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Background: Anabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk., Objectives: We investigated whether AAS influence coagulation parameters associated with VTE by assessing their changes during and after AAS use., Methods: The HAARLEM study enrolled 100 male amateur athletes voluntarily starting an AAS cycle between 2015 and 2018. We measured procoagulant and anticoagulant protein levels, D-dimer levels, endogenous thrombin potential (ETP), and clot lysis time (CLT) at baseline and during 2 years of follow-up. Changes in coagulation during AAS cycle, 3 months after its discontinuation, and 1 year after its inclusion compared with baseline were estimated using linear mixed models. The associations between AAS dose and duration of use with these outcomes were studied through adjusted multivariable linear regression., Results: Participants used AAS for a median of 13 weeks (IQR: 10-23) with a median weekly dose of 901 mg (IQR: 634-1345 mg). Mean levels of multiple coagulation factors (F) increased during use compared with baseline, whereas FVIII and von Willebrand factor levels remained unchanged. Protein S and D-dimer showed the biggest increase (22% [95% CI: 15-29] and 1.3-fold [95% CI: 1.2-1.5], respectively). CLT was 8 minutes longer (95% CI: 5-10) and ETP was 165 nM∗min (95% CI: -205 to -124) lower during the AAS cycle. A high weekly AAS dose and short cycle duration were associated with changes in protein S and ETP during use. All parameters returned to baseline values 3 months after discontinuation and remained similar after., Conclusion: During AAS use, procoagulant and anticoagulant protein levels increased in a reversible manner. The overall balance did not suggest a clear procoagulant state., (© 2023 Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients., Objectives: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD., Methods: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life., Results: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes., Conclusions: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Hirsutism is the excessive growth of terminal hair in a male pattern in a female. In most hirsute women, hirsutism is caused by increased androgens. However, not all women with hirsutism actually show elevated levels of circulating androgens with standard laboratory tests, in which case we speak of idiopathic hirsutism (IH)., Objectives: The aim of this paper is to investigate whether there are biochemical markers that can be used to unravel the cause in IH., Methods: An electronic search through the PubMed database was conducted to find studies describing potential biomarkers for IH., Results: The majority of included studies claimed an increased 5α-reductase (5α-RD) activity in women with IH by means of increased DHT metabolite levels. Studies investigating abnormalities of the androgen receptor (AR) and serum levels of indirect markers showed no significant differences., Conclusions: Our literature search showed that polymorphisms of the AR as well as indirect markers seem to be nonspecific, but that the dihydrotestosterone-reduced metabolite 5α-androstane-3α,17β-diol glucuronide is markedly enhanced in women with IH, suggesting an increased 5α-RD activity in these women. Further studies need to be performed to determine the clinical usefulness of 3α-diol G as a biomarker for IH., (Copyright © 2022. Published by Elsevier B.V.)

Background: Transgender women (people assigned male genders at birth with female gender identities) can choose to cryopreserve semen before their medical transition, to retain the possibility to parent genetically related offspring later in life. Our previous retrospective study showed that semen quality in transgender women was decreased compared with the general population. The etiology of this impaired semen quality remains largely unknown. However, impaired semen quality might be related to habitual behavior more typically observed in transgender women, for example, the desire to hide their testicles because of genital dysphoria. Therefore, we decided to conduct a consecutive study with prospectively obtained data on behavior and lifestyle in transgender women., Objective: This study aimed to study the influence of a low ejaculation frequency, wearing tight undergarments, and bringing the testes in the inguinal position (tucking) on semen quality in transgender women at the time of fertility preservation., Study Design: In this cohort study, transgender women were included between May 2018 and September 2020, at the time of fertility counseling, before the start of hormonal treatment. Data were collected on demographics, lifestyle factors, medical history, endocrine laboratory results, and semen parameters. Semen parameters were categorized using reference values for human semen of the World Health Organization and compared with semen quality in the general population. The odds ratios with 95% confidence intervals were calculated using multivariable logistic regression analysis to assess the impact of tucking, wearing tight undergarments, and a low ejaculation frequency on semen quality, correcting for potential confounders., Results: Overall, 113 transgender women were included. Median semen parameters were significantly decreased than the general population. Crude logistic regression analyses showed an association between always wearing tight undergarments (odds ratio, 3.06; 95% confidence interval, 1.11-8.49) and extensive tucking (odds ratio, 6.09; 95% confidence interval, 1.54-24.01) on having a total motile sperm count of <5 million. Multivariable analyses showed that the association with tucking was independent of demographic factors, lifestyle factors, and medical history (odds ratio, 7.95; 95% confidence interval, 1.66-37.99). However, this was not the case for the association with always wearing tight undergarments (odds ratio, 2.89; 95% confidence interval, 0.95-8.82). Ejaculation frequency did not influence total motile sperm count., Conclusion: Behavioral factors, including wearing tight undergarments and extensive tucking, may contribute to the lower semen quality in transgender women. These results will enable optimization of fertility counseling on how to adjust lifestyle before pursuing semen cryopreservation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate associations between testosterone and patient reported sexual problems and need for sexual care in head and neck cancer patients at time of diagnosis and 6 months after treatment., Patients and Methods: Data and samples were used of 40 patients (20 men, 20 women) before and 6 months after treatment. Outcome measures were total testosterone level (TT) and free testosterone index (FTI), testosterone insufficiency (TI), the EORTC QLQ-HN35 Sexuality subscale, the subscales of the International Index of Erectile Function (IIEF), Female Sexual Function Index (FSFI), and the Sexuality subscale of the Short-Form Supportive Care Needs Survey (SCNS-SF34)., Results: In men, higher FTI before treatment was significantly associated with better IIEF Orgasm (p = 0.020) and at 6 months follow-up with IIEF Desire (p = 0.019). Before treatment, insufficient testosterone was present in 5 males (25%) and in 3 at follow-up (15%) (2 patients who had TI before treatment plus one). In women, higher TT at follow-up was significantly associated with better EORTC Sexuality (p = 0.031) and FSFI Satisfaction (p = 0.020); FTI at follow-up was associated with FSFI Satisfaction (p = 0.012). Before treatment, TI was present in 2 women (10%) and in 3 (15%) at follow-up (the same 2 patients plus one)., Conclusion: This pilot study showed that testosterone seems to be associated with patient reported sexual outcomes among male and female head and neck cancer patients. It is estimated that 10-25% of HNC patients may have testosterone insufficiency before treatment and/or at 6 months after treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

