Monthly Archives: August 2015

4 August 2015 VITAMIN D: FOR INDOOR TYPES, HOW MUCH eg 50 000iu/d IS ENOUGH, AND SAFE? & 2million iu loading dose is not toxic for adults. Especially for infants, acute illness- ICU, INFECTIONS:


see previous vit D updates:  at  23 Mar 2015 womens’ day: the crucial role of vitamin D as HRT in reducing all major diseases . Salute Dr Walter Stumpf



PREFACE WARNING: nb black italics are abbreviated quotes; for the link click on blue italics  eg McKenna ea.            NB conclusions depend, are based on, apparently reliable formal  randomized controlled RCTs trials  and team experiences, (but RCTs, metaanalysis, reviews and case reports   are also notoriously  vulnerable to vested interests of authors and sponsors, statistical errors, omission of inconvenient results, even subtle blatant fraud and fabrication;  to small numbers, heuristics and bias   – confusing causality, type 2 statistical errors ie sheer random chance; per  eg per Nobel prizewinner – the American  Daniel Kahneman : Thinking, Fast and Slow: New York 2011; the Briton   Oliver  Gillie 2014; Vit D, Sunlight, mortality, causality  and The Scots   Paradox, the Swiss Paradox;  the Flu, MERS, AIDs-TB-ebola epidemics: Can Sun Exposure, or  Lack of it, Explain Major Paradoxes in Epidemiology;;biography); the Semmelweis Paradox;  the current epidemics in Central and South Africa, Saudi Arabia, South Korea, cities & refugee camp  ghettos, 1918-19 et seq;  the German Gerd Gigenzer

4 August 2015 update: why do new trials/ reviews keep referring to mediocre dose vitamin D3 as high dose?    Karen Hansen’s  Univ Wisconsin  trial compared placebo, with baseline  vit D3  24000iu /month and as high dose 5 fold more ie  124000iu/month- finding no significant benefits. BUT  124000iu/month is still only about 4000iu/day, which on average increases 25OH Vit D3 only by about 40ng/ml. This is hardly high dose when vigorous levels are at least double this ie close to 100ng/ml; and vigorous safe dose long term is around 50 000iu/day ; with up to 150 000iu/day, up to above 250ng/ml blood level,  having been taken for decades, or single dose of 2million units,  without toxicity... Of course safety depends on adequate water, magnesium and vit K2 intake, and not adding  calcium supplements since average city diet is low in magnesium, iodine  and vit K2, not calcium or toxic fluoride or bromine. 

                      2015 Aug 3  JAMA Intern Med. . Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. Hansen, Marvdashti ea . Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health. Objective  randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Univ Wisconsin   from  2010, completed 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied.  Interventions: Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels ≥30 ng/mL. Main  Results:  After baseline absorption was controlled for, calcium absorption increased 1% (10 mg/d) in the high-dose arm but decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and 1.3% in the placebo arm (P = .03 vs high-dose arm). We found no between-arm changes in bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores.  High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts’ recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL.
26 JULY 2015 UPDATE:
1,   Calcium supplements are no longer recommended for adults:  they promote vascular calcification and worse.

J Intern Med. 2015 Jul 14. Calcium supplements: benefits and risks. Reid , Bristow , Bolland .University of Auckland, New Zealand. Calcium is an essential element in the diet, but Calcium Study demonstrates no relationship between dietary calcium intake and rate of bone loss over 5 years in healthy older women with intakes varying from <400 to >1500 mg day. Thus, supplements are not needed within this range of intakes to compensate for a demonstrable dietary deficiency, but might be acting as weak anti-resorptive agents via effects on parathyroid hormone and calcitonin.  As a result, anti-fracture efficacy remains unproven, with no evidence to support hip fracture prevention (other than in a cohort with severe vitamin D deficiency) and total fracture numbers are reduced by 0-10%, depending on which meta-analysis is considered. Five recent large studies have failed to demonstrate fracture prevention in their primary analyses. This must be balanced against an increase in gastrointestinal side effects (including a doubling of hospital admissions for these problems), a 17% increase in renal calculi and a 20-40% increase in risk of myocardial infarction. Each of these adverse events alone neutralizes any possible benefit in fracture prevention. Thus, calcium supplements appear to have a negative risk-benefit effect, and so should not be used routinely in the prevention or treatment of osteoporosis.
        Rather it is vits D3, C,  K2 ;  and magnesia supps that are recommended for multisystem benefits-  magnesia especially for prevention of common renal stones- since the classic paper from Harvard  Am J Clin Nutr. 1967;20:393-9. Effect of daily 200mg MgO   and 10mg vitamin B6   administration to patients with recurring calcium oxalate kidney stones. Gershoff & Prien.
2. for preventing eg calcium stones and mortality etc, vit D3 in high enough dose to switch off hyperparathyroidism. eg Clin Nutr. 2015 Mar 24.    Vitamin D3 supplementation and body composition in persons with obesity and type 2 diabetes in the UAE Sadiya , Abusnana ea The study was executed in 3 phases in two arms vitamin D arm (n = 45) and placebo arm (n = 42); in Phase 1 the vitamin D arm received 6000 IU vitamin D3/day (3 months) followed by Phase 2 with 3000 IU vitamin D3/day. During follow up (phase 3) both the arms were un-blinded and supplemented with 2200 IU vitamin D3/day for another 6 months . On supplementation no significant changes in anthropometric dimensions was observed. S-25(OH) D peaked in phase 1 (77.2 ± 30.1 vs 28.5 ± 9.2, p = 0.003) followed by a decrease in phase 2 (62.3 ± 20.8, p = 0.006) paralleled by a decrease in parathyroid hormone in phase 2 (5.9 ± 2.4 vs 4.5 ± 1.8, p < 0.01) compared to baseline in vitamin D group. Supplementation was safe, improved s- 25 (OH)D also reducing the incidence of eucalcemic parathyroid hormone elevation.
      Crit Care Med. 2015 Jul 16.   A Randomized Study of a Single Dose of Intramuscular Cholecalciferol in Critically Ill Adults.  Nair, Center ea   Univ Sydney & Brisbane, Australia.  LMU, Munich, Germany.    To determine the effect of two doses of intramuscular cholecalciferol on serial serum 25-hydroxy-vitamin-D levels and on pharmacodynamics endpoints.Prospective randomized interventional study.
Fifty critically ill adults with the systemic inflammatory response syndrome.Patients were randomly allocated to receive a single intramuscular dose of either 150,000 IU (0.15 mU) or 300,000 IU (0.3 mU). Secondary hyperparathyroidism was manifested in 28% of patients at baseline. Parathyroid hormone levels decreased over the study period with patients achieving vitamin D sufficiency at day 7 having significantly lower parathyroid hormone levels (p < 0.01).  Although in-hospital mortality rate did not differ between the groups, patients who did not mount a parathyroid hormone response to vitamin D deficiency had a higher mortality (35% vs 12%; p = 0.05). No significant adverse effects were observed.
     3  universal vitamin D3 deficiency:   our local population, as in virtually all populations worldwide who no longer work and live bare in the sun and eat plenty of raw fish(eg unfiltered cod liver) (oil) have average blood 25 OH vit D levels at or below 20ng/ml, whereas it is  incontestable that all diseases decline steadily as this marker vit D3 level is elevated by sunshine to the probable maximum natural achievable level around 40ng/ml- and with vigorous supplements eg 50 000iu/wk  up to around 80ng/ml, but in sickness to around >100ng/ml.
 4.    But the vit D overdose literature shows that while the highest adult vit D3 doses that have been prescribed are about 640 000iu as monthly dose (Salhuddin N ea , Karachi Pakistan 2013- with 40% improvement in TB recovery after only 2 months compared to TB pts given antiTB Rx alone), and 40 000iu/day in South America for months  for serious pemphigus and albinism. The Pakistan Endocrine Society is a pioneer professional group in endorsing vigorous vit D3 dosing.
But the threshold for toxicity- hypervitaminosis D– seems to be above 2million units single dose in nonagenarians (Netherlands 2 pts) or 88 000iu/day longterm (Canada); and blood 25OHvit D above 250 – 500ng/ml. one 70yr old women was reported to present with Hypervit D only after 10 years  taking 100 000ium/d ie over ~300million iu.. Another women was reportedly  unharmed after 5  times that ie @ 150 000iu/day ,  1.5 billion vit D2 iu over 28yrs –Stephenson & Peiris 2009.
small Subcontinent people–  Pakistanis, Indians etc may be more prone to overdose with vit D, often from massive doses given by injection weekly ie no chance of reducing absorption plateauing as oral overdose increases, as normally happens.
VIT D2 VS D3:  note that as one of the most backward Govts in the world, RSA   STATE  authorities- at least in W Cape eg state hospitals and  day hospitals- still distribute and promote vit D2 for osteoporosis, altho these tabs falsely labelled Strong Calciferol are in fact fraudulently labelled,  only their manufacturer website Lennons-Aspen reveals that they are in fact ergocalciferol vit D2, which experts have long condemned as only about 1/4 the strength of vit D3, and which D2 in two studies actually worsens not improves rheumatoid arthritis. This in contrast to the all-disease beneficial  anabolic steroid vit D3 which wholesales in bulk at around R200/kg.a different independent website eg does reveal that Strong calciferol is in fact D2, but not that it is a xenohormone manufactured only by yeasts, not animals; and that it elevates 25OH vit D2– not D3- in our blood, thus blocking both our D3 receptors and formation.   Wiki does detail that it is made only by lichen, mushrooms and alphalpha- but not by any animals.
Already in 2006 Houghton and Veith (Univ Toronto Canada) published The Case Against vitamin D2.. Vitamin D2, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification… no successful clinical trials to date have shown that vitamin D2 prevents fractures..The poorer stability of and greater impurities in vitamin D2 powders may also lead to a higher risk of toxicity than that associated with the vitamin D3 metabolites. However, it is more likely that the weaker affinity of vitamin D2 metabolites to DBP produces higher and more biologically available proportions of free 25(OH)D2 and 1,25-(OH)2D2 and may thus be responsible for the greater risk of D2 toxicity .  Taken together, the most plausible explanations for the greater bioefficacy of vitamin D3 are conceivably due to the higher affinities of vitamin D3 and its metabolites than vitamin D2 for hepatic 25-hydroxylase, DBP, and VDR and because vitamin D3 is not directly metabolized to 24(OH)D as is vitamin D2.”D2may be safe in mega-overdose, but this  2009 abstract from a Tennessee Veterans’ Admin unit  begs the question of whether the D2 tablets were indeed genuine vitamin D, of any benefit to the patient? who apparently consumed over a billion iu of vit D2 in  half a lifetime – at least 20 times the aggressive dose of 50 000iu/week. :

