Context: Optimal levels of vitamin D have been a topic of heavy debate, and the correlation between 25-hydroxyvitamin D [25(OH)D] levels and mortality still remains to be established. Objective: The aim of the study was to determine the association between all-cause mortality and serum levels of 25(OH)D, calcium, and PTH. Design and Setting: We conducted a retrospective, observational cohort study, the CopD Study, in a single laboratory center in Copenhagen, Denmark. Participants: Serum 25(OH)D was analyzed from 247,574 subjects from the Copenhagen general practice sector. In addition, serum levels of calcium, albumin-adjusted calcium, PTH, and creatinine were measured in 111,536; 20,512; 34,996; and 189,496 of the subjects, respectively. Main Outcome Measures: Multivariate Cox regression analysis was used to compute hazard ratios for all-cause mortality. Results: During follow-up (median, 3.07 yr), 15,198 (6.1%) subjects died. A reverse J-shaped association between serum level of 25(OH)D and mortality was observed. A serum 25(OH)D level of 50–60 nmol/liter was associated with the lowest mortality risk. Compared to 50 nmol/liter, the hazard ratios (95% confidence intervals) of all-cause mortality at very low (10 nmol/liter) and high (140 nmol/liter) serum levels of 25(OH)D were 2.13 (2.02–2.24) and 1.42 (1.31–1.53), respectively. Similarly, both high and low levels of albumin-adjusted serum calcium and serum PTH were associated with an increased mortality, and secondary hyperparathyroidism was associated with higher mortality (P < 0.0001). Conclusion: In this study from the general practice sector, a reverse J-shaped relation between the serum level of 25(OH)D and all-cause mortality was observed, indicating not only a lower limit but also an upper limit. The lowest mortality risk was at 50–60 nmol/liter. The study did not allow inference of causality, and further studies are needed to elucidate a possible causal relationship between 25(OH)D levels, especially higher levels, and mortality.

Purpose. To evaluate the influence of time of day on the circulating concentrations of 21 hematology parameters. Materials and methods. Venous blood samples were obtained under standardized circumstances from 24 healthy young men every third hour through 24 hours, nine time points in total. At each time point, the level of melatonin, iron, transferrin, transferrin saturation, ferritin, cobalamin, folate, red blood cells and white blood cells was measured. The data were analysed by rhythmometric statistical methods. The biological variations were calculated. Results. Significant oscillation of melatonin (p < 0.0001) with an amplitude (amp) of 19.84 pg/ml and a peak level at 03:34 h confirmed the normal 24-hour rhythms of the participants. Erythrocytes (p < 0.0001, amp = 0.15 × 10¹²/L), hemoglobin (p < 0.0001, amp = 0.29 mmol/L), hematocrit (p < 0.0001, amp = 0.01), iron (p < 0.0001, amp = 4.00μmol/L), transferrin (p = 0.03, amp = 1.41μmol/L), transferrin saturation (p < 0.0001, amp = 6.37%) and folate (p < 0.0001, amp = 1.55nmol/L) oscillated significantly, with gradually falling mean levels through the day to nadir around midnight. Leukocyte count (p < 0.0001, amp = 0.78 × 10⁹/L), neutrophils (p = 0.001, 0.31 × 10⁹/L), eosinophils (p < 0.0001, amp = 0.04 × 10⁹/L), monocytes (p = 0.0009, amp = 0.06 × 10⁹/L), lymphocytes (p < 0.0001, amp = 0.49 × 10⁹/L) oscillated significantly with gradually increasing mean levels through the day peaking at midnight. Iron, leukocytes and hemoglobin had the highest 24 hour oscillations in proportion to the reference intervals of the parameters for healthy young men. Conclusions. Biochemical screenings are biased by diurnal variations, which must be considered when blood concentrations of these parameters are interpreted in the clinical setting.

