Henrik L. Jørgensen

A Reverse J-Shaped Association of All-Cause Mortality with Serum 25-Hydroxyvitamin D in General Practice: The CopD Study

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.

A Comprehensive Hip Fracture Program Reduces Complication Rates and Mortality

OBJECTIVES: To evaluate the rate of postoperative complications, length of stay, and 1‐year mortality before and after introduction of a comprehensive multidisciplinary fast‐track treatment and care program for hip fracture patients (the optimized program).

Biglycan Deficiency Causes Spontaneous Aortic Dissection and Rupture in Mice

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.

Preoperative endoscopic stent placement before pancreaticoduodenectomy: A meta-analysis of the effect on morbidity and mortality ☆

BACKGROUND Pancreaticoduodenectomy is the only potentially curative treatment for peripapillary pancreatic tumors. However, postoperative morbidity and mortality are high, and different approaches have been tried to improve results, such as preoperative biliary drainage in patients with jaundice. This meta-analysis investigated the effect on postoperative outcome of preoperative biliary drainage by endoscopic biliary stent placement in patients who are jaundiced and who have peripapillary pancreatic tumors. METHODS A Medline search for the period 1985 to 2001 was performed. Eight retrospective studies and 2 prospective randomized controlled trials were included. Selection criteria for the primary analysis were as follows: patients with peripapillary pancreatic cancer, endoscopic stent placement versus no stent, radical surgery, and assessment of postoperative morbidity and mortality. A secondary analysis included both radical and palliative surgery. RESULTS In the primary analysis, 337 patients underwent preoperative endoscopic biliary stent placement, and 412 patients had no endoscopic biliary stent placement (controls). The overall odds ratio for postoperative complications (stent vs. no stent) is estimated as 0.79: 95% CI [0.36, 1.73] and the estimated odds ratio for postoperative mortality is 0.81: 95% CI [0.33, 1.99]. In the secondary analysis, 1008 patients underwent preoperative EBS versus 720 control patients. The odds ratio for postoperative complications in this analysis was 0.93: 95% CI [0.65, 1.33] and for postoperative mortality is 1.12: 95% CI [0.62, 2.01]. CONCLUSION No evidence was found of either a positive or adverse effect of preoperative endoscopic biliary stent placement on the outcome of surgery in patients with pancreatic cancer.

Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios.

The purpose of this study is to investigate the association of serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter with peripheral measures of bone mass and with odds ratios for wrist and hip fracture in a case-control study of postmenopausal Danish women. The study included 66 women with lower forearm fracture, 41 women with hip fracture, and 206 age-matched controls. All had broadband ultrasound attenuation (BUA) and speed of sound (SOS) measured at the heel as well as bone mineral density (BMD) measured by DXA at the distal forearm. S-OPG was measured by ELISA. The A163G genotypes were determined by PCR-RFLP analysis. S-OPG levels correlated positively with age (r = 0.45; P ≪ 0.0001) and negatively with distal forearm BMD (r = −0.31; P ≪ 0.0001), heel BUA (r = −0.23; P ≪ 0.0001), and heel SOS (r = −0.22; P ≪ 0.0001). Comparing the highest quartile of S-OPG to the lowest, the odds ratio for osteoporotic fracture was 2.5 (95% CI, 1.3–4.7; P = 0.006). The G allele of the A163G was associated with significantly lower t-scores of both lower forearm BMD, heel BUA, and heel SOS as well as being significantly more frequent in the fracture patients compared to the controls. Patients with a combination of the highest quartile of S-OPG and presence of the G allele (n = 23) had a significantly elevated fracture odds ratio, 4.0 (95% CI, 1.7–9.9). A significant negative association between S-OPG with peripheral measures of bone mass and with increased fracture odds ratios was found. Furthermore, the A163G mutation in the OPG promoter had a significant influence on bone mass and fracture status independently of S-OPG level.

A Reverse J-Shaped Association Between Serum 25-Hydroxyvitamin D and Cardiovascular Disease Mortality: The CopD Study

CONTEXT 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. OBJECTIVE 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. DESIGN 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. SETTING Serum 25(OH)D was analyzed from 247 574 subjects from the Copenhagen general practice sector. PARTICIPANTS 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. MAIN OUTCOME MEASURES A multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke, and acute myocardial infarct mortality. RESULTS 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. CONCLUSIONS 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.

