The extremely high exposure levels evaluated in prior investigations relating elevated levels of drinking water arsenic and hypertension prevalence make extrapolation to potential vascular effects at ...lower exposure levels very difficult. A cross-sectional study was conducted on 8790 women who had recently been pregnant in an area of Inner Mongolia, China known to have a gradient of drinking water arsenic exposure. This study observed increased systolic blood pressure levels with increasing drinking water arsenic, at lower exposure levels than previously reported in the literature. As compared to the referent category (below limit of detection to 20 μg of As/L), the overall population mean systolic blood pressure rose 1.29 mm Hg (95% CI 0.82, 1.75), 1.28 mm Hg (95% CI 0.49, 2.07), and 2.22 mm Hg (95% CI 1.46, 2.97) as drinking water arsenic concentration increased from 21 to 50, 51 to 100, and >
100 μg of As/L, respectively. Controlling for age and body weight (
n
=
3260), the population mean systolic blood pressure rose 1.88 mm Hg (95% CI 1.03, 2.73), 3.90 mm Hg (95% CI 2.52, 5.29), and 6.83 mm Hg (95% CI 5.39, 8.27) as drinking water arsenic concentration increased, respectively. For diastolic blood pressure effect, while statistically significant, was not as pronounced as systolic blood pressure. Mean diastolic blood pressure rose 0.78 mm Hg (95% CI 0.39, 1.16), 1.57 mm Hg (95% CI 0.91, 2.22) and 1.32 mm Hg (95% CI 0.70, 1.95), respectively, for the overall population and rose 2.11 mm Hg (95% CI 1.38, 2.84), 2.74 mm Hg (95% CI 1.55, 3.93), and 3.08 mm Hg (95% CI 1.84, 4.31), respectively, for the adjusted population (
n
=
3260) at drinking water arsenic concentrations of 21 to 50, 51 to 100, and >
100 μg of As/L. If our study results are confirmed in other populations, the potential burden of cardiovascular disease attributable to drinking water arsenic is significant.
Elevated plasma factor VIII coagulant activity (FVIII:C, > 150 IU/dl) is a risk factor for venous thromboembolism (VTE). We hypothesized that increased FVIII:C may exert a prothrombotic effect by ...increasing basal thrombin generation. To test this hypothesis we have measured prothrombin fragment 1 + 2 (F1 + 2) and thrombin–antithrombin complex (TAT) in three groups: (i) patients with objectively confirmed VTE and elevated FVIII:C; (ii) patients with VTE and no detectable thrombophilia; and (iii) healthy age‐ and sex‐matched control subjets. In the group of patients with elevated FVIII:C, TAT and F1 + 2 levels were increased in 85% and 78% of individuals respectively. This frequency of coagulation activation is dramatically higher than that reported for other recognized constitutional thrombophilias. In the group of patients with VTE but no proven thrombophilia, increased thrombin generation was present in 30% of individuals. Basal thrombin generation was significantly higher in patients with elevated FVIII:C compared with individuals with VTE but no documented thrombophilia (median TAT = 8·65 µg/l versus 2·95 µg/l, median F1 + 2 = 1·5 nmol/l versus 0·87 nmol/l; P < 0·0001, P < 0·001). Overall FVIII:C levels were strongly correlated with levels of thrombin generation (r= 0·5, P < 0001). The clinical significance of such markedly increased F1 + 2 and TAT levels in patients with high FVIII:C levels remains unclear.
Scott syndrome (SS) is a bleeding disorder characterized by a failure to expose phosphatidylserine (PS) to the outer leaflet of the platelet plasma membrane. Because the adenosine triphosphate ...(ATP)–binding cassette transporter A1 (ABCA1) is implicated in the exofacial translocation of PS, we assessed its role in the pathophysiology of a patient with SS. Substantially reduced levels of ABCA1 mRNA were found in the patient's leukocytes, compared with controls. The SS patient was heterozygous for a novel missense mutation c.6064G>A (ABCA1 R1925Q), absent from unaffected family members and controls. Both mutant and wild-type alleles were reduced in mRNA expression, and no causative mutation for this phenomenon was identified in the ABCA1 gene or its proximal promoter, suggesting a putative second mutation in a trans-acting regulatory gene may also be involved in the disorder in this patient. In vitro expression studies showed impaired trafficking of ABCA1 R1925Q to the plasma membrane. Overexpression of wild-type ABCA1 in SS lymphocytes complemented the Ca2+-dependent PS exposure at the cell surface. These data identify a mutation in ABCA1 that contributes to the defective PS translocation phenotype in our patient with SS.
BACKGROUND/AIM Hereditary hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominant disorder characterised by elevated serum L-ferritin and bilateral cataracts. The ocular manifestations ...of this disorder are poorly studied. This study therefore sought to determine the origin of cataracts in HHCS. METHODS L-ferritin ELISA, immunohistochemical and ultrastructural analysis of a lens nucleus from an HHCS individual. RESULTS The HHCS lens L-ferritin content was 147 μg/g dry weight of lens compared with <16 μg/g for a non-HHCS control cataract lens. The cataract comprised discrete crystalline inclusions with positive staining with anti-L-ferritin but not anti-H-ferritin. CONCLUSIONS This unusual finding of crystalline opacities in the lens may be unique to HHCS and is likely to result from disturbed metabolism of L-ferritin within the lens or an abnormal interaction between L-ferritin and lens proteins.
Essentials
A strong association between bleeding severity and FXIII activity level (FXIII:C) was shown.
The range 5–30 IU dL−1 of FXIII:C was associated with a high variability of bleeding severity.
...The PROspective study confirmed the association between FXIII:C activity and bleeding severity.