No literature is available on the benign versus malignant breast lesion ratio in trans women (male sex assigned at birth, female gender identity). As hormone treatment in trans women results in breast tissue histologically comparable with cis (non-trans) women, breast pathology may be expected. Previously, an increased breast cancer risk compared with cis men have been observed. We aimed to investigate the frequency and outcomes of breast biopsies in trans women. Therefore, we retrospectively examined the medical files of 2616 trans women. To gain data on breast lesions, we linked our cohort to a national pathology database. In this study we found that 126 people (5%) had one or more breast biopsies (n = 139). Of these, 21 trans women had a breast biopsy before the start of hormone treatment, and 53 after the start of hormone treatment. Breast biopsies were performed predominantly because of abnormalities during physical examination (37%, n = 51/139 biopsies), or because of capsular formation or contraction (28%, n = 16/57 biopsies) in trans women with breast implants. The most common breast lesions after the start of hormone treatment were fibroadenomas (n = 20), breast cancer (n = 6), fibrosis (n = 5), cysts (n = 4), and infections (n = 4). The benign versus malignant breast biopsy ratio was 88:12, which is comparable to the ratio in cis women (90:10). This study shows breast lesions in a limited number of trans women. Since the indications and outcomes of biopsies in trans women were similar to those in cis women, it seems reasonable to follow breast care guidelines as developed for cis women., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To examine the feasibility and validity of obtaining International Classification of Primary Care (ICPC)-coded diagnoses of diabetes mellitus (DM) from general practice electronic health records for case definition in epidemiological studies, as alternatives to self-reported DM., Methods: The Netherlands Epidemiology of Obesity study is a population-based cohort study of 6671 persons aged 45-65 years at baseline, included between 2008-2012. Data from electronic health records were collected between 2012-2014. We defined a reference standard using diagnoses, prescriptions and consultation notes and investigated its agreement with ICPC-coded diagnoses of DM and self-reported DM., Results: After a median follow-up of 1.8 years, data from 6442 (97%) participants were collected. With the reference standard, 506 participants (79/1000 person-years) were classified with prevalent DM at baseline and 131 participants (11/1000 person-years) were classified with incident DM during follow-up. The agreement of prevalent DM between self-report and the reference standard was 98% (kappa 0.86), the agreement between ICPC-coded diagnoses and the reference standard was 99% (kappa 0.95). The agreement of incident DM between ICPC-coded diagnoses and the reference standard was >99% (kappa 0.92)., Conclusions: ICPC-coded diagnoses of DM from general practice electronic health records are a feasible and valid alternative to self-reported diagnoses of DM., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The transgender population that uses gender-affirming hormone therapy (GAHT) is rapidly growing. The (side) effects of GAHT are largely unknown. We examined the effect of GAHT on coagulation parameters associated with venous thromboembolism (VTE) risk., Methods: Factor (F)II, FIX, FXI, protein (p)C and free pS, fibrinogen, hematocrit, sex hormone-binding globulin, and normalized activated protein C ratio were measured in 98 transwomen (male sex at birth, female gender identity) and 100 transmen (female sex at birth, male gender identity) before and after 12 months of GAHT (oral or transdermal estradiol and anti-androgens in transwomen, transdermal or intramuscular testosterone in transmen). Mean paired differences in coagulation measurements were estimated with 95% confidence intervals (95% CI). Differences for route of administration and age were assessed with linear regression., Results: After GAHT, transwomen had more procoagulant profiles with a mean increase in FIX: 9.6 IU/dL (95% CI 3.1-16.0) and FXI: 13.5 IU/dL (95% CI 9.5-17.5), and a decrease in pC: -7.7 IU/dL (95% CI -10.1 to -5.2). Changes in measures of coagulation were influenced by route of administration (oral vs. transdermal) and age. A higher sex-hormone binding globulin level after 12 months was associated with a lower activated protein C resistance. In transmen, changes were not procoagulant overall and were influenced by age. Differences for route of administration (transdermal vs. intramuscular) were small., Conclusions: GAHT in transmen was not associated with apparent procoagulant changes, which provides some reassurance regarding VTE risk. In transwomen, GAHT resulted in procoagulant changes, which likely contributes to the observed increased VTE risk., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Depressive symptoms and impaired physical functioning are prevalent among older adults. Supplementation with vitamin D might improve both conditions, particularly in persons with low vitamin D status., Objective: The D-Vitaal study primarily aimed to investigate the effect of vitamin D supplementation on depressive symptoms, functional limitations, and physical performance in a high-risk older population with low vitamin D status. Secondary aims included examining the effect of vitamin D supplementation on anxiety symptoms, cognitive functioning, mobility, handgrip strength, and health-related quality of life., Methods: This study was a randomized placebo-controlled trial with 155 participants aged 60-80 y who had clinically relevant depressive symptoms, ≥1 functional limitations, and serum 25-hydroxyvitamin D [25(OH)D] concentrations of 15-50/70 nmol/L (depending on season). Participants received 1200 IU/d vitamin D3 (n = 77) or placebo tablets (n = 78) for 12 mo. Serum 25(OH)D was measured at baseline and 6 mo; outcomes were assessed at baseline, 6 mo, and 12 mo. Linear mixed-models analyses were conducted to assess the effect of the intervention., Results: The supplementation increased serum 25(OH)D concentrations in the intervention group to a mean ± SD of 85 ± 16 nmol/L compared with 43 ± 18 nmol/L in the placebo group after 6 mo (P < 0.001). No relevant differences between the treatment groups were observed regarding depressive symptoms, functional limitations, physical performance, or any of the secondary outcomes., Conclusions: Supplementation with 1200 IU/d vitamin D for 12 mo had no effect on depressive symptoms and physical functioning in older persons with relatively low vitamin D status, clinically relevant depressive symptoms, and poor physical functioning. This trial is registered with the Netherlands Trial Register (www.trialregister.nl) under NTR3845., (Copyright © American Society for Nutrition 2019.)