South Med J. 2009 Jul;102:765-8..  The lack of vitamin D toxicity with megadose of daily ergocalciferol (D2) therapy: a case report and literature review.   Stephenson & Peiris .The maximum daily dose of vitamin D currently recommended is 2000 IU. Ergocalciferol (D2) 50,000 IU orally weekly for 8-12 weeks is often used to treat vitamin D deficient patients (25(OH) vitamin D <20 ng/mL). The lack of vitamin D toxicity after massive doses of ergocalciferol has yet to be reported in the literature. We report a case of a 56-year-old woman who received supratherapeutic doses of ergocalciferol (150,000 IU orally daily) for 28 years without toxicity. We discuss the possible mechanisms which may account for a lack of toxicity despite intake of massive daily doses of ergocalciferol in this patient.
                    1 July 2015 update:  The  2008  report from Kimball & Veith, Toronto concludes:  The lowest observed adverse effect level for vitamin D, said to cause hypercalcaemia in normal adults, is officially 95 mg/day ie 4 000iu/d. But collective  reports  indicate that serum 25(OH)D concentrations need   to exceed 700 nmol/L ie 280 ng/ml chronically   before vitamin D3 toxicity becomes  evident ie from at least ~40 000iu D3 /day or perhaps a million iu monthly. .

update 30 June 2015: The Univ Toronto team  in the previous decade published more evidence of safety and benefit  of vit D3 up to 40 000iu a day 280 000iu/week; but   not 88 000iu/day: the warning is that calcium supplement should be avoided in such high vit D3 dosage. They were not yet advising supplement vit K2 and magnesium.                       Neurology . A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.   Burton JM1, Kimball S, Vieth R   ea  St  Michael’s Hospital, Toronto, Canada.     Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk; .  to assess the tolerability of highdose oral vitamin D prospectively, an open-label randomized prospective controlled 52-week trial matched patients with MS to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day (280 000iu/wk) over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks).. Calcium (1,200 mg/day) was given throughout the trial. Endpoints were mean change in  biochemical measures,  biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score.    RESULTS:   Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L 164ng/ml, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls.   Highdose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects.    This trial provides Class II evidence that highdose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on highdose supplementation. The trial, however, lacked statistical precision. , providing only Class level IV evidence for these outcomes.

          Ann Clin Biochem. 2008;.   Self-prescribed highdose vitamin D3: effects on biochemical parameters in two men.     Kimball S1, Vieth R.   , University of Toronto, Toronto, Canada. ..  The lowest observed adverse effect level for vitamin D, said to cause hypercalcaemia in normal adults, is officially 95 microg/day 4000iu/d. Serum 25-hydroxyvitamin D (25[OH]D) concentrations associated with hypervitaminosis D remain undefined. Reported 25(OH)D concentrations resulting from prolonged excessive vitamin D3 intakes have exceeded 700 nmol/L 280ng/ml. We report self-prescribed high dose of vitamin D3 over 5-6 years by two men.               Subject 1 had been taking 100 microg/4000iu day for 3 years followed by 3 years of 200 microg/8000iu/day. Serum 25(OH)D concentrations averaged 130 nmol/L 52ng/ml while taking 100 microg/4000iu day of vitamin D3. While taking 200 microg/8000iu/day of vitamin D3, mean serum 25(OH)D concentrations were 260 nmol/L 102ng/ml with no hypercalcaemia or hypercalcuria over the 6 years of vitamin D3 intake.                                                  Subject 2 was a 39-year-old man diagnosed with multiple sclerosis.  his own dose-escalation schedule  increased from 200ugm 8000iu  to 2200 microg/ 88000iu/day over 4 years. The  evidence of a potential adverse effect was that urinary calcium:creatinine ratios showed an increasing trend, which preceded serum calcium concentrations above the reference range (2.2-2.6 mmol/L). His serum 25(OH)D concentration was 1126 nmol/L 450ng/ml  when total serum calcium reached 2.63 mmol/L. He stopped vitamin D3 supplementation at this point. Two months later, all biochemistry values were within reference ranges; serum 25(OH)D concentrations fell by about one-half, to 656 nmol/L 260ng/ml . These results help to clarify the human response to higher intakes of vitamin D3. Close monitoring of biochemical responses confirmed that an increase in urinary calcium:creatinine ratio precedes hypercalcaemia as serum 25(OH)D concentrations rise.

update 28 June : a landmark trial in Brazil 2 years ago finally shows what a really high dose of Vit D3 – 35000iu/d  can do safely over 6 months, a cumulative safe dose of 6million iu A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis:  Dermatoendocrinol. 2013  Finamor,  Coimbra ea    University São Paulo, Brazil     Autoimmunity has been associated with vitamin D deficiency and resistance, and vitamin D metabolism gene polymorphisms   frequently described. May high dose vitamin D3  compensate for inherited resistance to its biological effects?.  To assess the efficacy and safety of prolonged high-dose vitamin D3 treatment of patients with psoriasis and vitiligo, 25 patients with psoriasis or  vitiligo received vitamin D3 35,000 IU once daily for six months ie >1million iu/mo,  >6 million iu over 6mo  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). Psoriasis patients were scored according to “Psoriasis Area and Severity Index” (PASI) . All patients presented low vitamin D status (serum 25(OH)D3 ≤ 30 ng/mL) at baseline. After treatment 25(OH)D3 levels significantly increased (from~16 to ~120ng/mL)  ie increase of +- 100ng/ml by 35000iu dly – a flattened highdose response curve, only 10ng/ml rise per 3500iu/d;    and PTH levels significantly decreased (from ~57 to 27 pg/mL. PTH and 25(OH)D3 serum concentrations correlated inversely. The PASI score significantly improved in all nine patients with psoriasis. 14 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. WHAT WAS THEIR BMI? my 25OHvit D level runs at ~90ng/ml on ~9000iu vit D3 a day; and my  patient’s level runs at ~150ng/ml on ~15000iu/d… so perhaps the Brazilians with these skin disorders (unlike us) have  resistance genes that block higher levels of 25OHvit D. So without doing costly genotyping, we in practice need to check vit D level response early where very high dose is indicated in severe disease. .