Cardiovascular disease is the major cause of death in the Western world, but the association between 25-hydroxyvitamin D [25(OH)D] levels and the risk of cardiovascular disease mortality remains unclear. The objective of the study was to determine the association between cardiovascular, stroke, and acute myocardial infarct mortality and serum levels of 25(OH)D. This was an observational cohort study, the Copenhagen vitamin D study, data from a single laboratory center in Copenhagen, Denmark. Follow-up was from 2004 to 2011. Serum 25(OH)D was analyzed from 247 574 subjects from the Copenhagen general practice sector. Examination of the association 25(OH)D levels and mortality from cardiovascular disease, stroke, and acute myocardial infarct was performed among 161 428 women and 86 146 men. A multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke, and acute myocardial infarct mortality. Of 247 574 subjects, a total of 16 645 subjects died in the ensuing 0-7 years. A total of 5454 died from cardiovascular disease including 1574 from stroke and 702 from acute myocardial infarct. The 25(OH)D level of 70 nmol/L was associated with the lowest cardiovascular disease mortality risk. Compared with that level, the hazard ratio for cardiovascular disease mortality was 2.0 [95% confidence interval (CI) 1.8-2.1] at the lower extreme (∼ 12.5 nmol/L) with a higher risk for men [2.5 (95% CI 2.2-2.9)] than for women [1.7 (95% CI 1.5-1.9)]. At the higher extreme (∼ 125 nmol/L), the hazard ratio of cardiovascular disease mortality was 1.3 (95% CI 1.2-1.4), with a similar risk among men and women. Results were similar for stroke and acute myocardial subgroups. In this large observational study, low and high levels of 25(OH)D were associated with cardiovascular disease, stroke, and acute myocardial mortality in a nonlinear, reverse J-shaped manner, with the highest risk at lower levels. Whether this was a causal or associational finding cannot be determined from our data. There is a need for randomized clinical trials that include information on the effects of 25(OH)D levels greater than 100 nmol/L.

Objective To investigate the association between hypothyroidism and mortality in both treated and untreated hypothyroid patients, and the consequences of over- and undertreatment with respect to mortality. Patients and methods Register-based cohort study of 235 168 individuals who had at least one serum TSH during 1995 to 2011 (median follow-up, 7.2 years). Hypothyroidism was defined as at least two measurements of TSH>4.0 mIU/L within a half year spaced by at least 14 days, or one measurement of TSH>4.0 mIU/L and two filled prescriptions of levothyroxine the following year. All-cause mortality rates were calculated using multivariable Cox regression analysis adjusted for age, gender and comorbidities, using the Charlson Comorbidity Index. Results Mortality was increased in untreated hypothyroid individuals (n=673) [HR 1.46 (95% Confidence Interval (CI), 1.26 to 1.69; p4.0 mIU/L and ≤10 mIU/L, p10 mIU/L, p=0.002). Mortality was increased in both treated and untreated hypothyroid individuals for each six months a patient had increased TSH [HR 1.05 (95% CI, 1.02 to 1.07; p<0.0001) and HR 1.05 (95% CI, 1.02 to 1.07; p=0.0009), respectively]. In patients who received levothyroxine, HR for mortality increased by a factor 1.18 (95% CI, 1.15 to 1.21; p<0.0001) for each six months a patient exhibited decreased TSH. This finding was essentially unchanged after stratification by disease severity (mild or marked hypothyroidism) and age (above and below 65 years). Conclusion Mortality was increased in untreated, but not in treated hypothyroid individuals, independently of age and severity of hypothyroidism. Duration of decreased TSH in treated individuals had a greater impact on mortality than did duration of elevated TSH. These results stress the need for close monitoring of treatment in individuals receiving thyroid hormone replacement therapy.

Background— For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine-rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan-deficient male mice died suddenly within the first 3 months of life. Methods and Results— Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender-related response to stress in the development of this vascular catastrophe only in male mice. Conclusions— The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans.