Different duration of at-risk mental state associated with neurofunctional abnormalities. A multimodal imaging study

Objectives: Neurofunctional alterations are correlates of vulnerability to psychosis, as well as of the disorder itself. How these abnormalities relate to different probabilities for later transition to psychosis is unclear. We investigated vulnerability- versus disease-related versus resilience biomarkers of psychosis during working memory (WM) processing in individuals with an at-risk mental state (ARMS). Experimental design: Patients with “first-episode psychosis” (FEP, n = 21), short-term ARMS (ARMS-ST, n = 17), long-term ARMS (ARMS-LT, n = 16), and healthy controls (HC, n = 20) were investigated with an n-back WM task. We examined functional magnetic resonance imaging (fMRI) and structural magnetic resonance imaging (sMRI) data in conjunction using biological parametric mapping (BPM) toolbox. Principal observations: There were no differences in accuracy, but the FEP and the ARMS-ST group had longer reaction times compared with the HC and the ARMS-LT group. With the 2-back > 0-back contrast, we found reduced functional activation in ARMS-ST and FEP compared with the HC group in parietal and middle frontal regions. Relative to ARMS-LT individuals, FEP patients showed decreased activation in the bilateral inferior frontal gyrus and insula, and in the left prefrontal cortex. Compared with the ARMS-LT, the ARMS-ST subjects showed reduced activation in the right inferior frontal gyrus and insula. Reduced insular and prefrontal activation was associated with gray matter volume reduction in the same area in the ARMS-LT group. Conclusions: These findings suggest that vulnerability to psychosis was associated with neurofunctional alterations in fronto-temporo-parietal networks in a WM task. Neurofunctional differences within the ARMS were related to different duration of the prodromal state and resilience factors

Bioremediation with White-Rot Fungi at Fisherville Mill: Analyses of Gene Expression and Number 6 Fuel Oil Degradation

Extracellular enzymes that white-rot fungi secrete during lignin decay have been proposed as promising agents for oxidizing pollutants. We investigated the abilities of the white-rot fungi Punctularia strigosozonata, Irpex lacteus, Trichaptum biforme, Phlebia radiata, Trametes versicolor, and Pleurotus ostreatus to degrade Number 6 fuel oil in wood sawdust cultures. Our goals are to advise bioremediation efforts at a brownfield redevelopment site on the Blackstone River in Grafton, Massachusetts and to contribute to the understanding of decay mechanisms in white-rot fungi. All species tested degraded a C10 alkane. When cultivated for 6 months, Irpex lacteus, T. biforme, P. radiata, T. versicolor and P. ostreatus also degraded a C14 alkane and the polycyclic aromatic hydrocarbon phenanthrene. Gene expression analyses of P. strigosozonata indicate differential gene expression in the presence of Number 6 oil and on pine and aspen sawdust.

Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease

BACKGROUND: The prevalence and characteristics of sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease (sCJD) are poorly understood. METHODS: Seven consecutive patients with definite sCJD underwent a systematic assessment of sleep-wake disturbances, including clinical history, video-polysomnography, and actigraphy. Extent and distribution of neurodegeneration was estimated by brain autopsy in six patients. Western blot analyses enabling classification and quantification of the protease-resistant isoform of the prion protein, PrPSc, in thalamus and occipital cortex was available in four patients. RESULTS: Sleep-wake symptoms were observed in all patients, and were prominent in four of them. All patients had severe sleep EEG abnormalities with loss of sleep spindles, very low sleep efficiency, and virtual absence of REM sleep. The correlation between different methods to assess sleep-wake functions (history, polysomnography, actigraphy, videography) was generally poor. Brain autopsy revealed prominent changes in cortical areas, but only mild changes in the thalamus. No mutation of the PRNP gene was found. CONCLUSIONS: This study demonstrates in sporadic Creutzfeldt-Jakob disease, first, the existence of sleep-wake disturbances similar to those reported in fatal familial insomnia in the absence of prominent and isolated thalamic neuronal loss, and second, the need of a multimodal approach for the unambiguous assessment of sleep-wake functions in these patients.