Mediocre chronic dose vit D3 supp  eg 2000iu/d , 25OHvitD well > 30ng/ml-   is not enough– it needs high loading eg >400 000- 600 000iu  for acute illness, and good maintenance dose eg >5o 000- 75 000iu/wk  for blood level >60ng/ml, for chronic prevention, to maintain good vit D level and thus real protection:    BMJ Open Respir Res. 2015 Jun   Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients:  retrospective cohort study.  Thickett , Christopher ea:      Boston, Massachusetts , USA     Intensive care units of Boston teaching hospitals.  1985 critically ill adults admitted between 1998 and 2011    Exposure of interest was prehospital serum 25(OH)D categorised as ≤10 ng/mL, 11-19.9 ng/mL, 20-29.9 ng/mL and ≥30 ng/mL.  In the cohort, the mean age was 63 years,     25(OH)D was ≤10 ng/mL in 8% of patients, 11-19.9 ng/mL in 24%, 20-29.9 ng/mL in 24% and ≥30 ng/mL in 44% of patients. Eighteen per cent (n=351) were diagnosed with acute respiratory failure.  Prehospital 25(OH)D  30ng/ml  in our critically ill patient cohort.  

Thorax. 2015 Jun 10.Double-blind randomised controlled trial of vitamin D3 suppl for the prevention of acute respiratory infection ARI  in older adults and their carers (ViDiFlu).    Martineau , Griffiths ea.Univ London.  clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing schemes and their carers in London, UK.    137 individuals were allocated to the active intervention (vitamin D3 2.4 mg = 100 000iu once every 2months +10 μg =400iu daily for residents= 62 000iu/mo; carers 3 mg once every 2 months =60 000iu/mo);  and 103 participants to placebo once every 2 months +vitamin D3 10 μg daily = 12000iu/mo for residents, placebo once every 2 months for carers) for 1 year. RESULTS:Inadequate vitamin D status was common at baseline:  92% of 240  participants had serum 25(OH)D concentration < 30ng/ml. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with 50% higher  risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI.   CONCLUSIONS: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen to average  ~2000iu/d did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI  over 400iu dly ie 12000iu spread over the month.

Thorax. 2015 May.   Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs).  Martineau ,Griffiths ea    London  University UK. Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma.  randomised controlled trial of vitamin D3 supplementation for  prevention of asthma exacerbation and URI. 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 120 000iu 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year.   206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. Bolus-dose vitamin D3 supplementation – 60 000iu/mo = average 2000iu/d – did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency.

update 27 June 2015  another review Safety of vitamin D3 in adults in multiple sclerosis  Kimball ,Vieth ea  2007 University  Toronto, Canada confirms that  up to at least 40 000iu daily for 28 weeks  is safe. Patients’ serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.

      update  20 June 2015 : the  10th  HIGHDOSE VIT D STUDY  (100 000 to  600 000iu stat, or up to 55 000iu/day):       Quraishi,  Bhan ea 2009 Harvard Univ Boston: Effect of  Highdose VIT D Supplement on Vitamin D Status and Cathelicidin Levels in Sepsis: Crit Care Med. 2015 Jun 17: RCT  to compare changes in vitamin D status and cathelicidin (LL-37) levels in 30  adult ICU patients given  Placebo (n = 10) vs 200,000 IU cholecalciferol (n = 10) vs 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock in a single Boston, MA teaching hospital.  Blood samples  at baseline (day 1) and on days 3, 5, and 7. At baseline, median (interquartile range) plasma 25-OHvitD  was 17 ng/ml,  peaked by day 5 in  intervention groups.  On day 5, median change in biomarkers for placebo, 200,000 IU vit D3 cholecalciferol , and 400,000 IU vit  D3 groups, respectively, were as follows: 1) total 25OHvitD, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25OHvitD, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37 : -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity CRP levels did not differ between groups. A positive correlation was observed between bioavailable 25OHvit D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25OHvitD and LL-37. CONCLUSIONS:High-dose vitD3 supplement rapidly and safely improves total  and bioavailable 25OHvitD  levels in patients with severe sepsis or septic shock. Changes in bioavailable 25OHvitD are associated with concomitant increases in circulating LL-37 levels.

Clin Nutr. 2015 Apr 14.    Increases in pre-hospitalization serum 25(OH)D concentrations are associated with improved 30-day mortality after hospital admission: A cohort study in Boston, Mass.. Amrein , Christopher ea   in two Boston univ. hospitals .Pre-hospital vitamin D status may be a modifiable risk factor for all-cause mortality among hospitalized patients.  4344 adults hospitalized between 1993 and 2011..  INTERVENTION(S):  None.  The main outcome was 30-day all-cause mortality.  In an adjusted logistic regression model, absolute changes of ≥10 ng/mL in patients with initial 25(OH)D  < 20 ng/mL (n = 1944) decreased the odds of 30-day all-cause mortality by 48% (adjusted OR 0.52, P = 0.026).  A causal relation may not be inferred from this observational study.
      Conversely, another new study this month confirms the hazard of gross overdose of anything:   Kaur, Mithal ea .India Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency  Clin Endocrinol (Oxf). 2015 Jun “Vitamin D toxicity, wrongly  considered rare, can be life-threatening,  with substantial morbidity, if not identified promptly. In 16 patients with vitamin D toxicity seen between January 2011 and January 2013  Clinical manifestations included nausea, vomiting, altered sensorium, constipation, pancreatitis, acute kidney injury and weight loss. Median (range) age was 64.5 (42-86) years. Median  serum 25(OH)D level  371 (175-1161) ng/ml, serum total serum calcium level  13.0 (11.1-15.7) mg/dl . Irrational Overdose of vitamin D caused by prescription of mega doses of vitamin D was the cause of vitamin D toxicity in all cases. Median (range) cumulative vitamin D dose was 3,600,000 (2,220,000-6,360,000)”– but the abstract doesnt mention the timespan . Generally, after loading dose for urgent risk,  maintenance dose  need  not exceed about 80 iu/kg/d eg 7000iu/day ie ~50 000iu/wk or 2500 000 iu/yr, ideally with ideally occasional blood vit D, calcium & creatinine tests. .

           UPDATE FOR KIDS: Pediatr Rheumatol Online J. 2015 May .  Vitamin D-update for the pediatric rheumatologists.    Vojinovic J1, Cimaz R2. University of Nis, Serbia.   ” So in accordance with new vitamin D recommendations, we recommend that a child with rheumatic disease, especially if treated with steroids, needs at least 2-3 time higher doses of vitamin D than the dose recommended for age (approximately 2000 UI/day). Vitamin D supplementation has become an appealing and important adjunct treatment option in PRD

      17 June update : Proc Natl Acad Sci U S A. 2015 Jun 15. pii: 201500909.           High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans.  .Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. Coussens ,  Jablonski   ea  from Univ. Cape Town & Stellenbosch conducted a longitudinal study in two  Cape Town ethnically distinct groups of healthy young adults, supplemented with 50 000iu weekly  vitamin D3  for 6 weeks  in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.
    16 June 2015  REVIEW: ADULTS: WHAT VIT D DOSE IS ENOUGH? Because of our increasingly government-encouraged soporific  TV lifestyle and western processed- food-factory low-fat high-carbs HCLF diet, vitamin D has turned out to be as important as >vitamin C as the seriously deficient primary major nutrients in far higher than scurvy/rickets prevention doses.
Just as we ‘only’ need vitamin C 10mg/d to prevent scurvy, the historical DAILY recommended allowance RDA dose of vitamin D for rickets is ‘only’ ~10mcg 400iu/d.
But current expert opinions advocate  effective multisystem chronic prevention against infections, cancer, neurological, cardiovascular and bone disease in adults  vit C between 1gm  and 30gm/day; and

       vit D between 100mcg 4000iu and 250mcg 10 000iu/d (ie 80-100iu/kg/d); or about 25000 to 70 000iu/week or equivalent spacing;
to a blood 25hydroxyvit D 25OHvitD level of ~60 (40 to 80ng)/ml for global prevention; but around ~100ng/ml depending on severity of illness being targeted.

