Scanning Thermal Microscopy and Ballistic Phonon Transport in Lateral Spin Valves.

Using scanning thermal microscopy, we have mapped the spatial distribution of temperatures in an operating nanoscale device formed from a magnetic injector, an Ag connecting wire, and a magnetic detector. An analytical model explained the thermal diffusion over the measured temperature range (2-300 K) and injector-detector separation (400-3000 nm). The characteristic diffusion lengths of the Peltier and Joule heat differ remarkably below 60 K, a fact that can be explained by the onset of ballistic phonon heat transfer in the substrate.

Histologically validated scoring system for the assessment of hock burn in broilers.

The assessment of bird-based welfare indicators plays an important role in the evaluation of bird welfare. The aim of the study was to histologically validate a visual scoring system for hock burn in broilers and to detect threshold values of a visual score to define welfare-relevant alterations in terms of mild lesions or ulcers of the hock. We collected 200 hocks of 39- to 42-day-old Ross 308 broilers after the slaughter process. Each hock was scored visually ("macro scores" 0-4) and evaluated histologically ("micro scores" 0-3), with high scores representing more severe lesions. Although we found a tendency for higher micro scores with increasing macro scores, an exact allocation of macro to micro scores was not possible. For example, macro score 1 could represent micro scores 1, 2 and 3, whereas macro scores 3 and 4 always represented micro score 3 (ulcer). The conditional probability of certain micro scores for given macro scores was estimated using a multinomial logistic regression model. Ulcer showed the highest probability at macro score 1, whereas mild lesions were not found to have an estimated highest probability at any macro score. The depth of inflammation of hock burn lesions increased with increasing macro scores up to macro score 3 with an average depth of 1019 µm. Visually more severe and deeper lesions were also histologically rated with higher scores. Thus, considering limitations, the herein validated macroscopic assessment scheme for hock burn allows an estimation of histological alterations in hocks of broilers.RESEARCH HIGHLIGHTS Histological validation of a visual assessment scheme for hock burn in broilers.Tendency for higher micro scores with increasing macro scores.Estimation of histological score via macro score possible with limitations.Histological depth of inflammation increased with an increasing macro score.

Glutamic acid decarboxylase and islet antigen 2 antibody profiles in people with adult-onset diabetes mellitus: a comparison between mixed ethnic populations in Singapore and Germany.

AIM: To gain insight into the presence of islet cell autoimmunity in an ethnic Asian compared with a white European population. METHODS: For this cross-sectional study we recruited people with adult-onset diabetes (age of diagnosis 20-60 years), at tertiary referral centres in Germany (n=1020) and Singapore (n=1088). Glutamic acid decarboxylase and islet antigen 2 antibodies were measured according to Islet Autoantibody Standardization Program protocols. RESULTS: The prevalence of glutamic acid decarboxylase antibody positivity was 13.9% (95% CI 12.1-16.0; P<0.001) in the white European cohort compared with 6.8% (95% CI 5.5-8.4; P<0.001) in the Asian cohort. Glutamic acid decarboxylase antibody positivity was 11.4% (95% CI 7.7-16.6) in Indian, 6.0% (95% CI 3.6-9.9) in Malay and 5.8% (95% CI 4.3-7.7; P<0.001) in Chinese participants. In the white European participants, the prevalence of islet antigen 2 antibody positivity was 7.8% (95% CI 6.4-9.4) compared with 14.8% (95% CI 12.8-17.0; P<0.001) in the Asian cohort as a whole, and among the three ethnicities in the Asian cohort it was 12.4% (95% CI 8.6-17.7) in Indian, 16.8% (95% CI 12.6-22.2) in Malay and 15.7% (95% CI 13.2-18.6) in Chinese participants. Double antibody positivity was seen in 5.7% (95% CI 4.5-7.1) of white European participants compared with 1.6% (95% CI 1.0-2.5; P<0.01) of Asian participants. In the white European cohort, those who were glutamic acid decarboxylase autoantibody-positive had a lower BMI than those who were autoantibody-negative, but this trend was absent in the Asian cohort. CONCLUSIONS: A marked prevalence of islet cell autoimmunity was observed in people with adult-onset diabetes. While glutamic acid decarboxylase antibodies were more frequent in the European cohort, islet antigen 2 antibody positivity was highest in the three ethnic groups in Singapore, suggesting ethnic-specific differences in antibody profiles.

