenopausal women due to the density of their breasts, and also fail to detect cancers smaller than half an inch.

Still denied by the ACS is clear evidence that premenopausal mammography poses significant risks of breast cancer. The routine practice of taking two films annually for each breast results in approximately 0.5 rad (radiation absorbed dose) exposure. This is about 500 times the dose from a single chest X-ray and is broadly focused on the entire chest rather than narrowly on the breast. This is also 25 times higher than is allowed by the Environmental Protection Agency for whole-body radiation from local nuclear industries (0.02 rad). Moreover, the breast is the most sensitive organ to ionizing radiation.

As warned by the prestigious National Academy of Sciences in 1972 but still ignored by the ACS, the premenopausal breast is highly sensitive to the risks of cancer from mammography, as each rad exposure increases the risks of breast cancer by 1 percent. This results in a cumulative 10 percent increased risk for each breast following a decade of routine screening. This can also accounts for the 19-percent increased incidence of breast cancer since 1975. Not surprisingly, the prestigious U.S. Preventive Task Force, supported by the National Breast Cancer Coalition, warned last year against routine premenopausal mammography. Also, not surprisingly, routine premenopausal mammography is practiced by no nation other than the U.S.

Risks of premenopausal mammography are some four-fold greater for the 2 percent of women who are carriers of the A-T gene (ataxia telangiectasia) and are highly sensitive to the carcinogenic effects of radiation. By some estimates, this accounts for up to 20 percent of all breast cancers diagnosed annually. Compounding these problems, missed cancers are common in premenopausal women due to the density of their breasts.

That most breast cancers are first recognized by women was admitted by the ACS in 1985. “We must keep in mind that at least 90 percent of the women who develop breast cancer discover the tumors themselves.” Furthermore, an analysis of several 1993 studies showed that women who regularly performed breast self-examination (BSE) detected their cancers much earlier than women failing to examine themselves. The effectiveness of BSE, however, depends on training by skilled professionals, enhanced by an annual clinical breast examination. Nevertheless, in spite of such evidence, the ACS dismisses BSE, and claims that “no studies have clearly shown [its] benefit.”

As reported in our 1999 publication in the International Journal of Health Services, an article in a leading Massachusetts newspaper featured a photograph of two women in their twenties. The article promised that early detection by mammography results in a cure “nearly 100 percent of the time.” Questioned by journalist Kate Dempsey, an ACS communications director responded: “The ad isn’t based on a study. When you make an advertisement, you just say what you can to get women in the door. You exaggerate a point — Mammography today is a lucrative [and] highly competitive business.”

If all 20 million U.S. premenopausal women submitted to annual mammograms, the minimal annual costs would be $2.5 billion. Such costs would be increased some fourfold if the industry, supported by radiologists, succeeds in its efforts to replace film machines, costing about $100,000, with high-tech digital machines, costing over $400,000, even in the absence of any evidence for their improved effectiveness.

With this background, it is hardly surprising that the National Breast Cancer Awareness Month neglects to inform women how they can reduce their risks of breast cancer. In fact, we know a great deal about its avoidable causes which remain ignored by the ACS. These include:

    • Prolonged use of the Pill, and estrogen replacement therapy.
    • Prolonged consumption of milk from cows injected with a genetically engineered growth hormone to increase milk production. This milk is contaminated with high levels of a natural growth factor, which increases risks of breast cancer by up to seven-fold.
    • High consumption of meat, as it is contaminated with potent natural or synthetic estrogens. These are routinely implanted in cattle before entry into feedlots, about 100 days prior to slaughter, to increase muscle mass and profits for the meat industry.
    • Prolonged exposure to a wide range of hormonal ingredients in conventional cosmetics and personal care products.
  • Living near hazardous waste sites, petrochemical plants, power lines, and nuclear plants.

The enthusiastic and continuing support of premenopausal mammography by the ACS is hardly surprising in view of its major conflicts of interest that still remain unrecognized. Five radiologists have served as ACS presidents. In its every move, the ACS promotes the interests of the major manufacturers of mammogram machines and films, including Siemens, DuPont, General Electric, Eastman Kodak and Piker. The mammography industry also conducts research for the ACS, serves on its advisory boards, and donates considerable funds. DuPont is also a substantial backer of the ACS Breast Health Awareness Program. It sponsors television shows touting mammography; produces advertising, promotional materials and literature for hospitals and doctor; and lobbies Congress for legislation promoting the availability of mammography. The ACS has been and remains strongly linked with the mammography industry, while ignoring or criticizing the value of breast self-examination, even following training by a qualified nurse or clinician.

The ACS conflicts of interest extend well beyond the mammography industry. The ACS has received contributions in excess of $100,000 from a wide range of “Excalibur (industry) Donors,” who manufacture carcinogenic products. These include petrochemical companies (DuPont, BP and Pennzoil), Big Pharma (AstraZenceca, Bristol Myers Squibb, GlaxoSmithKline, Merck & Company and Novartis), and cosmetic companies (Christian Dior, Avon, Revlon and Elizabeth Arden).

Samuel S. Epstein, M.D. is professor emeritus of Environmental and Occupational Medicine at the University of Illinois at Chicago School of Public Health; Chairman of the Cancer Prevention Coalition; and a former President of the Rachel Carson Trust. His awards include the 1998 Right Livelihood Award and the 2005 Albert Schweitzer Golden Grand Medal for International Contributions to Cancer Prevention. Dr. Epstein has authored 270 scientific articles and 20 books on cancer prevention, including the groundbreaking “The Politics of Cancer” (1979), and most recently “Toxic Beauty” (2009, Benbella Books: http://www.benbellabooks.com) about carcinogens, besides other toxic ingredients, in cosmetics and personal care products. Email: epstein@uic.edu. Web: http://www.preventcancer.com.

update 6 March 2014    Switzerland debates dismantling its breast cancer screening programme   BMJ 2014;348:g1625   “A row has erupted in Switzerland after the Swiss Medical Board  recommended that the country’s mammography screening programme for breast cancer be suspended because it leads to too many unnecessary interventions.
              In a report made public on 2 February, the board said that while systematic mammography screening for breast cancer saved 1-2 women’s lives for every 1000 screened, it led to unnecessary investigations and treatment for around 100 women in every 1000.1 “The desirable effect is offset by the undesirable effects,” said the report, which was based on study data from 1963 to 1991   comparing 1000 women who were screened with 1000 women who were not. The report also concluded that screening was not cost effective.…”

update 1 Mar 2014 Supporting informed decision making when clinical evidence and conventional wisdom, clash.   The nub of the screening mammography war – and all hard-sell marketing hype-  is elegantly analyzed by a USA multiUniversity Communications team in Against conventional wisdom: when the public, the media, and medical practice collide.      Jakob Jensen ea argue that “the screening mammography  controversy was driven by the systematic removal of uncertainty from science communication. To increase comprehension and adherence, health information communicators remove caveats, limitations, and hedging so science appears simple and more certain. This streamlining process is, in many instances, initiated by researchers as they engage in dissemination of their findings, and  is facilitated by public relations professionals, journalists, public health practitioners, and others whose tasks involve using the results from research for specific purposes.   Uncertainty is removed from public communication because many communicators believe that it is difficult for people to process and/or that it is something the audience wants to avoid. Uncertainty management theory posits that people can find meaning and value in uncertainty.                  CONCLUSIONS: Science is routinely simplified as it is prepared for public consumption.     In line with the model of information overload, this practice may increase short-term adherence to recommendations at the expense  of long-term message consistency and trust in science”. 

          The Mammography Saves Lives  screening campaign  was and is to recruit all older women to regular screening; it  was progressively oversold   by removing, ignoring the science uncertainty. “Science is routinely simplified as it is prepared for public consumption. In line with the model of information overload, this practice may increase short-term adherence to recommendations at the expense of long-term message consistency and trust in science”.


We see the same collusion between corporate marketeers and government regulators in so many high-profit industries:
  on Pubmed,  screening mammography features for 50 years, and continued to expand exponentially without hindrance until enough epidemiologists – led by the Cochrane Group- collectively  rang enough alarm bells the past decade. The zealous huge-profit USA  radiology-oncology industry simply shouted down the negative result of the massive Canadian Screening Mammography trial outcome   30 years ago in 90 000 women, and continue to do so with the 25year results now reported. The huge Breast Industry retaliates by threatening whistle blowers.

*at the same time around 50years ago, as many of us were starting medical studies, Keys and Stamler  et al in USA did bad epidemiological studies that subverted the facts of  healthy indigenous diets around Europe, Africa and Asia, and the healthy traditional English-speaking (USA and the British Empire) working population’s mainly fresh meat/fish  fat and farm produce diet,
      to claim that the reverse be promoted-  factory-produced low fat low cholesterol high carbohydrate (cereals, potato, white flour and white rice) –  and worse, quadrupling of fructose and sucrose intake, with increasing obesity;   and then noxious statins- for-all for the resultant carbs-inducedlipidemia “epidemic”;  and the  dangerous hypoglycemic drugs for mushrooming type 2 diabetes, and NSAIDs for arthritis; and numerous wannabe antiobesity drugs; and finally the new industry of bariatric surgery!.
        see the classic expose books: John Gofman’s  Preventing Breast Cancer 1996; James le Fanu ‘s  The Rise and Fall of Modern Medicine 1999 ; Gary Taubes’ The Diet Delusion (2007);  Ben Goldacre’s Bad Pharma 2012 and Peter Gotzsche’s Mammography Screening: Truth, Lies and Controversy 2013

*and as a result,  the past 30years,- against all rational food  science and biology – Montsanto’s Government- approved  rape  of healthy food agriculture by genetically modified crops laced with toxic environmentally persistent glyphosate C3H8NO5P- Roundup.

It is no irony that one of the leading medical scientists of the 20th century Dr John Gofman took part in  the Manhattan  nuclear Project, was a pioneer of VLDL lipidology, and then an activist for protecting women against the accumulating harm of mammography – “there is no safe dose of radiation”.

 at Exam. Resulting Risk of Mammogram-Induced Breast Cancer. 1998
Any age in 1 exam: 1 chance in about 1,100.
30-34 range. 5 exams: 5 chances/1100, or 1 chance in 220.
Any age in 1 exam: 1 chance in about 1,900.
35-49 range. 10 exams: 10 chances/1900, or 1 chance in 190.
Any age in 1 exam: 1 chance in about 2,000.
50-64 range. 15 exams: 15 chances/2,000, or 1 chance in 133.

Dr Emily Transue MD eloquently describes her personal disillusionment with screening mammography.

                                                                                                                                                                                     update 23 Feb 2014     Like Wikipedia on breast screening, Karen Kaplan in the L.A.Times this week challenges mammography radiologists: stop lying to patients about the benefits of screening mammography. As Dr David Katz in the Huffington Post muses, can we unmuddle mammography?                                                                            The USA National Cancer Association promotion conspicuously avoids mentioning the equal balance between benefits and risks of screening mammography, 
and Dr Charles Wright in the Toronto Globe and Mail  says   “It’s time for a new approach to mammograms  
     The New York Times review this week turns the report of the Canadian trial to focus on the importance of breast self-examination; their other review  agrees that  Vast Study Casts Doubts on Value of Mammograms.
It is damning that Cochrane studies   (which date from about 1994) -for mammography published only since year 2000 – have consistently found that screening mammography imaging has no material longterm survival benefit for women with apparently normal breasts, with numerous potential harms.
      The question remains, should people  without suspicious cancer  symptoms or bad family history  have any invasive screening (of breast and prostate) beyond regular appropriate physical examination? when all of us should follow  sensible lifestyle, diet and appropriate supplements to minimize both acute and chronic diseases, and thus die well in old age.
                If women without apparent high risk  will not be satisfied by clinical reassurance, prescreening  image recording without compression irradiation will depend on what is locally available.
The USA National Cancer Institute at the NIH , while dutifully promoting regular screening mammography, negates their promotion by listing  precisely  7 lines,  one benefit : Early detection of breast cancer with screening mammography means that treatment can be started earlier in the course of the disease, possibly before it has spread. Results from randomized clinical trials and other studies show that screening mammography may  reduce the number of deaths from breast cancer among women ages 40 to 70, especially for those over age 50..
            But it lists 46 lines of potential harms:”What are some of the potential harms of screening mammograms?      
1. “Finding cancer early doesnt  reduce a woman’s chance of dying from breast cancer or any cause. Even though mammograms can detect malignant tumors that cannot be felt, treating a small tumor does not always mean that the woman will not die from the cancer. A fast-growing or aggressive cancer may have already spread to other parts of the body before it is detected.                                                              
2. Fear: “Women with such detected  early tumors live a longer period of time fearing that they likely have a fatal disease… screening mammograms dont help prolong the life of a woman who is suffering from other, more life-threatening health conditions. Depression anxiety let alone suicide are increased .
3. “False-negative results occur when mammograms appear normal even though breast cancer is present. Overall, screening mammos miss about 20% of breast cancers that are present at the time of screening.. from  high breast density i.e., glandular tissue and connective tissue, together known as fibroglandular tissue) and fatty tissue.  Because fibroglandular tissue and tumors have similar density, tumors can be harder to detect in women with denser breasts more often among younger women than among older women because younger women are more likely to have dense breasts. As a woman ages, her breasts usually become more fatty, and false-negative results become less likely. False-negative results can lead to delays in treatment and a false sense of security for affected women.                              
4. “False-positive results occur when radiologists decide mammograms are abnormal but no cancer is actually present. All abnormal mammograms should be followed up with additional testing (diagnostic mammograms, ultrasound, and/or biopsy) to determine whether cancer is present… more common for younger women, women who have had previous breast biopsies, women with a family history of breast cancer, and women who are taking estrogen (for example, menopausal hormone therapy).        False-positive mammogram results can lead to anxiety and other forms of psychological distress in affected women. The additional testing required to rule out cancer can also be costly and time consuming and can cause physical discomfort. .                                                                                                            
5. “Overdiagnosis and overtreatment. Screening mammograms can find cancers and cases of ductal carcinoma in situ (DCIS, noninvasive tumor  cells that may become cancerous build up in the lining of breast ducts) that need to be treated. However, they can also find cancers and cases of DCIS that will never cause symptoms or threaten a woman’s life, leading to “overdiagnosis” of breast cancer. Treatment of these latter cancers and cases of DCIS is not needed leads to “overtreatment.” Overtreatment exposes women unnecessarily to the adverse effects associated with cancer therapy.      Because doctors often cannot distinguish cancers and cases of DCIS that need to be treated from those that do not, they overtreat .                                                                                                                              
6. “Radiation exposure. Mammograms require very small doses of radiation. The risk of harm from this radiation exposure is extremely low, but repeated x-rays have the potential to cause cancer. 

They fail to list other adverse effects:                                                                                       7. Pain and bruising of crush mammography- sometimes prolonged;                     8. spreading early and likely dormant cancer.                                                                   9. Increased incidence of breast cancer and thus more irradiation, mastectomy and all-cause mortality, and                                                                                                              10. complications of surgery, radiotherapy and chemotherapy.                                                 ………………………..

           the Rapid Responses to the 25year  Breast cancer incidence and mortality of the Canadian National Breast Screening Study show again the Great Divide between objective  epidemiological evidence,  and vested-interest belief by those whose careers and incomes depend on zealous pursuit of early (pre)cancers.
              Prof Michael Baum as a former UK Screening Mammography leader again trenchantly quotes reality to protect women from terrorism by screening mammography and mastectomy, in particular urging the same policy of watchful waiting to see the natural course of early  cancer-   that has saved so many men from harmful diagnostic and therapeutic invasion of asymptomatic prostate cancer.
                  We must stress that, if the patient refuses or is denied conventional oncotherapy, Watchful Waiting should always be supported including by all possible improvements in multibeneficial diet, lifestyle and supplements, and avoidance of cancer-promoting estrogenics .
…………………………………….
     Women who choose not to have mammography and oncotherapy for highly suspicious lumps or even advancing cancers, or have been classified by cancer clinics  as too advanced for oncotherapy- told they have very short life expectancy- illustrate the lesson of watchful waiting with active intervention. We  see surprising regression in breast lumps, breast cancer and quality life extension in those who refuse to accept the oncologists’  death predictions  and who apply strong faith and  some of the many evidence-based changes and preventative natural supplement remedies we have  collated,    before or  even after the gamut /  gauntlet  of crush mammography, biopsy, surgery and radio-chemotherapy.
                                                                                                                                                           update 21 Feb 2014 The Oncologist publishes epidemiologist Archie Bleyer’s   “Were Our Estimates of Overdiagnosis With Mammography Screening in the United States Based on Faulty Science”?   rebuttal of radiologist Prof Daniel Kopans’  denial of the overdiagnosis of breast cancer.
        The point Bleyer again makes is that women have the choice provided they are fully informed of the pros and cons, and the options to screening mammography  and biopsy.
                 16 Feb 2014 update:   a slew of new papers reinforces the futility and hazards of mammography screening for early breast cancer- and the divide between the vested interests of mammographers/ oncologists – those who make their living from finding every possible cancer-  and the welfare of women:
                    Natural News today reviews criticisms of mammography from USA.
   in  NEJM 13 Feb , 2014,       Lisa Rosenbaum MD , Univ Pensylvania:  sums up the dilemma of real but unprofitable evidence vs profiteering, culture  and feeling  : Misfearing” — Culture, Identity, and Our Perceptions of Health Risks  Despite knowing that heart disease kills more women each year than all cancers combined, most women fear breast cancer far more — and their health-related behavior reflects this difference. If our sense of risk is less about fact than about feeling, how do we adjust it?
                
BMJ Feb 11,  2014: 25year  Breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial   Anthony  Miller, Cornelia  Baines, Steven  Nar ea,  compared breast cancer incidence and mortality up to 25 years later  in 89 835 volunteer women aged 40-59 randomly assigned to mammography (five annual mammography screens) or control (no mammography) in 15 screening centres in six Canadian provinces, 1980-85 . .  Women aged 40-49 in the mammography arm and all women aged 50-59 in both arms received annual physical breast examinations. Women aged 40-49 in the control arm received a single examination followed by usual care in the community.  Main outcome measure Deaths from breast cancer.  Results During the five year screening period, 666 invasive breast cancers were diagnosed in the mammography arm (n=44 925 participants) and 524 in the controls (n=44 910), and of these, 180 women in the mammography arm and 171 women in the control arm died of breast cancer during the 25 year follow-up period. The overall hazard ratio for death from breast cancer diagnosed during the screening period associated with mammography was 1.05 (95% confidence interval 0.85 to 1.30). in those aged 40-49 and 50-59 . During the entire study period, 3250 women in the mammography arm and 3133 in the control arm had a diagnosis of breast cancer, and 500 and 505, respectively, died of breast cancer. Thus the cumulative mortality from breast cancer was similar between women in the mammography arm and in the control arm (hazard ratio 0.99, 95% confidence interval 0.88 to 1.12). After 15 years of follow-up a residual excess of 106 cancers was observed in the mammography arm, attributable to over-diagnosis.   Conclusion Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Overall, 22% (106/484) of screen detected invasive breast cancers were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial.
                        Editorial Too much mammography  11 February 2014   BMJ 2014;348:g1403 http://dx.doi.org/10.1136/bmj.g1403  Mette Kalager,Hans-Olov Adami, Michael Bretthauer, Norway.                                     Long term follow-up does not support screening women under 60.   Before being widely implemented, mammography screening was tested in randomised controlled trials in the 1960s to 80s. Meta-analyses of these trials showed a relative reduction in deaths from breast cancer of between 15% and 25% among women aged 50 to 69.1 2 3 Only the Canadian National Breast Screening Study showed no reduction in breast cancer mortality.1 2 3 This large randomised controlled trial compared physical breast examination with combined physical breast examination and annual mammography in women aged 40 to 59.1 2 3    In a linked paper (doi:10.1136/bmj.g366), Miller and colleagues present the results for up to 25 years of follow-up in the Canadian study.4 No difference in breast cancer mortality was observed between the mammography and control arms, whereas a significant excess incidence of invasive breast cancer was observed in the mammography arm, resulting in 22% overdiagnosis. This means that 22% of screen detected invasive cancers would not have reduced a woman’s life expectancy if left undetected. The major strengths of this study include its randomised design, intense intervention with five annual mammography screenings, high compliance, and complete, long term follow-up. The lack of mortality benefit is also biologically plausible because the mean tumour size was 19 mm in the screening group and 21 mm in the control group. This 2 mm difference—which might be even smaller if overdiagnosed cancers could be excluded from the screening group—represents a minimal proportion of the entire clinical course for breast tumours.  But the trial also has some potential limitations. No quantitative data are available on the degree of contamination in the control arm or possible confounding by screening mammography after the trial. It seems unlikely, however, that such potential limitations would conceal a clinically important benefit. The rate of overdiagnosis did not include ductal carcinoma in situ, and the trial provides no data for women older than 60.

               The Canadian study, launched in 1980, is the only trial to enroll participants in the modern era of routine adjuvant systemic treatment for breast cancer, and the women were educated in physical breast examination as advocated today.4 These important features may make this study more informative for a modern setting, compared with other randomised trials. The results of the study are strikingly similar—for both lack of efficacy and extent of overdiagnosis—to recent studies evaluating today’s screening programmes.5 6 7 The real amount of overdiagnosis in current screening programmes might be even higher than that reported in the Canadian study,4 because ductal carcinoma in situ, which accounts for one in four breast cancers detected in screening programmes,8 was not included in the analyses.

                Other studies also indicate that improved treatment rather than screening is the reason for the decline in breast cancer mortality during the past four or five years.5 7 Even though different studies arrive at different reductions in breast cancer mortality (from 10% to 25%), these benefits translate to only marginal differences in absolute effects. Much larger variation is seen in the estimates of overdiagnosis.6 In studies based on statistical modelling, overdiagnosis was less than 5%.6 By contrast, most observational studies report higher estimates of overdiagnosis, ranging from 22% to 54%,6 depending on denominator used.9 When the number of breast cancers detected at screening is used as the denominator (as in the Canadian study), the amount of overdiagnosis observed in the previous randomised controlled trials is strikingly similar (22-24%).4 10

How do the data on mammography screening compare with data on prostate cancer screening by prostate specific antigen, which is currently not encouraged in the United Kingdom and other countries owing to its small effect on mortality and large risk of overdiagnosis (www.screening.nhs.uk/prostatecancer)? The figure on bmj.com shows that the absolute harms (overdiagnosis) and benefits (mortality reduction) are not very different between the screening types. The 20 year risk of breast cancer for a 50 year old woman is 6.1% with screening (including 22% overdiagnosis 4),11 and 5.0% without screening; and the corresponding numbers for prostate cancer in a 50 year old man are 3.9% with screening (including 45% overdiagnosis 12) and 2.7% without screening.11 The 20 year risk of death from cancer for a 55 year old woman is 1.5% with screening (assuming a 20% reduction in mortality2)11 and 1.9% without screening; and the corresponding numbers for prostate cancer in a 55 year old man are 1.0% with (assuming a 20% reduction in mortality12) and 1.3% without screening.11

           Nevertheless, the UK National Screening Committee does recommend mammography screening for breast cancer but not prostate specific antigen screening for prostate cancer, stating that the “aim is to only implement programs that do more good than harm and that the informed choice is a guided principle of screening” (www.screening.nhs.uk/screening). Because the scientific rationale to recommend screening or not does not differ noticeably between breast and prostate cancer, political pressure and beliefs might have a role.

             We agree with Miller and colleagues that “the rationale for screening by mammography be urgently reassessed by policy makers.” As time goes by we do indeed need more efficient mechanisms to reconsider priorities and recommendations for mammography screening and other medical interventions. This is not an easy task, because governments, research funders, scientists, and medical practitioners may have vested interests in continuing activities that are well established.

                RESPONSES:  12 February 2014  BMJ 2014;348:g366 :                     1. rebuttal by USA  radiologists : Daniel B. Kopans, Professor of Radiology Harvard Medical School. Having been one of the experts called on in 1990 to review the quality of their mammograms I can personally attest to the fact that the quality was poor (1). To save money they used second hand mammography machines. The images were compromised by scatter since they did not employ grids for much of the trial. They failed to fully position the breasts in the machines so that cancers were missed because the technologists were not taught proper positioning, and their radiologists had no specific training in mammographic interpretation.   

The CNBSS’s own reference physicist wrote:“..in my work as reference physicist to the NBSS, [I] identified many concerns regarding the quality of mammography carried out in some of the NBSS screening centers. That quality [in the NBSS] was far below state of the art, even for that time (early 1980’s). ” (2)

In this latest paper (3) the authors gloss over the fact that only 32% of the cancers were detected by mammography alone. This extremely low number is consistent with the poor quality of the mammography. At least two thirds of the cancers should be detected by mammography alone (4). In their accompanying editorial (5) Kalager and Adami admit that ” The lack of mortality benefit is also biologically plausible because the mean tumour size was 19 mm in the screening group and 21 mm in the control group….a 2 mm difference.” Poor quality mammography does not find breast cancers at a smaller size and earlier stage and would not be expected to reduce deaths.

The documented poor quality of the CNBSS mammography is sufficient to explain their results and all of the above disqualifies the CNBSS as a scientific study of mammography screening, but it was even worse than that. In order to be valid, randomized, controlled trials (RCT) require that assignment of the women to the screening group or the unscreened control group is totally random. A fundamental rule for an RCT is that nothing can be known about the participants until they have been randomly assigned so that there is no risk of compromising the random allocation. Furthermore, a system needs to be employed so that the assignment is truly random and cannot be compromised. The CNBSS violated these fundamental rules (6). Every woman first had a clinical breast examination by a trained nurse (or doctor) so that they knew the women who had breast lumps, many of which were cancers, and they knew the women who had large lymph nodes in their axillae indicating advanced cancer. Before assigning the women to be in the group offered screening or the control women they knew who had large incurable cancers. This was a major violation, but it went beyond that. Instead of a random system of assigning the women they used open lists. The study coordinators who were supposed to randomly assign the volunteers, probably with good, but misguided, intentions, could simply skip a line to be certain that the women with lumps and even advanced cancers got assigned to the screening arm to be sure they would get a mammogram. It is indisputable that this happened since there was a statistically significant excess of women with advanced breast cancers who were assigned to the screening arm compared to those assigned to the control arm (7). This guaranteed that there would be more early deaths among the screened women than the control women and this is what occurred in the NBSS. Shifting women from the control arm to the screening arm would increase the cancers in the screening arm and reduce the cancers in the control arm which would also account for what they claim is “overdiagnosis”.                                                                                                                                          The analysis of the results from the CNBSS have been suspect from the beginning. The principle investigator ignored the allocation failure in his trial and blamed the early excess of cancer deaths among screened women on his, completely unsupportable, theory that cancer cells were being squeezed into the blood leading to early deaths. This had no scientific basis and was just another example of irresponsibility in the analysis of the data from this compromised trial and he finally retracted the nonsense after making front page headlines (6).

      The compromise of the CNBSS trial is indisputable. The 5 year survival from breast cancer among women ages 40-49 in Canada in the 1980’s was only 75%, yet the control women in the CNBSS, who were supposed to represent the Canadian population at the time, had a greater than 90% five year survival. This could only happen if cancers were shifted from the control arm to the screening arm. The CNBSS is an excellent example of how to corrupt a randomized, controlled trial. Coupling the fundamental compromise of the allocation process with the documented poor quality of the mammography should, long ago, have disqualified the CNBSS as a legitimate trial of screening mammography. Anyone who suggests that it was properly done and its results are valid and should be used to reduce access to screening either does not understand the fundamentals, or has other motives for using its corrupted results.

        2.  confirmation:   http://www.bmj.com/content/348/bmj.g366?tab=responses  Per-Henrik Zahl, MD & statistician Norwegian Institute of Public Health.   In this 30-year old study, the authors report no mortality reduction when screening with mammography and 22% overdiagnosis (1). The sensitivity of the mammography technique has improved tremendously in the last three decades. Ten years ago we got digital mammography and recently we have got tomosynthesis (2). The detection rate at mammography in the Canadian study was about 3 per 1000 in the second and later screening rounds (3). In digital mammography, the corresponding detection rate is 6 per 1000 screened woman and in tomosynthesis, the detection rate is 8 per 1000 (2). It could even have been higher if the pathologists had time to perform more biopsies (personal communications). In tomosynthesis a large number of stellate lesions appear, many more than in traditional mammography, and they are probably representing a reservoir of overdiagnosed breast cancers. In the last 15 years, the rate of interval cancer has been constant and is at the same level as in Canada 30 years ago (4). Thus, the level of overdiagnosis is far much bigger today than in Canada 30 years ago.

             update 6 Feb 2014 This column has noted  that in the 2012 report of the the giant ATLAS (and aTTom) trials in 37  countries the past decade (discussed in detail below), despite the claimed 80% cure rate of early silent  breast cancer (diagnosed by mammography screening at around 55yrs),   by 15 years after repeated screening mammography- surgery-radiotherapy,  tamoxifen for 5 or 10 years and annual screening mammography followup,   of the women who had died by age 70yrs and had autopsy,   some 43% had (silent) recurrence of breast cancer- although this had been detected in far fewer living women. The 15 year ATLAS results overall were depressing- in those originally early silent estrogen-receptor positive breast cancers, although only about 20% had clinical recurrence by a mean age of 70yrs, of the 22% who had died by then,  almost half ie 43% had recurrence of breast cancer at autopsy.
How successful was tamoxifen versus placebo?
Why was  the Atlas trial  felt not to justify a no-tamoxifen control group?
               Sir Richard Peto’s earlier Oxford review (Horm Res 1989;32:165) Effects of Adjuvant Tamoxifen and of Cytotoxic Therapy on Mortality in Early Breast Cancer. An Overview of 61 Randomised Trials Among 28,896 Women  sought information worldwide on mortality according to assigned treatment in all randomised trials that began before 1985 of adjuvant tamoxifen or cytotoxic therapy for early breast cancer (with or without regional lymph node involvement). Coverage was reasonably complete for most countries. In 28 trials of tamoxifen nearly 4,000 of 16,513 women had died,  reductions in mortality due to treatment  were significant when tamoxifen was compared with no tamoxifen (p < 0.0001), any chemotherapy with no chemotherapy (p=0.003), and polychemotherapy with single-agent chemotherapy (p=0.001). In tamoxifen trials, there was a clear reduction in mortality only among women aged 50 or older, for whom assignment to tamoxifen reduced the annual odds of death during the first 5 years by about one fifth. In chemotherapy trials there was a clear reduction only among women under 50, for whom assignment to polychemotherapy reduced the annual odds of death during the first 5 years by about one quarter. Direct comparisons showed that combination chemotherapy was significantly more effective than single-agent therapy. Because it involved several thousand women, this overview was able to demonstrate particularly clearly that both tamoxifen and cytotoxic therapy can reduce five-year mortality.
         A decade later  the 1998 Tamoxifen for early breast cancer: overview of the randomised trials:  Oxford Early Breast Cancer Trialists’ Collaborative GroupCorresponding Author (The Lancet, 1998: 351,: 1451 – 1467) confirmed Peto’s review:  In 1995, information was sought on each woman in any randomised trial that began before 1990 of adjuvant tamoxifen versus no tamoxifen before recurrence on 37 000 women in 55 such trials, comprising about 87% of the worldwide evidence. Compared with the previous such overview, this approximately doubles the amount of evidence from trials of about 5 years of tamoxifen and, taking all trials together, on events occurring more than 5 years after randomisation.
                Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18 000 with ER-positive tumours, plus nearly 12 000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30 000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment (χ21=52·0, 2p<0·00001). The corresponding proportional mortality reductions were 12% (SD 3), 17% (SD 3), and 26% (SD 4), respectively, and again the test for trend was significant (χ21= 8·8, 2p=0·003). The absolute improvement in recurrence was greater during the first 5 years, whereas the improvement in survival grew steadily larger throughout the first 10 years. The proportional mortality reductions were similar for women with node-positive and node-negative disease, but the absolute mortality reductions were greater in node-positive women. In the trials of about 5 years of adjuvant tamoxifen the absolute improvements in 10-year survival were 10·9% (SD 2·5) for node-positive (61·4% vs 50·5% survival, 2p<0·00001) and 5·6% (SD 1·3) for node-negative (78·9% vs 73·3% survival, 2p<0·00001). These benefits appeared to be largely irrespective of age, menopausal status, daily tamoxifen dose (which was generally 20 mg), and of whether chemotherapy had been given to both groups. In terms of other outcomes among all women studied (ie, including those with “ER-poor” tumours), the proportional reductions in contralateral breast cancer were 13% (SD 13), 26% (SD 9), and 47% (SD 9) in the trials of 1, 2, or about 5 years of adjuvant tamoxifen. The incidence of endometrial cancer was approximately doubled in trials of 1 or 2 years of tamoxifen and approximately quadrupled in trials of 5 years of tamoxifen (although the number of cases was small and these ratios were not significantly different from each other). The absolute decrease in contralateral breast cancer was about twice as large as the absolute increase in the incidence of endometrial cancer. Tamoxifen had no apparent effect on the incidence of colorectal cancer or, after exclusion of deaths from breast or endometrial cancer, on any of the other main categories of cause of death (total nearly 2000 such deaths; overall relative risk 0·99 [SD 0·05]).
            So, for corroboration we need the autopsy results of the women in the earlier tamoxifen vs placebo studies; and the 20 year results of the Atlas study. The ATLAS study reports clearly that silent breast cancer was more than twice as high in autopsied cases as in screening mammography during life. The conundrum remains whether  early cancer detection by regular repeated screening mammography, and early treatment by biopsy, surgery, radiotherapy and tamoxifen, is more beneficial or more harmful to women long term?
24 Jan 2014   Overdiagnosis    Overtreatment of Breast Cancer   .Am Soc Clin Oncol Educ Book. 2012;32:e40-e45. doi:  Alvarado M, Ozanne E, Esserman L. meetinglibrary.asco.org/sites/meetinglibrary.asco.org/files/Educational Book/PDF Files/2012/zds00112000e40.pdf  Dept Surgery Univ Calif San Francisco. write:   “Breast cancer is the most common cancer in women. Through greater awareness, mammographic screening, and aggressive biopsy of calcifications, the proportion of low-grade, early stage cancers and in situ lesions among all breast cancers has risen substantially. The introduction of molecular testing has increased the recognition of lower risk subtypes, and less aggressive treatments are more commonly recommended for these subtypes. Mammographically detected breast cancers are much more likely to have low-risk biology than symptomatic tumors found between screenings (interval cancers) or that present as clinical masses.                                                                                                                                
        Recognizing the lower risk associated with these lesions and the ability to confirm the risk with molecular tests should safely enable the use of less aggressive treatments. Importantly, ductal carcinoma in situ (DCIS) lesions, or what have been called stage I cancers, in and of themselves are not life-threatening. In situ lesions have been treated in a manner similar to that of invasive cancer, but there is little evidence to support that this practice has improved mortality. It is also being recognized that DCIS lesions are heterogeneous, and a substantial proportion of them may in fact be precursors of more indolent invasive cancers. Increasing evidence suggests that these lesions are being overtreated. The introduction of molecular tests should be able to help usher in a change in approach to these lesions. Reclassifying these lesions as part of the spectrum of high-risk lesions enables the use of a prevention approach. Learning from the experience with active surveillance in prostate cancer should empower the introduction of new approaches, with a focus on preventing invasive cancer, especially given that there are effective, United States Food and Drug Administration (FDA)-approved breast cancer preventive interventions.”                                                                                                                                                                                             5 January 2014:   Quantifying the Benefits and Harms of Screening Mammography.  H Gilbert Welch & Honor Passow  , Dartmouth Geisel school of medicine, NewHampshire  write:  JAMA Intern Med. 2013 Dec 30.                   Like all early detection strategies, screening mammography involves trade-offs. If women are to truly participate in the decision of whether or not to be screened, they need quantification of its benefits and harms. Providing such information is challenging, however, given the uncertainty-and underlying professional disagreement-about the data. In this article, we attempt to bound this uncertainty by providing a range of estimates-optimistic and pessimistic-on the absolute frequency of 3 outcomes important to the mammography decision: breast cancer deaths avoided, false alarms, and overdiagnosis. Among 1000 US women aged 50 years who are screened annually for a decade,                                                                        0.3 to 3.2  ie ~0.17%  will avoid a breast cancer death                                                490 to 670  ie ~58% will have at least 1 false alarm recall, and                               3 to 14 ie         0.85%  will be overdiagnosed and treated needlessly.                                            We hope that these ranges help women to make a decision: either to feel comfortable about their decision to pursue screening or to feel equally comfortable about their decision not to pursue screening. For the remainder, we hope it helps start a conversation about where additional precision is most needed
                                                                                                                                                                     A recent review of a new book by journalist Rolf Hefti- The Mammogram Myth–  consolidating the controversy for and against screening mammography is reviewed by Cape Ray. The book relies heavily on Dr John Gofman (1919-2007), a distinguished medical scientist,  a key member of the Manhattan Project that developed the first atomic bomb used on Nagasaki. In 1996 Gofman published a book entitled Preventing Breast Cancer: The Story of a Major, Proven, Preventable Cause of This Disease, in which he made the astonishing claim that 75% of all breast cancers were caused by women being exposed to ionising radiation from X-rays. As highlighted in a review in JAMA, Gofman’s claim — based on an extensive literature review and certain critical assumptions — was at variance with every other authority, including the National Academy of Sciences and the National Council on Radiation Protection.  Martin Yaffe of Toronto has recently shown that the risk of radiation-induced breast cancer from mammographic screening is not negligible, but this risk is small when compared to the expected reduction in mortality achieved through screening.
                                                                                                                                                                   So the dilemma for health professionals, and for  the target of the zealous Cancer Screening Industry-  healthy women in their prime-of-life middle years- remains:  why have xray mammography screening when the independent evidence from expert epidemiologists is that screening mammograpy  to find preclinical ie precancer does not in fact  meaningfully save lives, entend health or reduce breast surgery and cancer therapy, it actually increases all these risks compared to waiting till cancer presents clinically.                                                                                                                                             Zahl Jorgensen and Gotzsche  in their latest review show that Overestimated lead times in cancer screening has led to substantial underestimation of overdiagnosis.
and Gotzsche’s new book is an expose  of  Deadly Medicines and Organised Crime.  
                                                                                                                          20 July 2013   HUMAN PROGESTERONE  BREASTCANCER RISK  REVISITED: Its 3 years since this column last reviewed progesterone, in the context of osteoporosis,  bone building.   While the first Pubmed report on progesterone implants  is apparently sixty years ago (probably in veterinary reproductive use), Drs John Lee and Kathy Dalton promoted use of solo human progesterone P4 for (post)menopausal protection,  also  against cancer including breast cancer; which l’Hermite 2013 from France, and eg David Sturdee from UK, have recently favourably  summarized in respect of balanced transdermal estrogen and oral micronized progesterone P4. The evidence for P4 as  almost global protection as HRT   has largely been confirmed provided progesterone is used in moderation – ideally transdermally/ transvaginally  like estrogen (Genazzani ea);  some believe in the basal physiological bloodlevel of about 1 to 2 nmol/L,  in balance with basal levels of human estrogen and androgens.                                                                                                                                Vanadin Seiffert-Klauss ea in Munich have recently (2012) confirmed that “women in the (~10year) menopause transition lose trabecular bone at a rapid rate despite intermittently high and usually normal estrogen levels –  especially the lean women (BMI<20kg), and those with family fracture history”.  And in their PEKNO study, “Decreasing rates of ovulation, hormonal changes, and increasing bone loss pre-date menopause by several years.;  in addition to estradiol, progesterone may play a significant role in the interrelationship between the ovaries and the skeleton in women.  differentiation of human osteoblasts from perimenopausal women has been shown to be dose-dependent on progesterone at physiological concentrations.  Higher progesterone levels, as seen in the luteal phase of ovulatory cycles, may be associated with more bone formation and with slightly less bone resorption than anovulatory cycles in which progesterone levels are low (< 5.8 ng/ml)”.                 These data led to the initiation  in perimenopausal women of a large, prospective, 2-year observational PEKNO study – from which interim data indicate that a decrease in ovulation correlated with an increase in the loss of bone mineral density (BMD). A meta-analysis in women *with normal ovulation estimated a BMD increase of 0.5% per year, vs *with ovulatory disturbances (anovulation or short luteal phase) a BMD decrease of 0.7% per year in young women ; but * in postmenopausal women a 1.3% increase per year in BMD when receiving hormone replacement therapy with unopposed estrogens, and a further 0.4% increase in BMD in women receiving estrogens plus progestogens. The role of progesterone in bone metabolism in perimenopausal women who are estrogen-replete requires further study.”  
                                   Thus they show that postmenopausally, addition of progestin may boost BMD by 31% more than ERT alone. But currently some experts eg Kuhl and Schneider and David Zava   feel that evidence warrants caution, that oral human progesterone P4  may have a  role in breast cancer promotion;  although it has protective benefit against estrogen dominance in most circumstances eg against endometrial cancer. As this column has previously reviewed, longterm experience of experts like Greenblatt & Gambrell, Gelfand,  Lee Vliet  in N America;   Schleyer-Saunders, Whitehead & Studd (London) , Burger & Davis (Australia) ; and Davies ea (Cape Town) showed no increase but reduction in all postmenopausal morbidity including cancer with  non-oral eg implants of BIDHRT (estradiol balanced  with human antiestrogen eg testosterone and/or progesterone).
                                                                                                                                                              Now Stephenson ea  at the Tyler Women’s Wellness Center, Texas publish a 3  year study showing multiple benefits and no adverse effects of balanced   compounded bioidentical transdermal hormone therapy BIDHRT on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures in peri- and postmenopausal women. Conventional  nonhuman hormone therapy HT eg CEE and medroxyprogesterone results in increased thrombotic events, and an increased risk of breast cancer and dementia  in large prospective clinical trials including the HERS and the Women’s Health Initiative studies.  Physiologic human sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile, yet long-term studies of this treatment model are lacking.  In a  prospective, approved closed-label study, 75  women who met strict inclusion/exclusion criteria were enrolled; following baseline hormone evaluation,  women received compounded transdermal bioidentical hormone therapy of BiEst (80%Estriol/20%Estradiol), and/or Progesterone to meet established physiologic reference ranges for the luteal phase.          Subjects receiving  BIDHRT in doses targeted to physiologic reference ranges administered in a daily dose showed significant favorable changes in  menopausal symptoms, cardiovascular biomarkers, inflammatory factors, immune signaling factors, and health outcomes, despite very high life stress, and home and work strain in study subjects. There were no associated adverse events. This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in populations with high perceived stress and a history of stressful life events prior to, or during the menopausal transition.
                                                                                                                                                              This Texas   study supports the 2009 metanalysis by Holtorf:The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?   Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone.  Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. 
                                                                                                                                                                          And of course the recent 4year Kronos KEEPS study by Harman ea 2012 confirms that in early postmenopausal woemen, parenteral physiological-dose  estradiol has subtle benefits over oral premarin, with or without  parenteral progesterone, with no significant adverse effect..                                                                                                                                                                                                                                                                                                                                                                                                                  17 June 2013  SHOULD WE EVER TELL A PATIENT WITH A BREAST LUMP THAT IT’S CANCER?  or THAT IT MAYBE PRECANCER?  This was and is a  major dilemma in medicine. One of the big  lessons arising out of the high technology in living memory ie the past >century-our grandparents’ time-  is that before modern laboratory, imaging and surgical diagnostics, all we could do was wait and see, the trial of observation and therapy, prayer, meditation. Now we have gone to the other extreme in the aging,  bullying them to have risky invasive screening on the crass assumption that screening and early radical – invasive ie potentially  harmful-  treatment of silent ie precancer saves lives- when the evidence has become progressively clearer that unselective invasive screening of asymptomatic prostates and breasts simply creates worried well,  overdiagnoses silent disease which may never cause illness or death ,  and may hasten misery; whereas combining natural preventative remedies may benefit all systems  including regress cancer.
                                                                                                                                                             Silent hypertension and unrealised overweight/ metabolic syndrome  are radically different from cancer. With simple measurement  of asymptomatic arterial hypertension, visceral obesity and eg glycosuria, the earlier that risk factors are defined and addressed, and the earlier the adiposity/glycosuria/ hypertension corrected with lifestyle, abolishing smoking and boozing,  and diet improvements, supplements and if necessary the safest prescription drugs-  initially fish oil,  lowdose amiloretic and reserpine, metformin, and the basket of vitamins and minerals especially magnesium, zinc,  vits C and D3 –  the sooner is the progressive  risk  reversed to the heart, brain, mind, vision, lungs, digestive and excretory system, joints and legs, let alone to fertility, carcinogenesis and other immunoendocrine  functions                                                                                                                                                           So instead of driving well aging women witless with disease-mongering-  forced regular invasive xray screening mammography-  we should  instead respect the power of the mind over disease, and use simple careful history, and physiological  biometrics including behaviometrics to persuade and condition those at risk to take sensible precautions including if necessary supplements, exercise and corrective diet/psycho/hypnotherapy. The lesson of screening breasts and prostates for silent cancer  the past 20 years is that so many cases of silent dormant cancer regress spontaneously if left well alone, especially if they are left undiagnosed and instead just the score of common risk factors for  all common diseases addressed as this column keeps exploring. So when asymptomatic changes and lumps in breasts are detected by noninvasive means eg clinical or Sure Touch or thermal exam, there is no need to alarm the woman by labelling her a patient with breast disease – it is more than healing for her to show her that within a month, these changes can be reversed with  all the appropriate natural  steps as described in Combatting Breast Cancer , including the Magic Oils. If there were indeed (pre)malignant changes present, they too regress as normally happens in so many – so  leave well alone. As reviewed below,  up to  45% of apparently well adults who are killed  have silent cancers;    and in the giant ATLAS and aTTom trials in 37  countries the past decade (discussed in detail below), despite the claimed 80% cure rate of early silent  breast cancer (diagnosed at around 55yrs)  by 5 and 15 years after repeated screening mammography- surgery- and radiochemotherapy,  and annual screening mammography followup,   of the women who had died by age 70yrs and had autopsy, the similar 43% had (silent) recurrence of breast cancer. So  like men,  asymptomatic women should be discouraged from invasive screening; but the higher their risk score, the more readily they should be offered simple noninvasive breast screening, and thereby encouraged to optimize diet, habits, lifestyle, body build-fitness,  including with the battery of multibenefit preventative supplements . Like millions of partisans have sung in bitter wars and holocausts, Hirsh  Glik’s “Never Say that You Are Trodding the Final Path“- remains the hope-givimg mantra that all patients and caregivers  must hold to – the power of positive thought and action  if not prayer. Both mistakes and miracles happen.                                                                                                                                                                                                                                                                                 upate June 14 2013: a new review from Oxford University  Breast cancer mortality trends in England (1979-2009) and the assessment of the effectiveness of mammography screening concludes: In the Oxford region,  For all ages combined, mortality rates peaked for both underlying cause and mentions in 1985 and then started to decline, prior to the introduction of the NHSBSP in 1988.  There was no evidence that declines in mortality rates were consistently greater in women in age groups and cohorts that had been screened at all, or screened several times, than in other (unscreened) women, in the same time periods. Conclusions Mortality statistics do not show an effect of mammographic screening on population-based breast cancer mortality in England.update June 10 2013  a  review published today  by Coldman and Phillips on   Incidence of breast cancer and estimates of overdiagnosis after the initiation of a population-based mammography screening program   in Canada over 40years showed that ” the extent  of overdiagnosis of invasive cancer  was modest and primarily occurred among women  over the age of 60 years. However, overdiagnosis of ductal carcinoma in situ was elevated  for all age groups.”                                                                                                                                                                                                                                                                                                                   update 9 June 2013:    THE HARMFUL COERSIVE PRESSURE APPLIED ON WOMEN,  AND ON THEIR BREASTS, WITH SCREENING  XRAY  MAMMOGRAPHY:      Womens’ wishes must be respected when they  prefer no-xray no-squeeze prescreening, choose not to have xray mammography. Breast discomfort and breast trauma from xray mammography -breast sandwiching –   vary greatly between women and especially in young more hormonally-driven  breasts.. The pressure is manyfold:  not just in crushing the breasts, but in PTSD- post-traumatic stress disorder: Oxana Palesh & Cheryl Koopman report this month Breast cancer: PTSD—prevalent and persistent:  Receiving a diagnosis of breast cancer is likely to have aconsiderable impact on the psychological wellbeing of the patient. In a recent observational study, Vin-Raviv et al.1 reported that 23% of 1,139 women with newly diagnosed localized breast cancer experienced post-traumatic stress disorder (PTSD) symptoms. This is not to deny that many women experience post-traumatic character growth, as a recent Greek study discusses.   Posttraumatic stress disorder and posttraumatic growth in breast cancer patients.  But Elklit and Blum and O’Connor ea in Denmark a year earlier highlight  PTSD   as being highly relevant in oncology settings after early breast cancer.. This awareness has been reviewed on Pubmed from before 1997. A recent report says the physical crushing force applied in such breast compression  – snackwiching –  is briefly up to about  130 Newtons, ie 13 kg or  25 pounds force.    This compares to the gentle 1.5 to 2kg force applied briefly when having a mechanical tactile Sure Touch surface breast anatomical mapping, or professional clinical breast exam; or zero force with a no-touch infrared thermomammogram. Hence some  women report breast pain, bruising and discomfort for weeks after a compression xray mammogram. And because oncologists insist on followup regular xray mammography after cancer therapy with breast-conserving surgery & radiochemotherapy, women increasingly ignore breast lumps let alone any screening breast exams at all. It is common cause that stress, anxiety  increase cortisol, insulin  and thus estrogenic stimulation, and thus cancer risk to  breasts.  It is still unknown how much the longterm risk of breast problems and cancer is increased from rupturing breast cells (let alone spreading cancer cells) with repeated successive compression xray mammography and the cumulative xray dose used – especially when perhaps 1 in 10 women screened is recalled  by radiologists for more compression views, to find (by biopsy of perhaps 10 to 20 women per 1000) the 2 to 4 clinically undetected tiny breast (pre)cancers in each 1000 women so screened preventatively… And it is obvious that with denser more active breasts in young women- monthly high-turnover glandular cells (especially in those on cyclic synthetic estrogen-progestin contraception) –  both breast fragility and sensitivity are higher the earlier that xray mammography is commenced as radiologists insist.

              Hence Regulators in most countries have reduced recommendations for routine screening mammography to starting at age >50yrs and stopping by 70-75years (ie 10-12 times on average through midlife); whereas Radiology Associations ignore the risks and still advise screening annually from age 40 years,  for life  –   ie at least THREE times as many times from age 40years. So women are doubly exposed to harmful pressure both in being bullied that they need screening xray mammography – the lie that  ” screening mammography saves lives”  when the benefit of this is unproven, and in being forced to undergo breast crushing repeatedly. A woman who recently attended for Sure Touch in Port Elizabeth   objected to having her breasts snackwiched again by compression mammography. The flippant analogy is eerie when one considers how such women are expected to attend annually to have their breasts both flattened and irradiated – and more so with cumulative frying after therapeutic radiotherapy. No wonder some end up with a hard breast. . So while the young at heart may   love nudging breasts-,  and massage  heals, (and Bissell and Fletcher at the Berkley lab show that gentle nudging with about 50 gm pressure knocks errant breast ductal cells back into healthy behaviour) –   crushing force and coersion do women harm, not good; in contrast to men where forceful digital massage may (also with putative risk) relieve the infected painful prostate.. .

And Gøtzsche   and Jørgensen in  .Cochrane Database Syst Rev. have Jun 4 published update stats against Screening for breast cancer with mammographyfrom  PubMed and the WHO ‘s International Clinical Trials Registry  (to November 2012).  Eight eligible trials  included 600,000 women  in the age range 39 to 74 years. Three trials with adequate randomisation did not show a statistically significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90); four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87). We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly from differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on total cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all-cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03).  Surgeries – Lumpectomies and mastectomies (RR 1.20-1.31, 95% CI 1.08 to 1.42) were significantly more in the screened groups . The use of radiotherapy was similarly increased whereas there was no difference in the use of chemotherapy.              AUTHORS’ CONCLUSIONS: If we assume that screening reduces breast cancer mortality by 15% and that overdiagnosis and overtreatment is at 30%, it means that for every 2000 women invited for screening through 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 10%  will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.        To help ensure that the women are fully informed before they decide whether or not to attend screening, we have an evidence-based lay  leaflet http://www.cochrane.dk. Because of substantial advances in treatment and greater breast cancer awareness since the trials, it is likely that the absolute effect of screening today is smaller than in the trials. Recent observational studies show more overdiagnosis than in the trials and very little or no reduction in the incidence of advanced cancers with screening”.                                                                                                              

update 26 May 2013  Apart from the strident promotion of preventative mastectomy by a film star,  reports the past week prompt review of :  why and whether  aggressive breast cancer may have doubled  in young women 25-39years old; and  it’s prevention by natural steps.

update 22 May 2013:   WHY DO SO MANY  WOMEN HAVE  RELAPSE OF BREAST CANCER BY 25 YEARS AFTER  DIAGNOSIS AND APPARENTLY CURATIVE TREATMENT OF EARLY SILENT BREAST CANCER?:three landmark new papers shine more light on why 43% of women who died by 15 years after aggressive treatment of  initial silent preclinical breast cancer had relapse/recurrence  of breast cancer at autopsy  – the  depressing result of the monumental 180 000 women-year  ATLAS trial:

Lisa Willis, Karen Page, Trevor Graham, Tomás Alarcón, Malcolm  Alison    & Ian  Tomlinson  from Universities of London, Oxford, Cambridge, and Barcelona  this month dissect  “What Can Be Learnt about Disease Progression in Breast Cancer Dormancy from Relapse Data?   why Breast cancer patients have an anomalously high rate of relapse up to 25 years  after apparently curative surgery removed the primary tumour. Disease progression during the intervening years between resection and relapse is poorly understood. There is evidence that the disease persists as dangerous, tiny metastases that remain at a growth restricted, clinically undetectable size until a transforming event restarts growth. This suggests a natural question and  a surprising answer: why are interesting trends in long-term relapse data not more commonly observed?”       But they are observed: another recent  15 year followup study, from Denmark (Grantzau ea), furthermore shows that DXRT after early breast cancer almost doubles the risk of radiotherapy-associated second cancer to 1:200 of women so treated..

       Thus at least dangerous dormant micrometastases, and the enormous cumulative  radiation exposure from both screening mammography over decades, and DXRT itself, will explain much of the 43% recurrence rate of breast cancer by 15 years (at autopsy in those who had died by then, at a  mean of only 70 years) seen in the ATLAS trial.

  These reports raise yet further doubts about the wisdom  of  regular mass xrayscreening of well breasts from age 50 years let alone 40years, and worse-  zealous major surgery and DXRT for preclinical disease, and then even worse, ongoing xray mammographic surveillance into old age.

      They point in the opposite direction:  that xray screening of well breasts should be avoided;  DXRT avoided in localized early breast cancer; and surveillance for breast cancer limited to the many available non-xray methods;

     and that women must be encouraged instead to maintain prevention with combination of safe natural (and multisystem-protecting)  means as discussed repeatedly in this column – lifestyle, diet, exercise, and massage and oral use of safe natural preventative supplements. Anticancer antiangiogenesis factors from our diet  are legion, include  cannabis, mushrooms, resveratrol, green tea, black rasberry  and Royal jelly. One would not recommend soya against breast cancr because of its phytoestrogen potential.

               Xradiation has been known for decades eg 1978 1990 to be both an angiogenic and an antiangiogenic factor in tumour growth angiogenesis (Judah Folkman 1971) . so it is  obviously a double-edged sword that should certainly not be used in the witchhunt for silent and usually irrelevant precancer in well breasts.

                   So we have the ludicrous situation reported today in JAMA  that despite all the evidence for 20 years now to stop or at least halve  mass xray screening and thus (over)treatment of silent early breast cancer, Physicians, Patients Not Following Advice From USPSTF on Mammography Screening: In 2009, the US Preventive Services Task Force (USPSTF) recommended against routine screening mammography for women under 50 years and advised biennial rather than annual screening for women aged over 49yrs. But women and physicians ignored these recommendations.  A new study from Harvard  found that in 2005 to 2011, the percentage of women aged 40 to 49 years reporting that they had undergone mammography screening in the previous year was the same, about 47%. As for women aged 50 to 74 years, the percentage reporting mammography screening in the previous 12 months for each year analyzed also remained essentially the same, in the upper 50% range.”

        Update 21 April 2013FIFTEEN YEAR FOLLOWUP STUDIES OF BREAST CANCER AND ALLCAUSE  MORTALITY FROM MENOPAUSE ONWARDS:                                                                           Overall, long-term studies do not favour invasive breast screening or adjuvant therapy of early breast cancer,  but actually argue  against  early diagnosis and treatment of both silent breast and prostate  cancer.  Rather, the focus must be on safe natural prevention to reduce the occurrence of all common degenerative diseases of aging.

       It is instructive to juxtapose  the diverse 15 year followup studies in 14 countries (Nordic Cochrane- Gotzsche, Jorgensen ea) of women routinely xray- mammography screened or not, with the 15 year ATLAS study (that ended in 2010)  reviewed below in 36 countries,  of women zealously xray- screened for early breast cancer, prompt  biopsies and surgical/  radiotherapy treatment- the majority mastectomy-  and then randomized to tamoxifen for up to  10 years. and it is reported by the ATLAS authors that there was a major breach of protocol – The protocol stated that 20 000 patients would need to be randomised in ATLAS and the other trials of tamoxifen duration to detect reliably an absolute difference of 2–3% in mortality. Entry to ATLAS was halted in 2005 (with 12 894 patients, including 6846 with ER-positive disease) because the MA.17 trial  showed benefit from continued endocrine treatment after 5 years of tamoxifen..   Yet the MA17 trial was with a different drug- letrozole;  and bizarely, the trial conclusion was that “the results from the analyses based on the Cox model with time-dependent covariates  were similar for letrozole and placebo.”  ie that letrozole was no better than placebo.. Thus, like the Womens’ Health Initiative misguided early termination,  it is unclear why MA17 was used as reason to terminate the ATLAS trial.
             The 15 year ATLAS results overall were depressing- in those originally early silent estrogen-receptor positive breast cancers, although only about 20% had clinical recurrence by a mean age of 70yrs, of the 22% who had died by then,  almost half ie 43% had recurrence of breast cancer at autopsy.              Many new such trials are under way.
The aTTom trial  the UK arm of the ATLAS trial similarly “followed women with early breast cancer after initial treatment  for about 15 years:  it  randomly assigned 6934 women (39% ER-positive, 61% ER-untested) at the completion of 4 or more years of tamoxifen therapy to either 5 additional years of tamoxifen or cessation of tamoxifen therapy. With a median follow-up of 4.2 years, there was a slight, non-significant advantage for the 10-year tamoxifen arm (RR, 0.94; 95% CI, 0.81–1.09; P = .4). Thus, the optimal duration of therapy is not known, but it is at least 5 years”. For undisclosed reasons this trial has apparently  never been published in full although it was first reported in 2008- this raises the usual question by eg Booth and Tannock 2008  of bias against negative results, whether there was suppression by sponsors…  And the aTTom trial design was heavily criticised at the outset in 1996.
                The meta-analysis published the past week by Heidi Nelson ea for the USPSTF  confirms the ATLAS study, showed that tamoxifen/ raloxifen for 5 years reduced absolute mortality from breast cancer by about 0.16% per year. Neither reduced breast cancer-specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms.
         It then becomes apparent  that  having early breast cancer detected – without the adverse risk factors of xray mammography of repeated breast crushing, radiation,  biopsies and overtreatement,                             but with better application of safe preventative measures including vitamin D3, melatonin, metformin, iodine, DMSO, coconut oil,  fish oil, sutherlandia, I3C/DIM, vitamins and minerals                  – while women will live healthy longer,  few women  (perhaps <5% of all deaths) will die of breast cancer.  The common risk factors (for all common premature disease and deaths) are  m   anaged with the same basket of safe natural effective preventatives including supplements like appropriate balanced hormone replacement -that this column addresses.                                                                                                                                                                                                                                                    
Dr.  Northrup says“[Gilbert Welch] pointed to a study [from] way back, of women who died in car accidents in their 40s. They sectioned their breast tissues and found that 40 percent of them – this is normal healthy women dying in car accidents – had evidence of ductal carcinoma in situ that was never going to go anywhere. This is the big dilemma,” .   Welch and Black 1997 reported Among seven autopsy series of women not known to have had breast cancer during life, the median prevalence of invasive breast cancer was 1.3% (range, 0% to 1.8%) and the median prevalence of DCIS was 8.9% (range, 0% to 14.7%). Prevalences were higher among women likely to have been screened (that is, women 40 to 70 years of age).

     Erbas ea at Univ Melbourne studied all sources for the prevalence of ductal carcinoma in situ. “The reported prevalence of undiagnosed DCIS in autopsy studies, of approximately 9%, has been used to suggest a larger reservoir of DCIS may exist in the population”.

      Update 18 April 2013:  a  new study from  Italy   graphically illustrates the lower sensitivity of xray screening – U/S ie  ultrasound picked up ‘significantly’ more tiny asymptomatic breast cancers  missed in 22,131  women with negative mammography.  “The overall U/S detection was 0.185%, but 0.55% with previous cancer vs 0.145% in women without cancer history (p = 0.0004),  0.22% in dense breasts (p = 0.17) vs .156% in fatty breasts. The U/S- generated invasive assessment was 0.19%  The benign to malignant open surgical biopsy ratio was  thus 0.17.”  This is likely more overdiagnosis unless the women simply apply the preventative measures recommended below.

             But while no screening method can diagnose cancer (only invasive biopsy can), and none can guarantee there arnt cancer cells busy germinating especially if stirred up by severe anxiety,  radiation, crushing, biopsy etc, Sure Touch mapping is more accurate than even U/S for  reassuring while reducing referral rate for U/S.

UPDATE 14 APRIL 2013: Because of the evidence the past score years set out below  that xray screening actually does more harm than good, integrative  medical clinics world wide do not promote xray screening mammography. But such clinics including in Cape Town generally offer regular safe and lower-cost  anatomical eg Sure Touch mechanical tactile if not ultrasound or MRI, and physiological no-touch eg thermography ie bloodflow studies,  –  for those who need peace of mind. Some women choose to alternate Sure Touch and thermomammography.

     While only 1 in 200 women have the familial gene risk,  the majority of older women have  the common multiple risk factors eg longevity, estrogenic and heavy metal pollution, stress, overweight density, smoking, alcohol; and  there are many simple remedies described in these  columns that can reverse most of the risk factors – not just of even genetic breast cancer and increasing overweight,  but of all the major diseases of aging.

The problem remains the stubbornness of third party payers including governments to listen to both the evidence and to womens’ wishes, and pay for such safe, cheaper and arguably more accurate prscreening than crush xray mammography, if any is desired or desirable .

Dr Johnnie Ham MD MSc MBA Californian ObGyn discusses why xray screening mammography and aggressive medical assault on  well breasts- the witchhunt for the pot of hidden gold,  silent preclinical breast cancer –  is a giant  con by the  for-profit high-tech medical goliath  industry   terrorizing and mutilating  naive women.

Governments -WHO  silence on harms of screening mammography : What is tragicomedy is that worldwide, government Regulators seem to be standing silently firm, not saying a word about the harm likely exceeding the medical benefit- the screening and cancer  industry is far too profitable in jobs, taxes and votes. Search on the internet for Government warnings on harms of screening mammography does not yield a word of warning. Regulators and Medical Schemes piously promote quality screening, but say nothing about the harms versus benefits. The FDA still promotes annual screening mammography  on line without a word about the risks and harms of mammography; others like the UK NHS promote it every 2 to 3 years.    Yet the US Senate is actually considering a Republican Act to promote more xray breast imaging.

UPDATE 12 April 2013  The Wiki entry on breast cancer prognosis says now: “One result of media hype- breast cancer’s high visibility -(compared to other cancers in eg men, and other common major diseases) is that statistics may be misinterpreted, such as the claim that breast cancer will be diagnosed in one in eight women during their lives—a claim that depends on the unrealistic assumption that no woman will die of any other disease before the age of 95.[132] This obscures reality that about ten more women will die from heart disease or stroke than from breast cancer.[133]The emphasis on breast cancer screening may be harming women by subjecting them to unnecessary radiation, biopsies, and surgery. One-third of diagnosed breast cancers might recede on their own.[134] Screening mammography efficiently finds non-life-threatening, asymptomatic breast cancers and pre-cancers, even while overlooking serious cancers. According to Prof Gilbert Welch of  Dartmouth Institute, research on screening mammography has taken the “brain-dead approach that says the best test is the one that finds the most cancers” rather than the one that finds dangerous cancers.[134]

The latest  report  Lancet 2011) on the Relevance of breast cancer hormone receptors and other factors to efficacy of Tamoxifen protection after breast cancer looked at 20 trials (n=21,457) in early breast cancer . In oestrogen receptor (ER)-positive disease, about 5 years of tamoxifen halved recurrence rates throughout the first 10 years but  no further gain or loss after year 10; risk was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years. Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality.

       This is not surprising as tamoxifen like  all synthetic  sex hormones  /blockers has  a long list of adverse effects on bone, brain, cardiovascular, bladder, mood, immunity, body weight and metabolism,  womb etc.

But the Oxford UK-led (Davies ea)  landmark monumental  ATLAS trial (2012)  from 1996 -2010 in 36 countries and 180 000 women-years (mean presentation  age mid 50s, ER+ breast cancer about 1 cm size,   2/3 had mastectomy – which is now known to increase mortality) showed that after 6846 women taking tamoxifen  for up to 10 years, at about 15 years from diagnosis, tamoxifen in absolute terms  was only marginal benefit- marginally reduced the risk for breast cancer recurrence, compared with stopping tamoxifen (617 vs 711; P = .002), reduced breast cancer mortality  relatively by 8% (331 vs 397 deaths; P = .01) but that’s only about 1% in absolute terms, and reduced overall mortality by 10% (639 vs 722 deaths; P = .01). Over all, approximately 1/5 clinically relapsed,  1/7 deaths were from breast  cancer; but of those who died, webfigures 4a and 4b of  the supplementary appendix   of the main ATLAS  report showed that at autopsy almost half  (43%) indeed had recurrent breast cancer. This gives the lie to early screening and treatment-  15 years later, even with tamoxifen for  10 years, early xray mammography detection and conventional surgical-radio-chemotherapy treatment does not cure much more than half of women with preclinical ER+  breast cancer that screening detects.The risk for recurrence by year 15 was 21.4% in the continuers group and 25.1% in the control group. ie only 3.7% absolute reduction. In addition, breast cancer mortality by year 15 was significantly reduced by nearly 3%; it was 12.2% in the continuers group and 15.0% in the control group. ie only 2.8% absolute reduction. Thus even in these women with early breast cancer, the cure rate even with tamoxifen was poor- slight reduction in the 25% recurrence  and 15% breast cancer mortality rates. But almost  half of the women who died had recurrence.  Once again, the actual results published 4 months ago in the final Lancet report were much less impressive than the media release published 5 days later. Of these >6000 women allocated after initial surgery/ radio/chemotherapy to the tamoxifen or placebo  trial, 85% did not die of breast cancer. But the cure rate was at best still only about 75%, and only  half of those who died -by a mean of age 70 years – of any  causes were free of breast cancer.

11 April 2013  the SA Menopause Society Menopause Matters today  also features The Great Mammography Debate- concluding “The point being that the treatments of breast cancer are not benign and need to be drawn into the calculations when assessing the harms of screening mammography. If these treatments are carried out on a significant number of people who are not in danger of being harmed by their breast cancer in the first place (those over-diagnosed) then the scales of benefit versus harm from routine mammography may well tip in favour of harm. If so it may be unwise or even unethical to recommend screening by mammography.”

9 April 2013  Robert Stern at University of Arizona writes that “xray mammography alone is not a very good screening modality and has strikingly variable false positive, false negative, specificity, and efficacy rates, depending on what you read and who you believe.

   Worldwide, the days of simple repetitive yearly/ biannual mammograms for every living woman over some arbitrary age may be over soon.. breast cancer screening is about to evolve into a personalized, patient-centered program. It means you can’t just  order a mammogram when a  flag pops up saying it’s time.  It means understanding fairly complex risk stratification, the indications for these new technologies, and the clinical context for various imaging strategies”, mostly still based on irradiation;  as detailed in the American Medical Journal by Drukteinis ea at the Florida Mofitt Cancer Centre ..

8 April 2013: UPDATE:  see  vitamin D3 and Breast Cancer.

JAMA publishes on line from University Basel  Switzerland,   Shaw and Elger’s viewpoint on Evidence-Based Persuasionoften  an ethical imperative to  forcefully guide a hesitant patient into what seems to be the best decision, using arguments from Removal of Bias to Recommending Options and occasionally even Creating New Biases.      The eternal problem remains, what is truly right? Is mass flu vaccine right? Is screening xray  mammography truly lifesaving? especially if one quotes impressive but misleading relative risk reduction rather than in fact the crucial trivial absolute reduction?  Is Directive Counselling however well-meant exercising undue influence? They conclude that it  is an essential part of modern medical practice, without which it may be impossible to respect patients’ autonomy. Such necessary persuasion needs to meet 6 criteria.

A month ago BCAction held a webinar reported by Manie Clark

updating the risks and futility of screening xray mammography.

24 Mar 2013. THE COVERUP OF HARMS AND FUTILITY OF XRAY BREAST SCREENING CONTINUES IN USA Many opinions from around the world in recent NEJMs say it all about screening mammography:  most are subjective, emotive. There is no impartial objective evidence to support the gold standard xray mammography at all (except arguably  in cases of obvious cancer- when biopsy, and MRI scan is better and safer).   When there are acceptable prescreenings that do no harm and when combined,  give good sensitivity and specificity eg any two of  mechanical tactile imaging, thermomammography, breast ultrasound and (if affordable) MRI.
         Karla Kerlikowske ea  co-author already four peer-reviewed Pubmed-listed studies on xray  mammography this year..  the latest on screening well women from the  Breast Cancer Surveillance Consortium asks: Screening Outcomes in Older US Women Undergoing Multiple Mammograms in Community Practice: Does Interval, Age, or Comorbidity Score Affect Tumor Characteristics or False Positive Rates?Uncertainty exists about appropriate use of screening mammography among older women because comorbid illnesses may diminish the benefit of screening. We examined the risks from 1999 to  2006 on 140000  women aged 66 to 89 years at study entry undergoing mammo     . About 7% had  breast cancer,  in a data linkage between the Breast Cancer Surveillance Consortium and Medicare claims.  Cumulative probability of a false-positive mammo result was higher among annual screeners than biennial screeners irrespective of comorbidity: 48% of annual screeners aged 66 to 74 years had a false-positive result compared with 29% of biennial screeners. These women  who undergo biennial screening mammo had similar risk of advanced-stage disease and lower cumulative risk of a false-positive recommendation than annual screeners, regardless of comorbidity.
But their abstract abysmally fails to ask and answer the obviously far more important question:  – did screening mammo  give any  significantly lower mortality, surgery   or  radiotherapy at 15 or 20year followup compared to a matched  randomly selected cohort not screened over the same period, or compared to women who were screened only once at the outset??
   All independent studies show that women regularly screened by xray mammogram  do no better and sustain far more harms, in fact may die sooner than those not screened. Why did they not say this in their abstract, that xray mammo screening is unethical abusive harmful exploitation of women?
    The BCSC website registers over 8million screening mammograms done there 1996-2009 – 24% of women had 5 or more xray screens- ` yet similarly  fails to mention the crucial harms and mortality data in screened versus unscreened women.  The reason is obvious:  admitting the truth, that xray screening mammo is not only futile but harmful, would kill what must now be a $10billion a year   industry in USA for xray manufacturers, radiologists, breast surgeons, hospitals, medical schemes, oncologists and Big Pharma in the Find a Hidden  Breast Cancer Conspiracy against older women. . Indeed, the endgame would be that lawyers will swarm to call on women to sue the Breast Cancer Industry for wrongful assault.
23 Mar 2013Dr Enza Ferreri is a London-based  Italian journalist philosopher of science, christian human and animal  rights activist, including saving  Britain from an Islamist President Charles Windsor.. She yesterday wrote a devastating critique of screening xray mammography, its profiteering  oversell by  Scandinavian and English-speaking governments’ propaganda that omit  to explain all the risks and lack of benefits. “On one side you have the stories about women whose ” life  was saved” by breast screening, on the other  women whose life was made hell by discovery of a possibly benign DCIS, and those who endure a nightmare of false positives believing that she has breast cancer when she hasn’t. “
22 Mar 2013 Even this month’s  European Radiology Congress, and the South African Menopause Society  SAMS newsletter Menopause Matters, and the Annals of Family Medicine a new Copenhagen study- now question  screening xray mammography, including cumulative radiation damage to heart and lungs; and chronic psychological trauma from false positive reports.
False-positive findings on screening mammography causes long-term psychosocial harm: 3 years after a false-positive finding, women experience psychosocial consequences that range between those experienced by women  with a normal mammogram and those with a diagnosis of breast cancer. Not even a “positive” breast biopsy is a guarantee that it is cancer that needs treatment -apparently 4% of breast biopsies may be misread. so 2nd opinions are advised.
     the  SAMS author says: ”   the fundamental question  is “Does screening for cancer improve length or quality of life?”  The latest arguments from the UK ask if screening saves lives, if you take all causes of death into account (Baum BMJ 2013;346:f385).  Firstly, the author accepts that screening saves lives. If 10 000 women are screened for a decade then 4 deaths will be avoided. As treatments improve as they are doing all the time, then deaths avoided become lower, maybe 2 per 10 000 in the near future and thus screening becomes less valuable… current data about survival need to be used when making calculations about prolonging life.
     Secondly, overdiagnosis is important because if some women who do not have life-threatening disease are treated, they may die from the treatment. Mastectomy, radiation, chemo- or endocrine therapy are not trivial treatments. Surgery carries anaesthetic and sepsis possibilities, especially in obese patients.   Radiation is not without its risks, raising the incidence of ischaemic heart disease 27%  and of lung cancer 78%. These risks would be worth taking if there were no cases of overdiagnosis – but there are – somewhere between 10% and 50% -so any lives saved may be cancelled out by deaths caused.     So with all-cause mortality no longer showing benefit, it devolves to other factors such as the positive peace of mind screening provides or the negative over-investigation of false positives to sway decisions for or against screening. No wonder the editor of the BMJ (26th January 2013) asks “At what stage must we seriously consider whether this screening is a good use of £96m of  NHS budget?”  So how should we advise our patients? The statistics show the “lives saved” argument is neutralized. The cost of screening, time involved and morbidity from false positive tests are all non-fatal harms so these have to be weighed against  peace of mind of a negative result and these calculations are in the mind of the beholder.     The parallels with prostate specific antigen screening are uncanny and PSA testing is rapidly falling into disfavour or even disrepute. It seems those with vested interests are those promoting mammography screening. The moral position of doctors is becoming increasingly complex – can it be correct to say mammography screening in low-risk women is “the right thing to do”?
16 Mar 2013   Recently Bateman in Cape Town suggests  “PinkDrive intervention ‘over-rated’ : Breast health professionals are questioning the life-saving impact of the high profile non-profit breast cancer organisation PinkDrive.
      The Pink Drive website opens with some  fallacies eg  that:                                         xray mammo 23kg breast compression causes no pain or damage – wrong; that     It is a tool to diagnose breast cancer“-      wrong-only  histology does; and that diagnostic breast irradiation is no risk after age 40years ;  wrong- this column has quoted authoritative opinion and research eg Lemay,  Sherbrooke Univ 2011  to the contrary, the linear no-threshold model, although Mina Bissell’s  Berkley Lab 2011 research paper perhaps contradicts this – the jury is still out . .
          It is significant that of the seven Platinum Pink Drive sponsors, two are private Hospital chains with  major vested interest in the Breast Cancer Surgery and Reconstruction  Industry.
Contrary to the Pink Drive website stating  that mammograms diagnose breast cancer, a major new  study from Japan on xray mammography of almost 120000 women found histological cancer in 0.22% of those  who underwent mammography alone, 0.37% of those who underwent ultrasonography alone, and 0.5% of the 974 participants who underwent both mammography and ultrasonography. Recall rate due to mammographic abnormalities was 4.9% for women screened only with mammography and 2.6% for those screened with both modalities. The cancer detection rate was 0.22% for women screened only with mammography  and 0.31% for those screened with both modalities. Their conclusion that It is possible to reduce the recall rate in screening mammography by combining mammography and ultrasonography for breast screening is precisely the point, that  hazardous xray mammography screening with its immediate and  longterm risks is not needed when any two of the three well-tested lowcost zero-risk portable facilities are available eg Sure Touch Mechanical Tactile imaging, thermomammgraphy, and ultrasound, and two  combined give high sensitivity and specificity.
Neither of the above new abstracts raised the issue of overdiagnosis or longterm hazards.. In fact the NCI Nat Cancer Institute Journal itself published a study this month  from San Fran  University California showing that  in 140 000  women from 66years upward screened  between 1999 and 2006, Cumulative probability of a false-positive mammography result was higher among annual screeners than biennial screeners irrespective of comorbidity: 48%  of annual screeners aged 66 to 74 years had a false-positive result compared with 29%  of biennial screeners. Women aged 66 to 89 years who undergo biennial screening mammography have similar risk of advanced-stage disease and lower cumulative risk of a false-positive recommendation than annual screeners, regardless of comorbidity. Thus  even cancer comes and go. Reducing xray screening  in USA   to every second year reduced the frequency of false positive recall – overdiagnosis – from almost half – 48% – by above one third, without increase in advanced cancer.
A Comparative Table shows the many methods, procedures  for objective breast imaging (mammography) available.  Of the established procedures  it lacks only comparison with the gold standard- the oldest ie  manual clinical examination-  and with forty year old Infrared Thermography. As this column has stressed previously, mammography is not a patented word for xray breast imaging, it is simply a generic description of breast (mammo-) and image (-gram) . Any image of the breast is thus a mammo-gram, and the process is mammo-graphy.
SCREENING METHODS COMPARATIVE TABLE:                   this table shows the relative merits of some different methods of breast imaging. Mechanical Tactile Sure Touch Imaging leads the field  for combined sensitivity and specificity, portability, all-age utility without problems of breast density interference, cost, risks and reproducible mapping. Like a photograph, a  plaster or other cast of the bust would thus also be a mammogram image- and unlike plastic surgeons,  dermatologists and thermographers, other health professionals and patients alike too often forget to record a photograph to compare changes in the skin and breast serially. .
NEJM 28 Feb from Harvard, Adler and Colbert’s  “Mammography Screening Poll Results”  is a sobering commentary  on the health professionals’ wrong perceptions about routine X-ray mammography screening of all well breasts from midlife. What do readers say about the indisputable overwhelming independent evidence against routine X-ray screening mammography?
One has to question  the rationality of most NEJM readers – surprisingly few in total – who responded to the poll after Bleyer and Welch’s  , Mette Kalager’s  , Baum, Jorgensen and Gotzsche’s publications last year, that the majority of NEJM readers polled still  promote X-ray screening despite the hard evidence, the absence of benefit from screening irradiation of well breasts- significant reduction in mortality in such women – in the face of multiple hazards of such screening.
The risks, the  list of hazards – in five broad categories – is so great that as pointed out below last month, not even the NCI National Cancer Institute itself any longer clearly  promotes routine  X-ray mammography screening. As Colbert and Adler and the 2nd Canadian mammography trial 20 yrs ago noted (Miller and Baines) , the evidence for presymptomatic screening X-ray mammo is no better than clinical digital exam. Early diagnosis of silent  breast precancer by xray screening and biopsy does not save lives, it is a vast waste of money except for the career Breast Industry, that has been characterized as  terrorizing and damaging gullible submissive women (Winifred Cutler, Athena Inst).

There are certainly many safe natural ways we  reviewed recently of  reversing the  risks of breast  proliferation and cancer, thus justifying periodic safe low cost breast screening  – mammo-imaging – by independent  eg digital, mechanical tactile  ” Sure Touch ” , ultrasound and/ or thermo- means.26 Feb 2013. There is a flood of new progress against breast disease , breast cancer and  xray screening mammography: Contrary to  the for-profit Breast industry,  like all independent authorities including the Cancer Association of South Africa CANSA , the National Cancer Institute of America in 2013 no longer recommends routine xray mammography   screening-          it rates  the EVIDENCE on X-ray screening mammography          as FAIR evidence for its sole and arguable benefit –  Decrease in total and breast cancer mortality –        -*Consistency of studies is only Fair. External Validity: Good.  Internal Validity: Variable,.           But as GOOD evidence for the FIVE major  HARMS of  xray  screening    -* both  consistency, internal & external validity -are good –

  • Discomfort if not cellular rupture and bruising from violent 23 kg 50 lb crushing,
  • Overdiagnosis and Resulting Treatment – including mastectomy or radiochemotherapy- of Insignificant Cancers:
  • False-Positives with Additional Testing and Anxiety.
  • False-Negatives with False senseof Security and Potential Delay in Cancer Diagnosis.
  • Radiation-Induced Breast Cancer.

Winifred Cutler’s Athena Institute  team warns again that screening X-ray mammography on well women is dangerous , inflicts terror,  it does not reduce but may worsen the occurrence of invasive breast cancer. The  Berkeley  Institute’s  Dr Venugopalan  under profs Mina Bissell and Daniel Fletcher  show that simply gentle massage  helps – Compressing Breast Cancer Cells Can Stop Out-of-Control Growth Shelley Hwang ea show that in California simple lumpectomy for early breast cancer reduced deaths (up to 2009) by 28% compared to mastectomy. Belinski & Boyages at the  Westmead Centre in Australia show again that common very low vitamin D levels more than double the risk of breast cancer let alone colon and all other cancers. A  Harvard team (Liu ea) has just shown that the carnage of legalized poisoning (smoking  – lungcancer, vascular;  alcohol -liver disease, violence;  adulteration with refined sugar/fructose – diabetes, vascular disease, cancer)  aside,  breast cancer far outstrips the other common cancers (colon, prostate cancer) in  preventible  life years lost. Willaims ea show again the major benefit of metformin against lethal breast cancer. Amadou ea in France confirm again the strong  link between abdominal obesity and breast cancer from childhood throughout life. This again highlights the criminal stupidity of delaying metformin use till obesity let alone infertility or diabetes are established. Metformin can safely be introduced at any stage of life provided it is started at very low dose eg below 250mg/day and cautiously titrated to the maximum well-tolerated dose to avoid nausea and diarrhoea- and temporarily halved or stopped in case of intercurrent gastrointestinal upset. . Grani et al from Rome, Italy    and many others remind us that both thyroid and breast malfunction are common by middle age and need to be sought and managed together.    We know that in most aging populations, deleterious deficiency of especially  magnesium, iodine, selenium, sulphur, and  vits B, C, D and K , and melatonin and sex hormones is very common along with crippling multitoxic carcinogenic overload. So it is logical to use multisupplements, and massage anti- inflammatory anti-cancer antioxidant  chelating antiestrogenic deep – penetrating iodine, coconut oil and DMSO – into the breasts as multidisease prevention and part of treatment. Oz ea in Turkey show that DMSO is  more effective against breast cancer than thalidomide.  But more importantly, DMSO enhances transport of any anticancer  agents into cancer cells. Already in 2008 Frederick ea showed that Lugol’s Iodine is an important antiestrogen adjuvant against breast cancer. Hence we advise  the harmless combination of natural multisystem micronutrients- especially  fish oil, coconut oil, DMSO,   vitamin C, D, K, melatonin, metformin, selenium, Lugol’s iodine and appropriate progesterone/ testosterone/ DHEA  – as nutrient supplements against all chronic aging diseases especially in women at risk of breast cancer.  . At Univ  Newcastle on Tyne,   Dr Dorota Overbeck-Zubrzycka’s  landmark  PhD  thesis just published on    FOXP3 regulates metastatic spread of breast cancer via control of expression of CXCR4 chemokine receptor promises new gene therapy in future. and her parallel study with Harvey,  A. Griffiths & C. Griffith,  Randomised control trial of Breast Tactile Imaging as an assessment tool for diagnosis of breast lumps in 2009/10 is now being published in full in a leading UK journal, validating this ( Sure Touch) bedside and outpatient clinic procedure as an established no-risk screening procedure, objective breast mapping  record for anxious women as shown in USA, Indian and Chinese studies. Thus increasingly Authorities are accepting that screening X-ray mammography harms far outweigh trivial if any improvement in survival. But screening – by eg regular clinical exam and mechanical tactile mapping –  for early signs of breast degeneration allows gentle safe self – treatment of all multisystem diseases that reverses both the breast degeneration and multisystem risk factors.

4 Feb 2013 UPDATE: BREAST SCREENING: Time lag to benefit after screening for common internal problems:   routine high-tech mass screening is inappropriate insurance.
a lot of the prestigious British Medical Journal last issue of 23 January 2013 is dedicated to the Breast Screening controversy; with a number of critics questioning the November 2012 Government  (Marmot) whitewash of the gigantically costly- and risky- NHS  screening mammography program. Professor Michael Baum of London University in particular has argued against this process for the past decade, after being the lead UK breast surgeon to set up this program in the 1990s and realizing it’s folly and risks.

Editorial: Breast cancer screening: what does the future hold?

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f87  Cite this as: BMJ 2013;346:f8Cliona C Kirwan, National Institute for Health Research clinician scientist in surgical oncology          :  “Overdiagnosis remains a problem; quantifying its effects and minimising its impact are priorities.
The role of national breast screening programs and the quality and transparency of information given to participating women are increasingly the subject of heated debate. In the past 12 months alone, the BMJ, the Lancet, and the New England Journal of Medicine have published 24 articles debating the value of breast cancer screening. After calls for an impartial review of the value of breast screening in the United Kingdom, the findings of an independent panel of experts, led by Professor Marmot, were published in November 2012.1Currently in the UK, women aged 50-70 years are invited for screening every three years; 2.3 million women were invited during 2010-11. The rate of uptake currently stands at 73.4%, having steadily increased in the past decade.2The primary aim of screening is to reduce mortality from breast cancer. Reduced breast cancer related mortality is balanced against the cost of screening in terms of physical and psychological harm to women and the financial impact on health services.Much recent debate has concerned overdiagnosis—that is, diagnosis of a condition that would never cause symptoms or death during a patient’s lifetime. Although over-investigation can cause harm (pain and anxiety from mammography and biopsies), this is usually …”

Personal View     Harms from breast cancer screening outweigh benefits if death caused by treatment is included : Prof Michael Baum

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f385 (Published 23 January 2013)      Cite this as: BMJ 2013;346:f385

13 Jan  2013   As this column has long noted, routine high-tech mass screening is inappropriate insurance/prevention. Contrary to the gospel of the American Radiology, Breast and endoscopy costly screening industry,  and Curves International,  no human  survives   for  > 10 000 years to benefit from routine hightech screening  to avoid premature disease and death ie ‘save a life’ . . There is still grave doubt about the risk:benefit of routine prostate screening in the well.
A new January 2013 BMJ paper by a California University team Lee et al    looks at  ‘noninvasive’ cancer  screening of  breast (xray mammography) and colon (testing stool for occult blood)   in Europe and USA. It found that  at least 1000 patients must be screened for at least 10 years – ie >10 000 patient-years of screening- before screening for either cancer could be claimed to save  a life. The corollary is that such screening of the well has a very low  chance – below 1:10 000 in any year, ie  0.01%  –  of finding a silent killer cancer that will save/  extend a life.

Thus they advise against screening people with an expected lifespan of below about 10 years.   But who would undergo such bothersome risky screening even over 10  years for a proposed benefit  (in death risk reduction)  of 0.1% a decade ? They found the reasons against routine screening of those not at high risk ( ie no suspicious personal symptoms or familial history) are as usual   those of the ensuing anxiety, the  procedures – radiation and colonoscopy and biopsies – and overdiagnosis. The worst is of course the cumulative risk of breast irradiation, and perforation death from colonoscopy:        “For cancer screening,  about one in 10 patients who are screened (with xray mammography , or with fecal occult blood testing) will have a false positive result,  leading to recall worry and likely biopsy/  colonoscopy.  Serious complications (such as perforation, major bleeding, and death) occur in 3.1 colonoscopies per 1000 screened.  One in 100 routinely mammography-screened  women will be  biopsied, and one in 1000 will be subject to overdiagnosis (that is, diagnosed with a breast cancer that was unlikely to have been clinically evident during their lifetime) and possibly unnecessary treatment.”

The same arguments apply strongly against routine screening of men for prostate cancer, or smokers for lung cancer,  in the absence of symptoms. . It should be noted that even the Wikipedia Mammography review now strongly highlights the arguments against mass screening mammography. The introduction sums it up bluntly: “task force reports point out that in addition to unnecessary surgery and anxiety, the risks of more frequent mammograms include a small but significant increase in breast cancer induced by radiation.[3][4] The Cochrane Collaboration (2011) concluded that mammograms reduce mortality from breast cancer by an absolute amount of 0.05% or a relative amount of 15%, but also result in unnecessary surgery and anxiety, resulting in their view that it is not clear whether mammography screening does more good or harm.[5] They thus state that universal screening may not be reasonable.[6]     Mammography has a false-negative (missed cancer) rate of at least 10 percent. This is partly due to dense tissues obscuring the cancer and the fact that the appearance of cancer on mammograms has a large overlap with the appearance of normal tissues. A meta-analysis review of programs in countries with organized screening found 52% over-diagnosis.[6]

It can be argued that noninvasive screeing that finds suspicious premalignant signs can then motivate prevention by natural means- lifestyle diet and appropriate supplements. But since these preventative steps (including blood-pressure and waist/breast  girth measurements and monthly self-exam for breast changes)    hugely  reduce the risks of all serious  acute and  chronic diseases, accidents and premature disability and death, routine mass screening for common ‘silent’  internal cancers eg breast, prostate  colon lung womb and ovary , is irrelevant, risky and huge waste of resources for no benefit. Not applying sensible diet,  lifestyle, blood-pressure checks   and supplements is like failing to maintain  your car, house, computers and electrical appliances etc , until  these  crucial assets  break  down. The evidence against hightech screening of the well of course does not  stop the anxious well  from worrying. As a heavy cigarette-smoking prof  of lung medicine  said 30 years ago, if an anxious patient demands a scope despite reassurance that the risk:benefit doesnt justify it, it is wise to do it.  Or someone else will. At least in the context of the younger adult who will thereby be more motivated to apply prevention, non-xray non-invasive screening by eg Sure Touch breast mapping- from onset of menopause, or younger  in eg diabetics   and others more prone to cancer eg in AIDS,  – and ultrasound quantitative bone-density risk measurement  from toddlers upwards , in exercising ie sportspeople,  and in any serious chronic disease especially with hormone overtones  eg thyroid,  diabetes, COPD/ asthma, cancer, arthritis, paralysis, AIDS,TB, cardiacs, renal, liver disease –  are relatively low cost  and safe compared to the traditional  xray screening procedures. The brilliant new French movie The Intouchables is all about choices  of lifestyle and the risks entailed.  Thats what screening, and voluntary prevention, are about.  No  adult  should be pressurized – by vested interests –  into having hightech eg xray (breast, bone)  or more invasive (eg scope, biopsy) screening without understandable explanation of the possible  although  infrequent immediate and distant risks,  and remote if any  benefits. Only the frequent  incidental unexpected screening discovery of hypertension,  increased breast lumpiness/density,  and low bone density, and initiation of simple lifestyle diet changes  and safe supplement  therapy- the below- listed scores of supplements against all common degenerative diseases  (and if needed the best primary antihypertensive  – lowdose reserpine and co-amilozide – costs perhaps  $1  a month to control  most; and simple (breasts, arthritis, wound   or elsewhere)  antiinflammatory  self massage if indicated with Lugol’s iodine, and analgesic antioxidant coconut oil and DMSO),  gives huge early and permanent preventative  pain and inflammatory benefits without risks.  There are also  promising studies on Pubmed between 1989 and 2011 of the benefits of DMSO in management of prostate problems in rats, and humans for transrectal procedures  and intravenously as cancer adjuvant palliation. DMSO-MSM is cheaply and safely available . It comes back to basics that are anathema to politicians,  Government, profiteers, Big Business Pharma and the Disease Industry.  Motivating and enforcing better lifestyle and natural diet (minimizing sugar , aspartame, alcohol, processed food especially cornstarch) , and healthgiving realistic doses of supplements – vits (all –  especially B, C,  D3 and K), minerals  (especially Mg, Zn, I2, Se, P, Bo,) and biological (plant  and sealife – not land animal) extracts,  (including fish oil, metformin, bioidentical human hormones, tryptophan, MSM, DMSO, chondroglucosamine,  coconut oil, cinnamon, pepper, curcumin, arginine, carnitine, carnosine, ribose, coQ10, proline, rauwolfia) – reduces the occurrence of serious disease drastically with decades of health extension. This vastly reduces  profit to the Disease Hospital-Drug  and processed food- alcohol – tobacco industry in delayed disease till very old age, and thus loss of  skilled workers’  jobs – that need to be taken up  elsewhere. That’s called reinvention, recycling…

LUGOL’S IODINE THE QUINTESSENTIAL SUPPLEMENT: against all diseases including cancer; & infections from fungi & protozoa to TB & HIV:

update 7 November 2015: comments & feedback please.
Orthoiodosupplementation in a Primary Care Practice Jorge D. Flechas, M.D. its undated but the latest ref is 2004..
but informative 2014 iodine update video by Dr Jorge Flechas:
some points: “why women have so many more thyroid problems eg estrogen blocks iodine; whereas ovary hot nodules may cause thyrotoxicosis from secreting T2.  Iodine alerts the brain, so dont take at night! give no more than ~12mg/d ie 2 drops 15% in pregnancy, it stimulates the baby!
“Iodine ie I2 diffuses into cells whereas iodide need to be transported in; babies lack the symporter Iodide transporter, so babies need iodine not iodide.
ie thyroid, ovary and WBCs can make thyroxine- but preferably  they mop up low iodine intake. Thyroid supplements doesnt provide enough iodine for needs elsewhere .
” Millions of women in Japan and Korea on their marine diet used to normally ingest ~13.5mg iodine a day, producing very low neonate problem rates in pregnancy and with IQ far higher than average.
“in the west, Iodine has been taken out of bread and milk, and salt intake cut – associated with increased rate of ADD in USA 500% and more cancer thyroid, breast, ovaries, endomet, cretinism, goitre .. – as iodine intake and output in USA has been halved by admin policy…
the kidneys excrete excess ingested iodine, so avoiding overdose from high iodine intake.

“ie if sufficiency, a 50mg iodine load will excrete >90% . so the spot test for low iodine excretion, and 24 hr high iodine excretion, reflect defective sodium symporter problem. This corrects with ongoing iodine supplement. 80% of vegans in USA are iodine deficient due to skipping seaweed for iodine! Asians eat seaweed in everything.. the body can hold 1.5gms iodine; 50mg in the thyroid, 20% in the skin, 30% in muscles…
– if depleted of iodine, we cant sweat or use our muscles (fibromyalgia), brains, or control the breasts or ovaries.. .. just add ATP cofactor ie incl vits B2 & B3 to iodine…
“Bread & esp cooldrink’ iodine (eg Mountain Dew) has been replaced by bromine, which causes schizoid behaviour… .. Iodine reverses the immortality of cancer cells.
” 3000mg/d ester C , and highdose iodine, and B2+B3 , reverse the iodine symporter block, & abolish the fibromyalgia in 80% of sufferers. .

This Flechas review is encouraging for repletion with Lugol’s 50 to 100mg iodine /day ie 6 to 12 drops 15%; after perhaps a precautionary skin test dose for allergy.
especially for protecting breasts, cancer, diabetics, obesity, heart disease, immune, memory and stroke problems.. .

It does seem that as with vits C and D3, iodine has a minimal RDA as far as basic prevention goes ie ~0.15mg – 1mg/d for avoiding cretinism (cf scurvy with >10mg/d vit C, or frank rickets with 400iu/d vit D3) ; and at the other end of the spectrum ie treating severe disease, grams a day of iodine and vit C, and vit D3 >50 000iu ie >1mg/day..

Then longterm maintenance with eg ~12 mg iodine a day ie 2drops/d 15% Lugols,  cf 1 to 3 gm a day vit C, vit D3 ~7000iu ~ 0.2mg/day… .

perhaps the corollary may be that , (as with vit D3 eg 2million ie ~ 50mg), a massive accidental load dose eg 2gms iodine- 20ml 15% Lugols- (which apparently bypasses the detox reaction at lower ie buildup dose, and incidentally provides 1gm potassium) may be both harmless and will reload for who knows how many years- presumably provided one takes a good magnesium and selenium ie realfood Banting diet .

To test tolerance, and try to reverse my familial irreversible atrial fibrillation, I have built up my Lugols’ dose  so far  to 15% 1 to 2 tsp a day ie 4 to 8ml, ~800mg combined (I + I2) iodine with 400mg potassium K  a day;
whereas a load dose vit D3 eg 0.6 to a million units (6-10gms of standard max strength 100 cwt powder – with a good magnesium and vit K2 diet as in realfood Banting) will replete safely and harmlessly for less than a year.
Its a pity the simple IODINE urine test is- unlike the skin patch test duration- so tediously long and costly (and both can occasionally mislead),
whereas the blood  vit D calcium-creat levels are quick to take but costly  tests.. .

But in those who can afford them , the tests are essential to validate the clinical results we get with iodine and vit D3 .

update 27 Sept 2015
IODINE THE QUINTESSENTIAL SUPPLEMENT

see prev Healthspanlife.wordpress.com ie May 2014 update.

quotes from authorities are in italics: please feed back on errors and experience

Massive iodine deficiency is  as universal worldwide (compared to 50 years ago) as are
*deficiencies of:                                                                                                ..vitamin C (except those who live on fresh fruit and veg);
..vitamin D (except those who work outdoors in sunny climes);
..magnesium; and
..natural saturated fats in all except keen carnivores;
..and increasing deficiency of other vitamins in the food chain, forced on the public by government-sponsored industries and “health authorities” for 50 years now;
*and unnecessary dangerous food-chain toxins ( refined carbohydrates; calcium/bromine/ fluorine/salt, aluminium, mercury supplements, synthetics eg transfats, pesticides eg glyphos Roundup, GMO foodstuffs, antibiotics ; and steroids). .

But with seafood almost wiped out by greed and pollution, and increasing global nuclear pollution, and failure by food producers to supplement   iodine never mind vit D and magnesium in the depleted food chain,

iodine repletion with vigorous Lugols iodine (with its consort selenium) is even more of a priority than concomitant vitamin D (with its consort vit K2) and magnesium supplementation, and vitamin C, plus a broad balanced other score A to Z multisupplement ..

So the dangerous scaremongering myths need to be debunked about the “dangers” of iodine at over a mg a day – when the safe general therapeutic dose is not just ~12mg/d but up to 100mg/d for longterm prevention, and over a gm/d for major diseases; ie >10 000 x the RDA. The US recommended adult dose of iodine for nuclear exposure is about 120mg, without any mention of remotest risk of toxicity.

This 1000 x order of magnitude with iodine is like
*the almost 10 000x margin between minimalistic vitamin C 10mg/d dose (RDA now 60mg/d) to avoid scurvy, up to >3v-7gm a day to treat infections, and >30 gm/day (intravenously, or buffered orally) to treat cancer;

*and vitamin D3 (RDA now up to ~800iu/d) up to 250 x more eg from 200iu /d to prevent rickets vs 50 000iu/d to treat some serious diseases, vs 2million iu single doses and 150 000iu/d for decades that have no documentable toxic effects in adults.
Infants obviously need proportionate dosing of all, not left to depend on mother’s milk when she has received no more than the usual prenatal supp folate and iron.. . .

The heaviest essential metal iodine is perhaps the most rare essential mineral – Wiki: “Iodine is rare in the Solar System and Earth’s crust (47th/60th in abundance):”- hence iodine deficiency is universal – especially now it has become fashionable in our lifetime to stop adding iodine to foodstuffs; and instead food manufacturers pump in toxic halides like bromine and fluoride (like dangerous mercury and aluminium in vaccines, aluminium in antacids) that (unlike chlorine,  iodine and refined sugars) have no essential biological need and benefit , only risks;

and recognition that commercial pure white runny salt NaCl – overdosing chlorine- is adverse because of worsening hypertension with aging and fast foods, instead of encouraging seasalt. .
The myths have been debunked that
*(unlike our essential blood chlorine in moderation), either fluorine or bromine are essential trace element halogens, any more than commercial cane sugar or fructose are biologically essential in our diet;

*and the Wolff-Chaikoff Effect myths (that iodine is toxic at much more than a mg a day) debunked by Abraham & Brownstein’s  review of scientific evidence the past century  including  Wartofsky, et al   1970  that we overdose with iodine at only 20 x the RDA (0.15mg/d) ie over a mg/ day,

*and the myth that only potass KI /sodium NaI iodides should be supplemented. The most proven iodine is in Lugols iodide providing the balance between  KI and free I2.

*Another commercially driven myth is that blood thyroid hormone levels are adequate to diagnose biologically significant iodine sufficiency, and commercial thyroxine to treat patients– the commercial hormones dont address, may worsen the serious iodine deficiency throughout the body that contributes hugely to acute and chronic, common and rare diseases

Studies of traditional Japanese after WW2 showed that their far better cancer-, cardiovascular,- thyroid health (before they emigrated to America, or took up Western diet) was attributable especially to the kelp ie iodine intake in their then-safe seafood diet, giving them an average iodine intake of about 12 mg/day- at least 100 times the current American imposed RDA of 0.15mg/d. But who can trust kelp, seafood from the poisoned oceans and rivers any more?

I recently took for a day each approx 20drops Lugols 2% pd in water ie iodine ~9mg a day; then 15% 4 drops ie 30mg/d …then up to , then 10drops ~70mg/d to test for detox reaction. I carry on with ~50mg/d,  as  many patients take it . I suppose my lack of detox reaction is not surprising since I have been detoxing for years on about 6 gm a day of a 50 -supp -multiblend( half vit C).- but no more than a mg/d of potass iodide. I  find physical and mental stamina better, no longer have  angina from stress or walking fast- which I could not do a fortnight before due to angina and fatigue. . .

One shudders to think of the billions of people – especially kids- who are dull, not achieving their full potential for lack of iodine, either because health professionals dont think we need more, or because patients are dismissed as euthyroid based on the usual thyroid lab hormone tests (which ignore iodine deficiency/excess in the majority who dont fall clearly in the over-or underactive blood hormone range).

Conventional western medicine apparently no longer considers or measures iodine deficiency, forgetting that iodine is the primary essential deficient mineral (along with magnesium, selenium, sulphur, phosphate; and iron in kids and reproductive women) for all systems in the body, not just for thyroid hormone levels- which dont reflect iodine security anywhere outside thyroid hormone production by the thyroid. .

IODINE OVERDOSE?
Iodine is needed in microgram mcg amounts for the thyroid, milligram mg amounts for breast and other tissues, and therapeutically as anticancer in gram amounts.[2]- Dr. David Miller
The theoretical iodine lethal LD50 for humans ie 1/10th of rodent dose is about 2 gm / kg, eg 6gm for a newborn baby, 140gm for an adult… a bottle of 20ml 2% Lugols in water contains 400mg, a 100ml bottle of 15% in water contains 15gm iodine(ie a 20ml bottle 3g) ie a harmless dose except corrosive if swallowed neat,.

Hence retailers if at all dispense Lugols 2%; we dont lightly prescribe/dispense 15% Lugols except for topical massage. And for cancer and we stick to 20ml dropper bottles.
not even Dischem and Clicks at Cavendish stock Lugols- only 2% iodine tinct IN ALCOHOL ie strictly for burning scratches… so no retailer should sell 100ml of any Lugols prep, only 20ml 2% Lugols, as is enforced in USA. It is indeed apparently regulated in the same way here., ‘tho’ the SA Medicines formulary doesnt mention that (recommends it only preop for eg thyroid storm), nor the multidisease benefits of Lugols including on the brain, wounds, infections, cardiac, vascular, cancer lungs etc;

nor the usual DETOXIFICATION REACTIONS as heavy metals are mobilized, for which (like eg metformin) the Lugol’s dose must be started low and titrated to tolerance with lots of fluids including magnesium, seasalt, selenium , vits B. eg Brief symptoms from heavy metal detox include “headaches, agitation, palpitations, nervousness, the jitters or irritated thyroid symptoms; pimples; skin rashes; fatigue, muscle aches, fever, diarrhea, worsen sinus/asthma, and brain fog. “. http://nourishingplot.com/2014/08/30/detoxing-fluoride-bromine-and-chlorine-naturally/ , http://www.iodine-resource.com/lugols-iodine.html ,   http://www.tiredthyroid.com/blog/2013/07/15/iodine-protocol-asthma-hives-sulfite-sensitivities/ and http://drsircus.com/medicine/iodine/iodine-and-detoxification. If these heavy metal detox reactions occur, stop the Lugols a few days, increase the detox remedies, then resume Lugols at a lower dose that you dont react to.
Threads   indicate that detox problems go away once iodine dose exceeds 50mg/d- especially if taken with a multisupp incl vit C, magnes , BCo, & selenium; and plenty of seasalt in water. (the only one of these not in a multisupplement AntiAging blend is salt).

In perspectivethe thyroid holds 50 milligrams of iodine, the breasts hold 200 milligrams, the skin holds 400 milligrams of iodine, and the whole body holds 2,000 milligrams, and possibly much more. Iodine is found and used in every hormonal receptor in the body. in 1911, 900 milligrams 0.9gm/day!) were considered usual and safe dosage. At 6 grams 6,000 milligrams/day!), iodine has been used to cure syphilis, skin lesions, and chronic lung disease. Iodine makes us smarter, helps with mental functioning. Low iodine is associated with low IQ’s with a difference of up to 13.5 points in children; but iodine deficiency is also associated with mental functioning in adults, because iodine not only chelates lead, but, according to Dr. Jorge Flechas, iodine prevents lead from lodging in the body in the first place. Low thyroid function decreases brain circulation, which slows intellectual function. low thyroid function is associated with cognitive impairment, memory loss, depression, slowness of mind, anxiety, suicidal tendencies, and a variety of psychiatric disorders. Bleichrod’s meta-analysis of 17 studies showed iodine sufficiency increases IQ by 13.5 points in children. Iodine prevents heart disease. Iodine is needed with the use of cordless phones, cell phones and now smart meters to prevent hypothyroidism. Iodine decreases insulin needs in diabetics.

IODINE ALLERGY? The risk of iodine allergy is quite low – Drs. Abraham and Brownstein were only able to identify 3 of 4,000 people who had a negative response to the iodine. People do not become allergic to iodine per se, but people react to the displacement of bound heavy metals; and can become allergic to protein-bound iodine as is found in shellfish or to the binding agents, excipients, fillers, preservatives and/or synthetics (rather than the bioavailable form of iodine itself) commonly found in tablets, capsules, and even liquids. Actually, iodine can help eliminate food allergies according to Dr. Derry.
But dont take Lugols at the same time as vit C, which neutralizes the antimicrobial effects of Lugols. so take them at opposite ends of the day.

and because iodine attacks only pathogens and abnormal cells, not our good probiotic biome or healthy cells, it has none of the risks of pesticides , antibiotics, antivirals, radiotherapy, chemotherapy etc.

RESEARCH ON LUGOL’S IODINE?
despite Dr Jean Lugol having published his landmark 1829 work on his iodine complex  ie ~185 years ago, there is predictably little research on it published on Pubmed, for the obvious reason that Big Pharma and the Disease Industry and governments wont fund research on such a cheap cure, which would greatly increase survival, but in the short term reduce illness and thus need for health industry workers, hospital beds, pharmacies and new drugs.
There are apparently only three clinically relevant LUGOL’s papers listed on Pubmed ie in the past 50 years:-

from India 2012 Consul ea – confirming that painting the cervix with Lugols (the Schiller test ) and vinegar is as effective as Pap smear for screening; thus combined, the two simple cancer diagnostic paints make up for Lugols iodine for cervix cancer being only about 85% sensitive and specific ie not as reliable alone as a costly lab Pap smear…
Greece 2007 Theodoropoulou ea  confirming that preoperative Lugol’s iodine 80mg/d for 15 days in euthyroid people was accompanied by increased intrathyroid total iodine but no changes in intrathyroid hormone HI or demonstrable increases of serum T4 and T3 were observed. It is hypothesized that the maintenance of normal intrathyroidal HI is the result of the combined inhibitory effect of iodine on thyroid hormone synthesis and on the release of T4 and T3 from the thyroid.
and
Italy 1986 Marani ea  –Iodine is therapeutic in various pathologies where immunity plays a dominant role, eg it facilitates cure in tuberculosis, lepromatous, syphilitic and mycotic incl sporotrichosis lesions . This effect does not depend on iodine’s action on the micro-organism responsible, but on host immune boosting. . Iodine may also be used in Panniculitis, in erythema nodosum, in nodular vasculitis, erythema multiforme etc. . To establish relationship between dietary iodine and immune response, 607 infants in an area of endemic goitre were studied: 215 were given Lugol solution (2 drops- presumably 20mg? a week for about 8 months ; and 392 not. Immune response was assessed by the skin test tetanus toxoid (in the U.S. 80% of paediatric cases aged 2-10 years old were positive). A significant difference was noted in the average diameter of the infiltrations after the tetanus toxoid skin test in the two groups considered (P less than 0.001). The results indicate that an adequate iodine intake is necessary for normal retarded immune response – a fact that the disease industry and Big Pharma blatantly ignore. . . (Iodine does not have the adverse effect of antibiotics on our gut biome, or causing antibiotic-resistant pathogens)

But there are dozens of scientific Lugol’s studies not referenced by Pubmed:

The End of Antibiotics and the Rise of Iodine as an Effective Alternative 2008 Mark Sircus

Iodine and viral infection?
David Derry, MD, PhD Thyroid Science 2009 Iodine: the Forgotten Weapon Against Influenza Viruses

Mamo & Naissides International Journal of Infectious Diseases (2005) from Australia show Iodine Could be effective in the treatment of human immunodeficiency virus and AIDS-associated opportunistic infections. as it is in rodents and cats .

Inactivation of human immunodeficiency virus by iodine-releasing products Harbison & Hammer Boston, Massachusetts 1989  showed that “povidine-iodine completely inactivated HIV at concentrations of greater than or equal to 0.5% ie is highly effective at killing HIV.
Betadine is simply “a stable complex of povidone and elemental iodine, contains 9.0% to 12.0% available iodine ie 90-120mg/ml .. Free iodine slowly liberated from the povidone-iodine PVPI solution kills microbe (but not healthy mammalian) cells through iodination of lipids and oxidation of cytoplasmic and membrane compounds, thus exhibits a broad range of microbicidal activity against bacteria fungi protozoa and viruses. Slow release of iodine from the PVPI complex in solution minimizes iodine toxicity towards mammal cells.” This compares exactly with a similar iodine complex  15% Lugols which contains about 10% ie 100mg iodine /ml water .. at far lower cost than but identical safety and efficacy to the patented Betadine – a modern designer marketable patented crib of Lugol’s .. …

see also
http://jeffreydachmd.com/wp-content/uploads/2014/03/The-Guide-to-Supplementing-with-Iodine-Stephanie-Burst-ND.pd

and

Lugols for animal thyrotoxicosis

and IODINE, A CRITICAL NUTRIENT 2014 http://drlwilson.com/Articles/IODINE.htm

and

Iodine: Its Role In Health and Disease: New Exciting Concepts Michael B. Schachter, M.D. 2007:   Guy Abraham MD, former professor of obsts gyne & endocrinology at UCLA School of Medicine, has written papers about iodine that drastically changed my thinking about its role in health and the prevention and treatment of disease. I had been impressed by Dr. Abraham’s previous work, which showed that vitamin B6 and magnesium could be very helpful to women with premenstrual syndrome (PMS) and was eager to learn what he had to say about iodine. Through a series of articles termed “The Iodine Project,” Dr. Abraham proposed that the optimal daily dose of iodine for a WELL person is approximately 12.5 mg, which is 100 times the RDA of 0.125 mg, ie that the current prevailing medical opinion that more than 2 mg a day of iodine is toxic is wrong. He traces the source of this major blunder to a scientific experiment on rats that was published in 1948 by Drs. Wolff and Chaikoff, which erroneously concluded that iodine inhibits the thyroid gland at doses of about 20 times the recommended daily allowance (RDA) for iodine. This conclusion was later generalized to humans and can be found in medical textbooks, including endocrinology and nutrition textbooks. Guy Abraham wrote in 2005: In hypertension, iodine sufficiency resulted in normalization of blood pressure without medications; as reported by other physicians using this program. Best results were achieved when orthoiodosupplementation was combined with a complete nutritional program emphasizing magnesium instead of calcium. Obesity increases the requirement for iodine and up to 100 mg elemental iodine/day may be required to achieve and maintain sufficiency. Increased demand for iodine occurs with excessive amounts of goitrogens from the diet and lifestyle. eg, smoking increases serum thiocyanate levels, interfering with the sodium/iodide supporter function. Low thyroid iodine is associated with thyroid hyperplasia and cancer. Could thyroid hormones cause the same iodine depletion in breast tissue? The prevalence of breast cancer is higher in women on thyroid hormones. Medical iodophobia resulted in removal of iodate from bread 20 years ago, replacing it with the goitrogen bromate- which associated with increased obesity, diabetes, and hypertension, thyroid and breast cancer. Recent reports show association between low iodine intake in women during pregnancy and attention deficit and hyperactivity disorder (ADHD) in their offspring. The most plausible explanation is a decreased sensitivity of the nuclear thyroid hormone receptor to thyroid hormones. We previously reported evidence for improved receptor response to thyroid hormones following iodosupplementation. Therefore, iodine is not only necessary for the synthesis of thyroid hormones but also for their effect on target cells. This effect is probably due to iodination of the thyroid hormone receptor. The essential element iodine, which is the inorganic, non-radioactive forms, deserves more attention from researchers and clinicians. It maybe the missing link in patients currently resistant to conventional hormonal therapy.
and see
http://www.earthclinic.com/remedies/lugols-iodine-supplements2.html
re adding enough selenium, chromium, vit C, Magnesium, Vitamin B2/3
and

Until 2007, in the United States, Lugol’s solution was unregulated and available over the counter as a general reagent, an antiseptic, a preservative,[11] or as a medicament for human or veterinary application .

However, effective August 1, 2007, the DEA now regulates Lugol’s solution (and, in fact, all iodine solutions containing greater than 2.2% iodine) as a List I precursor because it may potentially be used in the illicit production of methamphetamine.[12] However, transactions of up to one fluid ounce (30 ml) of Lugol’s solution are exempt from this regulation. When buying Lugol’s Solution on places like Amazon, most sellers fail to indicate the DEA tracking requirement. On the other hand Lugol’s Iodine solution is available over the counter in Canada and Mexico.
Toxicity Because it contains free iodine, Lugol’s solution at 2% or 5% concentration without dilution is irritating and destructive to mucosa, such as the lining of the esophagus and stomach.
Doses of 10 mL of 5% solution have been reported to cause gastric lesions when used in endoscopy.[13] The LD50 for Iodine is 14,000 mg/kg [Rat] and 22,000 mg/kg [Mouse].[14]
Most guidelines accept that anything with an LD50 >2 g/kg (-5 g/kg in some countries) can be classed as having a low acute toxicity[citation needed] which classifies Iodine as having low toxicity. Potassium Iodide is not considered hazardous.[15
http://jeffreydachmd.com/breast-cancer-prevention-with-iodine/

Iodine Dosages
Treatment of Influenza and other Diseases iodine-dosages 2009 “After testing over 500 patients, I found that 94.7% of my patients are deficient in inorganic iodine. Dr. David Brownstein In this chapter I will present different views and practices from present as well as from the long past when iodine was vastly more popular as a medicine than it is today. For whatever irrational reason, doctors and patients fear iodine thus en mass do not use to its fullest potential.
Humans tolerate large doses of iodine but the ultra high doses that were used many decades ago are not required to get the most out of iodine therapy. Just a little goes a long way, as the governmental iodized salt programs showed but this dosage level was only effective for Goiter and its avoidance. It actually takes very little iodine to prevent this disease but no one ever said that was the only purpose and need for iodine in the body. Today people are more deficient then ever before because our need for iodine has increased in direct proportion to our toxic burdens especially of other competing halogens. Read on at http://drsircus.com/medicine/iodine/iodine-dosages
Pps
see lugols_dosage_chart.  . But for obvious reasons stick to 2% till you know you tolerate and need much stronger drops.

23 MARCH 2015: THE CRUCIAL ROLE OF ANABOLIC PROHORMONES – MELATONIN, VITAMIN C AND steroids- PROGESTERONE, SUNSHINE and SOLTRIOL=D3 – AS HRT IN REDUCING ALL MAJOR DISEASE. Salute Dr Walter Stumpf.

 REVERSE THE POST-WW2  GLOBAL SHIFT FROM  HEALTHY ANABOLIC  OUTDOOR (VIT D AND ANDROGEN ie DIET CHOLESTEROL– FAT  DOMINANCE) EXERCISE ABUNDANCE TO THE RECENT LETHAL CARBOHYDRATE-SUGAR- ESTROGENICS- CORTISOL INDOOR TV DOMINANCE AND FAMINE.

update 22 MARCH 2015: VIGOROUS DOSE VITAMIN D UPDATE

NEW STUDIES:

More Canadian and USA studies confirm that vigorous vitamin D  need  applies especially to those living in far northern USA-Canada  and  EurAsia etc;    but also to all of us  globally who spend little time well exposed to the sun- especially the more driven  who both live/work indoors and cover even our limbs and heads outdoors as eg more ‘observant’ adults of many faiths do. As a new Creighton Univ study shows, we are at minimal risk of kidney stones on vigorous supplement vit D3 provided we balance it with enough water and magnesium supplement,

This is why in this age of increasing stress, longevity, epidemics, and pollution of both environment and the food and medicine chains, we have for a couple of years now   been advocating   and taking  vitamin D3  – on a  century of voluminous evidence (62500 papers on Pubmed alone) since 1914  from top nutritional scientists like Drs Jack Drummond, Linus Pauling, Walter Stumpf, Chris Nordin, Chris Gallagher, Rob Heaney, John Cannell, Bill Grant,  Mike Holick, Cedric Garland,  ea  – at least  vit D3  50 000iu a week (~7000iu/d)  ie a million units every 20 weeks;   retail costing  R30 ie R6pm  for us aging frailer types (half that dose ie 50 000iu twice a month @R3/month for the poor/ well or small kids).. at R12/US$, that costs all of $3 to $6 a year.

On about 9000iu vit D3 average supplement/day, my total 25OH vit D bloodlevel runs about 90-100 ng/ml ie 220-250 nmol/l.  so only 400- 1000iu vit D /day will boost the vit D  bloodlevel and benefits little if not  trivially.

But  vigorous D3 dose must be buffered by vit K2  about >100mcg/day , magnesium about 400mg/d, and the usual basket of other ~50 vits, minerals and other natural supplements, to protect us from kidney and arterial calcification etc. We have previously  highlighted trials eg from Pakistan showing that even 600 000iu vit D3 a month ie ~20 000iu/day safely and greatly improves recovery and healing from severe PTB+- AIDS in eg frail Pakistatin patients; whereas overdose of 90year old patients with a  2million iu  vit D3 dose (in Netherlands)  produced no toxicity. Hence we load sick patients with (an antibiotic-like )  200 000 to 400 000iu dose before continuing weekly or fortnightly maintenance- with the sickest fattest getting the highest dose, and infants scaled down accordingly (after a loading dose of eg 25 000iu)   to eg 1000-2000iu/d,  or 50000iu 1/2 scoop ie 25000iu every 2 weeks- the older extrapolation (as for adults)  of ~100iu/kg/day.

For the concerned vegan, vitamin D is vegetarian:  supplement of vit D2 is extracted from yeast or mushrooms;  vit D3 by UV irradiation of cholesterol from lanolin. Like all life, since vitamin D soltriol  is a sun-induced sterol oil product (in this case of cholesterol which in turn is built via  vitamin C ascorbic acid from plant glucose-sugar),   vitamin D does not contain or be made from animal flesh ie animal protein nitrogen  any more than does fish oil.

          Vitamin D may keep low-grade  cancer from becoming aggressive:
http://www.sciencedaily.com/releases/2015/03/150322080155.htm    Taking vitamin D supplements could slow or even reverse the progression of less aggressive, or low-grade, prostate tumors without the need for surgery or radiation, scientists say. Taking vigorous vits C & D does this for all cancers, all disease.

 

               VITAMIN D DEFICIENCY IS ASSOCIATED WITH INSULIN RESISTANCE INDEPENDENT OF INTRACELLULAR CALCIUM, DIETARY CALCIUM AND SERUM LEVELS OF PARATHORMONE, CALCITRIOL AND CALCIUM IN PREMENOPAUSAL WOMEN.   Da Silva Ferreira T,  Sanjuliani AF ea .   Nutr Hosp. 2015 Apr 1;31(n04):1491-1498.

25-Hydroxyvitamin D in the range of 20 to 100 ng/mL doesnt increase  kidney stones.    Am J Public Health. 2014 Sep;104(9):1783-7  Garland, Heaney ea Creighton Univ, USA   Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones.We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3).           We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.       

A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D. Letter to Veugelers, P.J. and Ekwaru, J.P.,           Nutrients. 2015 Mar 10;7(3):1688-90. doi: 10.3390/nu7031688.  Nutrients 2014, 6, 4472-4475; doi:10.3390/nu6104472.   Heaney , Garland ea.    1Creighton University & University of California, San Diego,   GrassrootsHealth, Encinitas, CA .   Recently Veugelers and Ekwaru published data indicating that, in its dietary reference intakes for calcium and vitamin D, the Institute of Medicine (IOM) had made a serious calculation underestimation  [2]. Using the same data set as had the IOM panel, these investigators showed that the Recommended Dietary Allowance (RDA) for vitamin D had been underestimated by an order of magnitude. Veugelers and Ekwaru, using the IOM’s data, calculated an RDA of 8895 IU per day. They noted that there was some uncertainty in that estimate, inasmuch as this value required an extrapolation from the available data, which did not include individuals receiving daily vitamin D inputs above 2400 IU/day.[…].

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210929/        Nutrients. 2014 Oct; 6(10): 4472–4475.Statistical Error in the Estimation of  Recommended Dietary Allowance for VitaminD     Paul J. Veugelers* and John Paul Ekwaru   University of Alberta, Canada

The Institute of Medicine (IOM) issues dietary recommendations on the request of the U.S. and Canadian governments. One of these recommendations is the Recommended Dietary Allowance (RDA). The RDA is the nutrient intake considered to be sufficient to meet the requirements of 97.5% of healthy individuals [1]. The RDA for vitamin D is 600 IU per day for individuals 1 to 70 years of age and is assumed to achieve serum 25-hydroxyvitamin D (25(OH)D) levels of 50 nmol/L or more in 97.5% of healthy individuals [1]. Serum 25(OH)D is the established proxy for vitamin D status and levels of 50 nmol/L or more have been shown to benefit bone health and to prevent disease and injury [1].

The IOM based their RDA for vitamin D on an aggregation of 10 supplementation studies that were carried out during winter months and at locations with latitudes above the 50th parallel north to minimize the influence of cutaneous vitamin D synthesis [2,3,4,5,6,7,8,9,10,11]. As several of these 10 studies examined more than one supplementation dose, collectively they provided 32 study averages of serum 25(OH)D levels. These are replicated as the green diamonds in Figure 1. The IOM regressed the 32 study averages against vitamin D intake to yield the dose response relationship of vitamin D intake and serum 25(OH)D (green solid line in Figure 1). The IOM further calculated the lower and upper 95% confidence prediction interval based on the 32 study averages and the standard deviation of these 32 study averages (green dashed lines in Figure 1). On the basis of this, the IOM estimated that 600 IU of vitamin D would achieve an average 25(OH)D level of 63 nmol/L and a lower 95% confidence prediction limit (2.5 percentile) of 56 nmol/L. The latter value was rounded downwards to 50 nmol/L to accommodate uncertainty in the estimation [1]. This data point (600 IU vitamin D, 50 nmol/L) is the basis for the current RDA and for the IOM’s conclusion that an intake of 600 IU of vitamin D per day will achieve serum 25(OH)D levels of 50 nmol/L or more in 97.5% of individuals.

The correct interpretation of the lower prediction limit is that 97.5% of study averages are predicted to have values exceeding this limit. This is essentially different from the IOM’s conclusion that 97.5% of individuals will have values exceeding the lower prediction limit. To illustrate the difference between the former and latter interpretation, we estimated how much vitamin D is needed to achieve that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. For this purpose we reviewed each of the 10 studies used by the IOM. Eight studies reported both the average and standard deviation [2,5,6,7,8,9,10,11]. These eight studies had examined a total of 23 supplementation doses [2,5,6,7,8,9,10,11]. For each of these 23 study averages we calculated the 2.5th percentile by subtracting 2 standard deviations from the average (depicted by yellow dots in Figure 2). Next, we regressed these 23 values against vitamin D intake to yield the lower prediction limit (red line in Figure 2). This regression line revealed that 600 IU of vitamin D per day achieves that 97.5% of individuals will have serum 25(OH)D values above 26.8 nmol/L rather than above 50 nmol/L which is currently assumed. It also estimated that 8895 IU of vitamin D per day may be needed to accomplish that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. As this dose is far beyond the range of studied doses, caution is warranted when interpreting this estimate. Regardless, the very high estimate illustrates that the dose is well in excess of the current RDA of 600 IU per day and the tolerable upper intake of 4000 IU per day [1].

The public health and clinical implications of the miscalculated RDA for vitamin D are serious. With the current recommendation of 600 IU, bone health objectives and disease and injury prevention targets will not be met. This became apparent in two studies conducted in Canada where, because of the Northern latitude, cutaneous vitamin D synthesis is limited and where diets contribute an estimated 232 IU of vitamin D per day [12]. One study estimated that despite Vitamin D supplementation with 400 IU or more (including dietary intake that is a total intake of 632 IU or more) 10% of participants had values of less than 50 nmol/L [13]. The second study reported serum 25(OH)D levels of less than 50 nmol/L for 15% of participants who reported supplementation with vitamin D [14]. If the RDA had been adequate, these percentages should not have exceeded 2.5%. Herewith these studies show that the current public health target is not being met.              We recommend that the RDA for vitamin D be reconsidered to allow for appropriate public health and clinical decision-making.

update 1 March 2015Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? 

                   Since its founding, the  USPSTF has sought to provide a firm evidential base for early detection strategies, evaluating such screening methods as mammography and prostate-specific antigen testing. Although it has also evaluated a few interventions, its predominant focus has been testing for markers that identify persons at risk who are likely to benefit from preventive action. Only recently has the USPSTF ventured into the field—or perhaps the minefield—of nutrition, a territory distant from screening tests and risk assessment, with different and unfamiliar landmarks.

