Karin Amrein

Vitamin D and immune function.

Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes. In vitro data show that, in addition to modulating innate immune cells, vitamin D also promotes a more tolerogenic immunological status. In vivo data from animals and from human vitamin D supplementation studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity. In this review, currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.

Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults.

CONTEXT Sclerostin is produced by osteocytes and inhibits bone formation through the Wnt/β-catenin-signaling pathway. Only limited data are available on circulating sclerostin levels in healthy subjects. OBJECTIVE We aimed to evaluate the correlation between sclerostin and physical activity, anthropometric, and biochemical variables. DESIGN, SETTING, AND PARTICIPANTS We conducted a cross-sectional observational study in 161 healthy adult men and premenopausal women aged 19 to 64 yr (mean age, 44 ± 10). INTERVENTION(S) There were no interventions. MAIN OUTCOME MEASURE(S) Serum sclerostin levels were associated with body composition, bone mineral density, physical activity, and various biochemical parameters. RESULTS A positive correlation between age and sclerostin in both men (r = 0.37; P < 0.001) and premenopausal women (r = 0.66; P < 0.001) was found. Men had significantly higher sclerostin levels than women (49.8 ± 17.6 vs. 37.2 ± 15.2 pmol/liter; P < 0.001). However, after adjustment for age, bone mineral content (BMC), physical activity, body mass index (BMI), and renal function, sclerostin levels did not differ (P = 0.543). Partial correlation analysis adjusted for age, gender, and kidney function revealed a significant positive correlation between sclerostin levels and BMC, bone mineral density, BMI, and android/gynoid fat and a significant negative correlation with serum osteocalcin and calcium. The most physically active quartile had significantly lower sclerostin levels compared to the least active quartile in a univariate analysis. CONCLUSIONS In healthy adults, sclerostin serum levels correlate positively with age, BMI, and BMC and negatively with osteocalcin and calcium. Further studies in larger populations are needed to confirm our findings and to better understand their clinical implications.

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.

IMPORTANCE Low vitamin D status is linked to increased mortality and morbidity in patients who are critically ill. It is unknown if this association is causal. OBJECTIVE To investigate whether a vitamin D3 treatment regimen intended to restore and maintain normal vitamin D status over 6 months is of health benefit for patients in ICUs. DESIGN, SETTING, AND PARTICIPANTS A randomized double-blind, placebo-controlled, single-center trial, conducted from May 2010 through September 2012 at 5 ICUs that included a medical and surgical population of 492 critically ill adult white patients with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 (n = 249) or a placebo (n = 243). INTERVENTIONS Vitamin D3 or placebo was given orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months. MAIN OUTCOMES AND MEASURES The primary outcome was hospital length of stay. Secondary outcomes included, among others, length of ICU stay, the percentage of patients with 25-hydroxyvitamin D levels higher than 30 ng/mL at day 7, hospital mortality, and 6-month mortality. A predefined severe vitamin D deficiency (≤12 ng/mL) subgroup analysis was specified before data unblinding and analysis. RESULTS A total of 475 patients were included in the final analysis (237 in the vitamin D3 group and 238 in the placebo group). The median (IQR) length of hospital stay was not significantly different between groups (20.1 days [IQR, 11.1-33.3] for vitamin D3 vs 19.3 days [IQR, 11.1-34.9] for placebo; P = .98). Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28.3% [95% CI, 22.6%-34.5%] for vitamin D3 vs 35.3% [95% CI, 29.2%-41.7%] for placebo; hazard ratio [HR], 0.81 [95% CI, 0.58-1.11]; P = .18; 6-month mortality: 35.0% [95% CI, 29.0%-41.5%] for vitamin D3 vs 42.9% [95% CI, 36.5%-49.4%] for placebo; HR, 0.78 [95% CI, 0.58-1.04]; 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: 20.1 days (IQR, 12.9-39.1) for vitamin D3 vs 19.0 days (IQR, 11.6-33.8) for placebo. Hospital mortality was significantly lower with 28 deaths among 98 patients (28.6% [95% CI, 19.9%-38.6%]) for vitamin D3 compared with 47 deaths among 102 patients (46.1% [95% CI, 36.2%-56.2%]) for placebo (HR, 0.56 [95% CI, 0.35-0.90], P for interaction = .04), but not 6-month mortality (34.7% [95% CI, 25.4%-45.0%] for vitamin D3 vs 50.0% [95% CI, 39.9%-60.1%] for placebo; HR, 0.60 [95% CI, 0.39-0.93], P for interaction = .12). CONCLUSIONS AND RELEVANCE Among critically ill patients with vitamin D deficiency, administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay, hospital mortality, or 6-month mortality. Lower hospital mortality was observed in the severe vitamin D deficiency subgroup, but this finding should be considered hypothesis generating and requires further study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01130181.

Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study

IntroductionVitamin D deficiency is encountered frequently in critically ill patients and might be harmful. Current nutrition guidelines recommend very low vitamin D doses. The objective of this trial was to evaluate the safety and efficacy of a single oral high-dose vitamin D3 supplementation in an intensive care setting over a one-week observation period.MethodsThis was a randomized, double-blind, placebo-controlled pilot study in a medical ICU at a tertiary care university center in Graz, Austria. Twenty-five patients (mean age 62 ± 16yrs) with vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) ≤20 ng/ml] and an expected stay in the ICU >48 hours were included and randomly received either 540,000 IU (corresponding to 13.5 mg) of cholecalciferol (VITD) dissolved in 45 ml herbal oil or matched placebo (PBO) orally or via feeding tube.ResultsThe mean serum 25(OH)D increase in the intervention group was 25 ng/ml (range 1-47 ng/ml). The highest 25(OH)D level reached was 64 ng/ml, while two patients showed a small (7 ng/ml) or no response (1 ng/ml). Hypercalcemia or hypercalciuria did not occur in any patient. From day 0 to day 7, total serum calcium levels increased by 0.10 (PBO) and 0.15 mmol/L (VITD; P < 0.05 for both), while ionized calcium levels increased by 0.11 (PBO) and 0.05 mmol/L (VITD; P < 0.05 for both). Parathyroid hormone levels decreased by 19 and 28 pg/ml (PBO and VITD, ns) over the seven days, while 1,25(OH)D showed a transient significant increase in the VITD group only.ConclusionsThis pilot study shows that a single oral ultra-high dose of cholecalciferol corrects vitamin D deficiency within 2 days in most patients without causing adverse effects like hypercalcemia or hypercalciuria. Further research is needed to confirm our results and establish whether vitamin D supplementation can affect the clinical outcome of vitamin D deficient critically ill patients.EudraCT Number2009-012080-34German Clinical Trials Register (DRKS)DRKS00000750

Vitamin D status and mortality in chronic kidney disease

BACKGROUND Vitamin D deficiency is found in the majority of patients with chronic kidney disease (CKD) and may contribute to various chronic diseases. Current guidelines suggest correcting reduced 25-hydroxyvitamin D [25(OH)D] concentrations in CKD patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). Whether low 25(OH)D levels in these patients are associated with higher mortality is unclear. This issue was addressed in the present work. METHODS We examined 444 patients with eGFR <60 mL/min/1.73 m(2) from the Ludwigshafen Risk and Cardiovascular Health Study. This prospective cohort study includes Caucasian patients without primary kidney disease who were routinely referred to coronary angiography at baseline (1997-2000). RESULTS During a median follow-up time of 9.4 years, 227 patients died including 159 deaths from cardiovascular causes. Multivariate adjusted hazard ratios (HRs) (with 95% confidence intervals) in severely vitamin D-deficient [25(OH)D <10 ng/mL] compared to vitamin D-sufficient patients [25(OH)D ≥ 30 ng/mL] were 3.79 (1.71-8.43) for all-cause and 5.61 (1.89-16.6) for cardiovascular mortality. Adjusted HRs per 10 ng/mL increase in 25(OH)D levels were 0.63 (0.50-0.79) for all-cause and 0.59 (0.45-0.79) for cardiovascular mortality. There was no significant interaction with parathyroid hormone concentrations. CONCLUSIONS Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials.

Evidence for a U-shaped relationship between prehospital vitamin D status and mortality: a cohort study.

OBJECTIVE The objective of the study was to examine the association between prehospital serum 25-hydroxyvitamin D [25(OH)D]and the risk of mortality after hospital admission. DESIGN We performed a retrospective cohort study of adults hospitalized for acute care between 1993 and 2011. SETTING The study was conducted at two Boston teaching hospitals. PATIENTS A total of 24,094 adult inpatients participated in the study. INTERVENTION There was no intervention. MEASUREMENTS All patients had serum 25(OH)D measured before hospitalization. The exposure of interest was 25(OH)D categorized as less than 10 ng/mL, 10-19.9 ng/mL, 20-29.9 ng/mL, 30-49.9 ng/mL, 50-59.9 ng/mL, 60-69.9 ng/mL, and 70 ng/mL or greater. The main outcome measure was 90-day mortality. Adjusted odds ratios (ORs) were estimated by multivariable logistic regression with inclusion of potential confounders. RESULTS After adjustment for age, gender, race (white vs nonwhite), patient type (surgical vs medical), season of 25(OH)D draw, and the Deyo-Charlson index, patients with 25(OH)D levels less than 30 ng/mL or 60 ng/mL or greater had higher odds of 90-day mortality compared with patients with levels of 30-49.9 ng/mL [adjusted OR (95% confidence interval) for 25(OH)D <10 ng/mL, 10-19.9 ng/mL, 20-29.9 ng/mL, 50-59.9 ng/mL, 60-69.9 ng/mL, and ≥70 ng/mL was 2.01 (1.68-2.40), 1.89 (1.64-2.18), 1.34 (1.16-1.56), 0.94 (0.69-1.26), 1.52 (1.03-2.25), and 1.69 (1.09-2.61), respectively, compared with patients with 25(OH)D levels 30-49.9 ng/mL]. LIMITATIONS A causal relationship between either low or high 25(OH)D levels and increased mortality can not necessarily be inferred from this observational study. CONCLUSIONS Analysis of 24 094 adult patients showed that 25(OH)D levels less than 20 ng/mL and 60 ng/mL or greater before hospitalization were associated with an increased odds of 90-day mortality. Although previous reports have suggested an association between low vitamin D status and mortality, these data raise the issue of potential harm from high serum 25(OH)D levels, provide a rationale for an upper limit to supplementation, and emphasize the need for caution in the use of extremely high doses of vitamin D among patients.