Gender-affirming hormonal treatment (HT) in transgender people is considered safe in general, but the question regarding (long-term) risk on sex hormone-related cancer remains. Because the risk on certain types of cancer differs between men and women, and some of these differences are attributed to exposure to sex hormones, the cancer risk may be altered in transgender people receiving HT. Although reliable epidemiologic data are sparse, the available data will be discussed in this article. Furthermore, recommendations for cancer screening and prevention will be discussed as well as whether to withdraw HT at time of a cancer diagnosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use., Methods: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses., Results: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10 -7 ) and rs8034191 (p = 6.31 × 10 -7 ) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use., Discussion: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: It is hypothesized that transpeople show sex-atypical differentiation of the brain. Various structural neuroimaging studies provide support for this notion, but little is known about the sexual differentiation of functional resting-state networks in transpeople. In this study we therefore aimed to determine whether brain functional connectivity (FC) patterns in transpeople are sex-typical or sex-atypical, before and after the start of cross-sex hormone therapy (CHT)., Methods: We acquired resting-state functional magnetic resonance data in 36 transpeople (22 with female sex assigned at birth), first during gonadal suppression, and again four months after start of CHT, and in 37 cisgender people (20 females), both sessions without any hormonal intervention. We used independent component analysis to identify the default mode network (DMN), salience network (SN), and left and right working memory network (WMN). These spatial maps were used for group comparisons., Results: Within the DMN, SN, and left WMN similar FC patterns were found across groups. However, within the right WMN, cisgender males showed significantly greater FC in the right caudate nucleus than cisgender females. There was no such sex difference in FC among the transgender groups and they did not differ significantly from either of the cisgender groups. CHT (in transgender participants) and circulating sex steroids (in cisgender participants) did not affect FC., Conclusion: Our findings may suggest that cisgender males and females experience a dissimilar (early) differentiation of the right WMN and that such differentiation is less pronounced in transpeople., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Low-dose aspirin is the cornerstone of secondary prevention of cardiovascular disease. Previous studies suggested that the use of aspirin is associated with an increased fracture risk. However, there is uncertainty whether this is due to an effect of aspirin on bone mineral density (BMD)., Methods: Between 2008 and 2012, information on medication use and dual X-ray absorptiometry measured vertebral and femoral BMD of 916 participants was collected in the Netherland Epidemiology of Obesity study. The cross-sectional association between chronic low-dose aspirin use and BMD was estimated using linear regression, controlling for demography, body composition, comorbidity and other medication use which could affect BMD. A subgroup analysis in postmenopausal women (n=329) was conducted., Results: After full adjustment, there was no difference between aspirin users and non-users for vertebral BMD (adjusted mean difference: 0.036 (95% CI -0.027 to 0.100) g/cm 2 ) and femoral BMD (adjusted mean difference: 0.001 (-0.067 to 0.069) g/cm 2 ). Also in the subgroup of postmenopausal women, aspirin use was not associated with lower vertebral (adjusted mean difference: 0.069 (-0.046 to 0.184) g/cm 2 ) or femoral BMD (adjusted mean difference: -0.055 (-0.139;0.029) g/cm 2 )., Conclusion: Chronic use of low-dose aspirin is not associated with lower BMD in the general population. The increased risk of fractures observed in aspirin users in previous studies is therefore more likely to be the result of common causes of aspirin use and fractures, but not of direct effects of aspirin on BMD., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Most studies examining the association between type 2 diabetes (T2D) and amino acids have focused on fasting concentrations. We hypothesized that, besides fasting concentrations, amino acid responses to a standardized meal challenge are also associated with T2D. In a cross-sectional study of 525 participants (165 newly-diagnosed T2D, 186 newly-diagnosed impaired fasting glycaemia, and 174 normal fasting glucose), we examined postprandial amino acid concentrations and the responses (defined as the concentrations and responses 150 min after a standardized meal) of fourteen amino acids in relation to T2D. T2D was associated with lower postprandial concentration of seven amino acids compared to the normal fasting glucose group (lowest effect estimate for serine: -0.54 standard deviations (SD) (95% CI: -0.77, -0.32)), and higher concentrations of phenylalanine, tryptophan, tyrosine and (iso-)leucine (highest effect estimate for (iso-)leucine: 0.44 SD (95% CI: 0.20, 0.67)). Regarding the meal responses, T2D was associated with lower responses of seven amino acids (ranging from -0.55 SD ((95% CI): -0.78, -0.33) for serine to -0.25 SD ((95% CI: -0.45, -0.02) for ornithine). We conclude that T2D is associated with postprandial concentrations of amino acids and a reduced amino acid meal response, indicating that these measures may also be potential markers of T2D., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Both overall and abdominal adiposity are established risk factors for cardiovascular disease. Visceral adipose tissue (VAT) and total body fat (TBF) are strongly correlated and previous studies did not make this distinction., Objective: We aimed to distinguish individual contributions of TBF, VAT, and the ratio of VAT to abdominal subcutaneous adipose tissue (VAT/SAT) to subclinical atherosclerosis in men and women., Methods: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, we assessed VAT and SAT with magnetic resonance imaging, TBF with bio-electrical impendence analysis, and carotid Intima-Media Thickness (cIMT) with ultrasound. We performed linear regression analyses of standardized values of TBF, VAT, VAT/SAT with cIMT. We adjusted the models for confounding factors (age, sex, ethnicity, education, smoking, alcohol, physical activity), and either for VAT or TBF., Results: This analysis included 2451 participants, 53% men with mean (SD) cIMT of 615 (91)μm. After adjustment for confounding factors, the difference in cIMT (95% CI) per SD in VAT was 14 (8,21)μm in men and 18 (13,24)μm in women. After adjustment for TBF, this attenuated to 5 (-3,13)μm in men and 13 (5,20)μm in women. In the full model, differences in cIMT (95% CI) per SD of TBF were 14 (6,22)μm in men and 8 (0,16)μm in women, and per SD of VAT/SAT were 7 (-1,15)μm and 9 (3,16)μm respectively., Conclusions: In this population-based study, VAT contributed beyond overall adiposity to subclinical atherosclerosis, particularly in women. This implies a specific role of VAT in the early development of atherosclerosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Aim: Excess body fat is associated with altered autonomic function. We investigated whether this association is mediated by insulin resistance., Methods and Results: Cross-sectional analysis of a subgroup of the Netherlands Epidemiology of Obesity study with measurements of autonomic function (heart rate variability calculated as mean interbeat interval, standard deviation of all normal intervals (SDNN), low frequency (LF) power and high frequency (HF) power). We measured BMI(kg/m²), total body fat(%) and waist circumference(cm), and calculated the HOMA-index of insulin resistance (HOMA-IR). We examined the association between body fat and heart rate variability with multivariate linear regression analysis. To investigate whether the association was mediated by insulin resistance, we additionally adjusted for HOMA-IR. After exclusion of participants with glucose lowering medication (n = 19), 466 participants were included. Per SD of BMI, the difference in SDNN was -2.7% (95%CI: -5.5, 0.1) in the multivariate model. Additional adjustment for HOMA-IR attenuated this association to -1.2% (95%CI: -4.2, 1.7), suggesting that 55% of the association between BMI and SDNN was mediated by HOMA-IR. All measures of body fat were associated with mean interbeat interval, SDNN and LF power. Depending on the parameter of body fat or heart rate variability, 29-81% of the association was mediated by HOMA-IR., Conclusion: In this cross-sectional study, body fat was associated with heart rate variability. This association may at least partially be mediated by insulin resistance. Future studies should investigate whether a reduction in obesity and insulin resistance may prevent the adverse cardiovascular consequences of altered autonomic function., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Some studies have suggested an inverse association between acne vulgaris and the acne-related bacterium Propionibacterium acnes and prostate cancer (PCa). Self-reported acne might be an easily obtainable marker to identify men at relatively low risk of PCa and might be incorporated into PCa risk calculators. This study aimed to evaluate the association between self-reported acne and PCa in a large case-referent study., Methods and Materials: The case group comprised 942 patients with PCa recruited from a population-based cancer registry in 2003 to 2006, 647 of whom met the criteria for aggressive PCa. The referents (n = 2,062) were a random sample of the male general population. All subjects completed a questionnaire on risk factors for cancer, including questions about acne. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using multivariable logistic regression for PCa and aggressive PCa as separate end points, while adjusting for age and family history of PCa., Results: A history of acne was reported by 320 cases (33.9%) and 739 referents (35.8%). Self-reported acne was significantly associated neither with PCa (adjusted OR = 0.95, 95% CI: 0.80-1.12) nor with aggressive PCa (adjusted OR = 0.97, 95% CI: 0.80-1.18)., Conclusion: Self-reported acne is not suitable as a marker to identify men at low risk of aggressive PCa., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To examine the interplay between subclinical atherosclerotic disease and neuroticism in explaining variance in late-life depressive symptoms., Methods: This study was part of the Nijmegen Biomedical Study, a population-based survey; 1,517 participants aged 50-70 years were included. Depressive symptoms were measured by the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, representing a cognitive-affective symptom cluster and a somatic-affective symptom cluster. Atherosclerotic disease was measured by the intima media thickness (IMT) of the carotid arteries and neuroticism by the revised Eysenck Personality Questionnaire., Results: Multiple linear regression analyses using different measures of depressive symptoms as the dependent variable showed that neuroticism was strongly and significantly associated with the sum score of the BDI and with the two depressive symptom clusters. IMT, however, was only significantly associated with the somatic-affective symptom cluster but not with the cognitive-affective symptom cluster. Interestingly, we found a significant negative interaction between neuroticism and IMT in explaining the severity of the cognitive-affective symptom cluster but not with respect to the somatic-affective symptom cluster., Conclusion: The negative interaction between neuroticism and atherosclerosis indicates that neuroticism is less strongly associated with cognitive-depressive symptoms in the presence of more severe atherosclerosis. This may be explained by apathy due to cerebrovascular disease and fits with a hypothesis of vascular apathy., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Vitamin D status is currently diagnosed by measuring serum 25-hydroxyvitamin D [25(OH)D]., Objective: This study aimed to develop a risk profile that can be used to easily identify older individuals at high risk of vitamin D deficiency., Design: This study was performed within the Longitudinal Aging Study Amsterdam, an ongoing cohort study in a representative sample of the Dutch older population (n = 1509 for the development sample and n = 1100 for the validation sample). Prediction models for serum 25(OH)D concentrations <50 and <30 nmol/L were developed by using backward logistic regression. Risk scores were calculated by dividing the individual regression coefficients by the regression coefficient with the lowest β to create simple scores., Results: Serum 25(OH)D concentrations <50 and <30 nmol/L were present in 46.2% and 17.5% of participants, respectively. The model for the prediction of concentrations <50 nmol/L consisted of 13 easily assessable predictors, whereas the model for concentrations <30 nmol/L contained 10 predictors. The resulting areas under the curve (AUCs) were 0.78 and 0.80, respectively. The AUC in the external validation data set was 0.71 for the <50-nmol/L model. At a cutoff of 58 in total risk score (range: 8-97), the model predicted concentrations <50 nmol/L with a sensitivity of 61% and a specificity of 82%, whereas these values were 61% and 84%, respectively, at a cutoff of 110 in the total risk score (range: 6-204) in the model for concentrations <30 nmol/L., Conclusions: Two total risk scores, including 13 or 10 predictors that can easily be assessed, were developed and are able to predict serum 25(OH)D concentrations <50 and <30 nmol/L accurately. These risk scores may be useful in clinical practice to identify persons at risk of vitamin D deficiency.

Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD., Objective: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD., Design: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls., Results: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49)., Conclusions: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

Background: Venous thromboembolism (VTE) is a multicausal disorder involving environmental and genetic risk factors. In many thrombophilic families the clustering of thrombotic events cannot be explained by known genetic risk factors, indicating that some remain to be discovered., Objectives: We aimed to identify novel thrombosis susceptibility alleles in a large panel of small thrombophilic families: the Genetics In Familial Thrombosis (GIFT) study., Patients/methods: In the GIFT study, 201 families were recruited consisting of 438 siblings with an objectively confirmed VTE at a young age. Multipoint linkage analysis (402 SSR markers) and fine mapping were performed, followed by genotyping of tagging SNPs in positional candidate genes., Results: Established genetic risk factors such as factor V Leiden, ABO blood group non-O, prothrombin 20210A, fibrinogen gamma 10034T and deficiencies of antithrombin, protein C and protein S were more frequent in GIFT patients than in unselected VTE patients. Linkage supported the presence of novel thrombosis susceptibility loci on 7p21.3-22.2 (LOD score = 3.23) and Xq24-27.3 (LOD score = 1.95). Simulation analysis showed that the chr7 signal was genome-wide statistically significant (P = 0.022). Tagging SNPs (n = 157) in eight positional candidate genes (LOD drop 1.5 regions) were genotyped in GIFT patients and 332 healthy controls. Five chr7 SNPs associated with VTE. SNP THSD7A rs2074597 was responsible for part of the chr7 signal., Conclusions: The GIFT panel is rich in established genetic risk factors for VTE, but genetic factors remain unidentified in many families. Genome-wide linkage failed to identify the previously established genetic risk factors for VTE, but identified a novel VTE susceptibility locus on chr7., (© 2013 International Society on Thrombosis and Haemostasis.)

Objective: The relative importance of insulin resistance and hyperglycemia to the development of atherosclerosis remains unclear. Furthermore, adiposity may be responsible for observed associations. Our aim was to study the relative contributions of adiposity, insulin resistance and hyperglycemia to subclinical atherosclerosis., Methods: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, a cohort of persons of 45-65 years, BMI, waist circumference (WC), fasting glucose (FPG), HbA1c and insulin concentrations were measured and the revised HOMA-IR was calculated. The carotid Intima-Media Thickness (cIMT) was measured by ultrasound. We performed linear regression analyses between standardized values of FPG, HbA1c, HOMA-IR, BMI, WC with cIMT, and subsequently included age, sex, ethnicity, education and smoking, HOMA-IR, HbA1c and FPG, BMI and WC in the models., Results: After exclusion of participants with glucose lowering therapy (n = 356) or missing data (n = 252), this analysis included 6065 participants, 43% men, and mean (SD) cIMT of 616 (92) μm. Differences in cIMT (95% CI) per SD were: FPG: 16 (10,21); HbA1c: 12 (7,16); HOMA-IR: 11 (6,16) μm. These associations attenuated after adjustments, and attenuated most strongly after adjustment for WC. Differences in cIMT (95% CI) per SD in the full model were: FPG: 4 (0,7); HbA1c: 2 (-1,5); HOMA-IR: 0 (-3,3); BMI 16 (13,19); WC: 18 (14,21) μm., Conclusion: In middle-aged individuals, we observed similar contributions of insulin resistance and hyperglycemia to subclinical atherosclerosis. These contributions were largely explained by abdominal adiposity, emphasizing the importance of weight management., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification., Methods: In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR)., Findings: During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99–1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site., Interpretation: Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials., Funding: British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.

Background: Growth retardation in utero leading to small-for-gestational-age (SGA) newborns is associated with increased neonatal morbidity and mortality and with lifelong consequences such as poor cognitive function and cardiovascular diseases. Maternal total homocysteine (tHcy) concentrations have been linked to a wide range of adverse pregnancy outcomes and could possibly influence birth weight., Objective: We performed a systematic review of and meta-analysis on the association of maternal tHcy and birth weight., Design: A literature search of English, German, and French publications with the use of the PubMed database (January 1966-July 2010) found 78 abstracts. Search terms were as follows: homocysteine AND (birth weight OR small for gestational age OR intrauterine growth retardation). Studies were eligible if information on maternal tHcy and birth weight and the possible association between maternal tHcy and birth weight was available. Effect size estimates were converted to ORs as estimates of the RR of a woman to deliver SGA offspring when maternal tHcy exceeded the 90th percentile., Results: The search yielded 19 studies for analysis, consisting of 21,326 individuals. Pooled analysis resulted in a crude OR of 1.25 (95% CI: 1.09, 1.44). When this estimate was expressed as a linear effect, it corresponded to a decrease in birth weight of 31 g (95% CI: -13, -51 g) for a 1-SD increase in maternal tHcy., Conclusions: Higher maternal tHcy concentrations are associated with a small increased risk for SGA offspring. The small estimated birth weight difference might be of little clinical relevance for the individual newborn; however, it could be of greater importance at a population level.