The USPSTF presents its conclusions on testing for vitamin D deficiency (1), reporting that it was unable to find evidence for or against such testing. It noted that one of the likely reasons was the absence of a scientific consensus on both the level of vitamin D status that should be judged “deficient” and what the measurable manifestations of deficiency might be. These are also issues for many other nutrients, such as folate, ascorbate, calcium, and protein. Vitamin D may have seemed to offer a way out of this confusion because serum 25-hydroxyvitamin D [25-(OH)D] concentration is generally recognized as one of the best indices of status for any of a broad array of nutrients. Also, it is now readily measurable and widely utilized.

One of the reasons its promise has not been realized is that most studies of vitamin D efficacy have used a disease-avoidance model, which is the standard approach used by the Institute of Medicine (IOM) for most nutrients (2). Furthermore, disease prevention is the explicit focus of the USPSTF. Nevertheless, the IOM and USPSTF approaches effectively equate health with the absence of disease, an equivalence that nutritionists have long rejected. Instead, nutritionists focus on full nutrient repletion when possible. The inevitable gap between disease prevention and nutrient repletion is still largely unexplored territory. For many nutrients, it can be surprisingly wide, as suggested in this case by studies of the intake required to provide vitamin D in human breast milk in quantities sufficient to meet the needs of infants (3). The IOM’s adult requirement for vitamin D is 600 IU/d (4), which is judged to be sufficient to protect against osteoporotic fracture. In contrast, quantitative and empirical evidence indicates that vitamin D intake from breastfeeding needs to be approximately 6000 IU/d (3, 5). Although high compared with the adult recommendation, such an intake almost exactly reproduces the measured vitamin D status of contemporary Africans leading ancestral lifestyles (6). Such populations provide perhaps our best window on vitamin D levels prevailing during the millennia over which human physiology was adapted to its environment by natural selection.

Whatever the actual requirement or 25-(OH)D cutoff may be, there is another likely reason that the evidence is unclear. The USPSTF drew from systematic reviews and meta-analyses of studies of vitamin D effects, such as the one accompanying the current report (7). In general, the criteria for including studies in such reviews are methodological rather than biological. Of the 6 published biological criteria (8) for including published reports in meta-analyses, the review published in this issue met only 2 (comparable basal status and same chemical form), and several of its component studies met none. Including studies that could never have been informative in the first place (especially when they are large) inevitably biases any review toward the null.

What seems not to have been widely appreciated is that vitamin D exhibits flat response regions at both low and high values of vitamin D status, with a sharp rise in the approximate center of the physiologic range of 25-(OH)D values (8). Studies like the WHI (Women’s Health Initiative), which enrolled women with low vitamin D status values and used a vitamin D dose insufficient to move them into the response range, provide little useful information about vitamin D efficacy. Yet, precisely such studies were included in the review by LeBlanc and colleagues (7). This is not to criticize the WHI, which was designed more than 20 years ago (before vitamin D pharmacology was well-understood), but it is to criticize contemporary reviews and meta-analyses that fail to take advantage of newer information or to use critical biological criteria (8) for selection of studies for analysis of biological effects.

In addition, a disease-avoidance approach becomes problematic for micronutrients in general (and vitamin D in particular) when one understands that micronutrients do not actually cause any of the effects simplistically attributed to them. Although necessary for cell response, such micronutrients by themselves do not initiate or cause the response concerned. For example, vitamin D is a component of the biochemical apparatus that opens the genome to allow access to DNA information needed for a particular cell or tissue response. In terms of cell function, this dependence means that when supplies of the micronutrient are inadequate, cellular response is blunted. This is dysfunction, but not clinically manifest disease. Such dysfunction may indeed lead ultimately to various diseases, but disease prevention remains a dull tool for discerning the defect, and a disease-prevention approach clearly does not measure whether the organism has enough of the nutrient to enable appropriate physiologic responses, such as lactation.

Finally, and aside from the USPSTF’s findings, one must ask whether treating without first testing is sound practice. Certainly, it would be rational to do so if the condition being treated is prevalent and the treatment is safe and inexpensive. That is the case with another micronutrient, iodine, and the iodination of salt. However, the current situation is different because consuming sufficient iodine generally does not require conscious adherence to a particular regimen, whereas taking vitamin D does. Usually, testing improves patient adherence because it provides patient-specific, personally applicable information. General assurances that one probably needs extra vitamin D are not as compelling a motivator as knowing one’s number. Thus, whether the practitioner adheres to the widely divergent guidelines of the IOM (4), the Endocrine Society (9), or the American Geriatrics Society (10), measuring vitamin D status seems to be warranted, not so much to diagnose deficiency but to determine patient status relative to the selected guideline.

update  20 Jan 2015 a new USA study Ng et al. Vitamin D status and survival of metastatic colorectal cancer patients  at the 2015 Gastrointestinal Cancers Symposium found that patients with metastatic colorectal cancer with higher vitamin D levels survived a third longer than those with lower levels – 32.6 months compared to 24.5.

update 12 Jan 2015        As the poet Juvenal (died 130AD) wrote: Mens sana in sano corporis– a healthy mind in a healthy body. Its great how the prime  antistress homeostatic hormones- a pinch of natural  melatonin at night, with ENOUGH  daytime  anabolic soltriol calciferol vitamin D3, restores good sleep, orchestrate homeostasis of all other hormones especially of  the crucial adrenals and gonadals and thus thyroid hormones. ..

Sleep. 2015 Jan 12. Massa ea, Harvard.  Low Vitamin D and Poor Sleep in Older Community – Dwelling Men   :  vitamin D3 is important for sleep duration and quality. 16% of this study population had very low levels of vitamin D (< 20ng/mL 25(OH)D). Lower serum vitamin D levels linked with short (< 5 h) sleep duration,doubled the odds ratio [OR] 2.15 for the highest (≥ 40ng/mL) versus lowest (< 20 ng/mL) quartile of 25(OH)D,; Ptrend = 0.004) and lowering  sleep efficiency. And low vitamin D is a major associate of  major depressionJózefowicz ea Univ Lodz, Poland 2014..

Thanks to global human (mostly male)  greed enslaving the masses the past 7 millennia ie since at least Sumerian times, we have moved rapidly in our lifetime post WW2  from  global homeostatic (food, commodities) plenty to a world of dyshomeostasis- cacostasis stress chaos – in most countries  from Afghanistan to Zimbabwe. Just a few years ago South Africa led Africa in productivity and skills, and still has the biggest reserves of riches- minerals-  in the world; with boundless natural power (sun, sea) and manpower to drive industry and food production. But in  20 years post apartheid, the ruling ANC under Mbeki and the Zumas  has with  selfserving treasonous greed  brought South Africa to its knees with cacostasis, destruction of continuous water, electricity ; school education,  organized and quality  food provision ie agriculture, social security, the post office, the national airline, health services, Home Affairs and pensions). Now there are  rapidly increasing functionally illiterate or  old  16 million on state grants supported by the 6 million capable of meaningfully working and paying taxes if they dont emigrate. And state grants have now been extended to age 23yrs because state school leavers are practically unskilled for  anything but being labourers. .

The national powergrid and oil reserves have been degraded so that total indefinite blackouts are now imminent, never mind weekly “outages” crippling work-  the economy – and destroying appliances. Never mind increasingly pandemic influenza and HIV, antibiotic resistance puts us in the post-antibiotic era in this age of deadly resistant TB and STDs, with  reckless immoral  leaders  like Zuma and Vavi leading the mob in extramarital sex and provoked violence. .

So as never before, everyone from conception to grave needs realistic regular vitamin D3 supplement at about R3 a month to bolster mental and physical health of children, mothers and the working , never mind the ailing aging, to reduce illhealth costs. . Stress- through raised thyroid, sympathetic and cortisol levels and depressed gastrointestinal, cardiovascular, musculoskeletal and immune control, grossly disrupts homeostasis and shifts victims into catabolic estrogen-dominance , insulin resistance mode- which only the hormone supplements  D3 and melatonin, and the essential vitamins and minerals  if not  risk-laden androgenics can try to balance,

George Chrousos ea.  University Athens, Greece since Nat Rev Endocrinol. 2009 and now   Neuroimmunomodulation. 2015 write: Stress – glucocorticoids – and disorders of the stress system- cacostasis vs homeostasis.      All organisms must maintain complex dynamic equilibrium-  homeostasis- which is constantly challenged by internal or external adverse forces – stressors. Stress occurs when homeostasis is threatened or perceived; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by cacostasis – dyshomeostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic -pituitary-adrenal (HPA) axis and hormones arginine vasopressin, corticotropin-releasing hormone  and autonomic norepinephrine centers in the brainstem.  Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions.. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome.

VITAMIN D ECONOMY & GOAL OF SCREENING: Heaney and Armas, Creighton University  QUANTIFYING THE VITAMIN D ECONOMY: Nutrition Reviews  Dec 2014; and Screening for Vitamin D Deficiency: Is the Goal Disease Prevention or Full Nutrient Repletion? Ann Intern Med. Nov 2014   write:  sunlight and food  contribute only modestly  to the relevant optimal total serum vit D and 25OHvit D levels: unsupplemented individuals who average blood 25OHvit D of 20 ng/mL are receiving about 2,000 IU/day from nonsupplement sources (i.e food and sun) – whites double the amount  compared to dark blacks  from skin. . It has been established for 30 years that in fair-skinned individuals, a single exposure to UV-B at one whole-body minimum erythema dose can produce a rise in serum 25D that is equivalent to an oral dose of D3 in the range of 10,000 to 25,000 IU, ie by as little as 10–15 min of whole-body exposure at mid-day in mid-summer in a pale-skinned individual. Pale-skinned northern Europeans show a rise in serum 25D of 9 ng/mL (23 nmol/L) at the end of 4 weeks of exposure. By contrast, in dark-skinned individuals, the rise was  half  ie 4.5 ng/mL . Meat  eaters exhibit higher human 25D status . Input gaps left after estimating solar inputs (on the order of 1,300–1,600 IU/day, as noted above) could well be filled by hitherto unrecognized food sources. For example, Taylor et al.21 report a combined (D3 plus 25D) content of 112 IU vitamin D equivalents for 200 g of beef tenderloin or  an egg, associated with 2 ng/mL greater level of serum 25D.      The Grassroots Health project collects data on supplement type and has found no difference in the 25D concentration achieved with either 5,000 or 10,000 IU daily doses, irrespective of whether the D3 was delivered via a gel cap in oil or as dry powder in a tablet (unpublished data; S. McDonnell, personal communication). vitamin D could be absorbed from orange juice. On the other hand, fat malabsorption syndromes are known to lead to vitamin D deficiency, and the mechanism is generally considered to be a specific impairment in the absorption of fat-soluble vitamin D. However, poor absorption may reflect not so much mucosal dysfunction, as simple sweeping of any fat-soluble compound out of the gut, dissolved in the unabsorbed fat. Dawson-Hughes et al.,35 using pharmacokinetic methods in individuals with normal absorptive function, reported equal absorbability for D3 under fasting and high-fat meal conditions, with slightly better absorption from a low-fat meal. Mulligan and Licata,36 in an observational study of 17 poor responders to oral D preparations, reported greater absorption from a large meal containing fat than from intake on an empty stomach. However, the limited data, taken as a whole, suggest that the effects of dosage form or vehicle are probably small.

Finally, the issue of D2 versus D3 needs brief mention. Formerly considered controversial, there now seems to be a growing consensus37 that, for equimolar quantities, orally administered D3 raises serum 25D by about twice as much as D2.38–42 This has been shown for bolus doses, short-term continuous administration (12 weeks), and long-term continuous administration (12 months).

Intestinal absorption of D3 is mainly from the jejunum and ileum. Absorbed vitamin D can be found in both the portal venous blood and the lymph that drains the small intestine.  The lymphatic pathway may have particular physiological significance for orally acquired vitamin D, since it avoids a first pass of the absorbed vitamin D through the liver. This suggests that the quantitative relationship between vitamin D and 25D will be the same regardless of whether vitamin D enters from the skin or the gut.

Diffusion from the skin into the blood is slow, with a half-time of about 3 days.7 This half-time means that when regular sun exposure is the principal source of D3, serum D3 concentration will be essentially constant.

it is reasonably certain  that the concentration of vitamin D in fat tissue is substantially higher than the concentration in serum. – a given volume of fat tissue contains approximately 12 times as much vitamin D as the same volume of serum. However, a several-fold gradient is not surprising as D3 solubility in fat is effectively limitless, while DBP capacity, which is large, is finite.

Assuming a diffusional mechanism and a total body fat mass of 35% of body weight,  total body stores in an individual weighing 70 kg would range from 900 to 2,800 µg (37,000 to 113,700 IU). Using the calculations set forth in the prior section and applying them to an individual with a serum 25D level of 20 ng/mL, whose metabolic consumption would be ∼2,000 IU vitamin D/day, the total amount in the reservoir would provide enough of a reserve for 18–57 days at that same rate of utilization. At a serum 25D level of 40 ng/mL, that same reserve would support consumption for only 9–28 days. Neither estimate comes close to compensating for the “vitamin D winter” of most temperate latitudes. The smallness of this reserve explains why even outdoor summer workers who had high daytime skin exposure experienced reductions in 25D averaging approximately 20 ng/mL (50 nmol/L) by late winter. Of note, their 25D values had reached >50 ng/mL (125 nmol/L) by late summer, which is roughly the same as that reported for East Africans living ancestral lifestyles.48 This study indicates both that existing stores at the end of summer were not adequate to maintain the achieved summer level and that the late winter level (∼30 ng/mL) represented a utilization of approximately 3,000 IU/day.

Chemical partition
Extracellular 25(OH)D  The first step in the chemical conversion of D3 is 25-hydroxylation.Bikle et al.51 showed that skin cells contain all the requisite enzymatic apparatus to produce both 25D and 1,25D. However, it is doubtful that under ordinary circumstances, skin is a major source of the extracellular 25D measured in serum (D. Bikle, personal communication). Other sources remain to be identified.

The efficiency with which D3 is converted to 25D varies widely from individual to individual.  Various reasons can be put forth for these inter-individual differences that, though studied in somewhat less detail, have been reported by many investigators. One example is the variable methylation of the CYP2R1 gene and, hence, variable expression of the hepatic 25-hydroxylase.53 While there is currently no final answer, it is clear that differences in intestinal absorption of D3 could not explain the slow rise in participant B, relative to participant A. Moreover, the internal consistency in the shape of the respective curves virtually excludes methodological variability as a cause of the difference.

Extracellular 1,25(OH)2D  The second hydroxylation, which produces extracellular 1,25D, occurs predominantly in the proximal convoluted tubular cells of the kidney. While 25-hydroxylation is not highly regulated, the opposite is true for 1,25D, the synthesis of which is upregulated by parathyroid hormone and low serum inorganic phosphorus concentration and downregulated by fibroblast growth factor-23. Note that 1,25D is a principal regulator of intestinal absorption of calcium; during this process, it acts by upregulating expression of the calcium transport apparatus of the enterocyte. This is an endocrine effect as it is mediated through serum endocrine-like activity and exhibits a typical negative feedback control loop. Under usual conditions, 1,25D is necessary for regulation of calcium absorption. However, it is not the only factor involved in this process. It should also be noted that in the absence of other vitamin D metabolites, 1,25D by itself has been reported not to be sufficient to elevate intestinal calcium absorption.55,56

As would be expected for regulator molecules, the serum half-time of 1,25D is short (hours). Its concentration in serum is a reflection mainly of relative calcium need—being high in individuals on low-calcium diets or in those with calcium malabsorption and low in individuals with high calcium intakes. Also, 1,25D has long been recognized to be calcemic when used therapeutically. The mechanism is generally attributed to intestinal calcium absorption, but this cannot be a satisfactory explanation, as increased metabolic input alone (i.e., without considering output) is rarely sufficient to elevate the serum concentration of any metabolite. Moreover, 1,25D and its analogs do not elevate calcium absorption in patients with end-stage renal disease,57 a condition in which the calcemic effect of 1,25D is often readily apparent. While not adequately explored, there remains another possibility, i.e., an effect of 1,25D on bone-lining cells, where a fall in bone fluid pH to just below 7.0 is enough to solubilize bone mineral sufficiently to elevate serum calcium.58
Physical partition

The distinction between the endocrine and the autocrine pathways is one aspect of the physical partition between extracellular and intracellular processing of the vitamin. The prevailing assumption seems to be that most or all of the D3 entering the body is 25-hydroxylated and that the resulting 25D circulates in the blood, where it serves as the substrate for both renal and extrarenal 1 -α-hydroxylation, with the renal 1,25D product circulating in the blood like 25D and with the extrarenal 1,25D never being expressed in the only accessible body compartment, i.e., the blood.

As Hollis and Wagner59 have pointed out, D3 enters cells more readily than does 25D and, as noted above, there are several enzymes other than the hepatic CYP2R1 that are capable of 25-hydroxylation of D3.49,50 Hence, a physical partition of the vitamin D pathways prior to the 25-hydroxylation step has to be given serious consideration. That this is more than just a theoretical possibility is suggested by the fact, noted earlier, that oral 25D elevates serum 25D to a substantially greater extent than does oral D3.28–30 This was shown first by Barger-Lux et al.28 in a 10-week dosing study involving the two molecules. Figure 9 plots the 25D response to the two agents observed in a group of 54 healthy adults and shows a clear divergence of the dose response curves, with a greater than seven-fold difference in slopes. Cashman et al.,30 using a different design, found an approximate five-fold difference in response after 10 weeks of dosing, and Bischoff-Ferrari et al.,29 an approximate four-fold difference after 17 weeks of dosing.

Figure 9
Change in serum 25D plotted as a function of intake for varying oral doses of 25D and D3. Data from Barger-Lux et al.28
That there should be a greater rise in 25D when oral 25D is the source is, in a sense, trivial, as oral 25D is immediately reflected in the serum, while oral vitamin D must first be 25-hydroxylated, a process that, as described above, is necessarily slower, sometimes substantially so. Only a proper pharmacokinetic study that compares area-under-the-curve values for the two agents can fully quantify this difference. Such a study must either be long enough to allow the 25D plateau to be reached while on continuous dosing of D343 or, if using a bolus dose design, must follow the time course for the two agents for probably 4 months so as to allow full 25-hydroxylation of the administered D3 and full consumption of the administered 25D. No such data are currently available, and this aspect of the physical partition must remain speculative. Nevertheless, the issue is an important one, not just for the therapeutics of 25D but also for a full understanding of the vitamin D economy (see below).

The 25D half-time (as measured by Clements et al.60–62 using tracer-labeled 25D) presents certain puzzling features in its own right. A half-time of, say, 20 days (toward the lower end of the range found by Clements et al.) translates to a daily turnover of about 3.47% of the total mass of extracellular 25D. If the size of daily utilization is known, it is possible to calculate the size of the 25D mass from that fractional utilization rate. If all of the vitamin D input to the body is converted to extracellular 25D, then at a serum 25D concentration of 20 ng/mL (requiring, as shown above, a daily input of ∼50 µg), that 50-µg input is numerically equal to the daily turnover. So, total 25D mass would be 50/0.0347, or close to 1,500 µg. This figure is larger by an order of magnitude than that of the measurable total serum content of 25D, and the discrepancy becomes even larger at higher serum 25D concentrations or longer half-times. This seeming discrepancy has not been noted previously, with one potential reason being the computational difficulty of harmonizing biological units (IU), first with mass concentrations (µg/mL), then with SI units (nmol). However, if a substantial fraction of daily input of D3 is 25-hydroxylated intracellularly, after which it is immediately activated to 1,25D, then only the 25D in the extracellular compartment would be labeled by a tracer-based approach to kinetic analysis, and the calculated daily utilization of the circulating 25D would be lower and the corresponding 25D mass estimate would be closer to what is known from blood and soft tissue content. These calculations provide support for the suggestion of Hollis and Wagner59 that “parent compound D” has more functional significance than has usually been thought.

There is one quantitative aspect of the physical partition, whether occurring prior to or after the 25-hydroxylation step, which seems inescapable. Whether one takes as optimal a serum 25D concentration of 20 ng/mL or 40 ng/mL, the molar equivalent D3 inputs required to sustain either level are far higher than the moles of 1,25D required to support the calcium economy. As noted above, a serum 25D of 40 ng/mL requires approximately 4,000 IU/day, or 100 µg/day, and a serum 25D of 20 ng/mL requires approximately 2,000 IU/day, or 50 µg/day. By contrast, the calcium economy requires between 0.5 µg and 2.0 µg of 1,25D/day. (Higher doses, as noted above, produce hypercalcemia.) It follows that >90% of D3 utilization is occurring along the intracellular/autocrine pathway. If that is not the case, then most of the D3 input to the body is degraded metabolically and not used at all. The latter possibility seems quite improbable, particularly in view of the marginal or subadequate vitamin D status that seems nearly universal. Answering this question of the relative potency of oral D3 and 25D will illuminate the partition of D3 between the extracellular and intracellular pathways and will be an important step in unraveling the puzzle of the physical partition.

One instance in which the pre-25D intracellular pathway is operative is the transfer of vitamin D activity into human breast milk.59,63 25D does not transfer across the secretory mucosa of the mammary gland with sufficient efficiency to produce enough vitamin D activity in milk to nourish the infant, while D3 does. However, for this to occur, D3 must be present in the blood that bathes the mammary secretory apparatus. In earlier work, Hollis et al.63 showed that the concentration of vitamin D in human milk was about 28% of the concentration of D3 in maternal blood. In subsequent work (B. Hollis, personal communication), that figure was shown to be closer to 32%, and a recent study by Oberhelman et al.64 showed a transfer fraction that can be calculated to be about 44%. Based on recommendations of both the American Academy of Pediatrics and the Institute of Medicine for infant intake (400 IU vitamin D/day, which requires a milk concentration of about 520 IU/L, i.e., ∼34 nmol/L), these transfer fractions would require a maternal serum vitamin D concentration of about 30–40 ng/mL (78–120 nmol/L). (The corresponding 25D concentration would be >50 ng/mL [125 nmol/L]; see Figure 8.) Hollis and Wagner59 estimate that the total input of D3 needed to maintain a milk concentration sufficient to meet the infant’s needs for vitamin D was approximately 6,000 IU/day. The equivalence value derived above produces a needed input of approximately 6,000 IU/day, which is essentially identical to the empirical estimate of Hollis and Wagner.
Dosing schedules and serum D3 concentrations

Dosing frequency for oral vitamin D supplementation regimens will affect serum concentration of D3 in predictable and often very striking ways. This fact has been largely overlooked to date, as the serum concentration of D3 has been generally considered to be of no particular interest in its own right. The rationale for infrequent (or bolus) dosing is that it leads to better adherence and that an excess amount ingested today will be stored in fat for use tomorrow. However, this assumption overlooks the effect of infrequent dosing regimens on D3 blood concentrations.

Serum D3 has a half-time variously estimated to be in the range of 0.5–3.5 days, with most investigators favoring a value of about 1.0 days. In contrast, D3 produced in skin moves into the blood with a half-time of about 3 days. This means that when skin synthesis is the principal source of D3, serum D3 concentration will be essentially constant around the clock, as D3 input to the blood from the skin (though produced mainly at mid-day) is effectively constant. With oral ingestion, intestinal absorptive input of D3 occurs mainly during a 4-h period following ingestion. (In one study, a TMAX of as much as 12 h was reported.65 As this is well beyond the usual mouth-to-cecum transit time, the 12-h figure, if confirmed, would suggest appreciable colonic absorption, or small bowel mucosal retention, or a delay pool in the intestinal lymphatics.) In any case, assuming a 1.0-day half-time, serum D3 concentration will inevitably follow a sawtooth pattern, particularly if oral ingestion is the principal input. Figure 10 displays the patterns for purely cutaneous input and for daily, weekly, and biweekly oral administration. With a once-a-week schedule, as is evident from Figure 10, serum D3 concentrations are close to zero for several days each week and below the reference level for most of the interdose interval. Thus, in the practical order, a nursing woman who takes her total weekly dose of vitamin D once each week would produce milk with little or no D content for roughly 4 of the 7 days in each week. This irregular delivery will be even more pronounced with biweekly or less frequent dosing schedules.

Figure 10
Calculated time courses for serum D3 concentration for varying oral dosing intervals. The reference level is the serum concentration for continuous (as contrasted with intermittent) dosing. Each dosing scheme provides the same cumulative intake, according to one of the following regimens: once daily, or 7 times the daily intake once weekly, or 14 times the daily intake once every 2 weeks.
It should be stressed that Figure 10 illustrates the concept and is not a depiction of actually measured serum concentrations of D3. Under input conditions in excess of daily use, unused D3 will accumulate in fat, and its concentration there would be predicted to damp the oscillations of D3 concentration in serum to some extent.

An additional feature of interval dosing is the high D3 concentration peaks achieved in the days following each dose. The impact of such high D3 levels is unclear, although Vieth66 has pointed to the induction of the 24-hydroxylation pathway as a likely consequence, with a corresponding reduction in effective vitamin D activity. Further, as the binding capacity of DBP is approximately 4.7 µmol67 (or ∼78,000 IU/L), with true Stosstherapie, as in several recent studies,68,69 the DBP will be fully saturated by the ingested D3, resulting in displacement of both 1,25D and 25D off DBP and into circulation as free or unbound moieties for several days after dosing (i.e., until fat uptake lowers serum D3 sufficiently). This effect amounts to a transient vitamin D intoxication of uncertain physiological import. Unfortunately, there is essentially no published information about vitamin D concentrations in the immediate post-dosing period following large bolus doses. Whatever else may be said of Stosstherapie, it certainly is not physiological.
Factors influencing serum 25D concentration

Aside from the possible importance of D3 concentration as the substrate for autocrine activity of vitamin D, there is general agreement that serum 25D concentration is currently the principal indicator of vitamin D status.70 This is because extrarenal conversion of 25D to 1,25D operates at concentrations below the kM for the tissue 1 -α-hydroxylases; hence, serum 25D concentration limits the amount of 1,25D a tissue can synthesize when its cells are stimulated to produce a vitamin D-dependent response. While there is no consensus as to the optimal serum 25D concentration, there is also no disagreement about the importance of the substrate, regardless of which concentration may be deemed optimal.

Input of D3, a factor that manifestly affects 25D concentration, has been the subject of much of the previous discussion. Attention is now focused on the effect on serum concentration of 25D produced by variations in body size and in D3 output, i.e., utilization and/or degradation of the 25D in serum.
Obesity

One widely recognized influence on 25D concentration is obesity, with serum 25D being lower in obese individuals. This was originally attributed to a phenomenon termed “sequestration” (implying trapping of vitamin D in adipose tissue of obese individuals).71 However, Drincic et al.72 have shown that simple volumetric dilution is both a more logical explanation and one that fully explains the weight-based difference. Curiously, body mass index works in various regression models almost as well as body weight (and somewhat better in some datasets). This is surprising as body mass index is not a measure of mass but of fatness. The reason is presently unclear, and this observation suggests the possible existence of further mechanisms operating in obese individuals.
Parathyroid hormone-1,25D axis  Clements et al.60–62 showed that 25D half-time in serum ranged from 15 to >35 days, with 25D half-time being inversely related to parathyroid hormone concentration. The parathyroid hormone effect, noted both in patients with hyperparathyroidism and in animals subjected to calcium deprivation, was, in turn, mediated by serum 1,25D concentration. Why 25D utilization (or degradation) should rise in the face of calcium need is physiologically unclear, particularly as renal 1,25D synthesis is not as dependent on 25D concentration as the autocrine functions of vitamin D.

Inflammation.  The other major influence on serum 25D concentration is inflammation. It has been reported that vitamin D status is reduced in the face of systemic inflammatory processes.73–78 For example, Duncan et al.75 reported an inverse correlation of 25D with serum C-reactive protein, with 25D being 40% lower as serum C-reactive protein rose from <5 mg/L to >80 mg/L. Autier et al.,79 in a metaanalysis of the several reports on this relationship, confirmed the existence of the association but attributed the reduced vitamin D status to underlying illness rather than to the inflammation itself. That conclusion may be partly correct, at least for some chronic illnesses, but it cannot apply to the many documented cases in which vitamin D status drops acutely across an inflammatory episode, as with total knee arthroplasty.73,77 In one case study, Henriksen et al.73 reported a 12% drop in 25D by day 2 after total knee arthroplasty and a nearly 80% drop by post-surgery week 8. Reid et al.77 evaluated a series of 33 patients who underwent total knee arthroplasty and reported an approximate 40% drop in total 25D and a 33% drop in calculated free 25D by day 2 after surgery, which was associated with large increases in C-reactive protein.

Decreases in 25D of this magnitude and rapidity cannot be explained by decreased synthesis and must, therefore, reflect increased utilization, degradation, or loss. Depending on which values may be estimated for the total 25D mass (see above), reductions in 25D concentration of the size reported by Reid et al. translate to a loss of several hundred micrograms from the body, which is substantially greater than ordinary daily utilization of vitamin D. While increased utilization cannot be ruled out, it seems unlikely to be the sole explanation. Another possibility, which was suggested by Waldron et al.,76 is the loss of DBP (with its bound ligand) in the urine. In 30 patients undergoing elective orthopedic surgery, the ratio of DBP to creatinine in urine rose 2.5× by the second day post-surgery; this was associated with a >20-fold increase in C-reactive protein. Renal loss could certainly explain much or all of the change in 25D observed in these studies and could be the result of interference with the kidney’s megalin–cubilin system, possibly produced by the anesthesia or inflammatory cytokines associated with the surgery.

Although not directly related to the major focus of this review, the conclusion reached by several of the authors of the studies just reviewed, i.e., that, while inflammation clearly reduced D status, this reduction was without nutritional significance, is in no way supported by data in any of the papers concerned, nor is it consistent with the importance of serum 25D concentration as the principal limiting factor in the autocrine pathway.

METABOLISM AND UTILIZATION   the data assembled here make clear that, even with today’s widespread vitamin D inadequacy, total vitamin D inputs are far higher than previously thought, food sources are greater than previously recognized, and solar input, though theoretically capable of fully meeting any plausible vitamin D requirement, is actually only a minor present-day contributor to total vitamin D input at the population level. That does not mean that the human requirement is more easily met. Rather, it indicates that the requirement is higher than previously recognized, with populations still short of meeting that requirement by the amount needed to move prevailing serum 25D concentrations from current values to putatively healthier levels.

These analyses also make clear that at prevailing inputs (i.e., <4,000 IU/day), D3 is rapidly 25-hydroxylated and little D3 circulates in the blood or is shunted into adipose tissue for storage. Additionally, the recent recognition that oral 25D may raise serum 25D to a significantly greater extent than does oral vitamin D suggests the possibility of a hitherto little recognized or explored intracellular pathway in which the entire metabolic sequence is handled within certain target tissues and is not reflected in blood. A related finding in this respect is the importance of a maternal serum D3 concentration sufficient to support production of human milk capable of meeting infant needs for vitamin D.

Several of these insights have implications for the human requirement. For example, the vitamin D input needed to support an adequate amount of vitamin D in human milk has implications not just for lactation but also for human success as a species under presupplementation conditions. Inadequate vitamin D input in newborns would be expected to lead to skeletal abnormalities (for which the paleo-fossil record provides no evidence), in addition to possible consequences for immune system development.89 A total input of approximately 6,000 IU in modern humans equips them to feed their infants with a nearly full range of the nutrients needed for healthy growth.

CONCLUSION    Precise quantification of vitamin D inputs, transfers, conversions, and compartment sizes are essential for a full understanding of how the human body utilizes this essential micronutrient, why it is important, and what the consequences are of an inadequate vitamin D input.

Since its founding, the U.S. Preventive Services Task Force (USPSTF) has  provided  firm evidential base for early detection strategies, evaluating such screening methods as mammography and prostate-specific antigen testing. Although it has also evaluated a few interventions, its predominant focus has been testing for markers that identify persons at risk who are likely to benefit from preventive action. Only recently has  USPSTF entered  the (mine)field of nutrition, a territory distant from screening tests and risk assessment, with different and unfamiliar landmarks.

The USPSTF now reports it is unable to find evidence for or against vitamin D deficiency testing  (1),  the likely reasons being the absence of a scientific consensus on both the level of vitamin D status that should be judged “deficient” and what the measurable manifestations of deficiency might be. These are also issues for many other nutrients, such as folate, ascorbate, calcium, and protein. Vitamin D may have seemed to offer a way out of this confusion because serum 25-hydroxyvitamin D [25-(OH)D] concentration is generally recognized as one of the best indices of status for any of a broad array of nutrients. Also, it is now readily measurable and widely utilized.                 

One of the reasons its promise has not been realized is that most studies of vitamin D efficacy have used a disease-avoidance model, which is the standard approach used by the Institute of Medicine (IOM) for most nutrients (2). Furthermore, disease prevention is the explicit focus of the USPSTF. Nevertheless, the IOM and USPSTF approaches effectively equate health with the absence of disease, an equivalence that nutritionists have long rejected. Instead, nutritionists focus on full nutrient repletion when possible. The inevitable gap between disease prevention and nutrient repletion is still largely unexplored territory. For many nutrients, it can be surprisingly wide, as suggested in this case by studies of the intake required to provide vitamin D in human breast milk in quantities sufficient to meet the needs of infants (3). The IOM’s adult requirement for vitamin D is 600 IU/d (4), which is judged to be sufficient to protect against osteoporotic fracture. In contrast, quantitative and empirical evidence indicates that vitamin D intake from breastfeeding needs to be approximately 6000 IU/d (3, 5). Although high compared with the adult recommendation, such an intake almost exactly reproduces the measured vitamin D status of contemporary Africans leading ancestral lifestyles (6). Such populations provide perhaps our best window on vitamin D levels prevailing during the millennia over which human physiology was adapted to its environment by natural selection.

Whatever the actual requirement or 25-(OH)D cutoff may be, there is another likely reason that the evidence is unclear. The USPSTF drew from systematic reviews and meta-analyses of studies of vitamin D effects, such as the one accompanying the current report (7). In general, the criteria for including studies in such reviews are methodological rather than biological. Of the 6 published biological criteria (8) for including published reports in meta-analyses, the review published in this issue met only 2 (comparable basal status and same chemical form), and several of its component studies met none. Including studies that could never have been informative in the first place (especially when they are large) inevitably biases any review toward the null.

What seems not to have been widely appreciated is that vitamin D exhibits flat response regions at both low and high values of vitamin D status, with a sharp rise in the approximate center of the physiologic range of 25-(OH)D values (8). Studies like the WHI (Women’s Health Initiative), which enrolled women with low vitamin D status values and used a vitamin D dose insufficient to move them into the response range, provide little useful information about vitamin D efficacy. Yet, precisely such studies were included in the review by LeBlanc and colleagues (7). This is not to criticize the WHI, which was designed more than 20 years ago (before vitamin D pharmacology was well-understood), but it is to criticize contemporary reviews and meta-analyses that fail to take advantage of newer information or to use critical biological criteria (8) for selection of studies for analysis of biological effects.

In addition, a disease-avoidance approach becomes problematic for micronutrients in general (and vitamin D in particular) when one understands that micronutrients do not actually cause any of the effects simplistically attributed to them. Although necessary for cell response, such micronutrients by themselves do not initiate or cause the response concerned. For example, vitamin D is a component of the biochemical apparatus that opens the genome to allow access to DNA information needed for a particular cell or tissue response. In terms of cell function, this dependence means that when supplies of the micronutrient are inadequate, cellular response is blunted. This is dysfunction, but not clinically manifest disease. Such dysfunction may indeed lead ultimately to various diseases, but disease prevention remains a dull tool for discerning the defect, and a disease-prevention approach clearly does not measure whether the organism has enough of the nutrient to enable appropriate physiologic responses, such as lactation.

Finally, and aside from the USPSTF’s findings, one must ask whether treating without first testing is sound practice. Certainly, it would be rational to do so if the condition being treated is prevalent and the treatment is safe and inexpensive. That is the case with another micronutrient, iodine, and the iodination of salt. However, the current situation is different because getting sufficient iodine generally does not require conscious adherence to a particular regimen, whereas taking vitamin D does. Usually, testing improves patient adherence because it provides patient-specific, personally applicable information. General assurances that one probably needs extra vitamin D are not as compelling a motivator as knowing one’s number. Thus, whether the practitioner adheres to the widely divergent guidelines of the IOM (4), the Endocrine Society (9), or the American Geriatrics Society (10), measuring vitamin D status seems to be warranted, not so much to diagnose deficiency but to determine patient status relative to the selected guideline.

THE NEAR-IMPOSSIBILITY  OF OVERDOSING WITH VITAMIN D3 – except  by persistent repeated  injection  A Report  in Feb 2014 from Bansai & Arora ea New Delhi show how  extreme the overdose of vitamin D3 must be to cause hypercalcemic toxicity: an Asian  woman given 6million iu  imi over 10 days  after knee surgery presented 2 months later with 6 wks of persistent vomiting, fatigue, with moderate hypercalcemic renal failure  and 25OHvit D level of 150ng/ml; that normalized in 2 weeks.. So her peak level after the initial 2 weeks on an average ~50 000iu/day may have been around 500-600ng/ml..  Bansai and Arora quote two series from  endemically vit D deficient Kashmir (Pandita ea 2012 in Jammu and 2011  Koul ea Srinagar)   of a total 25 elderly  given chronic overdoses  D3 600 000iu monthly , who were found to have similar moderate hypercalcemia and renal failure with peak 25OHvit D of 100 – 300ng/ml: a mean vit D3 dose of between 20 000iu and >1million iu/day?, mean s. creat 2.5; mean 25OHvitD of 100 – 200ng/ml; mean calcium 13.1mg/dl. 20 000iu a day indefinitely in these frail small elderly averages at least 400iu/kg/day, at least 5 times the chronic recommended dose in the literature the past decades- and to boot, routinely given them with a highdose calcium supplement- when it is rather magnesium that should if any be boosted. .  Koul ea do note that about 100 000iu vit D a day ongoing  is required to cause hypercalcemia, the mean lethal dose being about 8million iu.

By contrast, previous reports below- eg from the Netherlands report of 2million iu single  overdose  in  90 year olds; and planned 600 000iu orally monthly dose in Pakistani men  wasted with TB (Salhuddin ea below)   showed no overdose signs.  So a single loading dose of 1 to 2  million units is unlikely to give overload. By these  precedents (eg 600 000iu p.o monthly- apparently official policy of the Pakistani Endocrine Society) one may  in acute infections  give up to 600 000iu as a loading dose (a million in an obese ill patient) in acute infection situations, then 50 000- 80 000iu weekly depending on weight, to maintain level around 90ng/ml.

Am J Clin Nutr March 2008  Pharmacokinetics of a single, large dose of cholecalciferol 100 000iu  IlahiArmas, and  Heaney   Creighton University Medical Center, Omaha,  Design: followed for 4 mo, 30 subjects were  supplemented with a single oral dose of 100 000 IU cholecalciferol. 10 subjects served as a control group to assess seasonal change of calcidiol.   The subjects were healthy with limited sun exposure (<10 h/wk) and milk consumption (<0.47 L daily);  excluded granulomatous conditions, liver disease, kidney disease, or diabetes or  taking anticonvulsants, barbiturates, or steroids.  Results: Serum calcidiol rose promptly after cholecalciferol dosing from a mean (±SD) baseline of 27.1 ± 7.7 ng/mL to a concentration maximum of 42.0 ± 9.1 ng/mL. Seven percent of the supplemented cohort failed to achieve 32.1 ng/mL at any time point. The highest achieved concentration in any subject was 64.2 ng/mL. The control group had a nonsignificant change from baseline of −0.72 ± 0.80 ng/mL during 4 mo.   Conclusions: Cholecalciferol (100 000 IU) is a safe, effective, and simple way to increase calcidiol concentrations. The dosing interval should be ≤2 mo to ensure continuous serum calcidiol concentrations above baseline.

THE IMPORTANCE OF IMMUNOSYNERGY BETWEEN ADEQUATE ANABOLIC HORMONES- VIT D3, MELATONIN (Berman 1926, Carrillo-Vico 2013), AND PROGESTERONE   in planned and current pregnancy, and aging?  Thangamani, Kim ea Purdue & Indiana Universities in   J Immunol. 2014 Dec 29:  Cutting Edge: Progesterone Directly Upregulates Vitamin D Receptor Gene Expression for Efficient Regulation of T Cells by CalcitriolThe two nuclear hormone receptor ligands progesterone and vit.D play important roles in regulating T cells.., we report that progesterone is a novel inducer of vit.D receptor (VDR) in T cells and makes T cells highly sensitive to calcitriol even when vit. D levels are suboptimal. This novel regulatory pathway allows enhanced induction of regulatory T cells but suppression of Th1 and Th17 cells by the two nuclear hormones. The results have significant ramifications in effective regulation of T cells to prevent adverse immune responses during pregnancy.

A recent review of vitamin D from Mike Holick (Boston Mass.) and a German team  again reminds us of two opposing forces limiting natural sunshine vitamin D supply: on the one hand the skin shuts down active vit D production if the sunlight burns, while on the other, there is simply not enough sunlight  beyond  35degrees latitude from the equator. Thus Germany and Canada-northern USA for example, at >45degrees north,  get far too little sunlight for vit D needs ; eg London is at 51degrees north; Cape Town-Florida-San Diego, Sydney-Buenos Aires, Hawai  and the Med. countries are at the 35degree south latitude. Even this close to the equator, many overdress- especially more observant religious  women-  and thus minimize  benefit from summer sunshine.

J Assist Reprod Genet. 2014 Dec 30.Vitamin D and assisted reproductionvitamin D should be routinely screened and repleted prior to ART? Pacis , Segars ea Dartmouth-Hitchcock Medical CenterLebanon NH  systematic review.  review  current literature regarding the role of vitamin D status & repletion  in pregnancy outcomes in women undergoing assisted reproductive technology (ART).  Thirty-four articles were retrieved, of which eight met inclusion criteria. One study demonstrated a negative relationship between vitamin D status and ART outcomes,  two studies showed no association. The remaining five studies concluded that ART outcomes improved after vitamin D repletion.The majority of reviewed studies reported a decrement in ART outcomes in patients with vitamin D deficiency. Cost-benefit analyses suggested that screening and supplementing vitamin D prior to ART might be cost effective.