Women Underrepresented on Editorial Boards of 60 Major Medical Journals

BACKGROUND Although there has been a continuous increase in the number of women working in the field of medicine, women rarely reach the highest academic positions as full professors or editorial board members. OBJECTIVE We aimed to determine the proportion of women on the editorial boards of top-ranked medical journals in different medical specialties. METHODS We analyzed the gender of editorial board members of 60 top-ranked journals of 12 Thomson Reuters Web of Knowledge Journal Citation Reports categories. A total of 4175 editors were included in our analysis. RESULTS Only 15.9% (10 of 63) editors-in-chief were female. In the 5 categories, critical care, anesthesiology, orthopedics, ophthalmology and radiology, nuclear medicine and medical imaging, currently not 1 woman holds the position of editor-in-chief. Less than one fifth (17.5%, 719 of 4112) of all editorial board members were women. There were significant differences among the evaluated categories, with the highest percentage of women in the category of medicine, general and internal and the lowest in the category critical care, followed by orthopedics. In every category, the proportion of women as editorial board members was substantially lower than that of men. CONCLUSIONS Women are underrepresented on the editorial boards of major medical journals, although there is a great variability among the journals and categories analyzed. If more women are nominated to serve on editorial boards, they will be a visible sign of continuing progress and serve as important role models for young women contemplating a career in academic medicine.

Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure

AIMS Renin is the key regulator of the renin-angiotensin-aldosterone system. Previous studies have reported conflicting results on the relation of plasma renin with fatal cardiovascular events. This study in a large cohort of patients sought to evaluate the association between plasma renin concentration (PRC) and cardiovascular mortality after long-term follow-up of almost 10 years. METHODS AND RESULTS Plasma renin concentration [median: 11.4 (6.0-24.6) pg/mL] was measured in 3303 patients (mean age: 62.7 ± 10.6 years; 30.3% women) referred to coronary angiography. After a median follow-up of 9.9 years, 554 participants (16.8%) with PRC measurement at baseline had died due to fatal cardiovascular events. Multivariable-adjusted Cox analysis revealed that when compared with participants in the lowest PRC quartile, those in the highest quartile were at increased risk of cardiovascular mortality (hazard ratio: 1.79, 95% CI 1.28-2.48). Analyses of specific causes of cardiovascular death showed that for each standard deviation increase in log-PRC there was a 22% (P = 0.006) increase in risk of sudden cardiac death and a 23% (P = 0.033) greater risk of death due to heart failure. The association of PRC with cardiovascular mortality remained stable after adjustment for established cardiovascular risk factors, ongoing antihypertensive medication, immunoreactive angiotensin II, and aldosterone levels. Age, N-terminal pro-B-type natriuretic peptide levels, coronary artery disease, the use of angiotensin-converting enzyme-inhibitors, beta-blockers, diuretics, and kidney function were important effect modifiers. CONCLUSIONS Plasma renin concentration is associated with long-term cardiovascular mortality in patients referred to coronary angiography. Further intervention studies should determine whether renin is a potential therapeutic target or only a marker of mortality risk in various cardiovascular risk groups.

Adverse events and safety issues in blood donation—A comprehensive review

Although blood donation is generally safe, a variety of risks and complications exist, the most common being iron deficiency, vasovagal reactions and citrate-related events. In the last decades, extensive efforts have significantly improved recipient and product safety, but there is still great potential to optimise donor care. Many therapies in modern medicine depend on the prompt availability of blood products, therefore it is crucial to maintain a motivated and healthy donor pool in view of a limited number of healthy volunteers willing and able to give blood or blood components. We present a comprehensive review on adverse events addressing all types of blood donation including whole blood, plasma, platelet, peripheral blood stem cell, leucocyte and bone marrow donation. In addition, we outline strategies for the prevention and treatment of these events and give a blueprint for future research in this field.

Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial

BackgroundIncreasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess.Methods/designOverall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease.The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1–84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints.DiscussionIn view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism.Trial registrationISRCTN33941607