[Urine analyses for workup of kidney stone disease--interpretation and therapeutic consequences]

Nephrolithiasis is a disease with a high and even rising incidence. It has a high morbidity, generates high costs and has a high recurrence rate. Urinalysis is of importance especially in recurrent stone formers. It allows the identification and quantification of risk factors and the establishment of individual risk profiles. Based on these individual risk profiles, rational therapy for metaphylaxis of kidney stones lowers stone recurrence rates significantly. This review article aims to give a focussed overview of the most important risk factors for kidney stones and reasonable urine tests for evaluation of recurrent kidney stone formers.

Efficacy of psychological therapy in schizophrenia: conclusions from meta-analyses

Over the past years, evidence for the efficacy of psychological therapies in schizophrenia has been summarized in a series of meta-analyses. The present contribution aims to provide a descriptive survey of the evidence for the efficacy of psychological therapies as derived from these meta-analyses and to supplement them by selected findings from an own recent meta-analysis. Relevant meta-analyses and randomized controlled trials were identified by searching several electronic databases and by hand searching of reference lists. In order to compare the findings of the existing meta-analyses, the reported effect sizes were extracted and transformed into a uniform effect size measure where possible. For the own meta-analysis, weighted mean effect size differences between comparison groups regarding various types of outcomes were estimated. Their significance was tested by confidence intervals, and heterogeneity tests were applied to examine the consistency of the effects. From the available meta-analyses, social skills training, cognitive remediation, psychoeducational coping-oriented interventions with families and relatives, as well as cognitive behavioral therapy of persistent positive symptoms emerge as effective adjuncts to pharmacotherapy. Social skills training consistently effectuates the acquisition of social skills, cognitive remediation leads to short-term improvements in cognitive functioning, family interventions decrease relapse and hospitalization rates, and cognitive behavioral therapy results in a reduction of positive symptoms. These benefits seem to be accompanied by slight improvements in social functioning. However, open questions remain as to the specific therapeutic ingredients, to the synergistic effects, to the indication, as well as to the generalizability of the findings to routine care.

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties.

Statistical Analyses and Reproducible Research

For various reasons, it is important, if not essential, to integrate the computations and code used in data analyses, methodological descriptions, simulations, etc. with the documents that describe and rely on them. This integration allows readers to both verify and adapt the statements in the documents. Authors can easily reproduce them in the future, and they can present the document's contents in a different medium, e.g. with interactive controls. This paper describes a software framework for authoring and distributing these integrated, dynamic documents that contain text, code, data, and any auxiliary content needed to recreate the computations. The documents are dynamic in that the contents, including figures, tables, etc., can be recalculated each time a view of the document is generated. Our model treats a dynamic document as a master or ``source'' document from which one can generate different views in the form of traditional, derived documents for different audiences. We introduce the concept of a compendium as both a container for the different elements that make up the document and its computations (i.e. text, code, data, ...), and as a means for distributing, managing and updating the collection. The step from disseminating analyses via a compendium to reproducible research is a small one. By reproducible research, we mean research papers with accompanying software tools that allow the reader to directly reproduce the results and employ the methods that are presented in the research paper. Some of the issues involved in paradigms for the production, distribution and use of such reproducible research are discussed.

Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders

Very recently, heterozygous mutations in the genes encoding transforming growth factor beta receptors I (TGFBR1) and II (TGFBR2) have been reported in Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant TGFBR2 mutations have been identified in Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). In the past, mutations of these genes were associated with atherosclerosis and several human cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the TGFBR1 and TGFBR2 genes in nine of 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1). To assess the pathogenic impact of these sequence variants, in silico analyses were performed by the PolyPhen, SIFT, and Fold-X algorithms and by means of a 3D homology model of the TGFBR2 kinase domain. Our results showed that in all but one of the patients the pathogenic effect of at least one sequence variant is highly probable (c.722C > T, c.799A > C, and c.1460G > A in TGFBR1 and c.773T > G, c.1106G > T, c.1159G > A, c.1181G > A, and c.1561T > C in TGFBR2). These deleterious alleles occurred de novo or segregated with the disease in the families, indicating a causative association between the sequence variants and clinical phenotypes. Since TGFBR2 mutations found in patients with MFS-related disorders cannot be distinguished from heterozygous TGFBR2 mutations reported in tumor samples, we emphasize the importance of segregation analysis in affected families. In order to be able to find the mutation that is indeed responsible for a MFS-related phenotype, we also propose that genetic testing for sequence alterations in TGFBR1 and TGFBR2 should be complemented by mutation screening of the FBN1 gene.