Is mortality after hip fracture associated with surgical delay or admission during weekends and public holidays?: A retrospective study of 38,020 patients

Background and purpose Hip fractures are associated with high mortality, but the cause of this is still not entirely clear. We investigated the effect of surgical delay, weekends, holidays, and time of day admission on mortality in hip fracture patients. Patients and methods Using data from the Danish National Indicator Project, we identified 38,020 patients admitted from 2003 to 2010. Logistic regression analysis was used to study the association between sex, age, weekend or holiday admission, night-time admission, time to surgery, and ASA score on the one hand and mortality on the other. Results The risk of death in hospital increased with surgical delay (odds ratio (OR) = 1.3 per 24 h of delay), ASA score (OR (per point added) = 2.3), sex (OR for men 2.2), and age (OR (per 5 years) = 1.4). The mortality rate for patients admitted during weekends or public holidays, or at night, was similar to that found for those admitted during working days. Interpretation Minimizing surgical delay is the most important factor in reducing mortality in hip fracture patients.

Association of a Common Allelic Polymorphism (C677T) in the Methylene Tetrahydrofolate Reductase Gene with a Reduced Risk of Osteoporotic Fractures. A Case Control Study in Danish Postmenopausal Women

Twin studies indicate a substantial genetic component in the development of osteoporosis. One of the latest studied candidate genes is the one coding for methylene tetrahydrofolate reductase (MTHFR) (C677T) in which a point mutation gives rise to a thermolabile variant of MTHFR. The aim of this study was to investigate the influence of this mutation on peripheral measures of bone density and on the odds ratios (OR) for hip and lower forearm fracture in a case control study of Danish postmenopausal women. A total of 74 women with lower forearm fracture, 41 women with hip fracture, and 207 age-matched controls were included. All had broadband ultrasound attenuation (BUA) and speed of sound (SOS) measured at the heel as well as bone mineral density (BMD) measured by dual X-ray absorptiometry at the distal forearm. The MTHFR (C677T) genotypes were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Only 2 of 21 individuals with the TT genotype had sustained a fracture as opposed to 46 of 142 with the CT genotype and 67 of 159 with the CC genotype (P = 0.007). Using logistic regression, the following odds ratios were found when comparing the individuals homozygotic for the C-allele with those homozygotic for the T-allele: lower forearm fracture OR = 3.93 (1.25; 12.40, P = 0.02), hip fracture OR = 6.99 (l.35; 36.92, P = 0.02) and the fractures combined OR = 4.33 (1.73; 10.81, P = 0.002). In this study, the MTHFR (C677T) genotypes were not significantly associated with BMD at the lower forearm or with ultrasound parameters measured at the calcaneus. However, a significant increase in the odds ratio of fracture was found for the wild-type C-allele.

Diurnal variation of hematology parameters in healthy young males: The Bispebjerg study of diurnal variations

Abstract 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.

Sunbed Radiation Provokes Cutaneous Vitamin D Synthesis in Humans—A Randomized Controlled Trial

We wanted to investigate whether the use of sunbeds with sunlamps emitting mainly UVA and only 0.5% or 1.4% UVB will increase the level of serum 25‐hydroxyvitamin D (25(OH)D). In a randomized, controlled, open study on healthy, Caucasian females (>50 years) sunbed radiation was given as follows: four 6‐min sunbed sessions (days 0, 2, 4 and 7) and four 12‐min sunbed sessions (days 9, 11, 14 and 16 ) with sunlamps emitting 0.5% UVB (n = 20) or with sunlamps emitting 1.4% UVB (n = 15). The controls (n = 21) had no intervention. Serum levels of 25(OH)D were measured on days 0, 9 and 18 in all three groups. The average increase in serum 25(OH)D from day 0 to day 9 was 12 nmol L−1 (SD 11 nmol L−1, P = 0.0002) in the 0.5% UVB group and 27 nmol L−1 (SD 9 nmol L−1, P < 0.0001) in the 1.4% UVB group. From day 9 to day 18 a further but not significant increase in serum 25(OH)D of 3 nmol L−1 (SD 9 nmol L−1, P = 0.2) in the 0.5% UVB group and 0.6 nmol L−1 (SD 18 nmol L−1, P = 0.9) in the 1.4% UVB group was seen. No significant changes were found in the control group. Increasing with UVB dose and exposure time, 37–64% of the sunbed sessions resulted in side effects such as erythema or polymorphic light eruption. The results showed that sunbeds emitting 0.5% and 1.4% UVB increased 25(OH)D serum levels. The increases were dose dependent but reached a plateau after few sessions. Sunbed use as vitamin D source is, however, not generally recommendable due to the well‐known carcinogenicity and high frequency of acute side effects.