To date, concentrations of the promising biomarker hepcidin have only been assessed in serum of relatively small series of healthy volunteers and patients. We assessed age- and sex-stratified reference ranges of serum hepcidin concentration in a selected reference set and performed regression analyses to study associations between hepcidin and (biochemical) variables in a large, well-phenotyped sample of the general population (n = 2998). All participants filled out a questionnaire on lifestyle, health status, and medical history. Serum measurements of iron parameters, liver enzyme alanine aminotransferase, creatinine and C-reactive protein were available. Serum hepcidin concentrations were lower for premenopausal than for postmenopausal women (median, 4.1 nM vs 8.5 nM, respectively). Hepcidin concentrations in men were constant over age (median, 7.8 nM). Serum hepcidin was strongly associated with serum ferritin in men and women: β-coefficient of log-transformed variables (95% confidence interval): 0.78 (0.74-0.82) and 0.83 (0.78-0.88), respectively. Additional significant, though less strong, associations were observed for C-reactive protein and total iron binding capacity in men and for total iron binding capacity, alanine aminotransferase, and glomerular filtration rate in women. Our study provides age- and sex-specific reference ranges of serum hepcidin concentration and indicates ferritin as the primary correlate of serum hepcidin concentration.

Season of birth - in particular winter birth - has been persistently related to increased schizophrenia risk. Variation in folate intake is among the explanations for this seasonal effect. Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate mediated methylation transfer reactions. Interestingly, the MTHFR gene has been related to schizophrenia risk in various studies. We investigated a possible interaction between MTHFR 677C>T polymorphism and winter birth in the development of schizophrenia in a group of 742 schizophrenia patients and 884 control subjects. All subjects were of Dutch ancestry. Winter birth (December up to and including February) was associated with a 20% increase in schizophrenia risk (odds ratio (OR) of 1.20 and 95% confidence interval (CI), 0.96-1.5; P=0.113). The MTHFR 677TT genotype was associated with an overall schizophrenia risk of 1.13 (95% CI, 0.82-1.57; P=0.454) compared with the MTHFR 677CC genotype. In the winter period the MTHFR 677TT genotype associated schizophrenia risk was 0.90 (95% CI, 0.47-1.70; P=0.744). In conclusion, neither winter birth nor MTHFR genotype were significantly associated with increased schizophrenia risk. There was no evidence for interaction between MTHFR 677TT genotype and winter birth in the development of schizophrenia., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) and psoriasis are common skin diseases characterized by cutaneous inflammation and disturbed epidermal differentiation. Genome-wide analyses have shown overlapping susceptibility loci, such as the epidermal differentiation complex on chromosome 1q21. Recently, a deletion on 1q21 (LCE3C&#95;LCE3B-del), comprising LCE3B and LCE3C, two members of the late cornified envelope (LCE) gene cluster, was found to be associated with psoriasis. Although the mechanistic role of LCE proteins in psoriasis has not been identified, these proteins are putatively involved in skin barrier formation and repair. Considering the potential genetic overlap between the two diseases and the recent finding that mutations in the skin barrier protein filaggrin are associated with AD, we investigated a possible association between LCE3C&#95;LCE3B-del and AD. Evaluation of four different cohorts of European ancestry, containing a total of 1075 AD patients and 1658 controls, did not provide evidence for such an association. Subgroup analysis did not reveal an association with concomitant asthma. Our data suggest that the potential roles of skin barrier defects in the pathogenesis of AD and psoriasis are based on distinct genetic causes.

Objective: We designed a large prospective study to explore the relationship between maternal homocysteine concentrations and related B vitamins and birthweight., Study Design: Blood was sampled from pregnant women at 30-34 weeks of gestation and their newborn infants (n = 366)., Results: Concentrations of all analytes were higher in umbilical cord compared with maternal samples. Birthweight was related negatively to maternal homocysteine (r = -0.12) but not related to maternal cobalamin, methylmalonic acid, and folate (r = 0.02, r = 0.06, and r = 0.04, respectively). Regression analysis revealed smoking (beta = -313; 95% confidence interval [CI], -479 to -149), gestational age (beta = 150; 95% CI, 118-182), female sex (beta = -146; 95% CI, -256 to -35), and parity (beta = 104; 95% CI, 37-171) as strong determinants of birthweight. Maternal homocysteine, cobalamin, methylmalonic acid, and folate were not determinants of birthweight in multivariate analysis., Conclusion: Maternal homocysteine and B vitamins are not related to birthweight in a multivariate model that was adjusted for potential confounders., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: The aim of this study was to investigate whether inflammatory markers (interleukin-6 [IL-6] and C-reactive protein [CRP]) in the acute phase of deep vein thrombosis (DVT) are associated with elevated venous outflow resistance (VOR), thrombosis score (TS), reflux and the development of clinical post-thrombotic syndrome (PTS)., Methods: In 110 patients with a first DVT, plasma concentrations of IL-6 and CRP were determined on the day of admission. VOR, TS and reflux were measured 7 days, 1 and 3 months after diagnosis. After 1 year patients were evaluated for PTS using the Clinical, Etiologic, Anatomic and Pathophysiologic (CEAP) classification and Villalta scale., Results: Median levels of IL-6 and CRP were 7 pg mL(-1) and 21 mg L(-1), respectively. After 3 months, VOR was elevated in 33 patients (30%), TS in 33 (30%) and reflux in 57 (52%). Incidence of PTS was 36.7% using CEAP>or=3 and 35.4% using Villalta-scale>or=5. Elevated levels of IL-6 and CRP were related to higher outcomes of VOR after 3 months [relative risks (RR) 2.4 (95% CI 1.5-3.9) and 1.4 (1.1-3.3), respectively] and for IL-6 to TS [1.5 (1.1-2.1)]. For reflux no relation was found. After 90 days, elevated outcomes of VOR, TS and reflux were related to PTS after 1 year. The association of IL-6 and CRP with PTS was weak using the CEAP classification with a RR of 1.2 (0.7-2.2) and 1.8 (0.9-3.3) and absent according to the Villalta scale 0.6 (0.2-1.4) and 1.2 (0.6-2.5), respectively., Conclusion: The results of this study suggest that inflammation might play a role in incomplete thrombus clearance, venous outflow obstruction and the development of PTS after 1 year.

Objective: The objective was to investigate whether it is justified to discourage trials with less than 80% power. Trials with low power are unlikely to produce conclusive results, but their findings can be used by pooling then in a meta-analysis. However, such an analysis may be biased, because trials with low power are likely to have a nonsignificant result and are less likely to be published than trials with a statistically significant outcome., Study Design and Setting: We simulated several series of studies with varying degrees of publication bias and then calculated the "real" one-sided type I error and the bias of meta-analyses with a "nominal" error rate (significance level) of 2.5%., Results: In single trials, in which heterogeneity was set at zero, low, and high, the error rates were 2.3%, 4.7%, and 16.5%, respectively. In multiple trials with 80%-90% power and a publication rate of 90% when the results were nonsignificant, the error rates could be as high as 5.1%. When the power was 50% and the publication rate of non-significant results was 60%, the error rates did not exceed 5.3%, whereas the bias was at most 15% of the difference used in the power calculation., Conclusion: The impact of publication bias does not warrant the exclusion of trials with 50% power.