     DONT REJECT A SUPPLEMENT AS OF NO VALUE JUST BECAUSE IT TESTED INEFFECTIVE  IN  LOW DOSE:   eg Martineau , Griffiths ea.Univ London Thorax. 2015 Jun   Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). CONCLUSION: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI.   BUT like so many trials,this trial in  240 London Seniors and carers is not about high dose, but mediocre dose, in small numbers: it  confirms that 100 000iu vit D3 every 2 mo ie average ~extra  1666iu/d is no better protection than just 400iu dly ie 12000iu spread over the month.

Since like all steroids the many vitamin Ds are vitamin C-cholesterol-derived oils stored and carried in fat, the fatter the patient the higher the maintenance dose vit D3 (eg 100 iu/kg/d) to maintain a good steady optimal bloodlevel.                                Fortunately, unlike the other essential physiological human anabolic steroids (eg androgens, progesterone and estrogens that are poorly absorbed , and trans-hepatically dangerous if swallowed), vitamin D3 is well absorbed either by mouth, by injection; or transdermally / intranasally; and apparently not degraded to risky byproducts in the liver as are the “sex” steroids. .

And of course for best absorption, fat-soluble essentials like vits A, D, E , K; CoQ10 & alphalipoic acid ALA are best eaten with fat not carbs eg veggies, cereals or on empty.
To minimize risk of stones and vascular calcification from imbalance, it is important to take vit D3 with                                                                                      *liberal water, magnesia and vitamin K2; perhaps                                                 *~30gms fresh marine oil /wk eg a tsp of cod liver oil 3 x a week; and                       * a few tsp/d of virgin coconut oil (and for cooking/frying in);
*at least half of daily non-protein energy as FATS- animal, dairy and avocado &
*while minimizing moderate omega6 as nuts and raw olive/ oil; and avoiding/minimizing diabesogenic insulin-resistance-causing refined carbs, and synthetic junk fats like margarine, and other seed oils- eg sunflower and canola – certainly not for frying.

A new university study from Ireland ( Endocr Connect. 2015 June. McKenna ea) confirms that average vitamin D levels there are still well below sufficiency let alone good levels, although it finds Rising trend in vitamin D status from 1993 to 2013: “The Institute of Medicine 2011 Dietary Report specified higher Vitamin D intakes for all age groups compared to 1997, but also cautioned against spurious claims about epidemic vitamin D deficiency and against advocates of higher intake requirements. 40 years have seen marked improvement in vitamin D status, but we are concerned about hypervitaminosis D. Time series sequence chart demonstrated a steady upward trend with seasonality. The average 25OHD increased by ~50% from ~15ng/ml in 1993 to ~23ng/ml in 2013. CONCLUSIONS: Vitamin D status improved over the past 40 years, but there is a dual problem:                             *groups at-risk of vitamin D deficiency, who need public health preventative measures; and                                                                                                     *random members of the public  taking unnecessarily high vitamin D intakes for unsubstantiated claims. “

       Last year Autier, Mullie ea from Lyon France and Bolland, Reid ea from Auckland NZ published major reviews concluding that “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 “vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions
But Gillie from Health Research Forum, London 2014 in Controlled trials of vitamin D, causality and type 2 statistical error  rebuts Autier ea, Bolland ea:    “In Lancet Diabetes Endocrinol, Autier, Mullie ea. (2013) , and Bolland, Reid ea. (2014) , concluded that low levels of vitamin D are not a cause but a consequence of ill health brought about by reduced exposure to the sun, an association known as ‘reverse causality’ Denial of the possible benefits of vitamin D, as suggested by insistent interpretation of studies with reverse causation, may lead to serious harms, some of which are listed.” So Gillie affirms the focus of this June 2015 review on vigorous dose vit D without chronic toxic overdose, that Autier ea and Bolland ea overlook, that their conclusions were based on lowdose vitamin D, not vigorous dose eg loading dose 600 000iu  monthly with or without ~50 000iu weekly that has been increasingly validated.

While  human sex hormones in good youthful balance are all essential physiological anabolic ie growth-promoting steroids, Atif ea at Emory University, Atlanta, 2009  and 2015   showed that in rats, Vitamin D with progesterone P4 supplement affords significantly better brain protection against excitotoxicity in cultured cortical neurons  and in traumatic brain injury in vivo than progesterone or vit D alone. In their 2009 braincell culture experiment, the optimal ratio of the hormones given was Prog:Vit D 1000:1 (Prog 20 umol/L: vitD 20nmol/L); whereas in their 2015 in life study the ratio was 8000:1– the rats were injected intraperitoneally  Prog 16mg/kg and VitD 1ug  one and 6 hours after the brain injury, and at 24 hours after brain injury they were killed and the brain damage compared. The optimal ratio, balance of the two steroid  hormones  for rat brain protection (1000:1 in a bench cellculture  and 8000:1 in an acute living rat model) is noteworthy for human dosing although the absolute doses cannot be extrapolated to living humans.   In humans this review below shows that the optimal acute dosing thus far reported seems to be  about 1000mg progesterone injection ie ~13mg/kg (some disputed trial evidence for protecting human brain injury after 50 years of research), and vit D for acute global protection about  600 000iu = 10 000iu/kg= 250 ug /kg ie P:vitD ratio about 50:1.

But vit D3, & androgens, and progesterone (eg Roeder 1986 & Starkov 1997), are the classic muscle-bone anabolic (ie growth- protein-water-salt-retaining) steroids. So we should always combine them in appropriate dose if needed for men, and even women. Estrogen is essential for reproduction, bone strength and femininity, but is muscle-anabolic only for the female reproductive tract; and for fat and glandular tissue ie breasts: estrogenic  dominance doubles cancer; adiposity;  sarcopenia;  and urinary incontinence ie weakens the pelvic floor; so should never be given unopposed by progesterone/androgen and vigorous vit D3 .

          ACUTE LOADING DOSE OF VIT D?: Like antibiotics, for acute (antimicrobial or ICU metabolic eg vascular, brain, cancer ) disease, adult vitamin D3 LOADING dose 540 000 to 600 000iu monthly – but not much lower loading dosing – has been recommended and proven major benefit, eg

1. New Zealand 2009 Osteoporos Int. ;20:1407-15.. Bacon ea :              High-dose 500 000iu oral vitamin D3 supplementation in the elderly were concerned that: vitamin D doses are frequently inadequate; compliance with daily medication is likely to be suboptimal; large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels; and monthly dosing is similarly effective only after 3-5 months. With baseline 25OHD > 20ng/ml, vitamin D supplement does not reduce parathyroid hormone PTH levels. This randomized double-blind trial RCT compares “high-dose” vitamin D3 regimens and estimates optimal 25OHD levels, from changes in PTH & procollagen type I propeptide (P1NP) in relation to baseline vit D . Sixtythree elderly participants were randomized to three regimens of vitamin D supplementation: a 500,000-IU loading dose; the loading dose plus 50,000 IU/month; or 50,000 IU/month. the Loading and Loading + Monthly groups showed increases in 25OHD of 23+/- 11ng/ml from baseline to 1 month. Thereafter, levels gradually declined to plateaus of 27 +/- 2 ng/mlL and 36 +/- 2 nmol/l, respectively. In the Monthly group, 25OHD reached a plateau of ~32 +/- 8 ng/dl at 3-5 months. There were no changes in serum calcium concentrations. PTH and P1NP were only suppressed by vitamin D treatment in those with low baseline 25OHD level.. CONCLUSIONS: Large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels in the frail elderly. Monthly dosing is similarly effective and safe, but takes 3-5 months for plateau 25OHD levels to be reached.

