Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter cohort study.

OBJECTIVE: High-dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX. METHODS: Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease-matched women and a group of women without autoimmune diseases (neither group was exposed to MTX). RESULTS: The study sample included 324 MTX-exposed pregnancies (188 exposed post-conception, 136 exposed pre-conception), 459 disease-matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 [6.6%]) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 [2.9%]) (adjusted odds ratio [OR] 3.1 [95% CI 1.03-9.5]) and the disease-matched cohort (14 of 393 [3.6%]) (adjusted OR 1.8 [95% CI 0.6-5.7]). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% [95% CI 8.0-25.3]) nor the risk of major birth defects (4 of 114 [3.5%]) was increased in the pre-conception cohort. Elective termination rates were increased in both of the MTX-exposed cohorts. There were no other significant differences among groups in other study end points. CONCLUSION: Post-conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre-conception cohort.

Statistical mechanics in the extended Gaussian ensemble

The extended Gaussian ensemble (EGE) is introduced as a generalization of the canonical ensemble. This ensemble is a further extension of the Gaussian ensemble introduced by Hetherington [J. Low Temp. Phys. 66, 145 (1987)]. The statistical mechanical formalism is derived both from the analysis of the system attached to a finite reservoir and from the maximum statistical entropy principle. The probability of each microstate depends on two parameters ß and ¿ which allow one to fix, independently, the mean energy of the system and the energy fluctuations, respectively. We establish the Legendre transform structure for the generalized thermodynamic potential and propose a stability criterion. We also compare the EGE probability distribution with the q-exponential distribution. As an example, an application to a system with few independent spins is presented.

Major environmental change and bonebed genesis prior to the Triassic-Jurassic mass extinction

We present new geochemical and sedimentological data from marginal marine strata of Penarth Bay, south Wales (UK) to elucidate the origin of widespread but enigmatic concentrations of vertebrate hard parts (bonebeds) in marine successions of Rhaetian age (late Triassic). Sedimentological evidence shows that the phosphatic constituents of the bonebeds were subjected to intense phosphatization in shallow current-dominated settings and subsequently reworked and transported basinward by storms. Interbedded organic-rich strata deposited under quiescent and poorly oxygenated conditions record enhanced phosphorus regeneration from sedimentary organic matter into the water column and probably provided the main source of phosphate required for heavy bonebed clast phosphatization. The stratigraphically limited interval showing evidence for oxygen depletion and accelerated P-cycling coincides with a negative 4% organic carbon isotope excursion, which possibly reflects supra-regional changes in carbon cycling and clearly predates the 'initial isotope excursion' characterizing many Triassic-Jurassic boundary strata. our data indicate that Rhaetian bonebeds are the lithological signature of profound, climatically driven changes in carbon cycling and redox conditions and support the idea of a multi-pulsed environmental crisis at the end of the Triassic, possibly linked to successive episodes of igneous activity in the central Atlantic Magmatic Province.

Effects of common origin and common rearing environment on variance in ectoparasite load and phenotype of nestling Alpine swifts

Knowledge of the quantitative genetics of resistance to parasitism is key to appraise host evolutionary responses to parasite selection. Here, we studied effects of common origin (i.e. genetic and pre-hatching parental effects) and common rearing environment (i.e. post-hatching parental effects and other environment effects) on variance in ectoparasite load in nestling Alpine swifts (Apus melba). This colonial bird is intensely parasitized by blood sucking louse-flies that impair nestling development and survival. By cross-fostering half of the hatchlings between pairs of nests, we show strong significant effect of common rearing environment on variance (90.7% in 2002 and 90.9% in 2003) in the number of louse-flies per nestling and no significant effect of common origin on variance in the number of louse-flies per nestling. In contrast, significant effects of common origin were found for all the nestling morphological traits (i.e. body mass, wing length, tail length, fork length and sternum length) under investigation. Hence, our study suggests that genetic and pre-hatching parental effects play little role in the distribution of parasites among nestling Alpine swifts, and thus that nestlings have only limited scope for evolutionary responses against parasites. Our results highlight the need to take into consideration environmental factors, including the evolution of post-hatching parental effects such as nest sanitation, in our understanding of host-parasite relationships.

Bistability driven by Gaussian colored noise: First-passage times

Herein we present a calculation of the mean first-passage time for a bistable one-dimensional system driven by Gaussian colored noise of strength D and correlation time ¿c. We obtain quantitative agreement with experimental analog-computer simulations of this system. We disagree with some of the conclusions reached by previous investigators. In particular, we demonstrate that all available approximations that lead to a state-dependent diffusion coefficient lead to the same result for small D¿c.

Exact solution to the mean exit time problem for free inertial processes driven by Gaussian white noise

We obtain the exact analytical expression, up to a quadrature, for the mean exit time, T(x,v), of a free inertial process driven by Gaussian white noise from a region (0,L) in space. We obtain a completely explicit expression for T(x,0) and discuss the dependence of T(x,v) as a function of the size L of the region. We develop a new method that may be used to solve other exit time problems.

Fractal dimension for Gaussian colored processes

The exact analytical expression for the Hausdorff dimension of free processes driven by Gaussian noise in n-dimensional space is obtained. The fractal dimension solely depends on the time behavior of the arbitrary correlation function of the noise, ranging from DX=1 for Orstein-Uhlenbeck input noise to any real number greater than 1 for fractional Brownian motions.

Exact solution to the exit-time problem for an undamped free particle driven by Gaussian white noise

In a recent paper [Phys. Rev. Lett. 75, 189 (1995)] we have presented the exact analytical expression for the mean exit time, T(x,v), of a free inertial process driven by Gaussian white noise out of a region (0,L) in space. In this paper we give a detailed account of the method employed and present results on asymptotic properties and averages of T(x,v).

Aberrant right hepatic artery with a prepancreatic course visualized prior to pancreaticoduodenectomy.

Liver vascularization is known to present with several different variations. Generally, a normal vascular anatomy is reported in up to 50-80 % of cases. For this reason, a precise preoperative mapping of the hepatic vascularization prior to pancreatic surgery is essential to avoid injuries and subsequent complications. We report here a case of a young patient scheduled for Whipple procedure, who presented an arterial pattern type Michels IV, variation reported in 0.6 to 3 % in the literature. Another interesting particularity of this case was the fact that the right hepatic artery had a prepancreatic course. We think that every surgeon performing hepatopancreatic surgery should have heard of this special and rare situation.

The mean-variance model from the inverse of the variance-covariance matrix

En este artículo, a partir de la inversa de la matriz de varianzas y covarianzas se obtiene el modelo Esperanza-Varianza de Markowitz siguiendo un camino más corto y matemáticamente riguroso. También se obtiene la ecuación de equilibrio del CAPM de Sharpe.

Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited late-onset neurodegenerative disorder, characterized both by neurological and cognitive deficits. It is caused by the expansion of CGG repeats (55 to 200 repeats) in the noncoding region of the fragile X mental retardation 1 (FMR1) gene. Abnormal immunological patterns are often associated with neurodegenerative disorders and implicated in their etiology. We therefore investigated the immune status of FXTAS patients, which had not been assessed prior to this study. METHOD: Peripheral blood mononuclear cells (PBMCs) were collected from 15 asymptomatic FMR1 premutation carriers and 20 age-matched controls. Concentrations of three cytokines (IL-6, IL-8, IL-10) were measured in PBMC supernatants using ELISA assays. RESULTS: We found a significant increase in the concentration of the major anti-inflammatory cytokine IL-10 in supernatants of PBMCs derived from premutation carriers, when compared with controls (P = 0.019). This increase correlated significantly with the number of CGG repeats (P = 0.002). CONCLUSIONS: Elevated IL-10 levels were observed in all premutation carriers, before appearance of the classical neurological symptoms; therefore, IL-10 may be one of the early biomarkers of FXTAS.

Combined written and oral information prior to gastrointestinal endoscopy compared with oral information alone: a randomized trial.

BACKGROUND: Little is known about how to most effectively deliver relevant information to patients scheduled for endoscopy. METHODS: To assess the effects of combined written and oral information, compared with oral information alone on the quality of information before endoscopy and the level of anxiety. We designed a prospective study in two Swiss teaching hospitals which enrolled consecutive patients scheduled for endoscopy over a three-month period. Patients were randomized either to receiving, along with the appointment notice, an explanatory leaflet about the upcoming examination, or to oral information delivered by each patient's doctor. Evaluation of quality of information was rated on scales between 0 (none received) and 5 (excellent). The analysis of outcome variables was performed on the basis of intention to treat-analysis. Multivariate analysis of predictors of information scores was performed by linear regression analysis. RESULTS: Of 718 eligible patients 577 (80%) returned their questionnaire. Patients who received written leaflets (N = 278) rated the quality of information they received higher than those informed verbally (N = 299), for all 8 quality-of-information items. Differences were significant regarding information about the risks of the procedure (3.24 versus 2.26, p < 0.001), how to prepare for the procedure (3.56 versus 3.23, p = 0.036), what to expect after the procedure (2.99 versus 2.59, p < 0.001), and the 8 quality-of-information items (3.35 versus 3.02, p = 0.002). The two groups reported similar levels of anxiety before procedure (p = 0.66), pain during procedure (p = 0.20), tolerability throughout the procedure (p = 0.76), problems after the procedure (p = 0.22), and overall rating of the procedure between poor and excellent (p = 0.82). CONCLUSION: Written information led to more favourable assessments of the quality of information and had no impact on patient anxiety nor on the overall assessment of the endoscopy. Because structured and comprehensive written information is perceived as beneficial by patients, gastroenterologists should clearly explain to their patients the risks, benefits and alternatives of endoscopic procedures. Trial registration: Current Controlled trial number: ISRCTN34382782.

Identification and validation of copy number variants using SNP genotyping arrays from a large clinical cohort.

BACKGROUND: Genotypes obtained with commercial SNP arrays have been extensively used in many large case-control or population-based cohorts for SNP-based genome-wide association studies for a multitude of traits. Yet, these genotypes capture only a small fraction of the variance of the studied traits. Genomic structural variants (GSV) such as Copy Number Variation (CNV) may account for part of the missing heritability, but their comprehensive detection requires either next-generation arrays or sequencing. Sophisticated algorithms that infer CNVs by combining the intensities from SNP-probes for the two alleles can already be used to extract a partial view of such GSV from existing data sets. RESULTS: Here we present several advances to facilitate the latter approach. First, we introduce a novel CNV detection method based on a Gaussian Mixture Model. Second, we propose a new algorithm, PCA merge, for combining copy-number profiles from many individuals into consensus regions. We applied both our new methods as well as existing ones to data from 5612 individuals from the CoLaus study who were genotyped on Affymetrix 500K arrays. We developed a number of procedures in order to evaluate the performance of the different methods. This includes comparison with previously published CNVs as well as using a replication sample of 239 individuals, genotyped with Illumina 550K arrays. We also established a new evaluation procedure that employs the fact that related individuals are expected to share their CNVs more frequently than randomly selected individuals. The ability to detect both rare and common CNVs provides a valuable resource that will facilitate association studies exploring potential phenotypic associations with CNVs. CONCLUSION: Our new methodologies for CNV detection and their evaluation will help in extracting additional information from the large amount of SNP-genotyping data on various cohorts and use this to explore structural variants and their impact on complex traits.