Adiponectin is secreted from adipocytes in different multimers, of which the high molecular weight (HMW) form is supposed to mediate favorable metabolic and anti-atherogenic effects. We determined adiponectin multimers in 29 female and 22 male patients with familial combined hyperlipidemia (FCH) and 51 age-, gender-, and BMI-matched controls in relation to cardiovascular disease (CVD). We observed a clear sexual dimorphism of total adiponectin and its multimers. Female, but not male, FCH patients had significant lower total adiponectin and both HMW and low molecular weight (LMW) adiponectin than controls. The adiponectin sensitivity index (ASI), reflected by HMW/total adiponectin, and the LMW/HMW adiponectin ratio did not differ significantly between FCH females and control females. However, FCH females with CVD exhibited significantly lower ASI (34.2+/-10.1% vs 46.0+/-7.1%) and higher LMW/HMW ratio (1.5+/-0.8 vs 0.7+/-0.3) compared to FCH females without CVD, reflecting a more atherogenic adiponectin multimer distribution.

Background: Evidence is emerging for the association of aberrant homocysteine-methylation cycle and increased risk of schizophrenia., Methods: We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in 252 patients with schizophrenia and 405 control subjects. All subjects were of Dutch ancestry., Results: The COMT 324AA genotype was not associated with an increased risk of schizophrenia (odds ratio (OR)=1.38 [95% CI: 0.88-2.16], P=0.162), and the MTHFR 677TT genotype showed a nearly significant increased risk for schizophrenia (OR=1.65 [95% CI: 0.97-2.82], P=0.067). The odds ratio for schizophrenia associated with joint occurrence of the COMT 324AA and MTHFR 677TT genotype was 3.08 (95% CI: 1.08-8.76) (P=0.035). Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia (test for trend, P=0.017)., Conclusions: Our findings do not support a major role for the COMT 324AA and MTHFR 677TT genotype alone, but the combination of both genotypes might increase schizophrenia susceptibility.

The Nijmegen Biomedical Study is a population-based cross-sectional study conducted in the eastern part of the Netherlands. As part of the overall study, we provide reference values of estimated glomerular filtration rate (GFR) for this Caucasian population without expressed risk. Age-stratified, randomly selected inhabitants received a postal questionnaire on lifestyle and medical history. In a large subset of the responders, serum creatinine was measured. The GFR was then measured using the abbreviated Modification of Diet in Renal Disease (MDRD) formula. To limit possible bias, serum creatinine was calibrated against measurements performed in the original MDRD laboratory. The study cohort included 2823 male and 3274 female Caucasian persons aged 18-90 years. A reference population of apparently healthy subjects was selected by excluding persons with known hypertension, diabetes, cardiovascular- or renal diseases. This healthy study cohort included 1660 male subjects and 2072 female subjects, of which 869 of both genders were 65 years or older. The median GFR was 85 ml/min/1.73 m(2) in 30-to 34-year-old men and 83 ml/min/1.73 m(2) in similar aged women. In these healthy persons, GFR declined approximately 0.4 ml/min/year. Our study provides age- and gender-specific reference values of GFR in a population of Caucasian persons without identifiable risk.

Background: Hyperhomocysteinemia has been associated with vascular disease in many epidemiologic studies, but only a few have reported on the relation between hyperhomocysteinemia and aneurysms of the abdominal aorta (AAAs). Although these studies showed higher homocysteine concentrations in patients with AAA than in controls, little attention had been given to possible confounding factors. Most patients with AAA are of older age, have an impaired renal function, and have other risk factors for cardiovascular disease. This matched case-control study investigated the relation between homocysteine concentration (before and after methionine loading) and AAA, taking into account possible confounders such as age, sex, and concentrations of creatinine and B vitamins., Methods: Patients with a history of AAA were recruited from the outpatient clinic; 60% had already undergone surgery for their AAA. They were asked to invite a friend or neighbor to participate as a control subject (age-matched and sex-matched). Concentrations of homocysteine, vitamin B6, vitamin B12, folate, and creatinine were determined in the fasting state, and blood was taken for methylenetetrahydrofolate reductase (MTHFR) mutation analysis. Six hours after oral methionine loading, the postmethionine load homocysteine concentration was determined., Results: Univariate analysis showed an odds ratio (OR) of 2.2 (95% confidence interval (CI), 0.9 to 5.5) for the risk of AAA for the highest quartile of homocysteine concentration. After adjustment for creatinine, the OR was markedly reduced to 1.24 (95% CI, 0.42 to 3.66), and this risk further attenuated in the multivariate analysis. Univariate analysis of the B vitamins showed an increased risk of AAA for the bottom quartile of vitamin B6 (OR, 3.75; 95% CI, 1.22 to 11.54), which even increased after adjustments. The relative risk associated with the MTHFR 677TT polymorphism was 2.1 (95% CI, 0.9 to 5.3)., Conclusion: Vitamin B6, but not homocysteine, is an independent risk factor for AAA. The role of vitamin B6 in the pathogenesis of AAA needs to be further elucidated.

The Vitamins and Thrombosis (VITRO) study investigated the effect of homocysteine lowering by daily supplementation of B vitamins on the risk reduction of deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients between 20 to 80 years old with a first objectively confirmed proximal DVT or PE in the absence of major risk factors and a homocysteine concentration above the 75th percentile of a reference group were asked to participate (hyperhomocysteinemic group). A similar study was conducted in a random sample of patients with a homocysteine below the 75th percentile of the reference group (normohomocysteinemic group). After informed consent was obtained, patients were randomized to daily multivitamin supplementation (5 mg folic acid, 50 mg pyridoxine, and 0.4 mg cyanocobalamin) or placebo and were followed for 2.5 years. End points were objectively diagnosed recurrent DVT or PE. A total of 701 patients were enrolled (360 in the hyperhomocysteinemic and 341 in the normohomocysteinemic group). The number of recurrent events of venous thrombosis was 43 of 353 in the vitamin group (54/1000 py) and 50 of 348 in the placebo group (64/1000 py). The hazard ratio associated with vitamin treatment was 0.84 (95% CI, 0.56-1.26): 1.14 (95% CI, 0.65-1.98) in the hyperhomocysteinemic group and 0.58 (95% CI, 0.31-1.07) in the normohomocysteinemic group. The results of our study do not show that homocysteine lowering by B vitamin supplementation prevents recurrent venous thrombosis.