2, Pakistan 2013 Salahuddin N ea:  600 000IU Vitamin D monthly for 2 doses improves clinical recovery from tuberculosis. 259 patients with pulmonary TB were randomized to receive either 600,000 IU of Intramuscular vitamin D3 ie ~20 000iu/day, or placebo for 2 doses. After just 12 weeks, the vitamin D supplemented arm demonstrated significantly greater ~40% improvement: mean weight gain (kg)+3.75, (3.16-4.34) versus+2.61 (95% CI 1.99-3.23) p 0.009 and lesser residual disease by chest radiograph; number of zones involved 1.35 v/s 1.82 p 0.004 (95% CI 0.15, 0.79) and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035.

3. Austria 2014  Amrein ea, 540 000iu loading dose in 475 ICU pts significantly reduced morbidity and mortality by 40% in 492 vit D deficient pts,  ie is anabolic ie reverses muscle wasting – sarcopenia. as also found by Aganostis 2015 metanalysis

4. Canada/USA universities 2014 Ekwaru, Holick ea: “in a survey, 17,614 Healthy volunteers reported vitamin D supplement ranging from     0 to    55000iu/day= ~1.65million iu/mo; and had serum 25(OH)D levels ranging from 4 to 160ng/ml. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 5ng/ml per 1,000 IU in the supplementation interval of 0 to 1,000 IU /day; and by 92% less eg 0.4ng/ml per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 8 and 3 ng/ml lower, respectively (P<0.001). We observed no increase in the risk for hypercalcemia with increasing vitamin D supplement.”

5. Pakistan 2015 April 22nd Endocrine Society seminar RCT : Vit D3 up to 600 000iu loading dose : Prof Muhammad Masood, Consultant Endocrinologist of Aga Khan University : “ How Much Vitamin D We Need?” vit D deficiency VDD has resurfaced as significant health problem in recent years. In Pakistan region, VDD is very prevalent despite adequate sunshine throughout the year. A huge number of studies associate Vitamin D deficiency with almost any disease. Recently, concerns about the safe upper level of vitamin D have been raised and a reverse J or U shaped relation has been described with 25-OHD level and mortality. Increasing number of patients are being reported with vitamin D toxicity because of excessive intake of vitamin D resulting from misinterpretation of prescription, manufacturing errors, inappropriate prescription of excessive vitamin D doses for vague musculoskeletal complaints without monitoring 25-OHD concentrations. A study conducted at our center revealed important implications, first a dose of VD3 ranging from 200,000-600,000 IU given orally or IM will correct the deficiency in more than 70% of individual at 2 months. A dose of vitamin D 600,000 IU given IM will correct the deficiency in more than 90% of individuals and maintained levels > 20ng/ml in 84% of individuals at 6 months. Multiple mega doses may pose the risk of toxicity.”
6 Belgium 2014.:Vitamin D status after a 100 000iu highdose cholecalciferol in healthy and burn subjects. Rousseau ea Burns patients are at risk of vitamin D (VDD) deficiency and may benefit from its pleiotropic effects in acute phase. Two groups received an oral dose of 100,000IU VD3 RESULTS:A total of 49 subjects were included: 29 in GHealth and 20 in GBurns. At D0, prevalence of VDD was higher in GB: 25OH-D was 21.5 (10.1-46.3) ng/ml in GH vs 11 (1.8-31.4) ng/ml in GB. DBP and ALB were lower in GB. At D7 In GB, changes in 25OH-D extended from -36.7% to 333.3% with a median increase of 33.1%. This study highlighted the differences in VD status and in response to a high dose VD3 in burn patients when compared to healthy patients. 25OH-D measurement needs cautious interpretation, should not prevent burn patients to receive VD supplements during acute care. Higher doses than general should probably be considered

7 Canada 2015 Jan; up to 300 000iu vit D3 loading: McNally Univ Ontario ea Rapid normalization of vitamin D levels: a meta-analysis.. systematic review of pediatric clinical trials of high-dose vitamin D with 25[OH]D.., selected 88 Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (≥1000 IU) calciferol. 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 >30ng/dl within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >30ng/dlL. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses 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). Loading doses >300 000 IU should be avoided until trials are conducted to better evaluate risk and benefit.
Australia: some Australians are fearful in claimed cautious ignorance: Sanders ea University of Melbourne 2013 ask Is high dose vitamin D harmful? With potential to minimize risk of many chronic diseases, and apparent biochemical safety of ingesting doses of oral vitamin D several-fold higher than current recommended intakes, recent research has focused on supplementing intermittent, high-dose vitamin D. However, two recent randomized controlled trials (RCTs) both using annual high-dose vitamin D reported an increase, rather than a decrease, in the primary outcome of fractures.” So annual megadose doesnt help in prevention?.
but they are planning bold highdose trial:                                                                                    8. BMC Cancer. 2014 Saw ea Melanoma Institute, SydneyAdjuvant therapy with 500,000 IU high dose vitamin D following primary treatment of melanoma; Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, or nodal micrometastases, have few options for adjuvant treatment. Recent studies suggest a role for vitamin D to delay and improve overall prognosis. This pilot placebo-controlled randomised phase II trial will assess feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients treated by wide excision…”

        9 INDIAN PEDIATR 2014 :   300,000 IU or 600,000 IU RCT. Mittal ea Delhi. 76 children (median age 12 mo) with rickets. Oral vitamin D3 as 300,000 IU (Group 1; n=38) or 600,000 IU (Group 2; n=38) in a single day. 25(OH)D levels increased from baseline to 12 weeks after therapy :[Group 1: 7.58 to 16.06 (12.71– 20.29) ng/mL, P<0.001]; Group 2: 6.57 (4.66–9.25) to 17.60 . ie 25(OH)D levels were deficient (

But while all the data above are too heterogenous to do a metaanalysis, we now know as well as the South Africans, Pakistanis, Indians, Americans, Canadians, ANZIOs and Austrians do from this literature analysis and collective experience that a level of 25OHvit D of 20 or 40ng/ml is not adequate protection; conversely a bloodlevel of ~>200ng/ml has to be exceeded long term to incur risk. And a loading adult dose orally in adults of at least 600 000iu vit D3 – more likely >1 million iu- (that’s 6gm of 100cwt vit D concentrate powder, costing perhaps $0.25 in South Africa) taken with fat -may be needed to achieve safe high enough bloodlevel to have acute protective effect- and the vit D bloodlevel will drop below vigorous levels within weeks without maintenance doses, as the Austrian study used after their loading dose 540 000iu..

so even 50 000iu every week – my standard chronic illness adult maintenance dose that I take- is ineffective initially for acute protection in eg TB adults (Daley ea India 2015) or ICU . It seems such adults (pneumonia, TB, acute AIDS, ICU) need ? 600 000iu (or ? a ~ million iu orally) to start, then eg 100 000iu/wk till better, then drop to maintenance. .