25 Dec 2014 ANOTHER AVOIDABLE TRAGIC  TB DEATH:   Dr Nerissa Pather and countless other infectious disease sufferers – health workers and their patients :

 Sunshine Cures:  why did TB  sanatoria work (before there were  antibiotics)? was it indeed the boost of copious sunshine secosteroid antimicrobial soltriol in the skin destroying the M TB porphyrins? or was it belief, then-cleaner  air, high altitude,    rest, care and better nutrition?

Not for nothing was  skin ie CTB  Lupus Vulgaris a relentless scourge  in the clothed  in darker climes and times, except perhaps in ancient sunny Pharanoic medicine, until the Danish Faroe Islander   physician Niels  Finsen-  trying to treat his own Niemann–Pick disease–  used his  invention phototherapy generator on his patients  and found that it magically rolled back skin TB (for which in  1903 he  got the only Nobel prize  apparently ever awarded for dermatology!). This light therapy antimicrobial effect has recently 2005 been attributed by Danish researchers    Møller,  Wulf ea  to the lethal effect of light oxidation on Mycobact  TB porphyrins.    However, this Danish study abstract ignores the antimicrobial benefit of cholecaliferol activated by light on the skin from  the Karolinska Inst in Sweden. A Georgetown Univ paper 2005 details the complexities of   Sunlight, Vitamin D, and the Innate Immune Defenses of the Human Skin , further set out in Optimal Skin Protection with  Vitamin D.    Unfortunately the circle is not yet squared off, there is still no study showing that vitamin D (like bcarotene and likely  melatonin) improves the disease porphyria?

A recent 2009 Mt Sinai NY report of a case of CTB cutaneous TB stresses how rare this skin complication is despite the increasing spread of TB with AIDS- perhaps partly because of the higher prevalence of HIV in poorer peoples in sunnier warmer ie relatively better sunshine-cholecalciferol-endowed climates.

We easily make our optimal vit D3 ~100iu/ kg per day living playing and working outdoors in warm lands. But since we dress more in cooler climates, with aging and dress-conservative cover-up tribal eg Arabic and Hasidic and Mormon customs; and avoid sunburn, and from early middle age lose 3/4 of our skin vitamin D production by 70years, we  aging thus need the bulk of our vit D requirements as supplements ie ~7000iu/day or 50 000iu/week.

A century ago, TB, polio, measles, scarlatina, and syphilis were rampant, and infections rather than wars killed most – ending in the 1919 flu holocaust that devastated the family of Dr Sir  Arthur Conan Doyle (whereas the Flu pandemic took just  one of my   parents’ score of siblings- and polio just left my Mom with a limp..)..

2014  is the centenary  of  recent  recognition of the  cod liver oil  antirickets steroid factor – calciferol/soltriol -briefly misnamed “vitamin”  D – by McCollum, Davis (USA 1913)  and Mellanby(UK); so that in 30 years  by 1945, rickets had been all but abolished in USA. But the recognition of the antirachitic factor was facilitated by discovery in the preceding decade of vitamins A, B and C. The antiscurvy benefit of fresh uncooked coloured crops (and thus their juice)  had indeed been recognized for millennia – eg the Royal  Navy limejuice- , but a specific micronutrient vitamin deficiency  was first only recognized in 1907. Vitamin C ascorbic acid  identification also took another 25years . For 90 years, it has been recognized that a  lightly cooked exclusively fatty meat diet can provide enough vitamin C (let alone all micronutrients)  for  health in eg  atheroma- and scurvy-free Eskimos and anyone who cares to eat thus (Stefansson ) .

Sadly, the lifegiving vitamins have  been diluted,  all but eliminated from retail bottled codliver oil, a ml  of which now generally supplies perhaps only 125iu vit D, and vitamin A 1000iu … So even a tablespoon supplies only about 1200iu vit D.. The Weston Price Foundation discusses  why modern commercial codliver oil is good with its balance of vits A and D– but the vitamin D level is  still  far too low for cooler darker countries.  However we recommend, (apart from far cheaper vit D3 powder 50 000iu/1ml scoop) – a tsp cod liver oil at least 3 times a week because it is the cheapest natural- and with Scandinavian manufacturing controls, safe-  source of vital  EPA+DHA available as well as some vitamins A and E.

As real summer begins here between the southern oceans,  cold winter in the northern hemisphere, we must constantly remind that vitamin D3 cholecalciferol  is NOT an  exogenous vitamin ie a biological  nutrient essential (Funk’s ‘vitamine’, shortened by Jack Drummond  because they are not amines to the more appropriate ‘vitamin’) in the human diet ( like vits A, B, C, E & K) because humans cannot make them. . But since we make  vit D  with light exposure of our skin, since most humans dont get enough sunlight on our skin,  it is certainly  a conditioned essential anabolic steroid, which like other anabolic steroids (the balance especially of androgens) is vital at optimal blood levels through life for optimal health,  healthspan.

Unlike the real vitamins and essential minerals,  Calciferol is (like eg  CoQ10,  alphalipoic acid, nitric oxide, EPA and DHA)   made in limited quantities in humans with adequate organ function and sunshine; but none of them generally in anywhere near optimal quantities for healthspan against all diseases. So given humans’ capacity to live well to a century, we need such supplements from youth to ensure chronic health so as to die of old age in good health. .

How does this relate to the death this month of Dr Nerissa Pather? Multiresistant TB contracted on duty 12 years ago  eventually killed her,    whether or not such  high-risk people are  ever advised to take the best prevention- zinc, selenium, multivites but especially highdose vit C and D3.

D3  bio-insufficiency fragility and  dysimmunity  is further complicated  since to  correct  it requires both plenty of skin sunshine exposure, eaten vitamin C and it’s daughter cholesterol,   and optimal kidney and liver  function. Even then optimal vitamin D3 bloodlevel and effect may be blocked by foolhardy cholesterol blockade eg statins, and  by excess intake and thus bloodlevel of vitamin D2 ergocalciferol – which   authorities eg in South Africa and USA  still negligently promote/ dispense as the dangerously misnamed “strong calciferol”. It is indeed D3 cholecalciferol, not D2   that is the miracle sunshine strong calciferol steroid;  egocalciferol dominance, like insulin and estrogen  dominance,  is  harmful, and can and must  be avoided. .

So it is increasingly apparent that, just as intake/manufacture of  vitamin C the true sunshine vitamin (those colourful veg/ fruit orchards etc) , and  thence cholesterol, should each be at least a few gms a day, the human  (clothed indoor-dwelling) adult synthesis +  intake  of sunshine hormone  vitamin D3 soltriol  should be nearer to 10 000iu ie 250mg/day, or more practically 50 000iu  vit D3 a week  (at a trivial supplement  cost of eg R6/month or $5 a year) for a bigger adult- especially in longer darker winter (starting with perhaps  about 25000iu every fortnight  for babies) .. of course balanced  in most societies with the other supplements especially water, vitamin K2, zinc, selenium iodine  and magnesium (and iron for children and reproductive mothers) .

So, how many more millions must suffer and die from lack of the cheapest, best, safest conditioned essential antimicrobial antioxidant anabolic nutrients available?

An undated (post 2003) Pharmacology Bulletin from Canterbury NZ at least gives conservative  realistic vit D3 advice: a loading dose of D3  500 000iu , then 50 000iu/month. This compares with our routine loading dose of about 200 000 to 400 000iu to start, then 50 000iu every week or two (proportionate to body mass and illness). But Lennons here negligently still continues to  advertise their Strong Calciferol datasheet (updated 2004) as calciferol- last year they in fact confirmed it is D2 ergocalciferol, not cholecalciferol. Only their website http://www.ndrugs.com/?s=lennon-strong%20calciferol confirms that their strong Calciferol is D2;  whereas they also make low strength D3 tabs.

From today’s press “The South African Medical Association (SAMA) extends heartfelt condolences on  the passing of 38yr old Dr Nerissa Pather on  18th December 2014 . Whilst on community service at a  Kwazulu Natal clinic, Dr Pather contracted well-publicised multi-drug resistant spinal TB in 2002 , that rendered her paralyzed and in constant pain. The loss  to a communicable disease acquired in the course of duty is an incalculable tragedy. SAMA reiterates its call to all health departments and facilities to ensure that  basic TB prevention methods are available to all healthcare workers in our facilities. Sadly, this is not the case in many of our hospitals and clinics and continues to place health professionals at enormous risk. The potential consequences of infection and even acquiring drug resistant TB are tragically evident in the death of Dr Pather.  SAMA bows its head to a colleague who has paid the ultimate price in caring for her fellow human beings.”

A current report from Tehran  Calcium and vitamin D plasma concentration and nutritional intake status in patients with chronic spinal cord injury: stresses the  obvious, the  terribly low intake and levels of vitamin D in spinal cord injury patients. Why are we inflicting this further deprivation on the most vulnerable patients?

The tragedy is that with general authoritarian nihilism about universal vitamin supplements- some calling their promotion  quackery- unrecognized  deficiency eg  vit D3, rickets,  and vit C scurvy  are on the increase even in the more affluent eg USA and in sunnier climates- especially with increasing geriatrics and the frail surviving with eg HIV, TB, cancer, chronic bowel disease,   gross overuse of warfarin (vit K deficiency) and  statin (CoQ10 deficiency) etc. .

Vitamin D Deficiency in Critically Ill Patients  is rarely considered or treated .. N Engl J Med 2009 Lee, Eisman & Center   studied vitamin D status in ICU patients  referred to   St. Vincent’s Hospital, Sydney in  2007. Among approximately 1100 ICU patients per year, the mean  25-hydroxyvitamin D in 42 referred patients was ~17ng per milliliter, with a high prevalence of hypovitaminosis D . Moreover, three patients died (from metastatic thymic carcinoma, glioma, and lymphoma), and  had undetectable levels of 25-hydroxyvitamin D.   The current study of  ICU patients reveals high prevalence of hypovitaminosis D that was associated with adverse outcomes, independently of hypocalcemia and hypoalbuminemia. Supplementation with  vitamin D (at a mean dose of 820 IU per day) before admission was not protective.   Vitamin D deficiency is associated with increased mortality.However, vitamin D has pleiotropic effects in immunity, endothelial and mucosal functions, and glucose and calcium metabolism. The association between hypovitaminosis D and common conditions (e.g., the systemic inflammatory response syndrome, septicemia, and cardiac and metabolic dysfunctions) in critically ill patients may be important. Vitamin D–deficient and vitamin D–insufficient states may worsen existing immune and metabolic dysfunctions in critically ill patients, leading to worse outcomes.  A total of 17% of  ICU patients in our study had undetectable levels of vitamin D. hypocalcemia was identified as a reason for referral in only 5% of the patients. These findings highlight the need for consideration of vitamin D status and supplementation in patients in the ICU.

Arch Intern Med. 2008;168:1629-37 25-hydroxyvitamin D levels and risk of mortality in the general population.   Melamed , Astor ea. Albert Einstein College of Medicine, NY tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the NHANES III linked mortality files.  In patients on  dialysis, therapy with  vitamin D agents is associated with reduced mortality. Observational data suggests that low  (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown.   Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000.    RESULTS:  In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL , while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models , compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%.    The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.

ANABOLIC STEROID SYNERGY?: the steroids cholecalciferol and androgen are both immune and anabolic -switch  protein/muscle/bone promoters, without apparent mutual antagonism or suppression; calciferol also lowers SHBG levels, freeing up more active unbound testosterone ie reducing estrogen dominance.

 Subst Abuse Rehabil. 2014 Dec 10;5:121-7. Effects of different doses of testosterone on gonadotropins, 25-hydroxyvitamin D3, and blood lipids in healthy men. Gårevik, Ekström ea. At the Karolinska Inst Sweden,   Twenty-five healthy male volunteers aged 27-43 years were given 500 mg, 250 mg, and 125 mg of testosterone enanthate as single intramuscular dosesAll doses investigated suppressed the LH and FSH concentrations in serum. LH remained suppressed 6 weeks after the 500 mg dose. These results indicate that testosterone has a more profound endocrine effect on the hypothalamic-pituitary-gonadal axis than was previously thought. There was no alteration in 25-hydroxyvitamin D3 levels after testosterone administration compared to baseline levels. The 250 and 500 mg doses induced decreased concentrations of ApoA1 and HDL, whereas the lowest dose (125 mg) did not have any effect on the lipid profile.

Pediatrics. 2014 Dec . Rapid Normalization of Vitamin D Levels: A Meta-Analysis.  McNally. Menon ea @Univs Ottowa, Thailand & Ireland  systematically reviewed pediatric clinical trials administering high-dose vitamin D to evaluate  (25[OH]D) response and characteristics of  final 25(OH)D levels . Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (≥1000 IU) ergocalciferol or cholecalciferol were selected. Two of 6 studies that administered daily doses approximating the Institute of Medicine’s Tolerable Upper Intake Level (1000-4000 IU) to vitamin D-deficient populations achieved group 25(OH)D levels >75 nmol/L within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >75 nmol/L. In meta-regression, baseline 25(OH)D, regimen type, dose, age, and time factors were associated with final 25(OH)D levels. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses <400 000 IU (or 10 000 IU/kg). Few studies in adolescents evaluated loading dose regimens >300 000 IU.
CONCLUSIONS:   Rapid normalization of vitamin D levels is best achieved by using loading therapy that considers disease status, baseline 25(OH)D, and age (or weight).

Diabetes Res Clin Pract. 2014 Dec A randomised controlled trial of ‘high” dose vitamin D in recent-onset type 2 diabetes .Elkassaby,  Fourlanos ea, Melbourne Australia.  Vitamin D insufficiency is associated with impaired pancreatic beta-cell function. Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000IU D (n=26) or placebo (n=24) daily for 6 months. In the D group, median serum 25D (ng/ml) increased from 24 to 60 (3 months). change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups.    ie modest Oral D3 supplementation   in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function.  this effect is unlikely to be biologically significant. This modest   dose D3  ie 42000iu/ week to eventual bloodlevel of only 50ng/ml therefore appears to offer little or no therapeutic benefit in type 2 diabetes.   THE DOSE THEY USED IN FACT PRODUCED STEADYSTATE VIT D3 LEVEL HALF THE POSTULATED TARGET LEVEL OF 90-100 ng/ml FOR SERIOUS ILLNESS.

J Asthma. 2014 Nov  Efficacy of high-dose vitamin D in pediatric asthma: a systematic review and meta-analysis.
Pojsupap , McNally ea Univ Ottowa :   studies  suggest a relationship between vitamin D status and asthma-related respiratory outcomes.  benefit of vitamin D supplementation for pulmonary function, symptoms and exacerbations is not well established.   Clinical trials reporting asthma-related respiratory outcomes following vitamin D administration at a dose equal or greater than 500 IU per day were included. Results:  five studies  met study eligibility and assessed final data synthesis. The median trial size was 48 participants (range 17-430) and the average daily dose of cholecalciferol ranged from 500 to 2000 IU/day. Meta-analysis suggested a statistically significant reduction (RR 0.41, CI 0.27-0.63) in asthma exacerbation with vitamin D therapy.

   J Infect Dis. 2013 Feb .  Vitamin D status and incidence of pulmonary tuberculosis, opportunistic infections, and wasting among HIVinfected Tanzanian adults initiating antiretroviral therapySudfeld,  Fawzi ea . Maintaining vitamin D sufficiency may decrease the incidence of pulmonary tuberculosis and other infectious diseases. We present the first prospective study of vitamin D among human immunodeficiency virus (HIV)-infected adults receiving antiretrovirals in sub-Saharan Africa.   Serum 25(OH)level was assessed at antiretroviral therapy (ART) initiation for 1103 HIVinfected adults enrolled in a trial of multivitamins (not including vitamin D) in Tanzania.After multivariate adjustment, vitamin D deficiency (defined as a concentration of <20 ng/mL) had a 3 fold significantly greater association with incident pulmonary tuberculosis, compared with vitamin D sufficiency (HR, 2.89;  [CI], 1.31-7.41; P = .027), but no association was found for vitamin D insufficiency (defined as a concentration of 20-30 ng/mL; P = .687). Deficiency was also significantly associated with incident oral thrush (HR, 1.96; 95% CI, 1.01-3.81; P = .046), wasting (HR, 3.10; 95% CI, 1.33-7.24; P = .009), and >10% weight loss (HR, 2.10; 95% CI, 1.13-3.91; P = .019). Wasting results were robust to exclusion of individuals experiencing pulmonary tuberculosis. Vitamin D status was not associated with incident malaria, pneumonia, or anemia.

update 22 Dec 2014:  as the solstice rolls by,  infections especially viral  flourish north and south,  from flu to gastro , HIV to ebola; HPV  to HZV to childhood exanthems;

so more reason to aim for optimal growth, mental and physical health with the peak anabolic antidepressant energizing anticancer antiinfective steroid –  cholecalciferol D3 – intake and levels.   About 65 000iu a week (with my multivit-multimineral combo)  puts my measured trough 25OHvit D  bloodlevel at 92ng/ml with normal blood calcium. Women can live long  without much androgen apart from frail bones, but not well without vigorous cholecalciferol D3 intake. Humans who live mostly bare  mostly outdoors- us  naked apes-  most of the year closer to the equator  make plenty of D3 from sunshine; but the darker our skins, the sooner vit D production shuts down; so  most of us need vigorous D3 supplement costing perhaps US$6 a year retail. .

update 19 Nov 2014  when this column on vit D started 5 years ago, there were 46000 vit D entries on Pubmed- this has mushroomed 40% to 61000 (compared now to 46000 on vit A; to 53000 on vitamin C; 37000 on vitamin E; 17000 on vit K; and 133000 on all  the 8 B vitamins ); whereas in 2009 there were 272500 entries on all vitamins– now up only 22% to 335 000. ie the papers on the secosteroid  vitamin D have risen at double the rate of the  vitamins.. (D3  C27H44O and D2 C28H44O, vs testosterone C19H28O2).

As the end-of-year solstice approaches, its time to review the crucial role of giving vigorous doses of vitamin D3, whether via   non-burn sunshine, or via the correct lowpressure tanning bed, or directly as vitamin D3  (not vit D2) supplement as appropriate TOGETHER WITH A MULTINUTRIENT PLUS EXTRA MAGNESIUM AND VIT K2. . Ironically, dermatologists would recommend vit D supplement not suntan for what many  consider the wrong reason- that suntanning does more harm than good, which it doesnt. :

at least THIRTEEN   VIT D  studies the past 16 years  SINCE 1998, from ~8 nations-  USA, Canada, Belgium, Spain , Germany, Denmark, UK  &  New Zealand,   – show  POORER   RESULTS  FROM TAKING TOO LITTLE VIT D; OR FROM USING VITAMIN D2 not D3, apparently by suppressing the crucial vit D3 level, and because vit D2 is metabolized faster. :

a new OBSERVATIONAL study in Am J Clin Nutr. Nov 2014  from the Cambridge EPIC-NORFOLK  group by  Kay-Tee Khaw,  Nicholas Wareham ea   Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study    examined prospective relation between serum  [25(OH)D] concentrations [which comprised 25(OH)D3 and 25(OH)D2] and subsequent mortality  in 14,641 men and women aged 42–82 y in 1997–2000  in Norfolk, UK followed up to 2012; categorized into 5 groups according to baseline serum concentrations of total vit D from below 30nmol/L to above 90nmol/L..  mean serum total 25(OH)D was 56.6 nmol/L 22ng/ml, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs  for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20-nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers.    Conclusions: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L ie 36ng/ml, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the Norfolk population had concentrations >120 nmol/L 48ng/ml.

Chowdhury , Franco  ea  also University of Cambridge,  UK. BMJ. 2014 Apr .   Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.    Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants). In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods.

in a systematic review and meta-analysisTripkovic ,, Lanham-New  ea . Univ Surrey  Am J Clin Nutr. 2012Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: In the collective 10 studies, 1016 participants aged 18–97 yrs, men to women  ∼1:3;  vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with  vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a  BOLUS dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation.. The studies were  in the United States, Canada, United Kingdom, Australia, Denmark, and Italy; all studies were single-center studies. Seven studies were conducted in healthy, free-living participants (4, 6, 7, 12, 13, 15, 17);

WE so far FIND AT LEAST 12 RELEVANT COMPARATIVE VIT D3/D2  TRIALS in humans and one in cows:

1.  Karen Hansen ea at Univ Wisconsin 2014  An evaluation of high-dose vitamin D for rheumatoid arthritis   show  that  giving vitamin D2  (not D3)  50 000iu fortnightly for a year is actually adverseIT DEPRESSES – perhaps halves – THE BIOLOGICALLY ACTIVE blood 25OHVIT D3 while boosting perhaps 5 fold the far less active blood 25OHvit D2 levels , and actually worsens  rheumatoid arthritis clinically and serologically .

     2. Vitamin D2 supplementation amplifies eccentric exercise-induced muscle damage in  athletes. Nutrients.  Nieman , Luo  EA. A, North Carolina  2013:6:63-75. Six weeks vit D2 (3800 IU/day) increased serum 25(OH)D2 fourfold  and decreased 25(OH)D3   by a fifth  versus placebo (p<0.001, p=0.036, respectively), with no influence on muscle function test scores, AND worsened  muscle damage .

    3. Swanson, Barrett-Connor, ea USA & Belgium May 2014 : In a cohort of older men,   Higher 25(OH)D2 is associated with lower 25(OH)D3 and 1,25(OH)2D3  , suggesting that vitamin D2 may decrease the availability of D3 and may not increase calcitriol.

4.Lehmann,  Dierkes ea  Germany 2013    in the same leading scientific journal  Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial-  giving vit D2 2000iu/day for 8 wks in healthy volunteers actually halves the crucial 25hydroxy vit D3 level;  whereas giving vit D3 2000iu/d  doubles the vit D3 level. Earlier studies have suggested that vitamin D2 is less biologically active  than vit D3.

5. Biancuzzo, Holick ea Boston Mass. 2013 Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation  in healthy adults 18 to 79 years consuming 1000 IU vitamin D2 or vitamin D3 per day for 11 weeks at end of winter was analyzed.  Of the adults, 82% were vitamin D insufficient (serum 25-hydroxyvitamin D [25(OH)D <30 ng/mL]) at the start of the study. Administration of vitamin D2 and vitamin D3 induced similar increases (from baseline ~20ng/ml 25OH vit D)  in total 25(OH)D as well as in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, respectively. Compared with placebo and adjusting for baseline levels, 1000 IU daily of vitamin D2 was associated with a mean increase of 7.4 pg/mL (95% confidence interval, 4.4-10.3) in 1,25(OH)2D2, and  decrease of 9.9 pg/mL (-15.8 to -4.0) in 1,25(OH)2D3. No such differences accompanied administration of 1000 IU daily of vitamin D3.

    6. Leventis P1, Kiely PD. London 2009 in  Scand J Rheumatol. Good Tolerability and biochemical effects of high-dose bolus vitamin D2 and D3 supplementation in patients with vitamin D insufficiency in 69 RHEUMATOLOGY patients with vitamin D insufficiency [25-hydroxyvitamin D (25(OH)D) <40 nmol/L]  50 patients study 1 received 300 000 IU i.m. vitamin D2 (ergocalciferol), 19 patients  in study 2 received 300 000 IU oral vitamin D3 (cholecalciferol) . Bolus i.m. vitamin D2 or oral vitamin D3 was well tolerated.  change from baseline in serum 25(OH)D was significantly greater at 6 and 12 weeks in study 2 (p<0.0001 ). In study 1, a modest increase in mean serum 25(OH)D at 6, 12, and 24 weeks was observed but no patients achieved a serum 25(OH)D concentration > or = 50 nmol/L. PTH remained elevated in 42% of patients with secondary hyperparathyroidism at 12 weeks. In study 2, 100% and 89% of patients had serum 25(OH)D>50 nmol/L at 6 and 12 weeks, respectively. All patients with elevated baseline PTH were fully suppressed at 12 weeks. No hypercalcaemia was observed in either group. The 300 000-IU bolus of vitamin D2 or D3 was practical, well tolerated, and safe. Vitamin D3 had greater potency than equimolar vitamin D2, with a higher, sustained serum 25(OH)D response and efficacious PTH suppression.


    7.  Sempos CT1, Picciano MF ea . USA  J Clin Endocrinol Metab. 2013 Jul;98(7):3001-9..  Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES.       A reverse J-shaped association between serum 25-hydroxyvitamin D (25[OH]D) concentration and all-cause mortality was suggested in a 9-year follow-up (1991-2000) analysis of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). We repeated  the analyses with 6 years additional follow-up  in 15 099 participants aged ≥ 20 years with 3784 deaths, to evaluate whether the association persists through 15 years of follow-up. The reverse J-shaped association became stronger with longer follow-up and was not affected by excluding deaths within the first 3 years of follow-up. Similar results were found from both statistical approaches for levels <20 through 119 nmol/L. Adjusted RR (95% confidence interval [CI]) estimates for all levels <60 nmol/L were significantly >1 compared with the reference group. The nadir of risk was 81 nmol/L 32pg/mL (95% CI, 73-90 nmol/L 29-36pg/ml). The association appeared in men, women, adults ages 20 to 64 years, and non-Hispanic whites but was weaker in older adults.  A reverse J-shaped association between serum 25(OH)D and all-cause mortality appears to be real. It is uncertain whether the association is causal.

    8.  Logan  Houghton ea   Br J Nutr. New Zealand 2013;109:1082-8.   Long-term vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months.  Public health recommendations dont distinguish between vitamin D2 and vitamin D3, yet disagreement exists on whether these two forms should be considered equivalent.  over the winter in healthy adults living in Dunedin, New Zealand (latitude 46°S), Participants aged 18-50 years were randomized   to 1000 IU vitamin D3 (n 32), 1000 IUvitamin D2 (n 31) or placebo (n 32) daily for 25 weeks beginning at the end of summer. After 25 weeks, participants randomised to D2 and placebo had a significant reduction in serum 25(OH)D3 concentrations over the winter months compared with vitamin D3-supplemented participants (both P< 0.001). Supplementation with vitamin D2 increased serum 25(OH)D2 but produced a 9 (95 % CI 1, 17) nmol/l greater decline in the 25(OH)D3 metabolite compared with placebo (P< 0.036). Overall, total serum 25(OH)D concentrations were 21 (95 % CI 14, 30) nmol/l lower in participants receiving vitamin D2 compared with those receiving D3 (P< 0.001), among whom total serum 25(OH)D concentrations remained unchanged. No intervention-related changes in PTH were observed. Daily supplementation of vitamin D3 was more effective than D2;

    9  Seijo M1Oliveri B. ea  Spain  Medicina (B Aires). 2012;72:195-200.  [Is daily supplementation with vitamin D2 equivalent to daily supplementation with vitamin D3 in the elderly?].    equivalence of cholecalciferol (D3) and ergocalciferol (D2) as well as their corresponding doses and administration route remain controversial to date. Twenty-one ambulatory postmenopausal women from Buenos Aires with a mean  age of 77 ± 6.8 years  were randomly assigned to one of the following groups: GD2 (n = 13): 800 IU (drops) and GD3 (n = 8): 800 IU (pills).  Nineteen out of twenty one women showed deficient levels of 25OHD at baseline (< 20 ng/ml): GD2: 14.0 ± 4.8 ng/ml and GD3: 13.2 ± 4.9 ng/ml (NS). Whereas only GD3 exhibited an increase (≈ 25%) at 7 days, both groups showed a significant increase at the end of the study. However, neither attained adequate 25OHD levels (GD2: 17.4 ± 5.5 vs. GD3:22.9 ± 4.6 ng/ml; p < 0.001). Administration of 800 IU of vitamin D3 during 45 days was more effective than D2 in increasing 25OHD, but both failed to achieve adequate levels of 25OHD (= 30 ng/ml). but neither succeeded in achieving adequate levels of 25OHD (= 30 ng/ml).

    10 Holick  Tannenbaum ea usa   J Clin Endocrinol Metab. 2008;93:677-81. Epub 2007 Dec 18.IN LOW DOSE eg 1000iu/d,   Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin A 1000 IU dose of vitamin D2 daily was as effective as 1000 IU vitamin D3 in maintaining serum 25-hydroxyvitamin D levels and did not negatively influence serum 25-hydroxyvitamin D3 levels. Therefore, vitamin D2 is equally as effective as vitamin D3 in maintaining 25-hydroxyvitamin D status.
     11 Armas ,  Heaney ea.Creighton Univ Nebraska.  J Clin Endocrinol Metab. 2004 ;89:5387-91. Vitamin D2 is much less effective than vitamin D3 in humans.Vitamins D(2) and D(3) are generally considered equivalent in humans. Nevertheless, physicians commonly report equivocal responses to seemingly large doses of the only high-dose calciferol (vitamin D(2)) available in the U.S. market. Relative potencies of vitamins D(2) and D(3) were evaluated by administering single doses of 50,000 IU of the respective calciferols to 20 healthy male volunteers, following the  serum vitamin D over 28 d.. The two calciferols produced similar rises in serum concentration, indicating equivalent absorption. Both produced similar initial rises in serum 25OHD over the first 3 d, but 25OHD continued to rise in the D(3)-treated subjects, peaking at 14 d, whereas serum 25OHD fell rapidly in the D(2)-treated subjects and was not different from baseline at 14 d. Area under the curve (AUC) to d 28 was 60 ng.d/ml for vitamin D(2) and 204 for vitamin D(3) (P < 0.002). Calculated AUC(infinity) indicated an even greater differential, with the relative potencies for D(3):D(2) being 9.5:1. Vitamin D(2) potency is less than one third that of vitamin D(3). Physicians resorting to use of vitamin D(2) should beware of its markedly lower potency and shorter duration of action relative to vitamin D(3)

    12 Trang,  Vieth ea  University of Toronto, Am J Clin Nutr. 1998Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. In all species tested, except humans, biological differences between vitamins D2 and D3 are accepted as fact.  Subjects took 260 nmol (approximately 4000 IU) vitamin D2 (n=17) or vitamin D3 (n=55) daily for 14 d.  With vitamin D3, mean (+/-SD) serum 25(OH)D increased from 41+/-18 nmol/L before to 65+/-17 nmol/L after treatment. With vitamin D2, the 25(OH)D concentration went from 434+/-18 nmol/L before to 57+/-13 nmol/L after. The increase in 25(OH)D with vitamin D3 was 23+/-16 nmol/L, or 1.7 times the increase obtained with vitamin D2 (14+/-11 nmol/L; P=0.03). There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration.  In the highest tertile [25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for comparison with each lower tertile). Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small, it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered.

13.  Hymøller L1, Jensen SK.Denmark   J Dairy Sci. 2011;94:3462-6.  Vitamin D₂ impairs utilization of vitamin D₃ in high-yielding dairy cows in a cross-over supplementation regimen.   D(3) given after D(2) is less efficient at increasing the plasma status of 25(OH)D(3) than D(3) given without previous D(2) administration.

A Vitamin D Expert’s Take on the Latest Warning to Stay Out of the Sun to Avoid Skin Cancer

By Dr. Mercola  16/11/2014  The US Surgeon General recently came out with a warning on skin cancer,1 claiming that the sun is dangerous and that you need to stay away out of it.

pioneer Dr. John Cannell, founder of the Vitamin D Council, has dedicated a large part of his professional career to the study of vitamin D and its health benefits, and he has a warning of his own to those who take this narrow-minded advice to heart.

It’s worth noting that the acting Surgeon General, Boris Lushniak, is a dermatologist. And of all the medical specialties out there, dermatologists are clearly the most biased against sun exposure, & as a result, against vitamin D.

This isn’t surprising, since they primarily see the ill effects of sun overexposure. But in taking an overly narrow view, the advice to avoid sun exposure as much as possible can have equally if not greater adverse health effects.                      The Connection Between Sun Exposure and Skin Cancer Unquestionably, UV   radiation can be dangerous; it can increase your risk for certain skin cancers such as squamous cell, basal cell, and melanoma. But there are significant differences even between these cancers, and appropriate sun exposure may actually be more beneficial than detrimental in some cases. Dr. Cannell explains:

“Squamous cell carcinoma is clearly associated with chronic sun exposure. It is more common on the face, the hands, and the scalp.

It is related to radiation burden over your lifetime, and together with basal cell carcinoma, which is sort of intermediate, it accounts for approximately 1,500 deaths a year in the United States…

Basal cell is sort of intermediate. There are studies showing that it is associated with chronic sun exposure, and there are studies showing that it’s not associated with chronic sun exposure.

And then there’s melanoma, which is responsible for almost 9,000 deaths a year and is the deadly skin cancer that is feared. The relationship that melanoma has with the sun is quite complicated.

It is clearly associated with sunburn, especially sunburns when you’re young (that’s incontrovertible) or sunburns in a sun tanning bed.”

However, there are at least two studies showing that melanoma is more common in indoor workers than outdoor workers. And the most likely places for melanoma to appear are actually NOT the face and the hands like squamous cell carcinoma, but rather the lower back and the upper leg—areas that are usually not chronically sun-exposed.

According to Dr. Cannell, there’s a vocal minority in the dermatological community that thinks the emphasis dermatologists have on avoiding sun exposure is wrong, because while sunburn is a risk factor, chronic sun exposure is not.

“A number of studies show that chronic sun exposure is related to melanoma, but they don’t separate out the sunburns, which is very hard to do because you have to do that by memory,” Dr. Cannell says.   Two Decades-Long Study Finds Sun Avoidance Doubles Risk of Death  Dr. Cannell notes a recent study2 done in Sweden, which followed nearly 30,000 middle-aged to older women for up to 20 years. The average follow-up was 15 years.

At the outset, they asked a number of questions about sun exposure, such as: Do you sunbathe? Do you take vacations in sunny areas in the winter? Do you garden with short sleeves and shorts? And, do you use sunbeds?

What they found, and this appears to be the only study of this kind, is that the women who avoided the sun were twice as likely to die over the course of the study. The researchers attributed this finding to a vitamin D mechanism.

What this study actually shows is that chronic sun exposure appears to be associated with less mortality. It’s also the first study to show that women who use tanning beds live longer than those who don’t.

This is in direct conflict to what almost every dermatologist will say, including the Surgeon General. It’s unfortunate, but the danger of almost any specialist is that they don’t take the broader perspective.

What the Surgeon General and almost every other dermatologist fail to take into account is the overall mortality, which is referenced in this recent study.  Risk-Benefit Analysis In addition to this study, dozens of others document the benefits of appropriate sun exposure. This includes a reduced risk of about 16 different cancers of Dr. Garland’s studies suggest this reduction is close to 50 percent.

So many hundreds of thousands of people are put at risk from other cancers as opposed to 10,000 people who are dying from skin cancer caused by sunburn. It’s really a matter of making an educated risk-benefit analysis.

“When you do a risk-benefit analysis and you look at all the data we have, the risk in my opinion appears to be in those who avoid the sun,” Dr. Cannell says.

“Now, if you avoid the sun, your risk for non-melanoma skin cancer goes down. That’s clear. But if you look at studies of either latitude or of 25-hydroxyvitamin D levels in relation to cancer, you find this inverse relationship: the higher the vitamin D level, the lower the internal cancer rate.”

Dr. William Grant of Sunlight, Nutrition, and Health Research Center (SUNARC) estimates that if everyone in the United States had a vitamin D level of 40 nanograms per milliliter (ng/ml), it would save approximately 150,000 lives a year.3

That’s 100 times the rate of squamous cell cancers, which are the only ones that are definitively linked to UV exposure. In Canada alone, it is estimated that 37,000 lives a year are lost due to vitamin D deficiency.4 Also, use of sunscreen has risen in the last 30 years, so if dermatologists were correct, there should be a decrease in stage 1 melanoma. But there’s not. As sunscreen use increased, stage 1 melanoma diagnosis increased…

“It’s thought that by blocking out UVB, patients are able to stay out in the sun longer than they would have otherwise and expose themselves to the more dangerous, or at least potentially dangerous, UVA radiation that’s in the sunshine,” Dr. Cannell says. “What we recommend is what’s called safe, sensible sun exposures. The Australian Cancer Council now recommends the same thing. I think in England there’s now a change in their recommendation from strict sun avoidance to some safe, sensible sun exposure. There are some movements in large organizations to realize that safe, sensible sun exposure is a healthy thing.”            

How Much Sun Exposure Is Sensible?    On its website, Cancer Research UK reports that “by enjoying the sun safely and avoiding sunburn, people can reduce their risk of skin cancer and enjoy the beneficial effects of the sun.” Cancer Research UK’s sun advice is endorsed by the British Association of Dermatologists, Cancer Research UK, Diabetes UK, the Multiple Sclerosis Society, the National Heart Forum, the National Osteoporosis Society, and the Primary Care Dermatology Society. The UK National Health Service5 also recommends sensible, individualized sun exposure to help optimize vitamin D.

It’s important to recognize is how quickly sunlight can make vitamin D in the skin. You don’t need to be outside for hours on end. But you do need more than just a few minutes of sun on your face and arms. According to Dr. Cannell, sunbathing at solar noon in the summer, at most latitudes in the United States you will make between 5,000-10,000 international units (IUs) of vitamin D within 30 minutes.

“You can ask yourself why nature would evolve a mechanism that made so much vitamin D so quickly,” Dr. Cannell says. “When I thought about that question, the only answer I could come up with is nature did it for a good reason. The organism needs vitamin D, so the system in the skin evolved to make it very quickly upon exposure to sunlight.

We recommend full-body sun exposure for up to anywhere from a few minutes to 30 minutes every day. On those days when you cannot get a full-body sun exposure, we recommend a vitamin D supplement or sensible exposure in a low-pressure UVB bed.”

If you’re getting regular sun exposure, I think the need for an oral supplement is really minimal to non-existent. When you swallow a pill, there’s no self-regulating ability. Your body doesn’t have an ability to selectively limit its absorption. But your skin has the ability to control how much vitamin D is being produced based on how much is in your blood.

I personally have not taken oral vitamin D for five years and my level runs from 50-70 g/ml. Lifeguards, roofers, and gardeners who work with their shirt off, all tend to have levels between 40 and 80 ng/ml in the summer. This also brings up an interesting question about the difference between normal and natural. Normal vitamin D levels are an average of what indoor workers have in both winter and summer. Natural are levels of a population with widespread sun exposure. The latter is going to be closer to ideal, or optimal.

vitamin d levels
References for establishment of optimal levelsThere are also other reasons to strive for sun exposure rather than swallowing a pill. As noted by Dr. Cannell, aside from producing vitamin D, sunlight also affects nitric acid levels and endorphins in the skin. Researchers at the University of Wisconsin recently discovered that there may be a system at 311 nanometers that is separate from the vitamin D system (which is at 298 nanometers), and that there may be an entirely new undiscovered biochemical system in the skin that makes yet another substance, besides vitamin D. Time will tell what comes out of that research, but there are indications that sunlight may be responsible for other biological processes that are unrelated to vitamin D production.

Dr. Cannell’s Recommendation on Tanning Beds There are basically two
types of tanning beds:

  1. 1. High-pressure UVA beds. They tan you the quickest because it’s UVA that tans the skin. They contain only a limited UVB spectrum, and will therefore give you color but not much vitamin D
  2. Low-pressure beds, which contain less UVB than sunlight at most latitudes, but still contain a significant amount of UVB. These are the beds Dr. Cannell recommends, provided you’re using a sensible approach that avoids sunburns. It’s important to realize that you can easily get burned after only a couple or a few minutes when using a tanning bed

Another important factor when selecting a tanning bed is the type of ballast it employs, to avoid excessive electromagnetic field (EMF) exposure. Most tanning units use magnetic ballasts to generate light. These magnetic ballasts are well known sources of EMF fields that can contribute to cancer. If you hear a loud buzzing noise while in a tanning bed, it has a magnetic ballast system. I strongly recommend you avoid magnetic ballast beds, and restrict your use of tanning beds to those that use electronic ballasts.

On days you cannot get either regular sun exposure or use of a tanning bed, Dr. Cannell suggests taking 5,000 IUs of vitamin D3. Other vitamin D experts recommend similar amounts. It’s worth noting that, according to the federal government’s Food and Nutrition Board (FNB), the no observed adverse effects level (NOAEL) of vitamin D is 10,000 IUs a day. This means there has never been a replicated reliable study showing that 10,000 units a day is in any way detrimental.

Many individuals who have reported side effects from taking high doses of oral vitamin D have noticed that when they supplemented with magnesium, they were able to tolerate the high oral doses of vitamin D. Dr. Carolyn Dean has written in her book, The Magnesium Miracle, that she has seen this so many times that she doesn’t advise taking more than 2,000 units of vitamin D without magnesium supplementation. Be sure to also have an adequate amount of vitamin K2 along with D to slow the progression of arterial calcification. Remember though that the best form of vitamin D is the one your body produces when it is exposed to sunlight that has sufficient amounts of UVB.

Five Tips to Get an Appropriate, Sensible Amount of Sun  Again, sunshine offers substantial health benefits, including vitamin D production, but you do need to exercise a few simple precautions to protect yourself from overexposure. Virtually all of the harm from sun exposure is related to sunburn. Here are my top five tanning tips:   *  Expose large amounts of your skin (at least 40 percent of your body) to sunlight for short periods daily. Optimizing your vitamin D levels may reduce your risk of as many as 16 different types of cancer, including pancreatic, lung, ovarian, breast, prostate, and skin cancers. If using a sunscreen, give your body a chance to produce vitamin D before you apply it. *When you’ll be in the sun for longer periods, cover up with clothing, a hat, or shade (either natural or shade you create using an umbrella).  *Consider the use of an “internal sunscreen” like astaxanthin to gain additional sun protection. Astaxanthin is a potent antioxidant (and pigment) produced by marine algae in response to their exposure to UV light. Typically, it takes several weeks of daily supplementation to saturate your body’s tissues enough to provide protection. *Consuming a healthy diet full of natural antioxidants is another useful strategy to help avoid sun damage. Fresh, raw, unprocessed vegetables and fruits deliver the nutrients that your body needs to maintain a healthy balance of omega-6 and omega-3 oils in your skin, which is your first line of defense against sunburn. Vegetables also provide your body with an abundance of powerful antioxidants that will help you fight the free radicals caused by sun damage that can lead to burns and cancer.

How Vitamin D Performance Testing Can Help Optimize Your Health  A robust and growing body of research clearly shows that vitamin D is absolutely critical for good health and disease prevention. Vitamin D affects your DNA through vitamin D receptors (VDRs), which bind to specific locations of the human genome. Scientists have identified nearly 3,000 genes that are influenced by vitamin D levels, and vitamin D receptors have been found throughout the human body.