Background: An elevated plasma total homocysteine (tHcy) level is a risk factor for many clinical conditions, including vascular disease and venous thrombosis. The tHcy levels are partly determined by genetic factors. Extensive candidate gene studies have identified several genetic variants, including the MTHFR 677C>T, that influence tHcy levels, but so far only part of the genetic variation in tHcy can be explained., Objective: In order to identify chromosomal regions that influence tHcy levels, a genome-wide linkage analysis was conducted., Patients/methods: Our study population consisted of 13 pedigrees and 469 subjects with data on fasting plasma tHcy levels. A set of 377 markers covering the genome was genotyped in 275 subjects. The variance component linkage method (SOLAR version 2.1.3) was used for the two-point and multipoint linkage analyses., Results: The heritability of the age- and sex-adjusted homocysteine levels was 44%. The multipoint linkage analysis identified one region with suggestive linkage on chromosome 16q (LOD score 1.76; nominal P = 0.0024). Weaker evidence of linkage was found for regions on chromosome 12q (LOD score 1.57; nominal P = 0.0036) and chromosome 13q (LOD score 1.52; nominal P = 0.0041)., Conclusions: In our families the plasma tHcy level was highly heritable. The multipoint linkage analysis identified three regions that showed weak to suggestive linkage to tHcy levels.

Venous thrombosis is considered as a multicausal disease. Hyperhomocysteinemia is considered as one of the risk factors for venous thrombosis. Because homocysteine levels are strongly influenced by the intake and concentrations of B vitamins, it is worthwhile to assess the role of these vitamins as a risk factor for venous thrombosis.

Familial combined hyperlipidemia (FCH) is characterized by hypercholesterolemia and/or hypertriglyceridemia and is associated with premature cardiovascular disease (CVD). Other features of FCH are obesity and insulin resistance. Serum leptin levels have been associated with obesity, insulin resistance and CVD. The aim of this study was to determine whether increased leptin levels contribute to the FCH phenotype and its increased risk for CVD. The study population comprised 644 subjects, including 158 FCH patients. Leptin levels were determined, using a commercially available ELISA. For both males and females, the mean leptin level (ng/ml) was higher in FCH patients compared to normolipidemic relatives and spouses. However, after standardization for BMI and insulin resistance, these differences disappeared. The 90th percentile of the leptin level, standardized for BMI, insulin resistance and gender, was associated with an increased risk for CVD in FCH patients (odds ratio=2.9, 95% CI=1.1-8.0) and in non-FCH subjects (odds ratio=3.4, 95% CI=1.3-9.0). The overall increased risk for CVD, associated with a leptin level >90th percentile, was 3.3 (95% CI=1.7-6.4). We conclude that in patients with FCH, leptin levels are increased in proportion to their higher BMI and the presence of insulin resistance. These increased leptin levels are associated with an increased risk for CVD both in FCH patients and non-FCH subjects, independent of BMI, insulin resistance and gender.

Although minimisation methods have frequently been advocated for treatment allocation in clinical trials, they are not widely used. As this may partly be due to the complexity of the methods, we devised a new and simple minimisation method to balance for prognostic factors, called sequential balancing. Each factor is dealt with sequentially and when a new subject enters the trial, he or she is allocated the treatment that leads to improved balance of the first factor over the treatments. If the balance of the first factor was already satisfactory, then the treatment is allocated that leads to improved balance of the second factor and so on. The algorithm requires no calculations. We simulated a realistic trial and compared the performance of this method to the performance of alternative allocation strategies: the variance minimisation method, simple randomisation and stratification. The sequential balancing method led to better balance than randomisation and stratification. In the case of four factors or less, the performance of the sequential balancing method and the variance minimisation method were comparable and the sequence of the factors was not very relevant. When more factors were introduced, the balance of the sequential method remained comparable with the balance achieved with the variance minimisation method for the first four factors, but it started to decrease from the fifth factor onwards. We conclude that the ease and simplicity of the new method make it an attractive option when balance is required for four factors or less. If there are more than four factors, the sequential balancing method may still be an acceptable option, but the advantage of simplicity has to be weighed against the loss of performance compared to other minimisation methods.

Familial combined hyperlipidemia (FCH) is characterized by increased levels of total cholesterol, triglycerides, and/or apolipoprotein B. Other features of FCH are obesity and insulin resistance. Adiponectin is a secretory product of the adipose tissue. Low levels of adiponectin are associated with insulin resistance and accelerated atherosclerosis. The aim of this study was to determine whether decreased adiponectin levels are associated with FCH and its phenotypes. The study population comprised 644 subjects, including 158 patients with FCH. Serum adiponectin levels were determined using a commercially available ELISA. For both males and females, the mean adiponectin level (microg/ml) was significantly lower in FCH patients [2.0 (1.8-2.2) and 2.5 (2.3-2.8), respectively] compared with normolipidemic relatives [2.3 (2.2-2.5) and 3.1 (2.8-3.3), respectively] and spouses [2.4 (2.1-2.7) and 3.2 (2.8-3.6), respectively]. These differences remain significant after adjusting for waist circumference and insulin resistance. Low adiponectin level in FCH patients was a superior independent predictor of the atherogenic lipid profile, including high triglyceride levels, low HDL-cholesterol levels, and the amount of small, dense LDL present, compared with both obesity and insulin resistance. Low adiponectin levels may contribute to the atherogenic lipid profile in FCH, independent of insulin resistance and obesity, as measured by waist circumference. This finding implies a role of adipose tissue metabolism in the pathophysiology of FCH.

Background: Vitamin status, methylenentetrahydrofolate reductase (MTHFR) genotype, age, sex, and lifestyle factors are all predictors of total homocysteine (tHcy) concentrations in adults. Limited data are available about the influence of these factors on tHcy in children., Objective: The objective was to describe tHcy and its predictors in Dutch children., Design: A sample of 234 white children aged 0-19 y was analyzed cross-sectionally., Results: The geometric mean tHcy concentrations were 5.1 (95% CI: 4.6, 5.6), 4.6 (4.2, 5.1), 6.2 (5.6, 6.9), 7.3 (6.7, 8.0), and 8.7 (7.9, 9.6) micromol/L in the 0-1, 2-5, 6-10, 11-14, and 15-19 y groups, respectively. Plasma folate and vitamin B-12 concentrations decreased markedly with age. The inverse association between tHcy and plasma folate seen at all ages was stronger than that between tHcy and plasma vitamin B-12. A negative association of plasma folate with tHcy was confined to folate concentrations <20 nmol/L. Homozygosity for the MTHFR 677C-->T polymorphism was identified in 8.2% of the children. The homocysteine concentration did not differ significantly between the MTHFR genotypes., Conclusions: This study provided age-specific data regarding tHcy concentrations and their predictors in the whole range of childhood. The tHcy concentration increased as a function of age in both sexes. Plasma folate was a concentration-dependent predictor of tHcy. The MTHFR 677C-->T polymorphism played a minor role in determining tHcy concentrations in children.

Context: It has been suggested that elevated total plasma homocysteine levels are associated with the risk of venous thrombosis., Objective: To assess the relationship of homocysteine and the MTHFR 677TT genotype and the risk of venous thrombosis by conducting a meta-analysis of all relevant studies., Data Sources and Selection: Studies (case-control or nested case-control) were identified by searches of electronic literature for relevant reports published before July 2003 on homocysteine and the MTHFR 677TT genotype and venous thrombosis as an end-point, by hand-searching reference lists of original articles (including meta-analyses) on this topic and by contact with investigators in the field., Data Extraction: A meta-analysis of 24 retrospective (n = 3289 cases) and three prospective studies (n = 476 cases) was carried out to examine the association of homocysteine with venous thrombosis. A meta-analysis of 53 studies (n = 8364 cases) of the MTHFR 677TT genotype (that increases homocysteine) was carried out to assess if this association is causal., Data Synthesis: A 5 micromol L(-1) higher measured homocysteine level was associated with a 27% (95% CI: 1-59) higher risk of venous thrombosis in prospective studies and a 60% (95% CI: 10-134) higher risk in retrospective studies. The 677TT genotype was associated with a 20% (95% CI: 8-32) higher risk of venous thrombosis compared with the 677CC genotype. In contrast with non-American studies, the 677TT genotype had no effect on venous thrombosis in North America, due probably to the higher intake of folate and riboflavin in North America., Conclusion: This meta-analysis of prospective and retrospective studies demonstrates a modest association of homocysteine with venous thrombosis. The elevated risk associated with the MTHFR 677TT genotype provides some support for causality.