Infantile bronchiolitis is a severe and common occurrence and killer under a year of age in South Africa as in the northern hemisphere; especially in tiny premmies; in the majority due to RSV respiratory syncytial virus rather than coronavirus, ‘flu etc; with no conventional therapy except support- leaving the doctor actively doing nothing except comfort, while the nurse nurses…
BUT eight papers since 2011 on Bronchiolitis strongly support vit D: that vitamin D deficiency/ polymorphism plays a major role from pregnancy on:
Three studies from 2011-2014 show that such bronchiolitis infants have low vitamin D or vitamin D polymorphisms that make them vulnerable; Two studies in 2014, from Harvard (Randolph ea ) and Ottawa (McNally ea) Universities in RSV bronchiolitis infants show vit D-binding haplotype, or Vitamin D receptor (VDR) polymorphisms;      And a 2011 study from Belderbos ea Utrech Univ Netherlands 2011 that Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis- Neonates born with 25-OHD concentrations <20ng/ml had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥ 30ng/dl. These studies thus point to brisk vitamin D supplement as likely major benefit against both RSV and subsequent asthma./COPD.

and Five recent team reviews 2011 to 2014 of RSV bronchiolitis from Italy—Baraldi ea ;   Canada- Poon ea ; Ireland – Clancy ea; and USA: Herzog ea-Cornell Univ NY, and Massachusetts-Maxwell ea – thus encourage the use of vigorous vitamin D and A and omega3 supplements in pregnancy or infancy to prevent  our  high RSA risk of bronchiolitis and future asthma/COPD.  eg
Curr Drug Targets. 2011.Herzog ea Cornell Univ. Immunologic impact of nutrient depletion in chronic obstructive pulmonary disease. Maternal smoking may diminish interferon response secondary to micronutrient deficiency, particularly of Vits A & D, and support persistence of RSV into adult life , Muscle wasting and cachexia systemic features of COPD. Nutritional depletion is related to poor survival and is a rational target for therapeutic intervention also in advanced and critically ill patients. Preliminary studies and suggest that supplementation with omega-3 and Vitamin A, Vitamin D3, and zinc may have beneficial effects in COPD.

now    2015  Salimi ea in Iran show in  Association between vitamin D receptor polymorphisms and haplotypes with pulmonary tuberculosis  in  Biomed Rep.   “The vitamin D receptor (VDR) is an important factor in activating immune response in different infectious diseases. Case control study on 120 PTB patients and 131 healthy controls with  Genetic analysis  by polymerase chain reaction.. The VDR Fok1 Ff genotype was associated with TB and the risk of PTB was two times higher in individuals with the Ff genotype. A higher frequency of f allele was observed in PTB patients and therefore, the f allele may be a risk factor for PTB susceptibility. In addition, haplotype analysis showed that the f-T-B and f-t-b haplotypes (Fok1, Taq1 and Bsm1) may have the potential to increase PTB susceptibility. In conclusion, the Ff genotype and f allele of the VDR Fok1 polymorphism were associated with PTB susceptibility. In addition, the f-T-B and f-t-b haplotypes may be the susceptible haplotypes for PTB.”

     THE RSA HOLOCAUST ESPECIALLY FOR WOMEN AND KIDS:  This new cumulative data above  is crucial given that while men fight ruthlessly for power, sex, money- even wars- the high birthrate in poor malnourished teenage girls in RSA, (especially with prevalent violence, alcohol, smoking and other drug abuses, AIDS and pulmonary and abdominal/ meningeal TB), who are thus ill-equipped both to breastfeed and parent with the myriad burdens of illiteracy and joblessness poverty, single parenting, starvation, male violence, refugee squatter survival, and then having to take ARVs, antiTB drugs or at least INH, cotrimoxazole and frequent other antimicrobials.

It is controversial, but Marks DF1.Br J Health Psychol. 2007 Department of Psychology, City University, UK argues that Literacy not intelligence moderates the relationships between economic development, income inequality and health: ” Kanazawa (2006) presented data allegedly supporting a racist version of evolutionary psychology that claims that the populations of wealthier and more egalitarian societies live longer and stay healthier, not because they are wealthier and more egalitarian, but because they are more intelligent. The objectives of this study are: (i) to determine the relationship between IQ and literacy in Kanazawa’s sample of countries and (ii) to reanalyse Kanazawa’s dataset using measures of literacy in lieu of national IQ test scores. RESULTS:National literacy scores across the countries in the sample are highly skewed. In spite of this, the literacy measures are highly correlated with alleged differences in national IQ (r = .83-.86). The measure of literacy together with economic development (GDPpc) and income inequality (Gini coefficient) control at least 59-64% of the variance in national life expectancy at birth.CONCLUSIONS:There is no scientific justification for believing that alleged intelligence differences play any role in explaining international differences in health status. Measures of alleged national IQ scores are highly confounded with differences in literacy. Literacy is a key factor in the health of any community and policies designed to enhance the literacy of a population are expected to lead to significant improvements in health status.
For these intellectually challenged illiterate women from remote rural villages  – many of whom cannot even write their initials let alone a signature, or understand English or Afrikaans-   anything but their tribal dialect-  pregnancy and AIDS/TB are the only relative escape from starvation and manual ie servile labour- which marginally paid drudgery is disappearing with the government-caused collapsed SA economy, power supply and industry. But the disability grant of ~R1500 ($125pm ie <$1/work hour) ) pm, and child welfare grant of perhaps R300 ($25)pm, is a drop in their ocean of despair. And given the mushrooming STD rates and costs thereof from male recklessness , from worsening corrupt central-government- led illiteracy and effective mass unemployment – state HIV-TB clinics and hospitals seldom have a little B6 or C to give these women, let alone regular supplies of ARVs or essential healing nutritionals eg vits A, Bco, minerals D, iodine, zinc, and biologicals eg  cod liver oil etc.

In the private sector, medical aid schemes also dont pay for supplements, only synthetic designer drugs that ignore underlying causal immunodeficiencies – since Only Disease Pays.
OVERDOSE? Between the two topic headings Hypervitaminosis D and Vitamin D toxicity, there are already 1798 refs on Pubmed alone. Hypervitaminosis D  428 reports on Pubmed since the first, from Harris & Moore, The Nutrition Lab, Cambridge 1929; Hypervitaminosis and vitamin balance: ..        and there are 1436 entries under Vitamin D toxicity since the first Vitamin D Toxicity by Leake 1936 at  UCLA .
ADULTS: But experts and numerous overdose reports ( only a few of which are noted below) reveal the truth,  that at least oral DAILY, well over 50 000iu to 1 MILLION iu/d of vitamin D for months, LONGTERM to up to 100 000IU/D for months to 365 million iu over 10 years has to be taken to cause illness ie symptomatic hypercalcemia .
Conversely, Chakraborty ea at Roy Research Center, Kolkata, India, report (Lab Med. 2015) A nontoxic case of vitamin d toxicity, a woman who developed very high serum Vitamin D levels (746 ng/mL, RI: 20 to 50) as a result of medication error. In spite of such high serum concentrations the patient was without any clinical symptoms and had normal serum calcium. The evidence base regarding the safety profile of Vitamin D supplementation in humans has been build through case reports, not dose titration RCTs to astronomical levels- which would be unethical.

So while routine maintenance dose eg 600 000iu/month, or 4000- to 10 000iu/d, or 100 000iu/wk in adults has never been reported to cause overdose toxicity,
on vigorous chronic vitamin D3 (not calcium or D2) dosing for disease, obviously ideally baseline (or at least after say 2-3 months of trial of conservative vitamin D replacement) calcium, vitamin D and kidney function levels should be measured since very rarely, unexpected silent hypercalcemia may already be present. .
But numerous reports eg from Netherlands 2014 show that a single overdose of even 2million iu vit D (=~100 000iu/d over 30days given the T 1/2 of vit D of 2 wks to 2 months), while kicking the bloodlevel up a few hundred ng/ml, does no harm even in two Dutch nonagenarians.

Relative hypovitaminosis D (bloodlevel below 30ng/ml) is prevalent locally and internationally in an indoor-working sunburn-fearing over-dressed city population not taking supplements more than the usual 400iu vit D in a daily multivite – especially in alcoholics, and the undernourished poor, and those following the government -recommended disease- promoting diabesogenic high- carbs low- fat diet marketed by commercial interests and bad science the past 50 years..