A Nonclassical Monocyte Phenotype in Peripheral Blood is Associated with Nonalcoholic Fatty Liver Disease: A Report from an EMIL Subcohort.

Nonalcoholic fatty liver disease (NAFLD) as the prototypic hepatic manifestation of metabolic syndrome is an independent risk factor for cardiovascular disease. Our study was designed to investigate the association between NAFLD and alteration in monocyte subsets as hallmark of cardiovascular disease. Seventy-three "Echinococcus Multilocularis and other medical diseases in Leutkirch" (EMIL) population-based cohort participants (mean observation period 11 years) were selected to study their monocyte phenotype by multiparameter flow cytometry. NAFLD was diagnosed using standard ultrasound based criteria excluding other causes of fatty liver disease. Three monocyte subsets ("classical" CD14++ CD16-, "intermediate" CD14++ CD16+, "nonclassical" CD14+CD16++ monocytes), and surface markers (CD36 and CD9) were determined. Classical risk markers covering inflammatory and dysmetabolic characters were also determined. Forty-three out of 73 subjects revealed a stable clinical phenotype, namely 17 subjects revealed NAFLD, whereas 26 subjects showed no fatty liver disease. Compared to the nonfatty liver group, the nonclassical monocyte fraction (p=0.049), total monocyte fraction and count were increased in NAFLD probands (p=0.028, and 0.035, respectively), while classical monocyte fraction (p=0.034) was decreased. Total monocyte fraction, nonclassical monocyte fraction, and waist circumstance were independent risk factors for NAFLD. The nonclassical monocyte fraction and classical monocyte fraction were significantly correlated with waist-to-hip ratio. This pilot long-term follow-up study suggests that nonclassical monocyte fraction and total monocyte fraction might have potential as a prognostic and modifiable biomarker in NFALD patients. This novel marker set might therefore be of interest to monitor druggable inflammatory pathways in individuals with hepatic manifestation of the metabolic syndrome.

Influence of plasma cortisol and other laboratory parameters on nonalcoholic Fatty liver disease.

The objective of the present study was to analyse the association between the plasma cortisol concentration and nonalcoholic fatty liver disease (NAFLD). A total of 1 326 subjects (age 18-65 years) were examined in the context of an epidemiological study of a population-based random sample. Medical history and anthropometric data of 662 women and 664 men were documented. In addition, laboratory examinations were performed and the fat concentration of the liver was estimated by ultrasound examination. Mean cortisol concentration in plasma was 260.4±156.8 nmol/l for women and 295.8±161.2 nmol/l for men. NAFLD was identified in 17.7% in women and 35.1% in men. Plasma cortisol concentration showed no association with the existence of NAFLD. NAFLD correlated positive with age, body-mass index (BMI), waist-to-hip-ratio (WHR), alanine aminotransferase (ALT), and triglycerides. The present study failed to establish any association of plasma cortisol concentrations and NAFLD.

Alterations in the coagulation system of active smokers from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Smoking is an important and preventable risk factor of cardiovascular diseases with effects on blood coagulation. Our aim was to analyze the influence of smoking on coagulation parameters. Concentrations or activities of blood coagulation factors were compared in 777 active smokers and 1,178 lifetime non-smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The association with mortality was examined using Cox regression. The findings show that AS had a tendency toward thrombosis. They displayed significantly higher values for fibrinogen, soluble fibrinogen, factor XIII, and tissue factor pathway inhibitor; whereas FVII, FVIII, FXII, von Willebrand factor (vWF), and thrombomodulin were decreased. The Cox regression analysis showed fibrinogen, FVIII, vWF, thrombomodulin, and tissue factor pathway inhibitor to be independent risk factors for mortality in active smokers with hazard ratios of 1.16 (95% CI: 1.02-1.31), 1.40 (1.22-1.59), 1.37 (1.22-1.56), 1.19 (1.07-1.31), and 1.22 (1.06-1.40) per increase of one standard deviation. We conclude that active smokers have an increased thrombogenic potential associated with significant changes in the coagulation system. Individual parameters of the coagulation system are independent predictors of mortality. Therefore, parameters of the coagulation system, apart from other risk factors for cardiovascular disease (e.g., lipids or life-style) should be determined for risk prediction in active smokers.