  14  Oct 2014 update:  MORE ON OPTIMAL VITAMIN D3  DOSE, AND THE DIFFICULTY OF ACHIEVING CLINICAL  OVERDOSE:      Four  new reports highlight  how  difficult, and important  it is to achieve adequate optimal bloodlevels of vitamin D with vigorous vitamin D3 supplements, let alone overdose with any significant adversity: note three   used the  recommended vitamin D3,   not the long-condemned mislabeled Lennons/Aspen vitamin D2 (which is misleadingly labelled  “caciferol” without disclosing that it is D2 not D3). Even a single  2 million iu overdose of vit D3 in nonagenarians had no adverse effect-since the bloodlevel was back to zero by 3 weeks, thats above 100 000iu/day on average….

 with serum 25-hydroxy vitamin D (25(OH)D) < 30 ng/mL  on  placebo or vitD3 (n = 35)   60,000 units/week for 6 weeks.   mean baseline level of 25(OH)D was 9.6+-9.6 ng/mL, and after 6 weeks doubled to 19.5 ± 4.3 ng/mL,  (P < 0.0001). After discontinuing supplement at 6 weeks, serum 25(OH)D level dropped moderately  by  12 weeks (16.1 ± 8.3 ng/mL) as compared with the baseline.  The change in serum 25(OH)D level from baseline to 6 weeks in the intervention group was inversely related to baseline 25(OH)D levels and patient’s weight. In the control group, change in 25(OH)D was not significant.  Thus  vit D3 about
10 0000iu/day in these small and often malnourished people raises bloodlevel by only about 10ng/mL.
        Kearns ,Tangpricha ea, Emory University Georgia USA   in Eur J Clin Nutr. 2014 Oct 1 describe    The effect of  single  250 000iu bolus of vitamin D3  in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.   At baseline, young healthy participants had a mean plasma 25(OH)D concentration of 17.5±6.1 ng/ml. Only two subjects exhibited plasma 25(OH)D concentrations >30 ng/ml. At 5 days, subjects on  vitamin D3 had  only doubled mean plasma 25(OH)D (39 vs 19 ng/ml, P<0.001). Plasma 25(OH)D concentrations returned to baseline by  90 and 365 days in the vitamin D3 group,  remained unchanged in the placebo group. PTH and calcium concentrations were unrelated to changes in 25(OH)D levels and similar between groups over time.

   van den Ouweland ,  Vollaard ea  Nijmegen, The Netherlands in    BMC Pharmacol Toxicol. 2014 Sep 30   describe  Pharmacokinetics and safety issues of an accidental oral overdose of 2,000,000 IU of vitamin D3 in two nonagenarian nursing home patients: a case report.    Oral overdose of 2,000,000 IU of vitamin D3 in two nonnagenarian  nursing home patients was monitored from 1 hr up to 3 months . Peak blood 25(OH)D3 concentrations were observed 8 days after intake (210  and 162ng/mL, respectively (ref: 20-80 ng/mL),   followed by a rapid decrease to undetectable levels after day 14.  Remarkably, plasma calcium levels increased only slightly up to 2.68 and 2.73 mmol/L, respectively (ref: 2.20-2.65 mmol/L) between 1 and 14 days after intake,; phosphate and creatinine levels remained within reference range. No adverse clinical symptoms were noted.   CONCLUSION:A single massive oral dose of 2,000,000 IU of vitamin D3 does not cause clinical toxicity requiring hospitalization. Toxicity in the long term cannot be excluded as annual doses of 500,000 IU of vitamin D3 for several years have shown an increase in the risk of fractures. This means that plasma calcium levels may not be a sensitive measure of vitamin D toxicity in the long term in the case of a single high overdose. 

            As previously reported, to avoid dehydration stones and vascular calcification – especially in hot dry climates – , the precautions with vigorous vit D3   are to add some vit K2 and magnesium to the supplement, and maintain good water intake .
           The fourth current paper, from Morocco, reports inexplicable use of dangerous massive dose of vit D2 in neonates- amounting to about 120 000iu/kg ie about 12 times the maximum adult dose reported :   Hmami , Bouharrou  ea Morocco University,  Arch Pediatr. 2014 Oct;21:1115-9.        [Overdose or hypersensitivity to vitamin D   Vitamin D intoxication with severe hypercalcemia is rare in the neonatal and infancy period. 9 babies between ages of 25 and 105 days were admitted  for treatment of severe dehydration  8 to 15% with  hypercalcemia, with preserved diuresis and loss weight between 100 and 1100 gm secondary to taking 600,000 units of vitamin D (Sterogyl(®). The pregnancies & deliveries  were normal. Clinical signs were dominated by weight loss, vomiting, and fever. The vitamin D values in nine patients were toxic (mean 220: 139 – 300 ng/mL, ; normal >20ng/mL; toxicity if >100ng/mL). Nephrocalcinosis was shown  in seven patients. DNA study  in eight patients, did not reveal a mutation of the vitamin D 24-hydroxylase gene (CYP24A1). Treatment consisted of intravenous rehydration with diuretics and corticosteroids. Serum calcium returned to  normal range within 4-50 days, with weight gain progressively over the following weeks. The follow-up (2 years for the oldest case) showed persistence of nephrocalcinosis. Genetic susceptibility and metabolic differences appear to modulate the threshold of vitamin D toxicity. However, respect for recommended doses, recognized as safe in a large study population, reduces the risk of toxicity.
and as in adults,    Yao ,  Huang  ea  Prediction of Allergies in Taiwanese Children (PATCH) Study Group in  J Pediatr. 2014 Oct 1 demonstrate a significant relationship between insufficient serum vitamin D levels and worse lung function in children in the community with a suggested dose-response effect.

VITAMIN D3 DOSE: We get excellent results in outpatient adults with loading oral dose of  vit D3 of about 200 000 to 400 000iu depending on illness severity and body mass; then pro rata about 50 000iu  per week till better, tapering to fortnightly when well; pro rata in kids. We monitor calcium and 25OH vitamin D3 levels occasionally  if affordable – but with the tapering regime, and published data, do not see or expect hypercalcemic problems from a mean conservative weekly maintenance dose of about 3500iu/d longterm, with predicted bloodlevel of 25OHvitD of about 35-40ng/ml.  As a senior with average chronic dis-ease load, I take ~63 000iu vit D3 weekly, but double it occasionally if I do get a bad cold; so I never miss a day’s work;   recent stress-related shingles (2nd attack in 30 years)  was just a nuisance, settled in 3 weeks with this regime plus multigrams of buffered vit C a day; oral lysine and alphalipoic acid each about 1/2 gm/day; and for a few days some weak steroid and humic acid cream topically for the neuritis and blistering, which has already healed to almost invisible.  This week at a family practice clinic I saw two successive women with shingles – now a frequent occurrence, even  without HIV…

Khan in Toronto in OHDM  this September  describes a ~60yr old man with tongue cancer who was treated inter alia with Vit D3 10 000iu a day; after a year his 25oH vitD level was ~106ng/ml,  when his dose was halved; his dose response  bore out the general experience that at average adult mass, vit D level rises by about 10ng/ml for every 1000iu vit D3 per day or pro rata dose weekly etc  eg 50 000iu/wk or 100 000iu fortnightly may give average vit D level of ~70ng/ml.  .

Singh & Bonham 2014 at Kansas University describe  A Predictive Equation to Guide Vitamin D Replacement Dose in Patients. The recommended daily allowance for vitamin D is grossly inadequate for correcting low serum concentrations of 25-hydroxyvitamin D in many adult patients.  In their population (average BMI 31.5) ,about 5000 IU vitamin D3/day is usually needed to correct deficiency, and the maintenance dose should be ≥2000 IU/day. The required dose may be calculated from the predictive equations specific for ambulatory and nursing home patients”   A BMI of 31.5kg at a mean height of about 1.7m gives a mean weight of 91kg, which at the consensus daily  vit D3 dose of 80iu/kg/d totals ~7100iu/d or 50 000iu/wk- perhaps a reasonable maintenance dose for winter, half  that in summer if reasonable weekly sun exposure. .

29 Sept 2014:       As detailed elsewhere in this column, there is at least 70 years of strong experience worldwide that  all microorganism infections are greatly diminished by natural  prevention (not synthetic vaccines loaded with toxic heavy metals and allergenics eg egg) , and  easily treated ie  thrown off, with vigorous immune-boosting supplements:  (mega)grams a day of vitamin C or as kgs/day of fresh produce;        vitamin D3 80+ iu/kg/d to  >10 000iu/d ie 300 000  to 600 000iu loading dose; then    +-50 000iu/wk,  plus  plenty of skin exposure to sunshine; iodine; zinc; selenium; silver; the other vitamins; Ecchinacea etc.  This applies both to acute and chronic infections and degenerative conditions.

To be used in highrisk cases eg MERS, AIDS, ebola etc: The  landmark trial  Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency– The VITdAL-ICU Randomized Clinical Trial  by Amrein, Dobnig ea ,   published   today in JAMA  from Austrian hospitals  is most encouraging about the immense value of vigorous dose and bloodlevels of vitamin D3 against all types of severe disease.  The dose used in this trial (loading dose 540 000iu  =~18000iu/d 1st month, but averaging only ~8000iu/d in the first 3mo) did not achieve vigorous vit D bloodlevel, presumably because the loading dose of vit D3 in oil (540 000iu) was given by tube into the stomachs of critically ill patients; it would have better been given by transdermal injection, or else a much higher loading gastric dose given so as to speedily achieve a bloodlevel of around 70 (60 to 80) instead of half of this that was achieved in the crucial first few weeks .                                      from May 2010 through September 2012 at 5 ICUs the trial recruited  492 medical (60%) and surgical (40%)  critically ill adult white patients , 35% women, BMI mean 27, mean age  64.6 years (SD, 14.7) with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 540 000 IU, or  placebo    given orally or via nasogastric tube; ;  followed by monthly maintenance doses of 90 000 IU for 5 months- ie= about 18000iu/day for the first mo, then 90 000iu   mthly ie only 3000iu/d.           .     RESULT: on placebo the 25hydroxyvit D3 level doubled  from 13 at baseline to 17 at a month to 26ng/ml at 6mo.. By contrast, on vit D3 supplement it doubled to 34 at days 3 and 7 and day 28, but up to 46 at 6 months ie only 80% higher than the control group – thus 1/3 to 1/2 of the optimal target; with this, where 100% of patients were below 25OHvitD at baseline ie on admission to ICU, by 7 days, 87% were still in this bracket and none above 60ng/ml on placebo vs 25%  below 20  and 13% above 60 on vit D3; and by 6mo 35% were still that low on placebo, vs 5%  at that low, but 22% above 60 on vit D3. So it is not surprising that Median hospital stay 20 days was not significantly different between groups  Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28% for vitamin D3 vs 35% for placebo; hazard ratio [HR], 0.81  P = .18; 6-month mortality: 35.0%  for vitamin D3 vs 42.9%  for placebo; HR 0.78  P  = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 19.5 days. Hospital mortality was significantly 40% lower with 28 deaths among 98 patients (28.6% ) for vitamin D3 compared with 47 deaths among 102 patients (46.1% ) for placebo (HR, 0.56 P for interaction = .04), but not 6-month mortality (34.7%] for vitamin D3 vs 50.0%  for placebo- ie 31% lower; HR, 0.60, P for interaction = .12). No serious adverse events were observed. The highest 25-hydroxyvitamin D levels measured were 107 ng/mL on day 7 and 106 ng/mL at month 6- well below the theoretical minimum toxic threshold of 150 or 250ng/ml..”

BUT  compared to the Austrian trial in overweight 27+kg BMI elderly whites given 540 000iu to start  by tube,              in   Salahudfin ea’s  randomized controlled trial in young emaciated   Pakistani men BMI 17.2kg, Vitamin D3 600 000iu  injection (which achieved twice the blood 25OH vit D3 level of the Austrian patients), had  accelerated clinical recovery from tuberculosis with  “impressive clinical (weight gain, chest xray and sputum clearing)  improvement  over 3 months on outpatient TB therapy (Directly Observed Therapy (DOTS) with 2 months of  4 antituberculous drugs followed by 6 months Isoniazid and Ethambutol)  with two doses 600 000iu vit D3 imi (vs placebo inj)  a month apart-  ie = ~20 000iu/d for the first 2 months, but equivalent to about 7 000iu/day over the 3 months treatment period . This dose  of vitamin D is as recommended for vitamin D supplement by the Pakistan Endocrine Society.  Trough  25OH vit D levels increased from about 20 to 90ng/ml.    After 12 weeks, the vitamin D supplemented pts (mean 28 yrs, BMI 17.2kg, 85% moderate to far advanced lung disease)  had  significantly greater mean weight gain (kg) + 3.75,  versus + 2.61, p 0.009; lesser residual disease by chest xray-  30% fewer zones involved 1.35 v/s 1.82 p 0.004,   and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035. Vitamin D supplementation led to significant increase in MTBs-induced IFN-g secretion in patients with baseline ‘Deficient’ vitamin D serum levels (p 0.021). Patients in the vitamin D arm and serum < 30 ng/mL (‘Insufficient’ and ‘Deficient’ groups) at enrollment had significantly greater improvements in TB severity scores compared to patients with normal baseline vitamin D levels; p 0.014.”

         “This corresponds with the earliest reports of the benefits of vitamin D in TB patients published in 1848 [21] that describes disease arrest, weight gain and reduction in mortality in patients with TB treated with cod liver oil compared to standard therapy alone. More recently, Martineau et al  [7]  demonstrated that a single oral dose of 2.5 mg (100,000 IU) of vit D2 significantly reduced growth of mycobacteria . A randomized, placebo controlled study on 67 Indonesian patients, by Nursyam et al , Jakarta  [22] reported that pulmonary TB patients given 420,000 IU of vitamin D over 6 weeks  ie 10 000iu/day had significantly higher sputum conversion rates as compared to placebo (p 0.002). Martineau et al. [8] showed that 100,000 IUs of 25-hydroxyvitamin D3 supplementation significantly improved sputum conversion rates in patients with the Taq1 25-hydroxyvitamin D receptor polymorphism of the tt genotype. ”                                                                    .

As Salahuddin ea note, the good results in Pakistan in only 3 months with vigorous  INITIAL dose vit D3  contrasts with Two recently published large randomised, controlled trials of conservative vitamin D3 over months  that achieved far lower blood vitamin D levels found no difference in clinical outcomes or mortality after 400,000 IU of 25-hydroxyvitamin D3 or placebo were given by   Martineau ea  in London, UK to 146 pulmonary TB patients – where mean (trough  or midpoint)  vit D level  (after 100 000iu vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment) – was surprisingly only  40ng/ml at 56days – ie after a mean of 7000iu/d by  56 days,  vs 10ng/ml  on placebo)- less than half of the bloodlevel  achieved on vit D3  in the Pakistan trial.

So the Austrian ICU patients would undoubtedly have done much better if given more effective  (ie in critically ill pts intramuscularly imi or subcutaneously) loading dose like the Salhuddin trial did.

 TIME   To SWOP FROM MISNAMED  “STRONG CALCIFEROL” VIT D2 TO THE REAL VIT  D3:     as the winter solstice approaches here, with fierce weather linking to  the expected influenza-like outbreak (while the MERS-CoV outbreak abates with summer in the severely vitamin D deficient Saudi Arabians), a new major study shows the supremacy of vitamin D3 for supplementation, and confirms that vitamin D2 benefit if any  is so mediocre as to be unethical..

Its sad that despite the strong evidence against using vitamin D2 supplement discussed last year,  it seems no one acted on  it despite the confirmatory paper from Bergen of last September.

Thus vit D3 is again confirmed as four times as potent as D2. But crucially, that giving vit D2 may actually SUPPRESS the optimal  serum vit D3  level.

We health professionals with our highly vulnerable populations in South Africa and worldwide   (epidemic/endemic  HIV, TB, cancer, drug addiction, MERS-CoV, asthma, diabetes, cardiovascular,  malnutrition, alcoholism and violence) therefore surely have no choice but to swop promptly from prescribing vit D2 “Strong Calciferol” (a dangerous misnomer) to prescribing vitamin D3 at vigorous dose (with if possible occasional blood level check of 25OHvit D3)- at a trivial imported and distributed cost (100cws)  to South African state clinics  of perhaps<1/4 of the cost of D2 eg  R1 per patient per month for a conservative 100 000iu monthly  (ie  after an appropriate germicidal  loading dose of eg 3000 iu/kg) if not the more realistic dose double that- still at only eg US$0.2 a month.

Health Authorities everywhere have an obligation to enforce the use of vitamin D3 and not vitamin  D2 globally ..

update 3 Sept 2014:  while the MERS outbreak in Arabia may at last be dying down, real highly infections plagues eg ebola malaria cholera typhoid, MRSA,  TB and HIV etc continue rampant, maiming and killing even more than the manmade wars raging on some continents. .

So it is ironic – or typical of the couldnt-care-less greedy politicians and potentates who run the world- that the medical authorities they employ  worldwide apparently continue to ignore the dramatic benefits of at least safe antimicrobial supplements like multivite, zinc, iodine, selenium,   and especially vigorous dose vitamin D3 at negligible cost, and highdose buffered vitamin C to tolerance, and colloidal silver.

Already 35 years ago Italian researchers published on Pubmed that vitamin D3 should be used orally  rather than injected D or as  oral vitamin D2:                   [Behavior of serum vit D in  humans after administration of vitamin D.   Boll Soc Ital Biol Sper. 1979   Coen G, Casciani CU ea.     “evaluated  Serum levels of 25 hydroxy-vit D  following injected and oral vit. D2 and D3 . While no rise in 25OHD3 serum levels was  observed after i. m. administration , a marked rise  was found following the oral administration. However the peak values were largely impredictable.”

We quote above  trials and evidence  that oral vit D2 may be actually harmful, that it is vit D3 in vigorous dose that is needed to at least treble if not quadruple the blood vit D level from the usual deficient levels we find, to between 60 and 100ng/ml during illness.  Unfortunately locally this is not only not grasped, but also the vit D assay kit  being used by  private laboratories measures only total 25OHvit D level, not the needed active 25OH vit D3 level  plus the potentially harmful (vitD receptor-blocking ) 25OHvit D2. This is a crucial omission which has been corrected by eg the Mayo Clini Lab, which routinely reports both D3 and D2 levels.

In the person not on vit D supplements, the mediocre ie insufficient total vit D level may mask that the crucial vit D3 level is actually seriously low- deficient.  In the person on vigorous vit D2 supplement (the spuriously named “strong calciferol” 50 000iu tab no longer prescribed in USA  but commonly in RSA,  that neglects to state it is D2 not D3), the total 25OH vit D assay will be even more misleading if the level  is well up, without the unwary being informed that it is harmful D2 that is elevated, and blocking the needed vit D3 level that the D2 is suppressing.

        15 June  2014 CRUCIAL EFFECTIVE VITAMIN D3 DOSING: A major new  metaanalysis of the benefit of Vitamin D3 and Respiratory Tract Infections RTI in PLOS 2013   at  Sweden’s Karolinska  Institute Bergman ea  showed that in the 11 relevant trials (published between 2007 and 2012 ie done through the first decade of this century) using vit D3,Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). And the average vit D level at baseline was only 24ng/ml, but with the mediocre  vit D3 doses used then  of average 2000iu/d (300 – 4000iu/day) given for between 7wks and 3 yrs, the average bloodlevel achieved on replacement was only 50% higher at 36ng/ml”.

     This confirms more direct experience  with higher doses that blood level increment, and benefit,  is proportionate to vit D3 dose, at least up to the proven speculative  safe upper dose of at least 10 000iu/day (whereas the proven safe longterm daily dose is up to 50 000iu/day). “More important, the protective effect was larger in studies using once-daily dosing compared to eg monthly  bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01)”. This concurs with our experience of major benefit  against respiratory infection that is  based on published studies giving a loading month’s dose of about 80-100 iu/kg/day  ie ~3000iu/kg; then that monthly dose split conservatively eg 50 000iu every week or two depending on mass, and severity of ill-health; to a more successful blood-level of 60 to 100ng/ml.

Similarly, the  2014 VIDA trial   across USA-    Effect of Vitamin D3 on Asthma Treatment Failures in Adults With Symptomatic Asthma and Lower Vitamin D Level, Castro ea,  showed “Vitamin D3 for 28 weeks did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma”But this trial had the same severe limitation as the Swedish metanalysis of vit D3 benefit- it also used only 4000iu/d. “While all were vitamin D insufficient ie below 30 ng/ ml  before the trial and half were deficient with levels below 20 ng/mL, supplementation brought levels above the 30 ng/mL threshold for 82% in that group – mean levels were 41.8 ng/mL at week 28 in the supplement group, while the mean stayed in the deficient range for those who got placebo. ”  So 4000iu/day merely doubled the bloodlevel to only about 40ng/ml – only about half of the putative optimal dose. 

These recent studies force us to conclude that bad weather, and  bad prevalent respiratory viruses,  and especially with major acute, or chronic illness as in those with or at risk of serious infections eg major trauma or sepsis,   MERS-CoV, Ebola, malaria, cholera, cancer, diabetics, smokers, asthmatics, bronchitics,   AIDS-TB., pneumonia and old age  sufferers, and especially hospital, laboratory  and clinic- health workers-  we should  give a loading dose of about 4000iu/kg, then 10 000 iu/d for an average 70kg adult,  or 50 000iu every 5 days, or more simply 75000iu (about 1.5ml of 100cws vit D3 powder) weekly; or at a stretch, 300000 if not 400 000iu monthly. . As  the common  imported powder concentrate  is 100 000 iu / Gm ie per 2 ml, it is simple to take the slightly sweetish powder up to  2 or more 4 ml teaspoons ie 200 000  -400  000 iu on the tongue.   

The majority of residents of developed countries now live urbanised with mechanized transport, do not live and work / walk  all day stripped in the sun. The poor malnourished  peasants  live crowded in ghettoes , and  the poorest are generally the darkest skinned and therefore make the least vitamin D3. So with rare exceptions, everyone needs the vigorous vitamin D 3 doses discussed above.

But at the prevalent bulk vit D3  powder price of  at most about  $0,o2 per 100 ooo iu, at a mean population age of around 20 to 25 yrs -outside  Europe- it would cost a country of eg 50 million people perhaps $o.5 per head per  year ie conservatively $25 million a year to prevent > 90% of common illnesses including drugging and violence consequences.  Of course no government can tolerate  such massive loss of jobs and taxes  in a decimated disease industry that turns over $ trillions annually – up to 18 % of national budgets.     So it’s up to individual adults, especially householders, educators and employees ,  to see that the cheapest cure- all  after clean water – vitamin D3 – is recommended and freely available.

We health professionals with our highly vulnerable populations in South Africa and worldwide   (epidemic/endemic  HIV, TB, cancer, drug addiction, MERS-CoV, asthma, diabetes, cardiovascular,  malnutrition, alcoholism and violence) therefore surely have no choice but to swop promptly from prescribing vit D2 “Strong Calciferol” (a dangerous misnomer) to prescribing vitamin D3 at vigorous dose (with if possible occasional blood level check of 25OHvit D3)- at a trivial imported and distributed cost (100cws)  to South African state clinics  of perhaps<1/4 of the cost of D2 eg  R1 per patient per month for a conservative 100 000iu monthly  (ie  after an appropriate germicidal  loading dose of eg 3000 iu/kg) if not the more realistic dose double that- still at only eg US$0.2 a month.
Health Authorities everywhere have an obligation to enforce the use of vitamin D3 and not vitamin  D2 globally ..

2 February 2014 VITAMIN D 3 DENIALISM:                                                       Dr John Cannell psychiatrist and nutritionalist  of the Vitamin D Council has posted a comprehensive rebuttal of the Autier review’s damnation of vitamin D at http://www.vitamindcouncil.org/blog/a-look-at-the-recent-lancet-review-study/.

Queries  and rebuttals    all over the world are questioning the negative French  (Autier ea)   Vitamin D status and ill health: a systematic review   published last month by the UK Lancet            Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

and the accompanying anonymous Lancet editorialchasing a myth?

Ongoing randomised clinical trials assessing the ability of vitamin D supplementation to reduce the risk of several non-skeletal disorders involve a population larger than that of Cambridge, UK, and will cost millions  of research dollars. VITAL, for example, will enroll 20 000 participants and has US$22 million in funding.  This vast investment of effort by patients, researchers,  and funders is laudable, as it is almost certain that it will be sufficient to answer a question that has long kept the medical community in the dark.
                 Vitamin D first became a medical success story when its importance in bone health and calcium homoeostasis was proven decades ago. Since then, epidemiological  evidence has been accumulating to support a role for vitamin D in the protection of individuals from various   non-skeletal disorders including cancer, cardiovascular diseases, autoimmune and inflammatory diseases, dementia, and diabetes; it might also reduce all- cause mortality. Many of these studies show a strong association between low vitamin D concentrations anddisease. However, the results of myriad recent small randomised controlled trials are almost unanimous in  concluding that vitamin D supplementation provides  protection from few, if any, of these outcomes.
      Vitamin D is a steroid hormone with pleiotropic and tissue-specific effects owing to the wide expression of  the nuclear vitamin D receptor in many different tissues,and the many genes that are targeted by its actions.  In the skeletal system, vitamin D promotes healthy development and remodelling of bone. In other tissues,   vitamin D is postulated to mediate potentially beneficial  effects via a wide variety of mechanisms: some evidence  suggests that it exerts anticancer activity by limiting hyperproliferation of certain cell types, that it promotes metabolic health by regulating lipid metabolism in adipocytes, and that it limits autoimmunity by  suppressing inappropriate immune responses.  In a systematic review in   The  Lancet Diabetes &  Endocrinology editorial , Philippe Autier and colleagues discuss a large number of observational studies suggesting  That high serum concentrations of vitamin D   might be protective.
      For example, those with high vitamin D had decreased risk of cardiovascular events      by up to 58%), diabetes (by up to 38%), colorectal  cancer (by up to 33%), and all-cause mortality (by  up to 29%). However, they also compare these findings with the results of randomised clinical  trials, which reveal a very different picture: no reduction in risk was found, even in trials involving adequate supplementation of participants with lowvitamin D levels at baseline (less than 50 nmol/L). Autier and colleagues also did a new meta-analysis  of 16 trials that assessed the effects of vitamin D supplementation on blood HbA1c, a biomarker mainly   used for monitoring disorders of glucose metabolism.
Although type 2 diabetes is associated with  low vitamin D, the results show that vitamin D supplementation does not reduce HbA1c
. Thus, it looks increasingly likely that low vitamin D is not a cause but  a consequence of ill health.
Despite the growing body of evidence indicating  that vitamin D is unlikely to prevent non-skeletal   disorders, there is strong support for its use from  many prominent members of the research community,  which is fuelled by the relatively low toxicity of vitamin D, the glimmer of positivity from some trials,and the large body of evidence from prospective  observational studies. For those who ‘believe’, the  lack of benefi t found in most trials completed thus  far can be attributed to issues including inadequate  supplementation, testing of a population not  sufficiently vitamin D deficient at baseline, incorrect
formulation, underpowering, or insufficient follow-up.  Vitamin D might not be safe in all settings, however.
Supplementing at high doses could cause harm in  people with already high concentrations of serum  vitamin D, particularly in those with liver, kidney, or  vascular problems. This is a concern, given the large  number of people taking vitamin D supplements (up  to 50% of adults in the USA).
Large clinical trials to assess the effects of vitamin D on non-skeletal health outcomes are  therefore justified. It would be a real boon to patients if the results are positive, but unless effect sizes for clinically important outcomes are large, the results will only confirm the neutral effect reported by most clinical trials thus far. Although this investment might  therefore have little effect on current guidelines, the results will at least allow the research community to  move on.
This French  review of Vitamin D is the sort of tactic regularly concocted by Big Pharma and the Disease Industry for the media,  to discourage patients and doctors  from taking/prescribing  effective doses of supplements (beyond a lowdose  multivite a day), instead force them to take Big Pharma poisons- synthetic new risky designer drugs- like antibiotics, antipain,  anticancer, anticholesterol, antiosteoporosis, antiplatelet,antihypertensive, vaccines, antiflu,  –    to make massive profits for the Disease Industry,  but not address or cure the deficiency causes of disease.     At the behest of Big Pharma like Roche, their lobbyists the FDA, the  European Medicines Authority and the UK NHS are  trying to push through legislation that will make anything but lowdose multisupplements available to the public solely on doctors’ prescription.
Meanwhile, Big Pharma companies are paying fines of over $10 billion  a year for promoting their snakeoil  prescription designer drugs by fraud, when these drugs are allowed to be registered for chronic use after small trials of only 6 to 12 weeks, and the researchers who  publish the trials for megadollar fees are regularly caught out, fired but rarely  jailed.                                                                            ……         The Big Pharma guys simply bill the cost of the fines into their marketing expenses- their bosses, and the politicians they buy off,  are too big to jail… Regulators then allow the drugs to be prescribed for years  until enough patients sicken and die for there to be an uproar and cancellation- as  happened recently with Prot(e)os the synthetic ranelate ‘osteoporosis’  snakeoil;.      Now a top Dutch researcher has been fired for falsifying trials to promote betablockers for hypertension – when these have been discredited as routine therapy  for this purpose  for over a decade.
yet the Regulators led by the FDA – which is massively funded solely  by Big Pharma as their ally- insists that vitamins, minerals and other long-proven natural supplement therapeutics, prime human hormones  like melatonin and physiological human sexhormone creams , have to undergo $multimillion trials before they can be marketed as already  long-evident safe effective therapies.

none of the vit D   trials used the dose of vit D3 now recommended on solid evidence  that we should all take   – 80 (to 100)iu/kg/day or 2400-3000iu/kg/month of vitamin D3- ie about 150 000 – 200 000 iu to start and then per month for average adults –  to maintain healthy 25OH vit D levels around 60-100ng/m (here our bloodlevels are usually between 10 and 20 !  because we take little dairy products, nuts and sunshine- we cover up and live indoors.)  .

Most  of the reported trials used only about 5% of the recommended  vit D  dose ie ~200 to 400iu/day ie 6 iu/kg/day!  this dose does nothing except partly prevent rickets-  in infants!  Pregnant women are still routinely given such weak near-nonsensical doses of vit D.

and as Cannell’s review of the Autier analysis  points out, the vitamin D  trials trials under way – * in USA-Boston VITAL study 20 000pts)   ,           Finland (FIND 18000 pts    and     UK(VIDAL 1600pts ) ,  in some 40 000 subjects, due for publication only  between 2017-2020-  are using only 1600 to  3200iu vit D a day or about 48  000 to 96000iu/month ie perhaps 32iu (25 to 40) /kg/day. So  they are testing still modest doses and blood level targets. .

Read about the fraud of the Disease Industry at https://healthspanlife.wordpress.com/2014/01/20/vitamins-c-d3-avoiding-vitamin-denialism/ – especially about the dodgy ” Strong Calciferol’ tabs (Lennons)- which are not what you expect (vit D3) but vit D2 (the label, and package insert, dont tell you this) . vit  D3 powder is half the price but apparently 4 times as strong as D2.

ideally you should check your 25OH vit D and calcium levels to make sure you are on the right dose- but always taking some magnesia supplement, and at least 2 liter of water/ sodawater/clear fluid a day to avoid dehydration, kidney stones and vascular disease (which  highdose calcium supplement eg 1000mg  & vit D3   400iu/day cause).

8 April 2013  UPDATE: VITAMIN D3 THE AMAZING SUPPLEMENT

It is sad to record that Dr Walter Stumpf died suddenly a few months ago during ongoing correspondence. The world  has lost a teacher  of the century in both biological sciences and the humanities, metaphysics and philosophy,..

This week – as flu mushrooms  in the southern hemisphere autumn- the Canadian Medical Association Journal  April 3-8 features  early-release articles on concerns about the Asian flu viruses and especially the SARS-nCorVirus. Is mass vaccination the answer?  or did this in fact worsen mortality in previous North American  epidemics of eg H1N1?  which brings us back to global protection against infections and all major diseases with lowcost safe VitaminD3 at say 50 000iu(~700iu/kg)/week plus the other all-system protective  supplements – eg multivitamins (especially vit C and K) and minerals especially  magnesium, zinc, idine  and selenium; and during epidemic times, major daily boost in vits D3 and C.

In December 2012 the University of San Diego published a useful researched update on vitamin D3 and breast cancer; pointing out again that while the increase in benefit obviously drops off with increasing dose, safe dose is up to at least 10 000iu a day or 70 000iu a week, to a bloodlevel around 100ng/ml; and toxic dose requires at least 40 000 iu a day chronically (if not 600 000iu/d as other evidence suggests). The projections for breast cancer reduction fit with the same team’s predictions in 2007.

So apart from maintaining good water intake, and avoiding taking ill-advised unbalanced solo calcium supplement, for optimal dosing   in those with cancer or any other high risk, blood levels of both 25hydroxy vit D3,   1,25 calciferol, calcium, phosphate  and creatinine, should be monitored occasionally, to avoid the rare risk of kidney stones and arterial/breast calcinosis.

Remember that magnesia, phosphate and vitamin C  and K2 supplements are amongst the most important of at least 40  to accompany vitamin D3.

Last month three new studies affirmed the importance of vigorous vitamin D3 levels for genetic, heart and all health.

Holick’s group at Boston University   show the profound .Influence of vitamin d status and vitamin d3 supplementation on genome wide expression of white blood cells. No studies have reported on how vitamin D status and vitamin D3 supplementation affects broad gene expression in humans. A randomized, double-blind, single center pilot trial was conducted for comparing vitamin D supplementation with either 400 IUs (n = 3) or 2000 IUs (n = 5) vitamin D3 daily for 2 months on broad gene expression in the white blood cells collected from 8 healthy adults.   in the winter.   CONCLUSION SIGNIFICANCE: Our data suggest that any improvement in vitamin D status will significantly affect expression of genes that have a wide variety of biologic functions of more than 160 pathways linked to cancer, autoimmune disorders and cardiovascular disease with have been associated with vitamin D deficiency. This study reveals for the first time molecular finger prints that help explain the nonskeletal health benefits of vitamin D

Tehran University  http://www.ncbi.nlm.nih.gov/pubmed/23517460  showed clearly that    Vitamin D Supplementation Improve the Severity of Congestive Heart Failure. In  100  heart failure patients with (NYHA) class I ,   Only 6% of the participants had a sufficient serum concentration of 25(OH) D >30 nmol/L. Patients with insufficient or deficient serum levels of 25(OH) D (<30 ng/mL and <20 ng/mL, respectively) received oral vitamin D3 for 4 months. Vitamin D supplement increased mean serum 25(OH) D from 12.6 nmol/L to 54 nmol/L (P<.001). After vitamin D supplement, the serum level of pro-brain natriuretic peptide markedly decreased (P<.001). Cholecalciferol significantly decreased high-sensitivity C-reactive protein level (P<.001). Restoration of serum 25(OH) D level was also associated with substantial improvement in hear tfailure (P<.001) and 6-minute walk distance (P<.001).

 and Robert Heaney’s group at Creighton University   http://www.ncbi.nlm.nih.gov/pubmed/23514768  that .  All-Source Basal Vitamin D Inputs Are Greater Than Previously Thought and Cutaneous Inputs Are Smaller.    

The magnitude of vitamin D inputs in individuals not taking supplements is unknown.. they reanalyzed 3000 subjects’  individual 25(OH)D concentration data from 8 studies involving vitD3  supplement.  The total basal input (food plus solar) was calculated to range from a low of 778 iu/d in patients with end-stage renal disease to a high of 2667 iu/d in healthy Caucasian adults. Consistent with expectations, obese individuals had lower baseline, unsupplemented 25(OH)D concentrations and a smaller response to supplements. Similarly, African Americans had both lower baseline concentrations and lower calculated basal, all-source inputs. Seasonal oscillation in 4 studies ranged from 5.20 to 11.4 nmol/L, reflecting a mean cutaneous synthesis of cholecalciferol ranging from 209 to 651 iu/d at the summer peak. We conclude that: 1) all-source, basal vitamin D inputs are approximately an order of magnitude higher than can be explained by traditional food sources; 2) cutaneous, solar input in these cohorts accounts for only 10-25% of unsupplemented input at the summer peak; and 3) the remainder must come from undocumented food sources, possibly in part as preformed 25(OH).

Update March 2010

August 2009  SUMMARY: Evidence is overwhelming  that the prime sun-induced steroid hormone Vitamin D3 cholecalciferol – soltriol- is  invaluable in  20fold   higher  dose ie   perhaps  5000 to 10 000iu/day rather  than has been preached to date (200- 400iu/d), as part of lifelong  hormone replacement  HRT to prevent all major chronic degenerative diseases in all humans living and working indoors.  Effective dose of vitamin D3 supplement can reduce deathrate and disease by an astonishing 20%- that is indeed a panacea almost as good as other natural micronutrient supplements eg  fish oil, metformin, and appropriate sex hormone replacement SHRT.   It is becoming clear that with rare exceptions everyone- especially those  with serious disease eg cancer, heart, lung, brain, nerve/muscle/bone/joint  or inflammatory bowel diseases or  chronic infections like TB  HIV  influenza  or human papilloma virus –   should take a daily supplement of about 10 000iu (1/4 mg)  vitamin D for as little as ~ R10 US$1  a month ; ideally  under supervision of some  health professional.  All that is required is occasional check of blood chemistry, and good diet and  fluid intake.

And obviously because of vitamin D3’s  benefits in lowering all diseases, when using vigorous dose vitamin D, one must  expect to need to lower  prescription drug treatments for diabetes, hypertension, depression, heart disease, lung disease, arthritis, infections  etc  as these ailments  improve from the vitamin D  replacement over months.

INTRODUCTION:  Battling to help some desperate patients this week – mostly women-  with cancer, vascular, rheumatoid, lupus, diabetic, depressive, osteoporotic  and infective disease- especially now the quadruple perils of infections  influenza; human papilloma virus; AIDS and tuberculosis – let alone nuisances like shingles  candida or  herpes –  prompts a thorough review of the polyfunctional vitamin of this decade- vitamin D3, cholecalciferol, soltriol (Stumpf WE).

This  review is especially appropriate on our Womens’ Day 9 August 2009 for a natural product so important for the health of women , that commemorates the year  1956 when 20 000 women marched in defiance of  male despots’  fascist apartheid pass laws. The ages-old discrimination against women is epitomized by the pragmatic liberal economist Professor Ken Galbraith’s lecture to the Royal Society of Medicine in 1973 on the problem of unequal development and centralization of power in male technostructure – profit maximization.

No-where in business is this better shown than in Big Business creating demand  by saturation marketing,  including the medicalization of health.  This  involves  disease-mongering through creating unnecessary  concerns so as to expand markets among the well  for  patents eg  blanket cholesterol or mammography or colonoscopy  screening,  or remedies   for eg female arousal disorder, anxiety, reactive depression, mild-to-moderate hypercholesterolemia – when very few have been proven to  need or benefit from such labels, procedures and drugs.

VITAMIN D3  SOLTRIOL : INFORMATION EXPLOSION:

The first  of 46200 entries on Medline  on vitamin D is  from Oxford by Heaton 1922 . There are 272 500 entries on vitamins since 1918,  the first specific one by Jack Drummond in 192o, but of course vitamin D was first identified by Mellanby 1919, preceded by vits A, B1 and C between 1909 and 1912. From a recent historical review (table 1) of hormones, vitamin D3  was  perhaps the 7th hormone recognized  after testosterone and  estrogen (China 2600 years ago) ,  thyroid (1891)  epinephrine secretin parathyroid and antidiuretic hormone.

Soltriol is an  exquisite description  for a sun-activated steroid, the  cardinal prohormone vitamin D3  made  from cholesterol via sunlight exposure. Soltriol is not in a 1964 Oxford Dictionary, nor is it’s etymology detectable on Google search; it was indeed invented by  the pioneer polymath neurologist Dr  Walter Stumpf . On Medline search for soltriol, the first result is  Corradino 1973…

It is intriguing to read that Dr Stumpf  graduated in medicine in 1952- and 50 years later  in 2005 he wrote on his website: “From the microautoradiographic target recognition and related actions it follows that vitamin D has healing potential for prevention and treatment of various deficiencies and ailments, including old age: a PANACEA? If there is any compound that deserves being designated a panacea, the multifunctional heliogenic vitamin D appears a suitable candidate.   Philosophical consideration: “Vitamin D”, the term does not reflect its significance. I have used instead SOLTRIOL in several publications as a more appropriate designation. – Is there not a link to Heraclitus emanation of “ ever-living fire ”? The cosmic solar fire (Soltriol) as the sustaining life force, providing wave length energies for Temperature, Visible Light , and Ultraviolet B “. ”  The Main Biological Role of Vitamin D is Seasonal Adjustment of Vital Functions: These include regulation of growth, reproduction, survival stress response; endocrine and exocrine secretion, cell proliferation, cognition and mood; neuro-motor, neuro-endocrine, and neuro-sensory functions, immune response, cardio-vascular and gastro-intestinal functions, regulation of calcium and other mineral levels, cell proliferation and protein synthesis-differentiation.

Considering the decades of vitamin D use for its other benefits, it is ironic that a 1999 University California website on The History of Vitamin D has never been updated to cover more than the anti-rickets protection from vitamin D. But as Prof Stumpf writes to  me today, ultimately it is the sun that is the panacea, transmitting it’s healing powers via the skin-activated messenger hormone vitamin D.

 

It is now almost  a year since this column last reviewed vitamin D3’s benefits against all major diseases   (see table) – during which year  scores of new randomized controlled trials RCTs of vitamin D have appeared- there are now some 1680 RCTs on it since  1965.  Carpenter 1999 reviews Forgotten Mysteries in the History of Vitamin D.

Women have a raw deal:  due to their prime role and innate sense for survival of the species, for nuturing and caring, they live  about 10% longer than their mates, but as a result endure far more illness, as well as assault, disability and murder (mostly  inflicted by the careless male).

PROTEAN STEROIDS, PROTEAN FUNCTIONS: Calcitriol is one of many human steroids that include the sex hormones, aldosterne and digoxin; as well as  nonhuman steroids which also have important medicinal use- like phytosteroids, equine steroids like the equilins eg premarin, and the important ecdysteroids in insects and some plants.   Stumpf has again stressed the wide distribution in humans  of vitamin D receptors VDRs, indicating their importance in protean human functions far beyond calcium regulation.

VITAMIN D AND ALL-CAUSE MORTALITY: it is just a year since Melamed ea from USA showed that  having low vitamin D (as opposed to high level)  increases all-cause mortality by 26%- thus taking submaximum safe dose of vitamin D  can improve chance of survival by about 20%.  This for as little as R10/month – $1-  in South Africa.

In 2000,  the Seven Country Study Group showed that  ” saturated fat,vitamin C and smoking are the major determinants of all-causemortality at the population level” ie the higher the fat and smoking intake and the lower the vitamin C, the higher the deathrate. We now know better-  serious vitamin D deficiency joins the list, which of course includes alcoholism. .

VITAMIN D AND CARDIOVASCULAR DISEASE CVD

Pizzorno 2009 reviews the strong evidence of the importance of balanced vitamins A D and K supplements in reversing the epidemics of both CVD and osteoporosis.

VITAMIN D AND DEPRESSIVE/NEURODEGENERATIVE DISEASE

over 20 articles already this year attest to the importance of vigorous vitamin D levels in reducing these diseases.

VITAMIN D AND AUTOIMMUNE / INFLAMMATORY BOWEL DISEASE AND MUSKULOSKELETAL DISEASE:

The much higher incidence of autoimmune diseases in women – especially SLE systemic lupus erythematosis and RA rheumatoid arthritis-    let alone far higher younger  female  risk for fractures- must have  been obvious for millennia.  So obviously genetic female factors play a major role in these diseases – now surely attributable   largely to  the reproductively necessary absence of the Y chromosome, and thus the 100fold lower testosterone: estradiol T:E2 ratio in women (perhaps 2:1) than in men (in youth, >200:1).. It is common cause that estrogen is immunostimulant whereas testosterone  and progesterone (like vitamin D) are immunomodulating. Hence testosterone and progesterone levels soar during pregnancy to prevent the mother rejecting her foetus. This partly also explains why vigorous vitamin D supplement also greatly improves fertility and pregnancy outcome.

VITAMIN D AND RHEUMATOID ARTHRITIS: many studies  show  the benefits of the prime anabolic steroids- vitamin D and androgen (Devis 1950)  supplements-  in treatment of all inflammatory disease, especially when inflammation itself weakens bone and all other tissues. The latest – last month (Chabchoub 2009)- shows “a possible role for XCI mosaicism in the pathogenesis of RA and thyroid disease  and may in part explain the female preponderance of these diseases”. But the first and only randomized controlled trial of the effect of vitamin D on modifying  RA  appears in  1973 (Brohult)  and the only open  trial (Andjelkovic  1999) in RA  showed that            “alphacalcidiol is a powerful immunomodulatory agent with fairly low hypercalcemic activity”.

VITAMIN D INTOXICATION:  The low toxicity of vitamin D3  is fortunate because while it is ideal to monitor vitamin D levels on effective replacement, the blood test costs about R660- $80- locally;  hence all one needs to do is exclude kidney problems (which may need even higher dose of vitamin D3), and risk of kidney stones- but perhaps checking blood calcium and creatinine  at baseline and occasionally, and ensuring balanced supplement of calcium-magnesium – boron-zinc-manganese-(iron if deficient)  and vitamins B, C, D and K.   Since vitamin D intoxication (toxic rise in blood calcium- hypercalcemia) in some opinions  requires ~>600 000iu/day for months, ths is inconceivable unless one were to swallow say twelve  50 000iu vitamin D every day for months.   So the only recognized form of vitamin D intoxication could be an industrial accident involving mistaken use of vitamin D concentrate in medicine.

HYPERCALCEMIA HIGH BLOOD CALCIUM: medical causes  are rare without gross calcium overdose (milk alkali syndrome) or other specific symptomatic diseases – eg primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma.And fortunately most patients with these diseases and hypercalcemia are far more likely to benefit from therapeutic treatment with vitamin D than worsen on it.

OVERDOSE:      HYPERVITAMINOSIS D: WIKI says   “Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a half-life of about 20 to 29 days.[17] Ordinarily, the synthesis of bioactive vitamin D hormone is tightly regulated, and prevalent thinking is that vitamin D toxicity usually occurs only if excessive doses (prescription forms or rodenticide[38] .   Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 70 ng/mL (80 to 175 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose. Symptoms include Dehydration Vomiting Decreased appetite (anorexia) Irritability Constipation Fatigue.

Overdose of vit D3 has been observed at 1925 µg/d (77,000 IU per day). Acute overdose requires between 600,000 and 1,680,000 IU per day over a period of several days to months, with a safe intake level being 10,000 IU per day.

A 2007 risk assessment suggested that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit.[39] In adults, sustained intake of 100,000 IU can produce toxicity within a few months.[2] For infants (birth to 12 months) the tolerable UL is set at 1000 IU, and 40,000 IU has been shown to produce toxicity within 1 to 4 months.  All known cases of vitamin D toxicity with hypercalcemia have involved intake of or over 40,000 IU)[42].

Although normal food and pill vitamin D concentration levels are far too low to be toxic in adults, people taking multiples of the normal dose of codliver oil may reach toxic levels of vitamin A, not vitamin D, [43] if taken in an attempt to increase the levels of vitamin D. Most officially-recorded historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents.[42]

Some symptoms of vitamin D toxicity are a result of hypercalcemia caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure.[45] Gastrointestinal symptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop.[2] In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity.[46] Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL.[47] Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible.[2]

Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity.[42] This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.[48] Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day.[42]”

VITAMIN D AND SEX:

Biologically, the most imperative function for species survival is sex- reproduction.   Vitamin D is clearly a potent  anabolic reproductive steroid like testosterone:   The first paper on this association on Pubmed appears in 1963 from Russia (Gokinaeva).

Stumpf 1989 at Univ N Carolina reported that “vitamin D (soltriol)  regulates and modulates reproductive processes in the female and male, controlling  reproductive processes from onset of puberty to  fertility, pregnancy, lactation, and probably sexual behavior.”

Mirzahossein in 1996 showed that,” given in the critical period of foetal imprinting, vitamin D  may  influence steroid hormone-receptor commanded events for life in a way similar to synthetic steroid hormone analogues”. So as with marine omega3., it is crucial that future parents take enough vitamin D.

Friedrich 2002 showed that  even prostate, colon and   normal cervical tissue and cervical cancer cells have VDRs – vit D receptors- and may be new targets for cancer prevention or cancer treatment.

Kalueff 2005 showed that it influences even neurological receptors eg grooming behaviour in mammals.

And now Blauer 2009 shows that it reduces growth by up to 60% in human uterus muscle and fibroids- leiomyomas.

VITAMIN D AND PAIN: this week Khan ea from Kansas University describe Effect of vitamin D supplement  on  joint pain and fatigue in women starting adjuvant letrozole treatment for breast cancer. But the first Pubmed reference on vitamin D and pain is from von Wendt 1951.  Gerwin 2005 recognized vitamin D deficiency as a cause of fibromyalgia- chronic fatigue syndrome.

and Glueck ea from Cincinnati show that vitamin D supplement for low vitamin D abolishes statin – induced  myalgia.

VITAMIN D AND SLE- SYSTEMIC LUPUS ERYTHEMATOSIS: on medline the first reference to immunosuppression with vitamin D was  by Bourdial  1963 on nasal allergy, and the first  for vitamin D and immunomodulation is by Nagler & Pollack 1986.:

However, the first paper  on the importance of Vitamin D3 deficiency   in  SLE appeared in Germany  1963, but the first paper in English and from an English country  only in 1979 (O’Regan).

The focus throughout has been on the benefit of vitamin D in reversing the hyperimmunity  of SLE, but of course vitamin D is equally important in preventing both the osteoporosis of inflammation, the fracture and wasting risks  of cortisone treatment, and the vascular disease associated with SLE.  In the last year alone there have been 10 such SLE – vitamin D major studies – 7 from the Americas and 3 from Europe.

SLE as well as plain lupus of the skin are  generally regarded as disease that requires protection from the sun.

Now this week Wright 2009 shows that in children,  SLE is  associated with vitamin D deficiency, particularly among those subjects with SLE who are overweight.

VITAMIN D, SUNLIGHT,  SLE AND CANCER:

The first case of SLE associated with cancer ( meningioma and cervix)-  is reported by Williams  1956. The latest – last month- highlights increased risk of  lymphoma, cervix and bronchus cancers.

Search for malignant melanoma MM and SLE finds the first reference in 1963. yet most of the papers are about reactions to interferon therapy, or immune markers- there is one solitary case report (1991 Sulkes, Israel) of a patient with indolent SLE who after 15 years developed and died of rapidly spread of MM. These authors comment on the infrequent association of SLE & solid cancers, the commonest  being uterus and bladder.

So it is exciting that while more sun exposure causes skin cancer and especially cutaneous melanoma  CMM, (Tuohimaa  2007),  sun exposure also improves survival from CMM-  and from a wide range of internal cancers – (especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder and kidney cancers). This favourable effect of more sunshine is obvious when comparing the lower cancer and heart disease deathrates in sunnier southern versus the darker northern countries. Only rare skin diseases eg porphyria cutanea tarda are contraindications to sun exposure of the skin. But at least one study Holme 2008 shows vitamin D deficiency in erythropoetic porphyria.

Professor Halstead 2008 (and many others)  conclude  that the high fructose corn syrup routinely used in fast foods and cooldrinks in first-world manufacturing is rapidly increasing obesity, lipidemia (and metabolic syndrome and cancer);  while folic acid  food fortification is causing low  B12 levels and thus possibly increasing dementia, vascular disease and advanced precancerous colorectal adenomas and breast cancer.   This trend is aggravated by at least  three scientifically unvalidated  obsessions of Regulators and the Medical hierarchy:

1.   low diet cholesterol in those with mild to moderate cholesterolemia;

ii.  low vitamin D –  low intake dairy products and less  sunlight exposure for fear of skin cancer; and

iii. warfarin (which blocks essential vitamin K) to reduce thromboses- whereas it worsens  both fracture risk  and vitamin D and K deficiency, and thus  arterial calcification, cancer and fractures;   all of which are reversed by vigorous vitamin B3-6-9-12 , C, D  & K supplementation.

Protection from both cancers and SLE is probably  associated with higher vitamin D level above ~100nmol/L.  Both lupus and cancers are due to altered immunity.  But SLE is due to increased autoimmunity- hence cancers   are infrequent during active SLE;  whereas cancers are due to reduced immunity – hence are associated with immune suppression, whether by cortisone (including stress) / chemotherapy, or deficiency of vitamin D – dietary and lack of sunshine..

It is now common cause that more  cancers occur with suppressed  blood  cholesterol – whether  the low cholesterol is cause d by or due to the cancer remains to be clarified; and at least one of the major statin cholesterol-lowering trials showed increase in breast cancer cases.

While there is no clear overall  relationship of statins to osteoporosis or cancer,  Kunitomo   1989showed that cholesterol reduces and corticosteroids enhance the toxicity of vitamin D in rats.  Montagnani 1994 showed that pravastain does not  interfere with the circulating levels of the main vitamin D metabolites.

VITAMIN D AND INFECTION:

For an acute infection, Cannell and Hollis 2008    suggest  vitamin D in an antimicrobial  dose of 2000iu/kg eg 120 000 iu a day for 3  days- to produce enough of the naturally occuring antibiotic cathilicidin.  Ginde 2009 show that those with high vitamin D levels have less respiratory infections. This column has previously reviewed the dramatic benefits of vitamin D on infection mortality in AIDs- TB patients.   Obviously one is going to be cautious pushing vitamin D  in a patient with known kidney stones, or hypercalcemia.

VITAMIN D : WHY THE INCREASING DEFICIENCY, NEED FOR SUPPLEMENT ?

Never mind the poor and chronically ill, the aging especially need much more vitamin D, and benefit the most. Even in a sunny fishing nation like Spain, elderly women do not get enough vitamin D from fish or other foods, and most have suboptimal blood levels of it.

Apart from  dietary intolerance and obsession reducing intake of cholesterol and dairy products, the vitamins and minerals in particular have been greatly depleted and imbalanced in commercially produced- and especially genetically-modified  food.   And while increasing longevity,  food scarcity -poverty and   mushrooming prices (cartel pricefixing that is ignored by well-paid politicians and regulators) – are prime causes,  Politicians and Regulators have worsened this by falling decades behind in ignoring the leading 20th pioneer nutritionist/ economists  like the USA’s Professors Linus Pauling the unique double Nobel prizewinner prophet of vitamin C and peace; Ken Galbraith; and  the UK’s  Sir Jack Drummond. The latter two respectively brought the Allies (under FD Rooseveld and WS Churchill)  through  WW2 by putting farming- healthy food production and pricing- as the painfully obvious priority- which selfserving  gluttonous politicians  like Nixon, Bush,  Kissinger, Mugabe and Mbeki, and most others leaders (who support, not just tolerate such despots)  simply ignore since they detest “surplus people”- the honest  poor;  if not also  hardworking farmers.

It is no coincidence that Pauling and Galbraith both graduated from agricultural colleges.  And no coincidence that all three nutritionists were the targets of  politician-business moguls because of the obstacles they posed to the profiteering national economic sabotage that is the lifeblood of ruthless businessmen-capitalists from before Nixon- Connolly- Reagan- Kissinger  and Thatcher, through to the Bushes and Blair and Montsano-GD Searle, Mbeki and Zuma,  and the arms, oil, banking, mining, media,  food, sex, tobacco-alcohol and medical-big pharma industry mafiosi cartel  who make or break  presidents and  governments.

James Ferguson makes a strong case for The Vitamin Murders, that Drummond (and his family) were butchered in  a Vitamin Industry contract  in France as a lesson to do-gooders because his advocacy of the primary role of good natural  nutrition and vitamins  was such an obstacle  to the fast food and synthetic drug industry.    Conspiracy theorists could argue that, like Pauling’s vitamin C, the Drug Industry have through the FDA managed to ensure that only this year is the FDA grudgingly moving to raise the Recommended daily Allowances of vitamin D (and C)  even fractionally above the present rickets- (and scurvy) preventing doses, as opposed  to their   modest 25 to 50fold  fold   higher intakes that have been known already for decades to be both safe and major benefit against all diseases.

John Le Carre’s The Constant Gardner echoes that ongoing conspiracy scenario, the battle between Big Pharma with it’s drug lobbyists (including the USA FDA and the European Union’s European Medicine’s Authority, and leading politicians) to promote their lucrative modern synthetic chronic  drugs (none of which have been shown to reduce all-cause disease and mortality as do natural supplements), versus nutritionists and informed consumers who know that broad natural supplements (vigorous vitamins, minerals and biologicals)  to bolster the failing adulterated food chain are more important and effective  than any patented designer drugs in combating all disease. Unfortunately the necessary advocacy for natural supplements has been muddied by fraudsters  like the Big Pharma- FDA- academia  cartel (who swamp the medical literature with trial and review papers favouring their snake oils), the Rath Foundation, and our local dissidents against reason  like  Mbeki, and Drs Manto Tshabalala-Msimang, Nkosasama Zuma and Olive Shishana.

CONCLUSION: In 2006 Dr Walter Stumpf in THE DOSE MAKES THE MEDICINE wrote:  “in recent years, discussion raged  about the negative effects of   estrogen-replacement therapy and its relationship to cancer.  In numerous articles, the side-effects of estrogen treatment were highlighted in a generalized fashion and, although consideration was given to the duration of treatment, the relationships to dose (let alone type and route of estrogen) were frequently left out. And yet, considerations of dose and time in pharmacology and toxicology are paramount.
Similarly, a
wareness of proper dosage is crucial to the development of future vitamin D therapies. Physiologic dosing of vitamin D does not cause hypercalcemia – hypercalcemia is related  to overdosing ie closer to 100 000iu/day. Considering the many target tissues that are unrelated to systemic calcium regulation, most therapeutic effects of vitamin D occur independently of the high-dose systemic calcium effects. Because of the biased focus on calcium, the many other effects tend to remain unnoticed and hidden.  Future research needs to give more consideration to dose-effect relationships by monitoring target functions independently of systemic calcium regulation.
New therapeutic applications of vitamin D can be established for cardiovascular, neurological, endocrine, immune, gastrointestinal, reproductive and other diseases, including posttraumatic and gerontological deficiencies, in which the polyfunctional effects of  the hormone not only come to bear, but can also be controlled and maximized for optimal health.”

Since the global population shift from rural to   city life and work the past century ie in our lifetispan,  humans have largely gone from being healthy longlived outdoor food-producing  workers living on their own fresh produce including organically grown unadulterated fresh  food and dairy products – or fish- (rich in micronutrients),   to working mostly indoors and consuming largely  micronutrient-depleted  food  as well as multiple noxious deliberate industrial pollutants- from sugar and alcohol  to estrogenics, pesticides, heavy metals, cornsyrup and aspartamate.

Like fish oil is the most important food extract we have (and businessmen are ruthlessly harvesting to extinction), vitamin D3  has become the anti-disease vitamin  of the past decade,  joining vitamins C & B as the  panacea vitamins that can and should be supplemented in far higher dose than anti-vitamin  “Regulators” and professional researchers and associations (with vested interests in protecting  their funder- Big Pharma) approve.

But as the more affluent age and increase in numbers,  the micronutrients that deplete (with longevity, the deteriorating food chain, and unnecessary drugs),- especially  vitamins  K, chondroglucosamine, N-acetyl cysteine, alphalipoic acid, Co-Q10, arginine, carnitine, carnosine,  riboseand the marine  EPA and DHA-   are  fast becoming the “vitamins”  of the next decade.

Tragically, edible marine products especially marine omega3 EPA+DHA are rapidly becoming so scarce that the vast majority of people  can  neither  source nor afford the minimum optimal gram a day, until science breaks through  to synthesize these uniquely beneficial free fatty acids. But at least the supply of minerals, and vitamins including D3, is inexhaustible and therefore freely available at reasonable cost.

ndb

dedicated to Dr Walter Stumpf, whose  >300 papers (~24% on vitamin D) on Medline apparently  span 1963 to 2008- on vitamin D the first  in 1979, the last  30years later appropriately on Vitamin D and the digestive system.  By comparison,  Pubmed lists only 3 papers by Albright,   in 1938-9.

update Dec 2014: TIME TO MANDATE LOWDOSE RESERPINE+ LOWDOSE AMILOZIDE+- AMLODIPINE(/ DIHYDRALAZINE) AS FIRST LINE THERAPY OF AVERAGE HYPERTENSION.

TIME TO COMPELL FIRST LINE POLYTHERAPY OF COMMON  HYPERTENSION WITH LOWDOSE RESERPINE+ LOWDOSE AMILOZIDE; with AMLODIPINE as 4th add-on if needed.

dedicated;  for inspiration and help,  to: Drs YK Seedat; Roy Keeton;  Norman Kaplan; Colin Dollery, Harry Seftel; Josh Barzilay; Tony Bunn; Mark Blockman;  and pharmacists  Allan Taylor and Joe Talmud.

neil.burman@gmail.com    for previous reviews see  https://healthspanlife.wordpress.com/?s=reserpine+

https://healthspanlife.files.wordpress.com/2009/04/reserpine_table.pdf

update:  16 Dec 2014 THE RISKS OF MODERN ANTIHYPERTENSIVE DRUGS:  Pubmed search for ANTIHYPERTENSIVE DERMATITIS REACTIONS brings up >156 papers from 1970 (on practolol, propranolol, atenolol, labetolol, hydralazine, ACEI); we first encountered practolol (BBlocker) problems  in the ’70s;  and captopril (ACEI) dermatitis about 1980; Dermatitis  has also been reported since 1987 with calcium channel blockers. WHY USE ACEI/ARBS and BETABLOCKERS -with their added airways and circulatory risks -EXCEPT AS LAST RESORT?   when these are now routinely combined with other synthetic designer drugs clopidogrel (a sulfonamide) , or /and non-sulfonamide warfarin, aspirin, other NSAIDs and statins; sulphonylureas, glitazones, which cause serious multiple complications including dermatitis.

The problematic Bblockers, ACEI, ARBs, aspirin, NSAIDs,  clopidogrel, warfarin  and  statins are rarely indicated; whereas  the hypersensitiviy  risk with thiazide (hydrochlorothiazide – a sulfonamide – halflife ~10hrs  ) PLUS AMILORIDE (halflife ~7.5hrs,  not a thiazide)  is rare;  and reserpine (not a sulfa, half-life ~10days)  actually suppresses allergic risk;

and natural extracts- fish oil, coconut oil,  vigorous vitamins B, C, D3, E, K2;   magnesium, zinc, selenium, boron, iodine,   garlic, curcumin, gymnema, metformin, reserpine, cayenne, MSM/DMSO, arginine, carnitine, ribose, CoQ10, proline, alphalipoic acid, acetylcysteine- do far more good without harm (than heavily marketed designer synthetics) in addressing the root causes of the common degenerative  diseases of aging rather than addressing just their symptoms, as drug companies do. .

Refs: 1. Immunopharmacol Immunotoxicol. 2013 :35:447-50 “Cutaneous antihypertensive adverse drug reactions (ADRs) have been frequently reported. Vena,  De Simone ea  University of Bari, Italy reported Eczematous reactions due to angiotensin-converting enzyme inhibitors ACEIs or angiotensin II receptor blockers ARBs  in 23 hypertensive patients patients aged 66-87 years; 19 of them were taking another drug in addition to the suspected antihypertensive medication and 15 were on polytherapy with three or more drugs to treat multiple comorbidities. The antihypertensive culprit agents were (ACE) inhibitors in 9 patients, ACEI combined to hydrochlorothiazide (HCT) in 7 subjects, ARBs  alone in 2 patients and associated with HCT in 5 cases. Eczema was generalized in 16 patients and localized in 7 cases, with predominant involvement of lower limbs. Such lesions developed after a latency of 4-30 months and were associated with moderate-to-severe itch, usually unresponsive to oral antihistamines. Histopathology  was spongiotic dermatitis with possible associated psoriasiform skin changes.”

2.  In the Textbook  Adverse Drug Reactions 2nd Ed by Anne Lee, Pharmaceutical press 2006,  the chapter Drug Skin Reactions exhaustively lists all causative drugs – only  reserpine/ rauwolfia is not mentioned since it prevents hypersensitivity:

  3. J Exp Med. 1985 Dec 1;162:1935-53. Reevaluation of reserpine-induced suppression of contact sensitivity. Evidence that reserpine interferes with T lymphocyte function independently of an effect on mast cells. Mekori YA, Weitzman GL, Galli. Harvard & Tel Aviv Universities  “ reserpine blocks expression of delayed hypersensitivity (DH) by depleting tissue mast cells of serotonin (5-HT), preventing a T cell-dependent release of mast cell 5-HT necessary to localize and to amplify the DH response; findings strongly suggesting that whatever effects reserpine might have on immunologically nonspecific host cells, it’s effects on sensitized T cells are sufficient to explain its ability to block cell-mediated immune responses in vivo.

No recent review gives objective evidence-based opinion free of drug industry vested influence about optimal initial antihypertensive  drug therapy that contradict the above evidence.

13 December 2014: latest analyses of all antihypertensive trials confirm that LOWDOSE (potassium-sparing) diuretic- eg amilozide-   LOWDOSE reserpine, and if needed as 4th drug, calcium channel blocker eg amlodipine,  each  individually lower all major events including MORTALITY, ( and refractory lowers refractory pain).  Betablockers, ACEI and ARBs do not reduce mortality- and have major adverse effects. .

Thomopoulos ea (Univs Athens & Milan) J Hypertens Dec 2014   Effects of various classes of antihypertensive drugs on outcome incidence in hypertension, asks which  BP-lowering drug classes  are  effective in reducing MORTALITY?  In 55 RCTs (~200 000 individuals) all  common antihypertensive drugs lowered  BP , stroke,  and major cardiovascular events; but in 2014 use, only  a diuretic (even lowdose); and calcium antagonists  gave  significant reductions of all outcomes including mortality.

PAIN SUPPRESSED BY RESERPINE:    S Afr Med J. 1991;80:176-8.  Significant cost-saving with modification of antihypertensive therapy. Keeton & Monteagudo, Univ.Cape Town.    30 patients  on nifedipine for hypertension or chest pain were followed up for 6 months after alternative therapy- Reserpine combined with a thiazide- was instituted: blood pressure control improved and no serious side-effects were encountered. This  reduced the monthly cost by  73%. Although a self-assessment depression inventory was completed by 21 patients, our study does not fully evaluate the impact on quality of life. The likelihood of side-effects is  small–provided  the maximum daily dose of reserpine does not exceed 0.1 mg. A more considered approach is needed in the choice of antihypertensive agents.

Arch Inst Cardiol Mex. 1977 ;47:101-8. Prinzmetal’s angina Response to  treatment with reserpine. Review of physiopathological mechanisms. Guadalajara , Horwitz , Trevethan  present a case of Prinzmetal angina refractory to classic medical treatment, in which the angina attacks were suppressed with  reserpine .Coronary spasm due to alteration in the regulation of the coronary arterial tone from  autonomic nervous system illness is established, an abnormal coronary vascular reactivity is also reviewed. It is emphasized that Prinzmetal angina is an original entity, different from  coronary arteriosclerotic heart disease, which may coexist with it but which cannot be treated in the same way, because its physiopathologic mechanisms are different.

Cardiovasc Dis. 1974;1:194-201. PRINZMETAL ANGINA PECTORIS WITH NORMAL CORONARY ARTERIOGRAMS: EFFECT OF LONG-TERM RESERPINE TREATMENT.   Hernandez-Casas, Leachman ea . Baylor  St. Luke’s Houston, Texas

7 December 2014:  Medscape 2013 : the modern theory  Pathogenesis of essential hypertension HBP  is highly complex: Multiple factors modulate blood pressure (BP) for adequate tissue perfusion : Humoral (ie in the blood- hormonal, immune, nutritional), Vascular reactivity , Circulating blood volume, Vascular caliber, Blood viscosity, Cardiac output, Blood vessel elasticity, Neural – autonomic stimulation.                          Over the course of its natural history, essential HBP progresses from occasional to established HBP.  After a long invariably asymptomatic period, persistent HBP develops into complicated HBP, in which target organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident.

The progression of essential HBP begins with prehypertension in persons aged 10-30 years (by increased cardiac output) and then advances to early HBP in persons aged 20-40 years (increased peripheral resistance ), then to established HBP in persons aged 30-50 years, and finally to complicated HBP in persons aged 40-60 years.

Hence to prevent HBP becoming established and complicated by midlife, both the lifestyle/ nutritional factors, and the neural- stress and the RAAS renal-aldosterone- angiotensin systems – need to be optimized in young adulthood, in the early workplace  if not childhood ie at school: with reintroduction at  school of compulsory physical education/sport;  banning of  tobacco,  refined sugar  and retail salt sale; universal ingestion  3 times a week at least of a tsp of codliver oil  equivalent (before it becomes unobtainable;)  and a tblsp of virgin coconut oil; and if bloodpressure does not normalize, addition of at least 3 times a week 1/2 reserpine  ie 0,125mg and 1/2 amilozide ie 27.5mg , to address most of the risk factors, as detailed below a week ago. .

Kostis  ea, Univ Harvard; Rutgers,. Columbia,Texas, Am J Cardiol. 2014 Feb examined Competing cardiovascular and noncardiovascular risks and longevity in the Systolic Hypertension in the Elderly   Program SHEP with  chlorthalidone-based stepped care (n = 2,365) or placebo (n = 2,371) for 4.5 years,. all participants were advised to take active therapy thereafter. At the 22year follow-up,  gain in life expectancy free from CV death in the active treatment group was 145 days  ( p = 0.012). The gain in overall life expectancy was smaller (105 days)because of a 40-day (95% CI -87 to 161) decrease in survival from non-CV death. Compared with an age- and gender-matched cohort, participants had markedly higher overall life expectancy ( p = 0.00001) and greater chance of reaching the ages of 80 (81.3% vs 57.6%), 85 (58.1% vs 37.4%), 90 (30.5% vs 22.0%), 95 (11.9% vs 8.8%), and 100 years (3.7% vs 2.8%). In conclusion, Systolic Hypertension in the Elderly Program participants had higher overall life expectancy than actuarial controls and those randomized to active therapy had longer life expectancy free from CV death but had a small increase in the competing risk of non-CV death

The 2013 Statement by the International & American Societies of Hypertension( including all continents and South Africa) includes amiloride-HCTZide  ; and reserpine 0.1 mg/day in the array of drugs to be combined for optimal  BP control.  “Thiazide-like Diuretics: reduction of major cardiovascular CVD and  stroke events have been established. Main side effects are metabolic (hypokalemia, hyperglycemia, hyperuricemia), which  can be reduced by using low doses (eg, 12.5 mg or 25 mg of HCTZ) or by combining these diuretics with  potassium-sparing agents eg angiotensin-blockers, amiloride etc .    Note: Thiazides plus   b-blockers are also an effective combination for reducing blood pressure, BUT since both  increase blood glucose concentrations,  use with caution in patients at risk for diabetes.  Angiotensin-converting enzyme inhibitor ACEIs’ main side effect is cough (most common in women and in patients of Asian and  African background). Angioedema is an uncommon but potentially serious complication that can threaten airway function, and it occurs most frequently in  black patients.

Given the above -quoted longstanding established dangers of bblockers and ACEI; and that the  majority of older State chronic  patients around Cape Town are black and Asian women,  overweight hypertensive diabetic smokers, it is negligence on the part of State authorities that most State patients are treated with deleterious betablockers (atenolol), Angiotensin blockers and HCTZ ; instead of primarily with the longproven optimal lowdose reserpine, amilozide and amlodipine.

    30 Nov 2014  NEW  studies below  confirm  that the renin-angiotensin-aldosterone system RAAS  and the autonomic nervous systems ANS  are the two networks that primarily regulate bloodpressure.   In baseline treatment of common essential HBP, Increasing recent research points to the prime role of amiloride  –  thiazide combination  eg Moduretic, Amiloretic –  and arginine (nitric oxide stimulant) – addressing the RAAS;  – with reserpine  addressing the  ANS and anxiety.   

This combination overcomes much of the pathophysiology of  essential HBP ie raised cardiac output, and  aldosterone excess  sodium retention vascular load increase, potassium-magnesium wasting,  endothelial swelling ie stiffness  from low nitric oxide; vascular spasm;  and insulin resistance from aldosterone (and  thiazide and betablocker);  and counterbalances the harms of higher-dose thiazide (glucose intolerance-lipidemia, potassium-magnesium-wasting, hyperuricemia), but also avoids the numerous adverse effects of  spironolactone (a steroidal antihormone) and triamterene;

and the cardiorespiratory risks of betablockers, and ARBs. The evidence in fact supports use of amiloride lowdose preventatively in a highrisk prehypertensive population. just as the prohormone metformin is used preventatively in reversing weight gain to prevent diabetes, atheroma and PCOS inferti9lity..

refs: 1.  Nutr Hosp. 2014 Dec.   ALDOSTERONE: A CARDIOMETABOLIC RISK HORMONE?    Pereira Bressan  ea.University of Viçosa, Brazil..  Aldosterone is a component of the renin-angiotensin-aldosterone system, classically known for its role in sodium and water retention. Besides its renal effects, aldosterone is associated with the pathogenesis and progression of metabolic syndrome components. Diet can affect plasma aldosterone levels; high fructose and fat intake can lead to increased aldosterone levels, whereas the effect of sodium intake remains controversial. Adipose tissue, particularly visceral tissue, appears to produce a lipid-soluble factor that increases aldosterone production. Patients with metabolic syndrome have higher aldosterone levels; moreover, an increased cardiometabolic risk associated with insulin resistance could be partially mediated by the action of aldosterone via mineralocorticoid receptors. Even a subtle activation of this hormonal system may have deleterious effects on the glucose and lipid metabolism related to metabolic syndrome.

2. Semin Nephrol Sept  2014 . . Pathophysiology and Treatment of Resistant Hypertension: The Role of Aldosterone and Amiloride-Sensitive Sodium Channels.    Judd EK1, Calhoun DA2, Warnock DG2. University of Alabama.    Resistant hypertension is a clinically distinct subgroup of hypertension defined by the failure to achieve blood pressure control on optimal dosing of at least 3 antihypertensive medications of different classes, including a diuretic. In the absence of demonstrable renal, vascular and common endocrine causes, pathophysiology of hypertension can be attributed to aldosterone excess in more than 20% of patients with resistant hypertension. Dogma attributes increase in blood pressure seen with increases in aldosterone to its antinatriuretic effects. However, emerging research,  has identified and defines the function of amiloride-sensitive sodium channels eNaC and mineralocorticoid receptors in the systemic vasculature, challenges impaired natriuresis as the sole cause of aldosterone-mediated resistant hypertension. It thus highlights the cardinal role of amilozide in hypertension therapy.

3. Pflugers Arch. 2014 Nov:  Salt controls endothelial and vascular phenotype.Kusche-Vihrog ,  Brand ea. University of Muenster,  Germany. High salt (NaCl) intake promotes  development of vascular diseases independent of  rise in blood pressure, whereas reduction of salt consumption has beneficial effects for the arterial system. We focus on  endothelial Na+ channel (EnNaC)-controlled nanomechanical properties, since high Na+ leads to an EnNaC-induced Na+-influx and subsequent stiffening of endothelial cells. Mechanical stiffness of the endothelial cell (i.e., the endothelial phenotype) plays a crucial role as it controls the production of the endothelium-derived vasodilator nitric oxide (NO) which directly affects the tone of the vascular smooth muscle cells. In contrast to soft endothelial cells, stiff endothelial cells release reduced amounts of NO, the hallmark of endothelial dysfunction. This endothelium-born process is followed by the development of arterial stiffness (i.e., the vascular phenotype), predicting the development of vascular end-organ damage such as myocardial infarction, stroke, and renal impairment. In this context, we outline the potential clinical implication of arginine, direct (amiloride) and indirect (spironolactone) EnNaC inhibition on vascular function.

4. J Clin Hypertens (Greenwich). 2014 Jan  Epithelial sodium channel eNaC inhibition by amiloride on blood pressure and cardiovascular disease risk in young prehypertensives.   Bhagatwala , Dong  ea, Regents University, Augusta, GA.. Overactivity of epithelial sodium channel (ENaC) is considered to be one mechanism underlying obesity-related blood pressure (BP) elevation. In a nonplacebo-controlled clinical trial , the authors aimed to comprehensively evaluate the effects of amiloride monotherapy, an ENaC blocker, on BP and cardiovascular risk in young adults with prehypertension (n=17). Following 10 mg daily amiloride for 4 weeks, peripheral systolic BP (SBP), central SBP, and carotid-radial pulse wave velocity were significantly reduced by -7.06±2.25 mm Hg, -7.68±2.56 mm Hg, and -0.72±0.33 m/s, respectively, whereas flow-mediated dilation was significantly increased by 2.2±0.9%. Following amiloride monotherapy for 4 weeks, a significant increase in serum aldosterone was observed (5.85±2.45 ng/dL). ENaC inhibition by amiloride may be used as an early intervention to halt the progression to full hypertension and cardiovascular disease in young adults with prehypertension.
5. J Hum Hypertens. 2013 Nov Diastolic blood pressure reduction ontributes more to the regression of left ventricular hypertrophy: a meta-analysis of randomized controlled trials.  Zhang  Huang ea Sun Yat-sen University, ChinaLeft ventricular hypertrophy (LVH) is an independent cardiovascular risk factor; however, the key strategy necessary for LVH regression in hypertensive patients is not clear. A meta-analysis was conducted to study the effect of blood pressure reduction on LVH regression. A total of 17 randomized controlled trials comprising 2196 hypertensive patients (mean age, 56.3 years; 64.1% were men) were identified. The most significant decrease in LVH was seen in patients with a mean age over 60 years in the DBPM10 group. The renin-angiotensin system inhibitor was found to be the most effective antihypertensive drug for LVH regression. This meta-analysis result indicates that proper DBP reduction plays an important role in the regression of echocardiographic LVH in hypertensive patients.

6. Hypertension. 2012 .Double-blind, placebo-controlled, crossover trial comparing the effects of amiloride and hydrochlorothiazide on glucose tolerance in patients with essential hypertension. Stears, Brown ea University of Cambridge.    Hypertension guidelines advise limiting dose of thiazide diuretics and avoiding combination with β-blockade, because of increased risk of diabetes mellitus. We tested whether changes in the 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with a thiazide and could be avoided by switching to amiloride. . For similar blood pressure reductions, there were opposite changes in glucose between the 2 diuretics (P<0.0001).  There was a negative correlation between Δpotassium and Δ2-hour glucose (r=-0.28; P<0.0001). In 2 crossover studies, 4 weeks of treatment with a thiazide diuretic impaired glucose tolerance. No impairment was seen with K(+)-sparing diuretic or β(1)-selective blockade. Substitution or addition of amiloride may be the solution to preventing thiazide-induced diabetes mellitus.

7.   Am J Physiol Endocrinol Metab. 2008  Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.  Gunawardana , Piston ea .Vanderbilt University, Nashville, TN. Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus both DMA and arginine have the potential to correct the secretory defect in diabetes by enabling or enhancing TDP. In the current study we  demonstrated the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of NOS is not the only mechanism through which DMA exerts its positive effects. Thus we also have explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase.

8.  Circulation. 1995 Comparison of five antihypertensives and placebo on nutritional-hygienic therapy in  Treatment of Mild Hypertension Study (TOMHS). Liebson, Stamler ea . St Luke’s Medical Center, Chicago, in a double-blind, placebo-RCT  of 844 mild hypertensive participants randomized to nutritional-hygienic (NH) intervention plus placebo or NH plus one of five  antihypertensive agents: (1) thiazide (chlorthalidone), (2) beta-blocker (acebutolol), (3) alpha-antagonist (doxazosin), (4) calcium antagonist (amlodipine ), or (5) ACEI (enalapril).  Changes in BP averaged 16/12 mm Hg in the active treatment groups and 9/9 mm Hg in the NH only group. All groups showed significant decreases (10% to 15%) in LVM from baseline that continued for 48 months.  chlorthalidone  caused the greatest decrease in LVM at each follow-up visit (average decrease, 34 g),  (average decrease among 5 other groups, 24 to 27 g). Participants randomized to NH intervention only had mean changes in LVM similar to those in the participants randomized to NH intervention plus pharmacological treatment. The greatest difference between groups was seen at 12 months, with mean decreases ranging from 35 g (chlorthalidone group) to 17 g (acebutolol group) (P = .001 comparing all groups). 

9.  Arch Intern Med. 1981  Multiclinic comparison of amiloride, hydrochlorothiazide, and hydrochlorothiazide plus amiloride in essential hypertension. Multicenter Diuretic Cooperative Study Group.   [No authors listed}  A randomized, double-blind, multicenter study comparing amiloride hydrochloride, amiloride hydrochloride plus HCTZ, and HCTZwas conducted in 179 patients with mild to moderate essential hypertension (diastolic pressure, 95 to 115 mm Hg). After 12 weeks of treatment, significant reductions in pressure were observed for all three treatment groups. Systolic pressure reduction was greatest for amiloride plus hydrochlorothiazide. Baseline vs 12-week average supine pressures were 153/101 vs 139/93ie -14/8 mm Hg for amiloride, 160/100 vs 137/90 ie -23/10mm Hg for amiloride plus HCTZ, and 154/101 vs 134/89 ie -20/12mm Hg for HCTZ. Baseline vs treatment mean serum potassium levels were 4.24 vs 4.47 mEq/L for amiloride, 4.24 vs 3.86 mEq/L for the combination, and 4.15 vs 3.56 mEq/L for HCTZ. The changes in serum potassium level from the baseline for amiloride plus HCTZ were significantly different from those for HCTZ throughout the study (except for week 6). All drugs were well tolerated, and no drug-related toxic reaction was detected. This study demonstrates the efficacy of amiloride and amiloride plus HCTZ as diuretic antihypertensive potassium-conserving agents.

27 Nov 2014 THE IMPORTANCE OF NORMALIZING RESISTANT HYPERTENSION : THE ALLHAT TRIAL Furberg ea  December  2002 was the biggest  trial that compared a thiazide with other standard antihypertensive drugs in highrisk patients, and confirmed thiazide’s  superiority over amlodipine, lisinopril, and especially doxazosin. This was confirmed in the smaller shorter CONVINCE multinational trial Black ea a few months later, which showed that as single therapy, verapamil was inferior to a thiazide or atenolol.

The latest report of the landmark  5 year USA ALLHAT trial by Munter ea  now reports  on apparent   Treatment-resistant hypertension aTRH  and the incidence of cardiovascular disease and end-stage renal disease: “These results demonstrate that aTRH increases the risk for cardiovascular disease by almost 50%, doubled end-stage renal disease, and increased all-cause mortality- heart and peripheral circulatory failure  – by 30%. Although a high prevalence of aTRH has been reported, few data are available on its association with cardiovascular and renal outcomes. We analyzed data on 14684 (ALLHAT) participants to determine association between aTRH (n=1870) with coronary heart disease, stroke, all-cause mortality, heart failure, peripheral artery disease, and end-stage renal disease. We defined  Apparent treatment-resistant hypertension aTRH as blood pressure not at goal (systolic/diastolic blood pressure ≥140/90 mm Hg) while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication with blood pressure at goal during the year 2 ALLHAT study visit (1996-2000). Use of a diuretic was not required to meet the definition of aTRH. Follow-up occurred through 2002.

24 Nov 2014  NOTE  how Big Pharma has lied in corrupting the Wikipedia section (in italics below)  on reserpine so as to try to further sideline this excellent natural drug: the adverse  highlights below  in red are based on ancient data from when Reserpine  was used decades ago in the West in 5 to 50 times higher doses than have been used without adverse effects in trials the past  20 years, and for centuries in India as the parent Rauwolfia:

Reserpine:because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today.Nonsense. This ignores the numerous side-effects of betablockers, ACEI, ARBs and CCBs other than amlodipine.  The reserpine-induced depression is considered by some researchers to be a myth, while others claim that teas made out of the plant roots containing ie lowdose reserpine has a calming, sedative action that can actually be considered antidepressant.[4] Notably, reserpine was the first compound shown to be an effective antidepressant in a randomized placebo-controlled trial.[5]      It may take the body days to weeks to replenish the depleted VMAT, so reserpine’s effects are long-lasting- a major advantage if patients take drugs irregularly. Tryptophan is the starting material in the biosynthetic pathway of reserpine, and is converted to tryptamine by tryptophan decarboxylase enzyme. Various enzymatic conversion reactions lead to the synthesis of reserpine from strictosidine.[8]

This depletion of dopamine can lead with reserpine overdose to drug-induced parkinsonism. THIS IS ONLY IN EXCESSIVE RESERPINE DOSE.  Reserpine has been discontinued in the UK for some years due to its numerous interactions and side effects. nonsense it was discontinued to protect Big Pharma newer antihypertensive drugs eg  Cardura, metoprolol, lisinopril; ARBs, Exforge etc .