Already in 1999 Vieth at Univ Toronto wrote in Am J Clin Nutr. “Vitamin D supplementation, 25-OH vit D concentrations, and safety. . for adults, the 5-microg (200 IU) vitamin D RDA may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism, and prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. The assembled data from many vitamin D supp. studies reveal a curve for vitamin D dose versus serum 25(OH)D response that is surprisingly flat up to 250 mcg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 40ng/ml, a total vitamin D supply of >100 microg (4000 IU)/d is required. Except with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <55ng/ml, which require a total vitamin D supply of 250 microg (10 000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of >/= 1000 mcg (40 000 IU)/d. Because vitamin D is potentially toxic, intake of >1000 IU/d has been avoided – even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 2000 Iu)/d is too low by at least 5-fold ie >10 000iu/d long term.”
O/Dose INFANTS: to avoid vitamin D poisoning and permanent damage to infants, of course dose needs to be scaled down accordingly on the 100iu/kg/d basis; but infants have a much bigger body surface area and thus meds requirement & tolerance. Human breast milk vit D is usually inadequate especially for swaddled darker-skinned babies and mothers; so conventionally at least 1000iu/d supplement vit D is for babies up to 6 months, 2500iu/d above 1year, and 4000iu/d from 9 years; or a pro rata loading dose, is advised eg Canada and USA Heaney ea Conversely, serum 25(OH)D concentration consistently >200 ng/mL is considered to be potentially toxic [5].” Without a fingerprick vit D and calcium assay (lab cost here is ~R300 ie $25), monitoring here is tedious and costly…
ALLERGY TO VITAMIN D3? That vigorous vitamin D3 replacement can improve immunodeficiency and even relieve dermatitis is common cause.
But since Vit D’s discovery in 1914 (USA McCollum and Davis) and soon commercial production and marketing the past 90 years, not a single documented verified ALLERGY case (not overdose) can be found on Pubmed or Google?.Such true allergy cannot be anything but very very rare, since with vit D3, like all other bioidentical human hormones, and vitamins, allergy (unlike overdose) is almost inconceivable- although receptor loss or blockade may create resistance to eg thyroid, testosterone, vit D etc. . Allergy could conceivably occur to some carrier/ additive to the vitamin D3- but not even in the lungs from inhalation of old high-vit D oil droplets in fish factory workers
VitaminDwiki puts it in perspective. Designer ie prescription synthetic meds, and common foods, and tap water, are more likely to cause problem.

None of the 14 refs on Pubmed reports allergy to vitamin D. Google merely notes some anecdotes from users.

The last and urgent word today  -on medical and parental responsibilities- is by Wolfgang Högler ,Birmingham Children’s Hospital, UK ,Clin.Endoc. 2015: Complications of vitamin D deficiency from the foetus to the infant: One cause, one prevention, but who’s responsibility? The supplier of bone Calcium and phosphorus is the hormone calcitriol, which originates from vitamin D, itself made by sunshine in human skin. Requirement for bone minerals is highest during phases of rapid growth, and no one grows faster than the foetus and the infant, making them particularly vulnerable. Deprivation of calcium, whether through low calcium intake or low vitamin D, leads to serious health consequences throughout life, such as hypocalcaemic seizures, dilated cardiomyopathy, skeletal myopathy, congenital and infantile rickets, and osteomalacia.                                                                                                                    These 5 conditions are often summarised as ‘symptomatic vitamin D deficiency’, are fully reversible but also fully preventable. However, the increasing prevalence of rickets and osteomalacia, and the deaths from hypocalcaemic cardiomyopathy, demand action from global health care providers. Clarification of medical and parental responsibilities is a prerequisite to deliver successful prevention programmes.     The foetus and infant have the human right to be protected against harm, and vitamin D supplementation has the same public health priority as vaccinations.

And Dr John Cannell of The Vitamin D Council comments today : Dr. Hogler does not discuss the growing evidence that maternal and infantile vitamin D deficiencies may lead to neurodevelopmental disorders such as autism. I have always thought that the only way obstetricians and pediatricians will prescribe adequate doses of vitamin D is if they are charged for malpractice from failing to identify and treat vitamin D deficiency. If it is established that vitamin D deficiency causes autism, the malpractice attorneys will swarm like sharks to blood. Given increasing evident harms from numerous vaccinations, and often lack of real longterm supporting evidence of good eg the (swine and seasonal) flu and cervix HPV vaccines, we must consider vitamin D supplementation as far more proven benefit and safety than intensive multiple vaccinations.
-And on sepsis and brain salvage:  Dr Cannell promotes   –  vitamin D is a viable treatment for sepsis?, the landmark work of Drs William Grant and Ray Matthews.

The evidence is strong that vigorous natural supplements (vits, minerals, human hormones and some natural biological like marine oil and chondroglucosamine) are priorities especially in both acute emergencies, chronic diseases and prevention, from conception at all ages, over vaccinations and antibiotics and all synthetic designer drugs. .

BMC Cancer. 2014 ;14:780 Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial Saw RP1, Thompson JF. ea Melanoma Institute Australia,North Sydney , Australia. .

  Indian Pediatr. 2014 ;51:265-72. 300,000 IU or 600,000 IU of oral vitamin D3 for treatment of nutritional rickets: a randomized controlled trial. Mittal , Gupta ea University College Medical Sci,, New Delhi.
Calcif Tissue Int. 2013 ;92(2):191-206. Is high dose vitamin D harmful? Sanders KM1, Nicholson GC, Ebeling PR., University of Melbourne

Med J Aust. 2005 Jul 4;183(1):10-2. Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Diamond TH1, Ho KW, Rohl PG, Meerkin M.University of New South Wales, Australia.

Geriatr Orthop Surg Rehabil. 2011 May;2(3):94-9. . Improving mobility and reducing disability in older people through early high-dose vitamin d replacement following hip fracture: a protocol for a randomized controlled trial and economic evaluation. Mak JC1,  Cameron ID ea. , University of Sydney, Australia .Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture and has been linked with poorer lower extremity functioning, falls, and fractures.

     J Nutr. 2014;144:2002-8. Vitamin D deficiency is associated with progression of knee osteoarthritis. Zhang FF1, McAlindon TE EA2.usa uNIVERSITIES

    Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2014 ;28(14):1031-3. [Effect of nasal instillation of vitamin D3 on patient with allergic rhinitis symptoms]. [Article in Chinese] Gong, Jiang Y EA

      Nutrients. 2014 ;6(9):3403-30. doi: 10.3390/nu6093403. Does sufficient evidence exist to support a causal association between vitamin D status and cardiovascular disease risk? An assessment using Hill’s criteria for causality.Weyland PG1, Grant WB2, Howie-Esquivel J3., University of California,
Eur J Clin Nutr. 2014 ;68(5):632-4..Pharmacokinetics of daily versus monthly vitamin D3 supplementation in non-lactating women.Meekins ME1,, Thacher TD2Mayo Clinic, Rochester,& University of Witwatersrand, Johannesburg,
Mol Med. 2009 ;15(9-10):328-36. Vitamin D affords better neuroprotection against excitotoxicity in cultured cortical neurons than progesterone alone. Atif F1, Sayeed I, Ishrat T, Stein Emory University, Atlanta, Georgia, USA
Am J Clin Nutr. 2008 ;87(6):1952-8. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Aloia, Yeh ea Winthrop University Hospital, NY.
Am J Clin Nutr. 2008:87(3):688-91.Pharmacokinetics of a single, large dose of cholecalciferol.  Ilahi M1, Armas LA, Heaney Creighton University Omaha, .
Curr Opin Lipidol. 2007 ;18(1):41-6. Vitamin D and vascular calcification.Zittermann Schleithoff Koerfer Ruhr University Bochum, Germany.
J Am Coll Nutr. 2003 Apr;22(2):142-6. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. Heaney RP1, Dowell MS, Hale CA, Bendich A.Creighton University, USA.

         Diabetes Care. 2015 May. pii: dc150323. Effect of LOWDOSE Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial. Krul-Poel YH1, Simsek S7 eu .

          Horm Metab Res. 2015 May 4 Effects of High-Dose Vitamin D Supplementation on Metabolic Status and Pregnancy Outcomes in Pregnant Women at Risk for Pre-Eclampsia. Karamali M1, Asemi Z ea.
J Am Geriatr Soc. 2014 ;62(8):1546-50..Effectiveness and safety of a high-dose weekly vitamin D (20,000 IU) protocol in older adults living in residential care. Feldman F1, Green TJ.ea. Simon Fraser University, Burnaby, BC, Canada.