C-reactive protein and lipoprotein-associated phospholipase A2 in smokers and nonsmokers of the Ludwigshafen Risk and Cardiovascular Health study.

Measurement of high sensitivity CRP (hsCRP) and lipoprotein-associated phospholipase A2 (LpPLA2) provides information on systemic inflammation and stability of atherosclerotic plaques. Data analyzing the effect of smoking on these parameters are sparse. The aim of our study was the analysis of these parameters in active smokers and never-smokers. The study included 777 smokers and 1,178 never-smokers, of whom 221 and 302 died during a follow-up, respectively. The values of LpPLA2 and hsCRP were significantly higher in smokers than in never-smokers. Mortality was highest in smokers and never-smokers with elevation of both biomarkers. Multivariate adjusted hazard ratios for patients in the highest tertile of both hsCRP and LpPLA2 compared with patients in the lowest tertile of both markers were 1.85 (1.04-3.28) in never-smokers and 1.94 (1.10-3.45) in smokers. Our data confirmed the predictive value of hsCRP and LpPLA2. However, there were a relevant number of patients with an increase of only one of these parameters. Therefore, beside other risk factors for cardiovascular disease, both parameters should be determined at least in high risk patients.

Association of bone turnover markers with mortality in women referred to coronary angiography: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

UNLABELLED: We examined the association of fatal events with beta-crosslaps (ß-CTX) and osteocalcin (OC) concentrations in women. We observed an independent association of ß-CTX and OC concentrations with fatal events in women at high to intermediate cardiovascular risk. INTRODUCTION: There is some evidence suggesting an association of ß-CTX and OC with fatal events in men and frail elderly subjects. We aimed to examine the association of fatal events with ß-CTX and OC in women. METHODS: We measured ß-CTX and OC in 986 women aged 65 (58-72) years referred to coronary angiography. RESULTS: Compared to the first ß-CTX quartile, the crude hazard ratios (HRs) for all-cause and cardiovascular mortality in the highest ß-CTX quartile were 2.50 (1.65-3.81) and 3.28 (1.82-5.91), respectively. In multivariate adjusted models, HRs for all-cause and cardiovascular mortality in the highest ß-CTX quartile were 1.72 (1.09-2.70) and 2.31 (1.24-4.32), respectively. The lowest 25-hydroxyvitamin D [25(OH)D] quartile was significantly associated with increased risk of all-cause and cardiovascular mortality in multivariate adjusted models. In those models, the highest ß-CTX quartile was associated with an increased risk of all-cause and cardiovascular mortality. For OC concentrations, we found a reverse J-shaped association with noncardiovascular mortality. Using the first quartile as reference, crude and multivariate adjusted HRs for noncardiovascular mortality in the second and third OC quartile were 0.41 (0.19-0.90) [multivariate: 0.40 (0.18-0.88)] and 0.51 (0.25-1.06) [multivariate: 0.43 (0.20-0.94)], respectively. The lowest 25(OH)D quartile was associated with a trend towards increased risk of noncardiovascular mortality in multivariate analysis. In that analysis, OC quartile 2 and 3 were significantly associated with lower risk of noncardiovascular mortality. CONCLUSIONS: We observed an independent association of high ß-CTX with all-cause and cardiovascular mortality and a reverse J-shaped association of OC with noncardiovascular mortality.

Prospective evaluation of renal function, serum vitamin D level, and risk of fall and fracture in community-dwelling elderly subjects.