A FXIII:C of 15 IU dL−1 is a proposed target to start prophylaxis for prevention of major bleeding.
Summary
Background
Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder associated with significant bleeding manifestations. The European Network of Rare Bleeding Disorders (EN‐RBD) study, performed from 2007 to 2010, showed a strong association between bleeding severity and FXIII activity in plasma of patients with FXIII deficiency. Among these patients, variable levels of FXIII activity, from undetectable to 30%, were associated with a wide range of bleeding severity.
Objectives and patients
The present cross‐sectional study, in the frame of the PRO‐RBDD project, a prospective cohort study, analyzed data of 64 patients with FXIII deficiency and different types of clinical and laboratory severity.
Results
The results of this analysis confirmed that FXIII coagulant activity in plasma is well associated with clinical severity of patients. In addition, 15 IU dL−1 of FXIII activity was identified to be the level under which the probability of spontaneous major bleeding sharply increases (from 50% for levels of 15 IU dL−1 to more than 90% for levels of 5 IU dL−1 or lower).
Conclusion
The PRO‐RBDD study suggests a FXIII coagulant activity level of 15 IU dL−1 as a target to start prophylaxis in order to prevent major bleedings, such as central nervous system or gastrointestinal tract hemorrhages.
Multi-voxel pattern analysis (MVPA) has led to major changes in how fMRI data are analyzed and interpreted. Many studies now report both MVPA results and results from standard univariate voxel-wise ...analysis, often with the goal of drawing different conclusions from each. Because MVPA results can be sensitive to latent multidimensional representations and processes whereas univariate voxel-wise analysis cannot, one conclusion that is often drawn when MVPA and univariate results differ is that the activation patterns underlying MVPA results contain a multidimensional code. In the current study, we conducted simulations to formally test this assumption. Our findings reveal that MVPA tests are sensitive to the magnitude of voxel-level variability in the effect of a condition within subjects, even when the same linear relationship is coded in all voxels. We also find that MVPA is insensitive to subject-level variability in mean activation across an ROI, which is the primary variance component of interest in many standard univariate tests. Together, these results illustrate that differences between MVPA and univariate tests do not afford conclusions about the nature or dimensionality of the neural code. Instead, targeted tests of the informational content and/or dimensionality of activation patterns are critical for drawing strong conclusions about the representational codes that are indicated by significant MVPA results.
•Significant multi-voxel pattern analysis results may reflect multidimensional coding.•MVPA is sensitive to magnitude of spatial variability in activation.•MVPA is insensitive to subject-level variability in mean activation.•Voxel-wise analyses are sensitive to subject-level variability in mean activation.•Differences between MVPA and voxel-wise results do not indicate multidimensionality.
Objective The purpose of this study was to investigate the role of leptin on reproductive hormones and ovulation. Study Design The BioCycle Study (2005-2007) followed 259 healthy premenopausal women ...not using hormonal contraceptives for ≤2 menstrual cycles (n = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone, and testosterone were measured ≤8 times per cycle. The association of time-varying leptin and reproductive hormones over the cycle was estimated with the use of linear mixed models that were adjusted for percent body fat and age with inverse probability weighting for time-varying physical activity, caloric intake, and other reproductive hormones. The odds ratio for sporadic anovulation (n = 42 cycles) was estimated with the use of generalized linear models that were adjusted for percent body fat and age. Results Geometric mean serum leptin levels increased from menses to the late luteal phase (16.7-20.4 ng/mL; P < .01), with a mid-cycle peak (21.7 ng/mL) at the time of the LH surge ( P < .01). A 10% higher leptin level across the menstrual cycle was associated with higher estradiol levels (2.2%; 95% CI, 1.5–3.0), luteal progesterone levels (2.1%; 95% CI, 0.5–3.7), ovulatory LH levels (1.2%; 95% CI, 0–2.3), testosterone levels (0.6%; 95% CI, 0.3–0.9), and lower follicle-stimulating hormone levels (–0.7%; 95% CI, –1.1 to –0.4). Leptin at the time of the expected LH surge was moderately inversely associated with sporadic anovulation (per log increase in leptin; adjusted odds ratio, 0.58; 95% CI, 0.28–1.22). Conclusion The association that was observed between leptin level and reproductive function points to a possible relationship between serum leptin level and enhanced fertility.
Bayesian network analysis is an attractive approach for studying the functional integration of brain networks, as it includes both the locations of connections between regions of the brain ...(functional connectivity) and more importantly the direction of the causal relationship between the regions (directed functional connectivity). Further, these approaches are more attractive than other functional connectivity analyses in that they can often operate on larger sets of nodes and run searches over a wide range of candidate networks. An important study by Smith et al. (2011) illustrated that many Bayesian network approaches did not perform well in identifying the directionality of connections in simulated single-subject data. Since then, new Bayesian network approaches have been developed that have overcome the failures in the Smith work. Additionally, an important discovery was made that shows a preprocessing step used in the Smith data puts some of the Bayesian network methods at a disadvantage. This work provides a review of Bayesian network analyses, focusing on the methods used in the Smith work as well as methods developed since 2011 that have improved estimation performance. Importantly, only approaches that have been specifically designed for fMRI data perform well, as they have been tailored to meet the challenges of fMRI data. Although this work does not suggest a single best model, it describes the class of models that perform best and highlights the features of these models that allow them to perform well on fMRI data. Specifically, methods that rely on non-Gaussianity to direct causal relationships in the network perform well.
•Review of Bayesian network analysis, in a general framework•Recently discovered problems of Bayesian network analyses in fMRI are discussed.•Review improvements in Bayesian network analysis for fMRI•Direct readers to most appropriate class of Bayesian network analyses for fMRI.
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