    Maturitas. 2015 Mar 27. Sarcopenia in post-menopausal women: Is there any role for vitamin D? Anagnostis P1, Goulis DG ea Greek Universities
J Adolesc Health. 2015 Apr 11. Vitamin D =<2000iu/d Fail to Increase 25-Hydroxyvitamin D Levels or to Alter Cardiovascular Risk Factors in Obese Adolescents: A Pilot Study.
Shah S1, Wilson DM2, Bachrach LK2.

     Lancet Infect Dis. 2015 May;15(5):528-34.Adjunctive vitamin D 400 000iu in 6 weeks for treatment of active tuberculosis in India no benefit : a randomised, double-blind, placebo-controlled trial. Daley P1, Vieth R4, , Mathai D ea .
Thorax. 2015 May;70(5):451-7. doi: 10.1136/thoraxjnl-2014-206449. Epub 2015 Feb 27.
PLoS One. 2015 Feb 23;10(2):e0117123. doi: 10.1371/journal.pone.0117123. eCollection 2015. Vitamin D₃ supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial. Steenhoff AP1, Stallings ea .
Eur J Endocrinol. 2015 Mar;172(3):235-41. doi: 10.1530/EJE-14-0870.Vitamin D3 increases in abdominal subcutaneous fat tissue after supplementation with vitamin D3. Didriksen , Jorde R3 ea

44-9987.12279. Epub 2015 Feb 6. Effects of a single, high oral dose of 25-hydroxycholecalciferol on the mineral metabolism markers in hemodialysis patients. Merino , 2, Quereda ea, .
Pediatr Neurol. 2015 ;52:160-4.Vitamin D supplementation in children with epilepsy and intellectual disability. Snoeijen-Schouwenaars , Majoie MH ea .:.
J Acad Nutr Diet. 2015 Feb;115(2):225-30. .Dietary fat increases vitamin D-3 absorption.Dawson-Hughes B, Rasmussen H.
Eur J Clin Nutr. 2015 ;69(2):193-7 The effect of a single, large bolus of vitamin D 250,000 IU in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.Kearns MD1, Tangpricha V3

Sleep Breath. 2015 May;19(2):579-83. doi: 10.1007/s11325-014-1049-y. Epub 2014 Aug 23. The effect of vitamin D supplements on the severity of restless legs syndrome. Wali S1, Krayem A.

Endocr Pract. 2014 ;20(12):1258-64..The vitamin d dose response in obesity.Dhaliwal R1, Aloia JF1.

BMC Infect Dis. 2013;13:22. Vitamin D accelerates clinical recovery from tuberculosis: Salahuddin N ea.
Curr Drug Targets. 2011;12(4):489-500. Immunologic impact of nutrient depletion in chronic obstructive pulmonary disease. Herzog R1, Cunningham-Rundles , Cornell University, NY.

    Ital J Pediatr. 2014 Oct 24;40:65. Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants. Baraldi , Corsello EA -Società Italiana per le Malattie Respiratorie Infantili, Italy.
Pharmacol Ther. 2013;140(2):148-55.Vitamin D deficiency and severe asthma. Poon AH1, Mahboub B, Hamid Q. McGill University,
Clin Exp Allergy. 2014 Feb;44(2):231-7. doi: 10.1111/cea.12247.Vitamin D-binding protein haplotype is associated with hospitalization for RSV bronchiolitis. Randolph, Bont EA Harvard Medical School.
Pediatr Pulmonol. 2014;49(8):790-9. Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: a systematic review and meta-analysis. McNally1, Little ea. Univ Ottawa, Canada.
Pediatrics. 2011;127):e1513-20. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Belderbos, Bont ea, University Utrecht,Ndl.

     J Matern Fetal Neonatal Med. 2013;26;639-46.Vitamin D and neonatal immune function. Clancy ea Ireland
Nutr Rev. 2012;70:548-52. Better newborn vitamin D status lowers RSV-associated bronchiolitis in infants.Maxwell CS1, Carbone ET, Wood RJ. University of Massachusetts, Amherst, USA.
Am J Clin Nutr. 1999 ;69:842-56.Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Vieth.   University of Toronto, Canada.

     Clin Endocrinol (Oxf). 2015 Jun . doi: 10.1111/cen.12836. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Kaur, Mithal ea Delhi.

     J Steroid Biochem Mol Biol. 2015 Apr;148:14-8. Iatrogenic vitamin D toxicity in an infant–a case report and review of literature. Ketha, Singh EA

    Einstein (Sao Paulo). 2014;12(2):242-4. Vitamin D intoxication: case report.
[Article in English, Portuguese] Marins TA1, Korkes H1.ea Hospital Israelita Albert Einstein, São Paulo, Brazil.
J Clin Endocrinol Metab. 2011;96(12):3603-8. .Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States.Araki T1, Holick MF, Newman LG.ea

Ann Pharmacother. 2011 ;45(10):e52. Hypervitaminosis D associated with a vitamin D dispensing error. 4.5million iu over 3 mo. Jacobsen , Schilling ea.

Am J Public Health. 1995 ;85(10):1418-22. Subclinical health effects in a population exposed to excess vitamin D in milk. Scanlon, Falk H.ea
N Engl J Med. 1992 ;326(18):1173-7. Hypervitaminosis D associated with drinking milk. Jacobus CH1, Holick MF, Seely EW.:ea .

Q J Med. 1986 Oct;61(234):911-9. The osteodystrophy of hypervitaminosis D 365million iu over 10 years: a metabolic study. Davies M, Mawer EB, Freemont AJ. A patient received 2.5 mg vitamin D2 ie 100 000iu/d daily for 10 years ie 365 million iu total, presented with increasing skeletal pain and hypercalcaemia. The limbs were painful to touch especially at the insertions of ligaments and tendons, and radiographs showed osteosclerosis with calcification in the periosteum, blood vessels, tendoachilles and plantar fascia. A negative external calcium balance was documented in the presence of enhanced intestinal calcium absorption and an increase in urinary hydroxyproline excretion. Cortisone improved calcium balance and corrected the hypercalcaemia by reducing serum 1,25-dihydroxyvitamin D levels and urinary hydroxyproline excretion.

Nouv Presse Med. 1981;10(36):2965-7.[Vitamin D metabolites in a new case of drug-induced hypercalcemia (author’s transl)]. [ French] Ulmann A, Bourdeau A, Lair M, Bader C. the authors report on a new case of severe hypercalcaemia induced by prolonged oral treatment with high doses of vitamin D2. (6 mg ie 240 000iu/day ie for 9 months ie 23million iu).

     Lancet. 1978 ;2(8090):621-3. The continuing risk of vitamin-D intoxication.
Davies, Adams . Eight cases of vitamin-D poisoning are described.
Arch Intern Med. 1975 Jul;135(7):986-8. Protracted vitamin D intoxication.
Shetty , Hagen ea   A 56-year-old woman underwent subtotal thyroidectomy for Graves disease in 1963. After the operation, hypoparathyroidism developed and therapy was begun with vitamin D2 (ergocalciferol), 100,000 units daily.  Four months later, ie 12 million iu vit D, after hypercalcemia (14 mg/100 ml) had been noted, vitamin D therapy was discontinued

    Dtsch Med Wochenschr. 1975 ;100(9):415-6, 419-23. [Observations in vitamin D and dihydrotachysterol poisoning]. [German] Ziegler R, Delling ea. In three women intoxication with vitamin D or dihydrotachysterol occurred. Two patients died from complications despite successful lowering of the serum calcium, the third died after a pulmonary embolus during hypercalcaemia 5 months after cessation of vitamin D. .

    Br Med J. 1972 ;3(5820):205-7. Vitamin D intoxication treated with porcine calcitonin. Buckle RM, Gamlen TR, Pullen IM.Southampton UK Porcine calcitonin was used to treat three Southampton women in their sixties with hypercalcaemia due to accidental chronic vitamin D intoxication with 30 000 to 500 000iu/d for 4 to 13 weeks (vit D 9 million iu over 4wks; 4.5million iu over 13 week; and 29 million iu over 2 months). Normocalcaemia was achieved in 3 to seven days, with rapid full recovery.