SUMMARY: This prospective study in elderly showed that kidney function plays a minor role in explaining the high prevalence of vitamin D deficiency seen in noninstitutionalized elderly subjects. However, 25-hydroxyvitamin D levels were clearly inversely associated with risk for first fall, which was especially seen in subjects with calcium levels above median. INTRODUCTION: Few prospective studies in elderly exist that have investigated the association of renal dysfunction and vitamin D status on risk of falls. The aim of this study is to evaluate the association of renal function with 25-hydroxyvitamin D (25-OH-D) levels and, secondly, to assess the role of both factors on the risk of falls and subsequent bone fractures. METHODS: This is a prospective population-based cohort study among noninstitutionalized elderly subjects during a 1-year follow-up. 25-OH-D levels and renal function were estimated, the latter by cystatin C-based equations. Information on falls was assessed prospectively. RESULTS: Overall, 1,385 subjects aged 65 and older were included in the study (mean age 75.6 years), of whom 9.2 % had a 25-OH-D serum level above 75 nmol/L (US units 30 ng/mL); 41.4 %, between 50 and 75 nmol/L (US units 20 to 29 ng/mL, insufficiency); and 49.4 %, <50 nmol/L (US units <20 ng/mL, deficiency). We found no association of chronic kidney disease with risk of first fall. In contrast, 25-OH-D serum categories were clearly associated with risk of first fall and we found evidence of effect modification with calcium levels. In the group with a calcium level above the median (≥ 9.6 mg/dL), subjects with 25-OH-D serum level between 50 and 75 nmol/L and with concentrations <50 nmol/L had a hazard rate ratio (HRR) of 1.75 (1.03-2.87) and 1.93 (1.10-3.37) for risk of first fall. 25-OH-D serum levels were also associated with several markers of inflammation and hemodynamic stress. CONCLUSIONS: We demonstrated an association of 25-OH-D serum levels and risk of first fall, which was especially evident in subjects with serum calcium in upper normal, independent of renal function.

Magnetic damping: domain wall dynamics versus local ferromagnetic resonance.

Magnetic relaxation is one of the dominating features of magnetization dynamics. Depending on the magnetic structure and the experimental approach, different magnitudes of the damping parameter are reported even for a given material. In this study, we experimentally address this issue by accessing the damping parameter in the same magnetic nanotracks using different approaches: local ferromagnetic resonance (α=0.0072) and field-driven domain wall dynamics (α=0.023). The experimental results cannot fully be accounted for by modeling only roughness in micromagnetic simulations. Consequently, we have included nonlocal texture induced damping to the micromagnetic code. We find excellent agreement with the observed increased damping in the vortex structures for the same input Gilbert alpha when texture-induced nonlocal damping is included.

Associations of fatty liver disease and other factors affecting serum SHBG concentrations: a population based study on 1657 subjects.

Sex hormone binding globulin (SHBG) is a glycoprotein expressed predominantly in the hepatocytes. It regulates the transport of sex steroid hormones in the blood stream to their target tissues. The expression of the SHBG gene is subject to multifactorial regulation including hormonal, metabolic, and nutritional aspects. Against this background, we investigated the effect of fatty liver and metabolic syndrome, together with other parameters, on serum SHBG concentrations in a population-based cohort in Germany. This cross-sectional study included 870 women and 787 men (average age 42.3±12.8 years), who underwent ultrasound screening for fatty liver in addition to providing a complete medical history and undergoing physical and laboratory examination. Fatty liver was diagnosed on ultrasound criteria in 159 women (18.3%) and 287 men (36.5%). Fatty liver was shown to exert a significant influence on serum SHBG concentrations in men and in premenopausal women. Men with grade 1 fatty liver had a 1.96-fold increased risk (95%-confidence interval=1.28-3.02; p=0.0022) and postmenopausal women with grade 1 fatty liver a 2.4-fold risk (95%-confidence interval=1.11-5.27; p=0.0267) for low SHBG concentrations. Among metabolic parameters, HDL-C represented as affecting factor in men (p=0.0058) and premenopausal women (p=0.0002), while cholesterol only showed an association in premenopausal women (p=0.0439) and triglyceride in postmenopausal women (p=0.0436). No association of concentrations of SHBG and metabolic syndrome was observed. Age, BMI and waist-to-hip ratio also influence the SHBG concentration. Based on these findings, we conclude that fat accumulation in the liver influences SHBG concentrations in men and premenopausal women.

Association of bone turnover markers with mortality in men referred to coronary angiography.

UNLABELLED: We aimed to examine the association of fatal events with osteocalcin (OC) and beta-crosslaps (ß-CTX) levels in men. We observed a U-shaped association of OC and ß-CTX levels with fatal events in a large cohort of men at high cardiovascular risk. INTRODUCTION: Accumulating evidence suggests an association of low OC levels with metabolic disturbances. Whether OC levels are related to fatal events is, however, less clear. Further, high ß-CTX levels are linked to increased mortality. We aimed to examine the association of fatal events with both OC and ß-CTX in men. METHODS: We measured OC and ß-CTX in 2,271 men referred to coronary angiography (1997-2000). RESULTS: We observed a U-shaped association of OC and ß-CTX with fatal events. Crude hazard ratios (HRs) for all-cause and non-cardiovascular mortality in the highest OC quintile were 1.38 (1.04-1.83) and 1.47 (0.89-2.40), respectively, and 2.11 (1.61-2.75) and 2.06 (1.29-3.29) for men in the lowest compared to the third OC quintile. In multivariate-adjusted models, HRs for all-cause, and non-cardiovascular mortality in the lowest OC quintile were 1.63 (1.23-2.16) and 1.79 (1.10-2.92), respectively, compared to the third OC quintile, whereas the association of high OC with mortality lost its significance. Crude and multivariate-adjusted HRs for cardiovascular mortality in the lowest OC quintile compared to the third OC quintile were 2.08 (1.49-2.90) and 1.74 (1.24-2.46), respectively. Moreover, high as well as low ß-CTX levels were independently associated with all-cause (quintile 1 vs. quintile 3: HR 1.42 (1.05-1.92); quintile 5 vs. quintile 3: HR 1.79 (1.31-2.45)) and cardiovascular mortality (quintile 1 vs. quintile 3: HR 1.55 (1.05-2.28); quintile 5 vs. quintile 3: HR 1.85 (1.23-2.77)). CONCLUSIONS: We observed a U-shaped association of OC and ß-CTX with fatal events in a large cohort of men at high cardiovascular risk.

The broad clinical phenotype of Type 1 diabetes at presentation.

Immune-mediated (auto-immune) Type 1 diabetes mellitus is not a homogenous entity, but nonetheless has distinctive characteristics. In children, it may present with classical insulin deficiency and ketoacidosis at disease onset, whereas autoimmune diabetes in adults may not always be insulin dependent. Indeed, as the adult-onset form of autoimmune diabetes may resemble Type 2 diabetes, it is imperative to test for diabetes-associated autoantibodies to establish the correct diagnosis. The therapeutic response can be predicted by measuring the levels of autoantibodies to various islet cell autoantigens, such as islet cell antibodies (ICA), glutamate decarboxylase 65 (GAD65), insulin, tyrosine phosphatase (IA-2) and IA-2ß, and zinc transporter 8 (ZnT8) and evaluating ß-cell function. A high risk of progression to insulin dependency is associated with particular genetic constellations, such as human leukocyte antigen risk alleles, young age at onset, the presence of multiple autoantibodies, including high titres of anti-GAD antibodies; such patients should be offered early insulin replacement therapy, as they respond poorly to diet and oral hypoglycaemic drug therapy. Hence, considering the broad spectrum of phenotypes seen in adult-onset diabetes, treatment targets can only be reached by identification of immune-mediated cases, as their management differs from those with classical Type 2 diabetes.

Uric acid is predictive of cardiovascular mortality and sudden cardiac death in subjects referred for coronary angiography.

BACKGROUND AND AIMS: High serum uric acid (SUA) is suggested to be causally involved in the pathogenesis of vascular disease. The present study aimed to investigate whether SUA independently predicts all-cause mortality, cardiovascular mortality and sudden cardiac death in subjects scheduled for coronary angiography. METHODS AND RESULTS: We studied participants of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. A total of 3245 individuals were included in the analysis. There was a follow-up for all-cause mortality, cardiovascular mortality, and sudden cardiac death with a mean (±standard deviation) duration of 7.3 (±2.3) years. Sex-specific quartiles of SUA were established and multivariate statistical models were used. A total of 730 deaths occurred during the follow-up. Among these, 473 (64.8%) were accounted for by cardiovascular diseases. Sudden cardiac death occurred in 184 (25.2%) cases. Adjusting for sex and age subjects in the fourth SUA quartile had increased all-cause (hazard ratio (HR) = 1.68, p < 0.001) and cardiovascular (HR = 2.00, p < 0.001) mortality compared to individuals in the first quartile. Furthermore, high SUA was a risk factor for sudden cardiac death (HR = 2.27, p < 0.001). These associations remained significant including cardiovascular risk factors and the severity of coronary atherosclerosis as covariates in the models. After additional adjustment for medication use statistical significance for the association between the SUA quartiles and all-cause mortality disappeared. CONCLUSION: High SUA independently indicates increased risk for cardiovascular and sudden cardiac death in subjects referred for coronary angiography.