Background: Venous thrombosis is a multicausal disease involving both genetic as well as acquired risk factors. Hyperhomocysteinemia is associated with a 2-fold increased risk of recurrent venous thrombosis (RVT). Recently, the 894 G > T variant of endothelial nitric oxide synthase (eNOS) was postulated to be associated with hyperhomocysteinemia., Objectives: We hypothesized an interrelation of hyperhomocysteinemia, the eNOS 894 G > T variant and RVT risk., Methods: The eNOS 894 G > T variant was studied in 170 cases with a history of RVT and 433 controls from the general population., Results: The eNOS 894 TT genotype may increase RVT risk [odds ratio (OR) 1.3 (0.7-2.6)], but no association of the eNOS 894 G > T variant with elevated homocysteine was found in controls. Interestingly, in RVT cases the coexistence of both the 894 TT genotype and elevated tHcy levels (> 90th percentile) was more frequently present than in controls, which led to a substantially increased risk of recurrent venous thrombosis [fasting tHcy OR 5.3 (1.1-24.1), postload tHcy OR 6.5 (1.6-29.5)]., Conclusion: The results of the present study demonstrate that the eNOS 894 G > T variation interacts with elevated tHcy levels, leading to an increased risk of recurrent thrombotic events. This interaction points in the direction of S-nitrosation as a mechanism by which homocysteine exerts its detrimental effects on the hemostatic system.

Familial combined hyperlipidemia (FCH) is characterised by hypercholesterolemia and/or hypertriglyceridemia and associated with an increased risk of cardiovascular disease (CVD). The plasma lipid and lipoprotein levels in subjects with FCH are relatively moderately elevated and do not fully explain the increased risk of CVD. Hyperhomocysteinemia is a disorder of methionine metabolism and also a well-known independent risk factor for CVD. We investigated whether subjects with FCH have higher plasma homocysteine concentrations than controls, and whether homocysteine contributes to the increased risk of CVD in FCH. Furthermore we evaluated whether parameters of lipid and lipoprotein metabolism and/or insulin resistance are associated with the homocysteine level. In total 667 subjects, including 161 subjects with FCH, 109 spouses who referenced as control group and 397 normolipidemic relatives were studied. FCH was defined by the presence of plasma total cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. The mean homocysteine concentration of the FCH group did not significantly differ from the control group. The risk for CVD due to hyperhomocysteinemia in subjects with FCH was not higher than in subjects without FCH. No associations were observed between plasma homocysteine concentration and plasma lipid and lipoprotein levels, including small dense low density lipoprotein, nor between homocysteine concentration and insulin resistance.

Elevated levels of total homocysteine and low folate in blood are independent and graded risk factors for arterial occlusive disease. An impairment of folate distribution can be an important cause of hyperhomocysteinemia. Glutamate carboxypeptidase II (GCPII) regulates the absorption of dietary folates. In the present study, we examined the relationship of a 1561C-->T variant in the GCPII gene with fasting, post-methionine load plasma homocysteine, folate and vitamin B(12) levels and the risk of cardiovascular disease (CVD) in 190 vascular disease patients and in 601 apparently healthy controls. Fasting as well as post-load homocysteine concentrations associated with the 1561TT genotype tended to be lower, whereas the homocysteine concentrations of the 1561CT individuals were not different from their 1561CC peers. The 1561C-->T polymorphism significantly increased both red blood cell folate and plasma folate concentrations (ANOVA P=0.013; test for linear trend P=0.03, respectively), but had no effect on vitamin B(12) levels (ANOVA P=0.35). Since not only homocysteine itself is considered to be positively associated with the risk of CVD, but also a decreased folate status, the results of this study indicate that the 1561C-->T polymorphism may affect the predisposition to CVD.

Objective: Deep vein thrombosis (DVT) is a multifactorial disease. Recently, inflammation has been suggested as a risk factor for DVT. The question is whether inflammation is a cause of venous thrombosis or rather a result of the thrombotic process., Methods: We studied the inflammatory response in the acute phase of DVT with interleukin-6, interleukin-8, and C-reactive protein (CRP) as inflammatory markers. Plasma concentrations were measured on the day of admission (day 0) in 40 patients with acute DVT confirmed with phlebography and in 33 patients with clinical suspicion of DVT but negative phlebography results (controls). In patients with DVT, inflammatory markers were also examined on five subsequent days., Results: On day 0, the median concentrations in plasma of interleukin-6, interleukin-8, and CRP were 15.0 pg/mL (range, <3 to 70 pg/mL), 7.0 pg/mL (range, <3 to 76 pg/mL), 37.5 mg/L (range, <7 to 164 mg/L), respectively, in the patient group and less than 3 pg/mL (range, <3 to 11 pg/mL; P <.001), 6.0 pg/mL (range, <3 to 52 pg/mL; P =.08), and 5.0 pg/L (range, <7 to 66 pg/L; P <.001), respectively, in the controls. During the next days, interleukin-6 concentration showed a gradual decline in patients with DVT from 15.0 to 5.5 pg/mL (P <.001), interleukin-8 concentration was relatively constant in time, and CRP concentration declined from 37.5 to 21.5 mg/L (P =.01)., Conclusion: Our data show an apparent inflammatory response with highest measured concentrations of inflammatory markers on the day of admission and a subsequent decrease during the next days. This response supports the hypothesis that elevated inflammatory markers are a result rather than a cause of venous thrombosis.

Several studies have shown a relation between hyperhomocysteinaemia and arterial vascular disease. We looked at the association between hyperhomocysteinaemia and venous thrombosis which could be clinically important as hyperhomocysteinaemia is easily corrected by vitamin supplementation. We studied 185 patients with a history of recurrent venous thrombosis and 220 controls from the general population. Homocysteine concentrations were measured before and 6 h after oral methionine loading. We defined hyperhomocysteinaemia as the homocysteine concentration above the fasting or the postmethionine value found for the 90th percentile of the controls. Of the 185 patients with recurrent thrombosis, 46 (25%) had fasting homocysteine concentrations above the 90th percentile or the controls (odds ratio is 3.1 [1.8-5.5]). After adjustment for age, sex, and menopausal status the odds ratio was 2.0 (1.5-2.7). Similar results were found for the post-methionine value (unadjusted odds ratio 3.1 [1.7-5.5], adjusted 2.6 [1.9-3.5]). Hyperhomocysteinaemia is a common risk factor for recurrent venous thrombosis and can lead to a two-fold or three-fold increase in risk.