“THE Reserpine-THIAZIDE  COMBINATION (WITH OR WITHOUT OTHER OLD DRUGS EG POTASSIUM-SPARERS AND HYDRALAZINE)  is one of the few antihypertensive medications that have been shown in randomized controlled trials to reduce mortality:

“The Hypertension Detection and Follow-up Program,[14] the Veterans Administration Cooperative Study Group in Anti-hypertensive Agents,[15] , the Systolic Hypertension in the Elderly Program, and now the Chinese reserpine trial 2011- which outstanding results  the Wiki article  doesnt bother to  mention. .

Reserpine is rarely used in the management of hypertension today. NONSENSE – that is merely the explicit wish and intent of Big Pharma.  Reserpine is listed as an option by the JNC 7.[17] Reserpine is a second-line adjunct agent for patients who are uncontrolled on a diuretic when cost is an issue.[18]   The daily dose of reserpine in antihypertensive treatment is as low as 0.1 to 0.25 mg – IN FACT 0.0625 t0 0,125MG/dAt doses of less than 0.2 mg/day, reserpine has few side effects, the most common of which is nasal congestion- SO WE NEVER PERSIST WITH  above 0.125mg/d

ONLY IN GROSS OVERDOSE:”There has been much concern about  Reserpine causing: depression leading to suicide; nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric ulceration , stomach cramps,diarrhea.. . hypotension, bradycardia; Congested nose,erectile dysfunction drowsiness, dizziness,.. nightmares. Parkinsonism … General weakness, fatigue … may worsen asthma ; hyperprolactinemia… dangerous decline in blood pressure at doses needed for treatment. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. . The above litany conveniently omits that these problems were reported in uncontrolled studies using reserpine doses averaging 0.5+ mg per day.[22][23] they do not occur at effective  low antihypertensive reserpine dose combined with lowdose diuretic. “

Nine years ago we reviewed in the BMJ  why reserpine plus thiazide is  The best-proven two-drug hypertension regime in primary care,

update 20 Nov 2014  the Sept  2014 influential French review Prescrire Int reviews the available evidence Treating essential hypertension- As in 2004, the first choice is usually a thiazide diuretic TZD  .. The current treatment threshold for hypertensive adults without diabetes or cardiovascular or renal disease is blood pressure above 160/90-100  mmHg. Apart from certain diuretic-based combinations, the use of combinations of antihypertensive drugs as first-line therapy has not been evaluated in terms of the complications of hypertension. systematic  meta-analyses of  tens of thousands of patients have compared the main classes of antihypertensive drugs against each other and against placebo. Compared with placebo, only low-dose TZDs and angiotensin-converting enzyme (ACEI) inhibitors have been shown to reduce all-cause mortality in hypertensive patients. They prevent  about 2 to 3 deaths and 2 strokes per 100 patients treated for 4 to 5 years. Systematic reviews conclude that neither calcium-channel blockers CCBs, ACEI nor beta-blockers BBs are more effective than thiazide diuretics TZDs  in reducing mortality or the incidence of stroke. The efficacy of the TZD chlorthalidone is supported by the highest-level evidence, three comparative clinical trials versus placebo, an ACEI, or a CCB, in more than 50 000 patients. In one of these trials, chlorthalidone was superior to the ACEI lisinoprilin preventing stroke; and  to the CCB amlodipine in preventing heart failure. The effect of hydrochlorothiazide HCTZ , combined with amiloride or triamterene, on cardiovascular morbidity and mortality has been demonstrated in three comparative clinical trials versus placebo, BBs, or a CCBHCTZ appeared more effective than the BB atenolol in reducing the incidence of coronary events.  Indapamide another TZD is less convincing that it is more effective than chlortalidone or HCTZ. None of the antihypertensive drugs appears to have a better overall adverse effect profile than the others. Thiazide diuretics can provoke hyperglycaemia and diabetes, although this does not reduce their efficacy in the prevention of cardiovascular events. As in 2004, in 2014, the first-choice treatment for hypertension in nondiabetic adults without cardiovascular or renal disease should be a thiazide, possibly combined with amiloride or triamterene. When a diuretic cannot be used, it is better to choose an ACEI: captopril, lisinopril or ramipril.

But TZDiuretic halflife is at best 15hrs (HCTZ); and for smoother hypertension control they need to be gentle and not major diuresis-inducing,  so that they do not disturb sleep or daytime function. and TZDs dont damp down compensatory heart speedup and arrhythmia, or lipidemia-hyperglycemia- which reserpine does. and lowdose reserpine doesnt cause the cough or breathlessness that ACEI, ARBs or BBs may.

This review needs to be read with Shamon & Perez‘  2009 University of British Columbia Canadian Cochrane report : the first systematic review of reserpine for essential hypertension  “Many antihypertensive agents exist today for primary hypertension (systolic blood pressure >/=140 mmHg and/or diastolic blood pressure >/=90 mmHg).  Reserpine was  a second-line therapy in some of those trials.   Included studies were truly randomised controlled trials comparing reserpine monotherapy to placebo or no treatment in patients with hypertension.  MAIN RESULTS: Four RCTs (N =237) were found that met the inclusion criteria. The overall pooled effect demonstrates a statistically significant systolic blood pressure (SBP) reduction on reserpine compared to placebo (WMD –8mm, 95% CI -14.05, -1.78).   None of the included trials reported withdrawals due to adverse effects.   AUTHORS’ CONCLUSIONS: Reserpine is effective in reducing SBP roughly to the same degree as other first-line antihypertensive drugs. But this analysis is outdated because it has long been common cause that  the best firstline treatment of hypertension is the balanced combination of reserpine with a potassium-sparing diuretic.

Lowdose Reserpine is the sole anxiolytic antidepressant antipsychotic antiserotoninergic antihypertensive drug that lasts, acts  for weeks  rather than days (amlodipine) or  hours (the TDZs, ACEI, ARBs)- and has no adverse effects; so it doesnt matter when it is taken;  when stopped, it takes weeks for it to completely wear off. And severe stress anxiety insomnia is so often a major component of severe essential hypertension. “Reserpine is an ancient tranquilizer, derived from a plant used in India for centuries. It has a powerful tranquilizing action, has been used to treat hypertension, and was found to be an antidepressant (Davies and Shepherd, 1955)”

Hence combining lowdose eg 0.125mg/d or less reserpine – even 3 days a week ie 0.05mg/d-  with amilozide 13-27mg/d as a morning or midday  dose  is ideal- especially when nighttime systolic hypertensionNSBP  is the strongest predictor of CVEs cardiovascular events, as shown in a new international study in Europe, Brazil, and Japan by Universities of USA, UK and Europe:  Roush, Zamalloa ea The ABC-H Investigators ; Journal of Hypertension (Oct 2014)   Prognostic impact from clinic, daytime, and night-time systolic blood pressure NSBP in nine cohorts of 13 844 patients with hypertension;     To determine which SBP measure best predicts cardiovascular events (CVEs- coronary artery disease CAD and stroke) independently, systematic review was conducted for all patients with hypertension,>1+ years follow-up..   Nine cohorts (n = 13 844) were from Europe, Brazil, and Japan. Results: Overall, NSBP’s dispersion exceeded DaySBP’s dispersion by 22.6% with nonoverlapping confidence limits. Within all nine cohorts, dispersion for NSBP exceeded that for ClinicSBP and DSBP ( P = 0.004)  Considered individually, increases in NSBP, DSBP, and CSBP each predicted CVEs: hazard ratios (95% confidence intervals) = 1.25 (1.22-1.29), 1.20 (1.15-1.26), and 1.11 (1.06-1.16), respectively. However, after simultaneous adjustment for all three SBPs, hazard ratios were 1.26 (1.20-1.31), 1.01 (0.94-1.08), and 1.00 (0.95-1.05), respectively. Cohorts with baseline antihypertensive treatment and cohorts with patient-specific information for night-day BP classification gave similar results. Within most cohorts, simultaneously adjusted hazard ratios were greater for NSBP than for DSBP and CSBP:  In hypertensive patients, NSBP had greater dispersion than DSBP and CSBP in all cohorts. On simultaneous adjustment, compared with DSBP and CSBP, increased NSBP independently predicted higher CVEs in most cohorts, and, overall, NSBP independently predicted CVEs, whereas CSBP and DSBP lost their predictive ability entirely. This trial confirms the 2012 Hosomi ea Japanese trial showing that to minimize (repeat) stroke from night BP variance, Antihypertensive medication taken in the evening or at bedtime is the most effective in treating morning hypertension when the patient adheres to the medication regimen.

Weiss’s Herbal Medicine  2001 pp 151-157 reviews why lowdose reserpine/rauwolfia is the prime baseline antihypertensive, via the central especially  autonomic nervous system as a major anxiolytic.

There is no evidence in chronic treatment of common essential hypertension to justify loop diuretics eg furosemide , as is common practice locally. .

update 12 Oct 2014     For the past decade we have advocated  for uncomplicated patients the gold-standard evidence-based combination of reserpine  0.0625 to 0.125 mg with  1/4  Amilozide (ie hydrochlorothiazide  HCTZ 12,5mg and amiloride 1.25mg) ie HAR daily as the most cost-efficient baseline treatment of hypertension.    Sometimes patients require the lower doses 1/4 tab each reserpine and Amiloretic 55mg) only 3 times a week for good control once on some cod liver oil, coconut oil and multivite-multimineral  to reverse arteriosclerosis, insulin resistance, reactive oxygen species,  and promote nitric oxide.

For more resistant cases we add  dihydralazine 25 mg/d or amlodipine 5 to 10mg as add-ons if required  – if necessary both-  occasionally for optimal HBP control around 120  to 130 systolic (the new international  Guideline target). With this regime of up to five drugs all more than 40 years in use, for hypertension we rarely find need to add the more costly / troublesome old eg methyldopa, or betablockers, spironolactone,   or new eg ACEI or ARBs ,  with   their  cardio-respiratory risks that are so rare with the  multi-low dose reserpine- amilozide- amlodipine- dihydralizane  combination.

There are now 250 000 antihypertensive drug studies on Pubmed since 1947.

 The latest  and definitive study  published on reserpine for HBP in Clin Drug Investig. 2011;31:769-77 is   Long-term efficacy and tolerability of a fixed-dose combination of antihypertensive agents: an open-label surveillance study in China a  massive  3 year (4500 patient-years) study  by  Wu Y, Li L. ea of   Peking University Health Science Center, China   .  A fixed-dose combination (FDC) of four compounds, hydrochlorothiazide  HCTZ 12.5 mg, triamterene 12.5 mg, dihydralazine 12.5 mg and  reserpine 0.1 mg (HTDR), is widely used as an antihypertensive treatment in China. Although used in China for more than 30 years, there have been few comprehensive evaluations of this treatment.          METHODS  open-label surveillance study in Shanghai in local primary healthcare settings. Subjects  with  essential hypertension, aged ≥35 years at the time of enrolment. Patients with secondary hypertension, myocardial infarction or stroke within 6 months of screening, impaired renal or hepatic function, history of cardiomyopathy or chronic heart failure, or were pregnant or lactating were excluded. HTDR was administered as one or two tablets per day in the morning. If necessary, additional HCTZ was added. Blood pressure (BP) was measured every 3 months.    RESULTS: A total of 1529 patients (65%  female; mean age 65.7 years) entered the study with mean BP 149/89. After the 36-month treatment period, 93.1% of patients had achieved the SBP target, 97.9% had achieved the DBP target, and 92.1% had achieved both. The mean decreases in SBP and DBP were 15.3 mmHg and 9.9 mmHg, respectively. Overall, 127 adverse events in 119 patients (7.8%) occurred during the follow-up period, most of which were mild to moderate. Plasma lipids, uric acid and potassium improved.                                                               CONCLUSION: HTDR was found to have good long-term efficacy and tolerability in Chinese patients with essential hypertension.

The mean  15/10  BP lowering  from a mean baseline BP of 149/89 after 3 years of the four-drug Chinese combination  in China   compares  starkly with the mean ~51/30 mm Hg lowering (from untreated HBP of 200/120 down to ~149/90)  over 4 months reported  below  by Alan Taylor in his 1989 thesis study in local rural Africans with similar doses of reserpine, HCTZ and dihydralazine- Taylor’s study achieving in rural Blacks  in 4 months the starting BP of the Chinese some 25 years later.  But  the long Chinese study speaks to to the tolerance of the HTDR combination.

The China reserpine study  of 1500 pts, 4500 pt years, strongly complements the ~13 trials  of reserpine   between 1977 (the Veterans’ Admin trial) and 1997(the German reserpine research group trials)  in 7500 patients for 1 to 3 years;   showing that low dose reserpine (and lowdose  thiazide ) together are  as good as or better than all more modern drugs- especially when augmented by amiloride.

(As Prof YK Seedat reported  here  in 2000), the China   paper reports zero noteworthy dihydralazine  risks at 12.5mg/d :     J Hum Hypertens. 2000 ;14:739-47. Hypertension in developing nations in sub-Saharan Africa. Seedat YK. University of Natal,  South Africa.  There is a rapid development of  ‘second wave epidemic’ of cardiovascular disease that is now flowing through developing countries and the former socialist republics. It is now evident from WHO data that coronary heart disease and cerebrovascular disease are increasing so rapidly that they will rank No. 1 and No. 5 respectively as causes of global burden by the year 2020. In spite of the current low prevalence of hypertensive subjects in some countries, the total number of hypertensive subjects in the developing world is high, and a cost-analysis of possible antihypertensive drug treatment indicates that developing countries cannot afford the same treatment as developed countries. Control of hypertension in the USA is only 20% (blood pressure <140/90 mm Hg). In Africa only 5-10% have a blood pressure control of hypertension of <140/90 mm Hg. There are varying responses to antihypertensive therapy in black hypertensive patients. Black patients respond well to thiazide diuretics, calcium channel blockers vasodilators like alpha-blockers, hydralazine, reserpine and poorly to beta-blockers, angiotensin-converting enzyme inhibitors and All receptor antagonists unless they are combined with a diuretic.  There are social, economic, cultural factors which impair control of hypertension in developing countries. Hypertension control is ideally suited to the initial component on an integrated CVD control programme which has to be implemented.  The existing health care infrastructure needs to be orientated to meet the emerging challenge of CVD, while empowering the community through health education.

Interestingly, a new  metaanalysis of HCTZ trials  by Musini ea Cochrane Database Syst Rev. 2014 May   Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. shows that BP lowering  over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews. 

2009:     ABSTRACT: When modern antihypertensive drugs cost far more than the old and tried, and have around 40% risk of adverse effects (Girerd 2002 Paris),  and give inferior risk reduction, it is unethical for routine hypertension patients initially to  be  prescribed modern drugs singly or in combination in uncomplicated cases before trying the gold standard old risk-free lowdose reserpine-amilozide combination.

2009 has been a landmark year of published studies on first-line  hypertension treatment.

IT IS COMMON CAUSE THAT:

i. hypertension  (with or without overweight- excessive waist girth) is today the commonest presenting, simply detectable, monitorable and controllable chronic lifestyle degenerative disease;

ii. the bedrock prevention and therapy  of essential hypertension is  public- patient  education – exercise, stopping smoking,  and minimizing salt (since 1904) , sugar, alcohol and cooked fat intake so as to reduce overweight;

iii. genetics and the above risk factors aside, three  of the primary “endogenous”  and easily correctable causes of essential hypertension are water deficiency; marine omega3 (EPA eicosapentanoic and DHA docosahexanoic acid) deficiency; and insulin resistance if not frank adiposity/overweight and diabetes.

So adequate water intake, and fish oil, and metformin/galega to tolerance, (in appropriate adipose/overweight  cases) are cornerstones of antihypertensive therapy along with diet and lifestyle changes before any antihypertensive drugs are added.

Recently there have been contentious suggestion  (eg Law and Ward UK 2009)  that target bloodpressure should be that of youth- 120/70 down to 100/60 – as long as it does not fall so low that the patient gets dizzy on standing up. But the non-contentious gold standard remains  that no one should be left with bloodpressure above at most 140/90 sitting.

ANTIHYPERTENSIVE DRUGS: There are over 34 000 RCTs, reviews and metaanalyses  (since 1965) on Pubmed on these drugs.

Controlling   hypertension asymptomatically  before it causes damage and symptoms is the heart of successful prevention.

It is now claimed  that hypertension risk starts as low as >120/70, that we should be targeting this level if tolerated.

This can only be done gently and slowly, if possible by optimising diet , lifestyle and natural supplements.

But prevention in asymptomatic patients must especially be at most a once-a-day regime, and avoid causing symptoms, and still give stable cover even if taken erratically. Only reserpine provides gentle cover lasting weeks, thus avoiding wide BP variation due to erratic dosing.

Apart from the notorious adverse effects of the older antihypertensives like guanethidine, methyldopa and atenolol, search of Pubmed under  ‘ARBs, ACEI Cough;’ and under metaanalysis ‘antihypertensive cough’  with the established drugs, reveals 10 abstracts since the mid 1990s.

The nub of the matter is, the lowest-cost multiple-combination therapy (lowdose reserpine -amiloride – hydrochlorothiazide) gives the best bloodpressure and risk reduction with zero adverse effects – especially when combined with probably the best pluripotential drug of all,  fish oil..   A new Cochrane metaanalysis from Univ Brit Columbia confirms that lowdose thiazide gives the best reduction of all antihypertensives in both all-morbidity and mortality outcomes -RR 0.89 (CI 0.82-0.97, p=0.0067 = highly significant) . And that metaanalysis didn’t deign to mention reserpine in the abstract.

There are at least a dozen trials each of reserpine and thiazide  showing that they are the best,  ideally in lowdose combination .   As always, one fixed-dose combination pill (eg Brinerdin, Rautrax Imp) may work for many. But it is both cheaper, more efficient and scientific to prescribe the components separately so that reserpine and amilozide can  each be titrated individually to tolerance, starting with eg reserpine (0.25mg tab ) 1/4/day and amilozide (55mg tab) 1/4 a day (costing locally retail  perhaps US$0.5/month, $6/year) …

In some patients eventually this dose 3 days a week is all that is needed. With sensible advice about omitting sugar and smoking, and minimal alcohol, salt and cooked fats, and adding a multinutrient including magnesium, vitamins and the many favourable biologicals (including appropriate physiological sexhormone replacement), few patients need more than 1/2 a tab each of reserpine and amilozide for optimal BP and metabolic-vascular risk control. In the rare still- resistant cases, amlodipine is the next safest effective antihypertensive  drug to add, starting with 2.5mg/d. But of course in those with insulin resistance (ie most cases), metformin is the most appropriate pluripotential drug.

Yet no trial has shown  lower cost, and better superiority and safety  of any modern-drug  or combination over the triple-combination  lowdose amilothiazide (thiazide since 1956, amiloride since 1967)  with  lowdose reserpine (from the ages-old rauwolfia – extracted  as reserpine since 1949). Since the German Reserpine trials, and results of ALLHAT and SHEP showing that reserpine as add-on gave  by far the best clinical outcomes, no head-on trials against modern drugs dare be done by drug companies or the clinicians they employ.

Over a year ago this column   reviewed that fifty year old treatments of overweight -hypertension – diabetes are still best, echoing an SAMJ analysis 24 years ago of New antihypertensive drugs–blessing or costly nemesis? .

In 1989 pharmacist Alan Taylor published his MPharm thesis (Rhodes University)  on Cost Effective Antihypertensive Therapy at A Day Hospital. – showing in a prospective randomized controlled trial for 4 months that stepped outpatient care (starting with a mean untreated BP of about 200/120) achieved the target BP ( then <165/95) in 73% compared to 11.5% on individualized treatment, and with a cost saving of 36%, with somewhat lower incidence of side effects. Hydrochlorothiazide HCT 12.5 to 25mg/d was the first step;  methyldopa 250-500mg/d or reserpine  0.1mg/d  as the 2nd; hydralazine 10-50mg/d  low dose as the 3rd, alternatively atenolol  100mg as the 3rd or 4th step. Individualized treatment reduced bloodpressure by a mean  32.6/19 whereas stepped-care did so by 51.6/29.5mm Hg.. The HCT-Reserpine- Hydralazine-atenolol regime was the most frequently prescribed (in 61.6%),

Obviously today methyldopa, hydralazine  and atenolol have become last-ditch add-ons, with amlodipine being the 1st- choice 4th drug to add to reserpine and amilozide. ,

and  in 2007 Rayner, Blockman ea from the Hypertension Clinic    at Groote Schuur Hospital found that at two community  health clinics  in Cape Town, only 40% of patients achieved a bloodpressure below 140/90, on a mean of 2.4 drugs per patient   – clinics where reserpine and amilozide were unwisely  removed from the available drug list years ago, for no plausible reason, leaving hydrochlorothiazide, atenolol, hydralazine and amlodipine as the choices- with invariably poor results in poor patients attending such free clinics.

MODERN DRUGS?  But why should patients be subjected to the multiple and indisputable major risks of modern antihypertensive drugs compared to the gold standard lowdose reserpine and low dose amilozide?

eg

ABs angiontensin blockers – ACEI agiotensin converting enyme inhibitors and ARBs angiotensin receptor blockers like enalapril, candesarten  – pervasive cough, rashes, but far worse, lifethreatening angiodema, asphyxiation, skin sloughing; and now well-recognized acute or slowly progressive loss of kidney function- which doesnt always reverse on stopping the drug (Onuigbu ea  2008, 2009); Suissa ea  2006 at McGill University published the first major longterm – > 10year- followup (1982-1997)  of hypertensive diabetes patients, showing that compared to thiazide, only  ACEI increased the risk of endstage kidney failure 4.2 fold.

betablockers like atenolol, metoprolol – too slow heart rate, cold extremities, more depression, impotence,  asthma, glucose intolerance/ diabetes, heart failure, deaths;

and even calcium channel blockers -the gold standard of which is amlodiopine- have a formidable list of potential adverse effects (that lowdose reserpine and amilozide lack), of which some may be major nuisance if not dangerous eg (from the Sandoz product sheet): Often: dizziness; palpitations; muscle-, stomach– or headache; dyspepsia; nausea – in 1 in 100 users; Sometimes: blood disorders, gynecomastia, impotence, depression, insomnia, tachycardia – in 1 in 1,000 users;  erratic behavior, hepatitis, jaundice – in 1 in 10,000 users; Very rarely: hyperglycemia, tremor, Stevens-Johnson syndrome – in 1 in 100,000 users. ”

From the trials and experience, lowdose amlodipine is certainly the modern drug of choice to add if counselling plus ceiling doses of reserpine and amilozide, plus fish oil plus  metformin for underlying adiposity/insulin resistance,  do not adequately control hypertension and other risk factors.

Why use modern drugs with their major potential hazards  except for special circumstances last ditch?; when lowdose reserpine plus lowdose amilozide titrated to best effect rarely need a 4th drug added for good BP control;  and practically – unlike methyldopa, guanethidine and more modern drugs-  never causes persisting symptoms.

THIAZIDE ADVERSE EFFECT possible in even very low dose: anaphylaxis: Goetschalckx ea in 2007 could find exactly 49 case reports of allergic thiazide-induced pulmonary oedema in the literature after 50 years of use ie millions of patient-years. Thiazides are obviously sulphonamides, but fortunately serious- anaphylactic- reactions like lupus vascullitis and shock – are extremely rare. Wikipedia does not even mention these under thiazides, and no abstracts on Pubmed even guess at their rare  incidence. 50 cases in at least 10million patient years is an incidence of below 5 per million.

RESERPINE:   In 2007 Jos Barzilay ea documented Getting to goal blood pressure: why reserpine deserves a second look.

We last year examined closely the trials on thiazides and reserpine 1, 23.

and we published on line the only ever tabulation of all accessible trials  of thiazides and reserpine, showing in the ~12 thiazide trials between 1985 (the UK MRC trial)  and 2003 (the CONVINCE trial) that  in 115000 patients for a mean of 4 years,  thiazide is as good as or better than all more modern drugs;

and that reserpine in ~13 trials between 1977 (the Veterans’ Admin trial) and 1997(the German reserpine research group trials)  in 7500 patients for 1 to 3 years is as good as or better than all more modern drugs. Of course  the 2003 ALLHAT  and CONVINCE papers were by far the biggest trials validating thiazide as the gold standard in 50 000 patients for  3 and 5 years respectively;

and the VA trials of 1977, 1982 and  and 1990 in 1479 patients showing reserpine as equal or superior to betablockers,  and the German trials of 1997  in 400 patients (Griebenow, Pittrow ea 1997) validating reserpine as equivalent to thiazide or a CCB, and the combination of thiazide and reserpine superior to an ACEI.

Now in 2009:

Shamon ea’s Cochrane review last month confirms that reserpine  alone is at least equivalent  in antihypertensive effect to any  modern first line antihypertensive alone ;

Wald and Law’s metanalysis of single or combination antihypertensives confirms that  “The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.”

Wright ea’s Cochrane review confirms that

“thiazides reduce all-cause mortality by 11%;   Low-dose thiazides (8 RCTs) reduced CHD  by 28%;

Beta-blockers and CCB reduced stroke by 17% and 42%, but not CHD  or mortality .        ACE inhibitors reduced mortality 17%; stroke  35%.

No RCTs were found for ARBs or alpha-blockers.”

However, that abstract does not enumerate the major adverse effects of betablockers and ABs.

Wright ea’s   ALLHAT reanalysis confirms that thiazide was superior to the ACEI, CCB, betablocker and especially the alphablocker doxazocin. neither alpha-blockers, ACEI nor CCBs  surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF. new-onset DM associated with thiazides does not increase CVD outcomes.”

Costanzo ea’s Italian study confirms that CCBs reduce the risk of stroke by 14% compared to ACEI; reduce allcause mortality by a trivial 4%; increase heart failure by 17% compared with ‘active’ treatment;

Hoffman ea’s review from New York confirms that, in autopsies of Alzheimer cases, those on antihypertensives had far less plaques that those without hypertension.

Sozen ea confirms that “ABs- Drugs with blocking effects on the renin-angiotensin-aldosterone system –  do not improve endothelial dysfunction long-term in hypertensive patients”.

Mackenzie ea’s Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension shows that central Pulse Pressure was only reduced significantly by perindopril, lercanidipine, and bendrofluazide, whereas atenolol had no effect. Lercanidipine reduced the augmentation index, whereas atenolol increased it. Aortic pulse wave velocity was not changed by any of the drugs. In summary, despite similar reductions in peripheral systolic and PPs with the 4 classes of drug, changes in central pressure and augmentation index varied. Because central PP and increased wave reflections are considered important risk factors in patients with isolated systolic hypertension, the choice of therapy may be influenced by these findings in the future.”

Landmark’s Norwegian abstract confirms that thiazides (and betablockers)  increase insulin resistance and blood glucose risk (let alone lipidemia), but simply – selectively- as usual ignores that neither lowdose amilozide nor reserpine do this.

Nothing illustrates better why the triple combination of amilozide and reserpine is the best.

It has previously been pointed out that in the long term Cache County study, potassium-sparing diuretic was the only antihypertensive that lowered- in fact by 75% – the incidence of new Alzheimers disease;  and amilozide-like combinations are more effective than either component alone in safely and effectively lowering hypertension. – Patterson Dollery & Haslam in 1968; Rosenfeld in 1980; and the Multicenter Diuretic Cooperative Study Group in 1981.

CONCLUSION:  Reserpine has indisputable central and peripheral benefits in lowering central pressure via peripheral vasodilation, and via mild lowering of anxiety, cardiac rate and cardiac output; while thiazide and amiloride both lower both excessive body salt and water, while thiazide vasodilates and conserves calcium,  and amiloride  reverses the  potassium -magnesium depletion  seen in hypertension and with thiazide. .

Since the lowdose combination of reserpine and amilozide is superior to all other first-line drugs alone or in combination, and retail costs about   US$1 a month in South Africa, (with negligible adverse effects compared to all other antihypertensive drugs), this combination is the mandatory  firstline therapy for all  hypertensive patients, with rare exceptions. This regime  starts with amilozide 13.75mg (1/4 tab) and reserpine 0.0625mg (1/4tab) /d- and many patients can eventually be controlled with these doses just 3 days a week; with other antihypertensives added only if hypertension is not controlled with these increased to the ceiling tolerated eg of amilozide 27.5mg/d and reserpine 0.125 mg/d (maximum reserpine 0.25 mg 5/week ie 0.18mg/d if tolerated).

Since roleplayers are there to serve patients, not the Drug and Disease Industry, all roleplayers ( National Hypertension societies, provincial and national health and medical school authorities, medical schemes and all health practitioners)  have no choice but to obey the gold-evidence-based medicine set out herein, and reinstate reserpine and amilozide as mandatory 1st-line therapy of essential hypertension, with motivation  for alternatives to be provided in the  exceptional cases.

Unlike the USA and the East  where reserpine is still in national recommendations,  Authorities, regulators, suppliers and prescribers  in South Africa, Australia, the UK and Europe can no longer continue to defraud the public and deny patients this best treatment, since the two tablets (cheap amilozide and reserpine) are freely and universally available for  at most the retail South African prices quoted (less in bulk buy).

There is no shortage of reserpine, HCT or amiloride;  and the evidence for them over all modern antihypertensives  is binding under  rules of evidence and therefore medical ethics. The current evidence discussed shows that this  old lowdose combination is superior to all modern drugs and modern marketted combinations in both reduction of all-cause endpoints, adverse effects, and cost.

As Henry Black said recently, triple antihypertensive therapy is simply Back to the Past – and it can be both very low cost and risk-free..

And if proof is wanted, we must agree on a simple long term multicentre trial of the lowdose reserpine-amiloretic regime versus modern marketed combinations.- as in  ALLHAT but comparing combinations..But who is to pay for yet another trial to prove what is already so well proven?

35 years after Illich’s Medical Nemesis, it is very sad to have to be fighting overwhelming profiteering vested interests for what is now by far the commonest and most easily correctable major common degenerative disease – mild to moderate hypertension.

UPDATE: FOR MILDER PAIN, WHY USE NSAIDS (LET ALONE DICLOFENAC) OTHER THAN PARACETAMOL -ACETAMINOPHEN?

update

Aspirin,  paracetamol, other NSAIDs,  and codeine  in periodic conservative analgesic use have  not been reported to cause hypoglycemia eg a few gm a day solo or in combination  in well adults-  despite  deliberate overdose of these being  notorious for causing fatal bleeding or  liver failure with hypoglycemia, or respiratory failure.

But increasingly tramadol is incriminated in dangerous hypoglycemia: Tramadol Use and the Risk of Hospitalization for Hypoglycemia in Patients With Noncancer Pain Fournier, Suissa, eaJAMA Intern Med.December      Tramadol is an increasingly widely used  weak opioid analgesic , associated with adverse events of hypoglycemia.  Analysis  in United Kingdom Clinical Practice of treatnent with tramadol or codeine for noncancer pain between 1998 and 2012  included 334 034 patients, of whom 1105 were hospitalized for hypoglycemia during follow-up (incidence, 0.7 per 1000 per year) and matched to 11 019 controls. Compared with codeine, tramadol  associated with  increased risk of hospitalization for hypoglycemia  in the first 30 days of use (OR, 2.61 [95% CI, 1.61-4.23]). This 30-day increased risk was confirmed in the case-crossover analyses (OR, 3.80 [95% CI, 2.64-5.47]). Conclusions  tramadol (in contrst to codeine), TRIPLED risk of hypoglycemia requiring hospitalization. Additional studies are needed to confirm this rare but potentially fatal adverse event.

update 4 March 2013  BAN DICLOFENAC?  four years on, another call comes  for the virtual banning of diclofenac, from no less than the Canadian Medical Association Journal , based on a new metanalysis of NSAID risks by University  Toronto’s McGettigan and Henry .

As this column has long pointed out, diclofenac is apparently still the only NSAID that can kill suddenly without warning.  There are many far safer alternatives eg naproxen, ibrufen; and no compelling clinical evidence or reason to use it let alone cox2 inhibitors  except false beliefs and heavy marketing.

So as this columnist concluded in 2009,  it is blatant fraud, negligence and potential indefensible homicide  to continue recommending  let alone  using diclofenac simply for profiteering.

21June 2009 It is 4 months since this column last addressed nonsteroidal anti-inflammatory drugs NSAIDs.

A new study (from USA, UK and Canada – Ray 2009) of NSAIDs  claims that in those with ischemic heart disease, the popular NSAIDS -diclofenac, ibuprofen or rofecoxib(Vioxx) – increased serious heart disease/ death by about 50-67% compared to nonusers; whereas naproxen over some 111000 patient years of use gives no significant risk or benefit.

A new study from Denmark (Fosbol 2009) this year looked at a million healthy individuals with no hospital admissions or selected therapy. Compared to no NSAID use, ibruprofen and naproxen gave no added risk of death/ myocardial infarction; diclofenac gave 67% increased risks, and the two coxibs (rofecoxib Vioxx; celecoxib Celebrex)  increased risk 100%.

So we are led to believe that naproxen or ibuprofen is the NSAID  mild-to-moderate analgesic  of choice. Naturally the American Colleges and academia – who represent the Disease Industry, not patients- recommend yet other potentially toxic drugs- like  the magical proton pump inhibitors- to counteract the adverse NSAIDS..

But is this just a myopic view beloved of big pharma, to promote their snake oils.?

Another new study from Denmark (Gislason 2009) of 110 000 patients after admission for heart failure in the 12 years 1994-2005, showed that 57% died; 9000 (8%) were rehospitalized with acute heart attack  and 40 000 (38%) were rehospitalized with heart failure. Thus heart failure in a well-nourished population has a poor prognosis. In 36 000 who had used NSAIDs compared to non-users, risk of death was doubled on  diclofenac; increased~67% on  (rofe-or cele)coxibs; and was  significantly increased 22-31% by all other NSAIDs including naproxen and ibruprofen.

It is common cause after 20 years that injected diclofenac is the only NSAID that can unpredictably cause sudden death. So it’s administration risks culpable homicide when it is totally unwarranted. No cases of sudden death from any oral NSAID   including aspirin appear on Medline, apart perhaps from the risk of hyperacute asthma (Asamoto 1999).

But what of gastrointestinal bleeding  risks of NSAIDS? a 2007 study in Japan (Yajima) scoped all orthopaedic patients who took NSAIDs for more than 4 wks: oral diclofenac increased risk of erosive gastric lesions sixfold. A new review from Seattle (Schlansky 2009) refers to Helicobacter synergism in all NSAID use.

WHAT IS THE NEED FOR NSAIDS? The Wikipedia entry on NSAIDs  sums it up: it has almost four times as much text on the numerous  adverse effects of NSAIDs as on their uses- in fact the  article does not discuss the advantages of NSAIDS as analgesics; in fact it states plainly  that alone  just  “their gastrointestinal effects  are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States”.

All designer drugs are dangerous in overdose. Without overdose, paracetamol has no risk – and the Wikipedia entry thereon is balanced and highly favourable even for infants. We know well that paracetamol- a fatal liver toxin in overdose- should not be marketed without a built-in simple liver (and antineuritic) protective of  eg (carbo-or N-acetyl-)cysteine, alphalipoic acid and vitamin BCo.  But the Disease – Big Pharma Industry is not interested in prevention- Only Disease Pays. And Regulators, lobbyists and legislators  protect their source of work and income- the Drug Industry.

Fish oil (EPA+DHA) is probably  the most beneficial NSAID supplement we have (- perhaps ahead of other front-runners like vitamins C, D, magnesium and CoQ10-) halving all sudden deaths, and reducing by at least a third all major chronic degenerative diseases from CVD to diabetes, arthritis, learning, depression, behaviour disorders. Industry wont pay for head-on comparative trials. But the trial evidence suggests that fish oil and oral EDTA have better risk-benefit than aspirin and other antiplatelet agents, NSAIDs and warfarin.

We know that for moderate trauma and small – medium (even knee) joint pain/  contusions, self-massage with any natural NSAID like arnica or wintergreen is all that is needed, combined if necessary orally with up to 3 to 4gm paracetamol /day +- if needed a little codeine.   Prior 2002 found no significant difference in pain relief between paracetamol and naproxen in tension headache.

For more serious pain,  short of strong opioids, there is in fact no overall trial evidence that weak opioids or NSAIDs are better than eg hypnotherapy, or acupuncture,  or judicious paracetamol; to which latter if necessary a little codeine can be added as step-up analgesia. The latter  agents have none of the deadly risk of NSAIDs. Amadio 1984 showed that of Peripherally Acting Analgesics: ” paracetamol at up to 4 g per day compares favorably in analgesic potency to aspirin and other NSAIDs, and  should be considered the treatment of choice for mild-to-moderate pain”.  Skovlund 1991 showed no significant difference between naproxen and paracetamol in postpartum uterine spasms.

Six RCTs – five in mostly European peoples and one in Hong Kong- found paracetamol equal to diclofenac (Voltaren) – March 1994 in arthritis; Brevik 1999 and Kubitzek 2003 in dental surgery; Hoogewijs 2000 and Woo 2006 after trauma; and Munishankar 2008 after Caesarian section.  In a Cochrane analysis 2003, Towheed showed that in the one placebo-controlled RCT in osteoarthritis, paracetamol was clearly superior to placebo with a similar safety profile. And the general principle of therapy applies, that if required, combination of analgesics from different groups is better than single drug therapy. But given the many potentially fatal risks of the NSAIDs – compared to paracetamol, opioids and if indicated  aspirin –  there is no compelling reason to add NSAIDs  for pain.

We know that it is negligent to initially sentence people with  spontaneous mild-moderate head/neck/backache or tendonitis at the shoulder, elbow, knee etc to bedrest, NSAIDS, opioids or referral for xrays, scans or surgery. 95% will settle rapidly with reassurance, posture instruction and simple topicals and paracetamol analgesia. Otherwise most pain will disappear with firm reassurance with brief simple laying on of hands eg massage and traction with gentle rotational manipulation and instruction in auto-reinforcement –  pressure point eg earlobe pressure, or acupuncture, or hypnosis. And most of the remainder resolve quickly with  simple targeted injection with a little local anaesthetic plus depot steroid.

And we know that with judicious use, topical corticosteroid injection – never mind judicious brief systemic steroid (corticosteroid, calciferol, testosterone) has little or no risk and far greater target and multisystemic benefit than NSAIDs; and for chronic conditions, like fish oil at least address the underlying pathogenic mechanisms/causes- whereas NSAIDs and paracetamol ignore these.

Is drug-speeded resolution of inflammation essential and beneficial except for the drug vendor? A careful RCT by Bradley ea from Indiana University in 1992 observed that “joint tenderness and swelling, presumptive evidence of synovitis, may not be a priori indications for use of an antiinflammatory drug, or predict greater responsiveness to treatment with an antiinflammatory drug than to a pure analgesic, in symptomatic treatment of patients with knee osteoarthritis”.

So why are synthetic  NSAIDs and especially the Coxibs  still used? Why do academics and Regulators still allow, promote  them for  routine use, other than to profit Big Pharma, and cause perhaps a quarter million deaths a year globally?

SPECIALIST NATURAL MEDICINE CLINIC 2015

SPECIALIST NON-XRAY PAIN, BONE, BREAST, BRAIN,  HEART, CHEST, GENITOURINARY, HORMONE RISK SCREENING  @ NATURAL MEDICINE CLINIC

for appointments for consultations,   or non-xray procedures by registered practitioners :  Sure Touch breast prescreening on  Saturday mornings next on  7 February 2015  by Sister Zeneath Ismail – cash R650 (then R450 if followup scan desired within 3 months);   -QUS  ultrasound quantitative bone density  cash R450 -tariff item 3612-  anytime;  Unlike radiologists’  and thermography reports (which describe only  the imaging finding), the rates quoted include relevant breast or bone consultation and management planning  by specialist nurse & physician.

IF BOOKED TOGETHER, (not necessarily the same morning) then combined breast and bone screening is R1000.

OTHER SERIOUS health problems ARE DEALT WITH BY CONSULTATION DURING THE WEEK (OR ON A DIFFERENT SATURDAY MORN) : heart- ECG,  fatigue, HRT, sexual health, hypertension, depression, memory/dementia, lung & lungfunction, anaemia-haematology; kidney/bladder/pelvic, hormone-endocrine, depression, osteoporosis, sleep, diabetes, thyroid, adrenal; cramp; skin,  infection including STDs & HIV/AIDs, stroke, epilepsy-neurology, dizziness, heartburn/digestive/liver,  neuropathy,  sexual health, menopause, HRT, genitourinary; immune problems, or arthritis relief;

Thermography no-touch infrared screening  for suspicious  cancer /inflammatory  changes:  by Radiographer Melinda-next 23 March 2015.   R900 breasts; R1100  head and  upper;  or lower body & pelvis;  R1300 whole body.

Bookings/queries contact Evelyn/ Reyhana / Val at  the Natural Medicine Clinic, 1st Floor no 15, Grove Medical Bldg, opp ABSA (parking ABSA Parkade )  near Warwick/Cavendish  Square Claremont Cape Town RSA, ph +27216831465 or a/h +2783 4385248 or reyhanadaya@yahoo.com  .

For the disabled – by arrangement  drive  up the ramp  to the Clinic door on the Grove Bldg 1st floor  parking deck.

Under CMS Council for Med Schemes Reg 10(6), open Medical schemes eg hospital plans  have to pay from their own funds (not members’ savings) for appropriate outpatient consultation (tariff item 0191) for  PMBs ie major conditions eg  cancer,   depression, neck/spinal problems, serious heart, lung, other disease., etc. Breast and osteoporosis concerns are generally part of menopause consultations N95.9   (if not already eg breast cancer code C50) and thus are often billable  med scheme benefits. The menopause billable item only applies if you are 45yrs upwards, unless you have had total hysterectomy.

On patients’ requests, appropriate invoice can be prepared and submitted to your scheme for refund of your due benefits. Some schemes eg hospital plans  falsely deny due benefits until reported to their regulator  CMS. For medical plans where the billable tariff benefit rate is higher than the breast screening fee paid, the med plan rate 0191  will be charged eg R790 by the contracted  specialist,  and refundable by Discovery to the member. some basic schemes eg Keycare, Bonitas require preauthorization, or referral by their contracted GP  .