The fatty liver index is associated with increased mortality in subjects referred to coronary angiography.

BACKGROUND AND AIMS: Fatty liver index (FLI), a surrogate parameter for nonalcoholic fatty liver disease, is an emerging risk factor for cardiovascular diseases and mortality. We aimed to evaluate whether FLI is associated with all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer in a cohort of subjects routinely referred to coronary angiography. METHODS AND RESULTS: FLI was calculated using BMI (body mass index), waist circumference (WC), triglycerides (TG) and gamma-glutamyl transferase (GGT) in 3270 subjects who were referred to coronary angiography (1997-2000). The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, cardiovascular causes, non-cardiovascular causes, and fatal cancer. After a median follow-up time of 7.7 years, 740 subjects (22.6%) had died. There were 437 deaths due to cardiovascular disease and 303 deaths due to non-cardiovascular disease. Age-, sex-, and BMI-adjusted HRs (with 95% confidence intervals) for all-cause, cardiovascular, and non-cardiovascular mortality in the highest compared to the lowest FLI quartile were 2.56 (1.90-3.43; p < 0.001), 2.17 (1.47-3.22; p < 0.001), and 3.49 (2.16-5.66; p < 0.001), respectively. In age-, sex-, and BMI-adjusted analyzes, we found no significant association of FLI with fatal cancer. Multivariate adjusted HRs for all-cause, cardiovascular, non-cardiovascular mortality, and fatal cancer in the highest compared to the lowest FLI quartile were 2.17 (1.58-2.99; p < 0.001), 1.64 (1.07-2.51; p = 0.023), 3.72 (2.22-6.24; p < 0.001), and 2.33 (1.01-5.41; p = 0.048) respectively. CONCLUSION: In subjects referred to coronary angiography, high FLI levels are independently associated with increased all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer.

[Odontogenic tumours in the dog and cat]. / Odontogene Tumoren bei Hund und Katze.

OBJECTIVE: Odontogenic tumours in the dog and cat, as well as in other domestic animals and in man occur rarely and can be difficult to diagnose. In the present study a great number of canine and feline odontogenic tumours were investigated histopathologically and classified to provide an appropriate basis for the evaluation of these tumours. MATERIAL AND METHODS: In a retrospective study of a total of 1390 canine and 317 feline oral tumours from the years 1977 to 2007, the tumours of odontogenic origin were selected, characterized histopathologically and classified according to the current human WHO-classification of odontogenic tumours (2005) and the current veterinary WHO-classification of odontogenic tumours (2003). RESULTS: 18% (n=250) of the canine and 3.2% (n=10) of the feline oral tumours proved to be of odontogenic origin. They could be divided into benign (epithelial, epithelial and ectomesenchymal, ectomesenchymal) and malignant (carcinomas and sarcomas) odontogenic tumours with a total of 12 different entities. The odontogenic fibroma was the most common canine (n=167) and feline (n=4) odontogenic tumour. The second most common odontogenic tumour for canines was ameloblastoma (n=74) and that for felines was ameloblastic fibroma (n=2). Four of the 12 entities could be classified according to both WHO-classifications of odontogenic tumours. Seven and two of the 12 entities could only be classified according to the current human WHO-classification and veterinary WHO-classification, respectively. CONCLUSION AND CLINICAL RELEVANCE: The prognostic evaluation of tumours is of the greatest clinical relevance and calls for an absolutely certain diagnosis. Particularly in the case of the rare and histomorphologically complex odontogenic tumours the current veterinary WHO-classification does not meet this requirement and needs to be revised and extended. The human WHO-classification proved to be more efficient when compared to the veterinary one.

Sequence homology of the diabetes-associated autoantigen glutamate decarboxylase with coxsackie B4-2C protein and heat shock protein 60 mediates no molecular mimicry of autoantibodies.

Molecular mimicry between viral antigens and host proteins was often suggested to be involved in induction of autoimmune diseases. In type 1 diabetes where pancreatic beta cells are destroyed by autoimmune phenomena, a linear sequence homology between a major autoantigen, glutamate decarboxylase (GAD), and the 2C protein of coxsackie B4 was identified. In addition, a sequence homology between GAD and the mycobacterial heat shock protein 60 was described and the suggestions were made that molecular mimicry between GAD, coxsackievirus B4-2C protein, and/or heat shock protein 60 (hsp60) may be actively involved in an autoimmune reaction towards the pancreatic beta-cells. Our group was the first to isolate human monoclonal autoantibodies to GAD (MICA 1-6) from a patient with newly diagnosed type 1 diabetes. The MICA allowed a detailed characterization of the diabetes associated self-epitopes in GAD and represent a set of GAD autoantibodies present in sera from patients with type 1 diabetes. Using deletion mutants of GAD we demonstrated that the regions of GAD covering the homology sequences to coxsackievirus B4 and to the hsp60 were absolutely required for binding of the MICA to GAD. We now designed an antibody-based analysis to ask whether molecular mimicry between GAD and coxsackie B4-2C or hsp60 is relevant in type 1 diabetes. Since part of the MICA recognize conformational epitopes, they allow to test for conformational molecular mimicry in viruses that have been incriminated in the development of type 1 diabetes. Our data reveal no crossreactivity between the diabetes associated GAD epitopes defined by the MICA and hsp60, rubellavirus, cytomegalovirus, and coxsackie B1-B6 virus antigens. Neither coxsackie B4-specific antibodies in sera from normal individuals nor GAD-positive sera from patients with type 1 diabetes indicated a crossreactivity between coxsackie B4-2C and GAD. Although the regions in GAD homologous to coxsackie B4-2C and hsp60 represented parts of GAD indispensible for binding of diabetes associated autoantibodies they did not mediate a crossreactivity of autoantibodies between GAD and these two proteins. No evidence for molecular mimicry between GAD and a whole panel of foreign antigens was detected by autoantibodies in type 1 diabetes.

Association of vitamin D status with serum androgen levels in men.

OBJECTIVE: Studies in rodents indicate a role of vitamin D in male reproduction, but the relationship between vitamin D and androgen levels in men is largely unexplored. We aimed to investigate the association of 25-hydroxyvitamin D [25(OH)D] levels with testosterone, free androgen index (FAI) and SHBG. Moreover, we examined whether androgen levels show a similar seasonal variation to 25(OH)D. DESIGN: In this cross-sectional study, 25(OH)D, testosterone and SHBG levels were assessed by immunoassay in 2299 men who were routinely referred for coronary angiography (1997-2000). MEASUREMENTS: Main outcome measures were associations of 25(OH)D levels with testosterone, SHBG and FAI. FAI was calculated as testosterone (nmol/l)/SHBG (nmol/l) x 100. RESULTS: Men with sufficient 25(OH)D levels (> or =30 microg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20-29.9 microg/l) and 25(OH)D-deficient (<20 microg/l) men (P < 0.05 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels (P < 0.05 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (12.2 microg/l, 15.9 nmol/l and 40.8, respectively) and peak levels in August (23.4 microg/l, 18.7 nmol/l and 49.7, respectively) (P < 0.05 for all). CONCLUSION: Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal variation. Randomized controlled trials are warranted to evaluate the effect of vitamin D supplementation on androgen levels.

Sex steroids and mortality in men referred for coronary angiography.

OBJECTIVE: Accumulating evidence suggests that sex steroids are associated with various chronic diseases. We aimed at evaluating whether total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG) are associated with all-cause mortality and specific fatal events. DESIGN, SETTING AND PARTICIPANTS: We measured TT and SHBG levels in 2078 men who were routinely referred for coronary angiography (1997-2000). FT was calculated according to Vermeulen. MEASUREMENTS: The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non-cardiovascular causes and from cancer according to SHBG, FT and TT. RESULTS: Multivariable-adjusted HRs (with 95% confidence intervals) in the fourth compared to the first SHBG quartile for all-cause, non-cardiovascular and cancer mortality were 1·61 (1·16-2·23), 2·44 (1·39-4·28), and 2·86 (1·03-7·32), respectively. There was no significant association of SHBG levels with cardiovascular mortality. All-cause mortality was significantly reduced per 1 SD increase in FT in the multivariate-adjusted analyses [0·49 (0·30-0·81)]. We observed no significant associations of FT with cardiovascular and cancer mortality, and TT levels were not independently related to any fatal events. CONCLUSION: High levels of SHBG are associated with adverse health outcomes in a large cohort of older men referred for coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms for our findings.