Blebbing confers resistance against cell lysis

The plasma membrane constitutes a barrier that maintains the essential differences between the cytosol and the extracellular environment. Plasmalemmal injury is a common event during the life of many cells that often leads to their premature, necrotic death. Blebbing - a display of plasmalemmal protrusions - is a characteristic feature of injured cells. In this study, we disclose a previously unknown role for blebbing in furnishing resistance to plasmalemmal injury. Blebs serve as precursors for injury-induced intracellular compartments that trap damaged segments of the plasma membrane. Hence, loss of cytosol and the detrimental influx of extracellular constituents are confined to blebs that are sealed off from the cell body by plugs of annexin A1 - a Ca(2+)- and membrane-binding protein. Our findings shed light on a fundamental process that contributes to the survival of injured cells. By targeting annexin A1/blebbing, new therapeutic approaches could be developed to avert the necrotic loss of cells in a variety of human pathologies.

[Molecular biology of malignant lymphomas for non-specialists]

Lymphomas comprise a variety of entities with remarkable clinical heterogeneity. This review summarizes the current knowledge on the pathogenesis of major mature B-cell lymphoma subtypes for clinicians working outside the field of hemato-oncology. The understanding of the pathogenesis of lymphomas is linked to the knowledge on normal B-cell differentiation. The clinical diversity is manifested in the different mechanisms involved in lymphomagenesis that include characteristic chromosomal translocations deregulating proto-oncogenes, and inactivation of tumor suppressor genes through deletions and mutations. Gene-expression profiling has dissected certain lymphomas into morphologically indistinguishable, but clinically important subgroups and uncovered pathways suitable for specific therapeutic interventions.

Changes in cell proliferation, but not in vascularisation are characteristic for human endometrium in different reproductive failures--a pilot study

Reproductive failure, determined as recurrent spontaneous abortions (RSA) or recurrent implantation failure (RIF) in women is not well understood. Several factors, including embryo quality, and cellular and molecular changes in endometrium may contribute to the insufficient feto-maternal interaction resulting in reproductive failure. Prior clinical studies suggest an inadequate endometrial growth and development of the endometrium, leading to a lesser endometrial thickness.

Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels leads to single-channel activity characteristic of heart failure

BACKGROUND: Increased activity of single ventricular L-type Ca(2+)-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary beta-subunits as a possible explanation. METHODS AND RESULTS: By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC beta-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac beta-subunits: Unlike beta(1) or beta(3) isoforms, beta(2a) and beta(2b) induce a high-activity channel behavior typical of failing myocytes. In accordance, beta(2)-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac Ca(V)1.2 also reveal increased single-channel activity and sarcolemmal beta(2) expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing ("Adaptive Phase"), reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered beta(2) expression. Additional evidence for the cause-effect relationship between beta(2)-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca(V)1.2 and inducible beta(2) cardiac overexpression. Here in non-failing hearts induction of beta(2)-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure. CONCLUSIONS: Our study presents evidence of the pathobiochemical relevance of beta(2)-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.

An empirical comparison of methods for meta-analysis of diagnostic accuracy showed hierarchical models are necessary

OBJECTIVE: Meta-analysis of studies of the accuracy of diagnostic tests currently uses a variety of methods. Statistically rigorous hierarchical models require expertise and sophisticated software. We assessed whether any of the simpler methods can in practice give adequately accurate and reliable results. STUDY DESIGN AND SETTING: We reviewed six methods for meta-analysis of diagnostic accuracy: four simple commonly used methods (simple pooling, separate random-effects meta-analyses of sensitivity and specificity, separate meta-analyses of positive and negative likelihood ratios, and the Littenberg-Moses summary receiver operating characteristic [ROC] curve) and two more statistically rigorous approaches using hierarchical models (bivariate random-effects meta-analysis and hierarchical summary ROC curve analysis). We applied the methods to data from a sample of eight systematic reviews chosen to illustrate a variety of patterns of results. RESULTS: In each meta-analysis, there was substantial heterogeneity between the results of different studies. Simple pooling of results gave misleading summary estimates of sensitivity and specificity in some meta-analyses, and the Littenberg-Moses method produced summary ROC curves that diverged from those produced by more rigorous methods in some situations. CONCLUSION: The closely related hierarchical summary ROC curve or bivariate models should be used as the standard method for meta-analysis of diagnostic accuracy.

The role of landuse and natural determinants for grassland vegetation composition in the Swiss Alps

The Alps provide a high habitat diversity for plant species, structured by broad- and fine-scale abiotic site conditions. In man-made grasslands, vegetation composition is additionally affected by the type of landuse. We recorded vegetation composition in 216 parcels of grassland in 12 municipalities representing an area of 170 x 70 km in the south-eastern part of the Swiss Alps. Each parcel was characterized by a combination of altitudinal level (valley, intermediate, alp). traditional landuse (mown. grazed), current management (mown, grazed, abandoned). and Fertilization (unfertilized, fertilized). For each parcel we also assessed the abiotic factors aspect, slope, pH value, and geographic coordinates, and for each municipality annual precipitation and its cultural tradition. We analysed vegetation composition using (i) variation partitioning in RDA. (ii) cover of graminoids. non-legume forbs, and legumes, and (iii) dominance and frequency of species. Species composition was determined by, in decreasing order of variation explained. landuse, broad-scale abiotic factors, fine-scale abiotic factors. and cultural tradition. Current socio-economically motivated landuse changes, such as grazing of unfertilized former meadows or their abandonment, strongly affect vegetation composition. In our study, the frequency of characteristic meadow species was significantly smaller in grazed and even smaller in abandoned parcels than in still mown ones, suggesting less severe consequences of grazing for vegetation composition than of abandonment. Therefore. low-intensity grazing and mowing every few years should be considered valuable conservation alternatives to abandonment. Furthermore. because each landuse type was characterized by different species. a high variety of landuse types should be promoted to preserve plant species diversity in Alpine grasslands. (C) 2007 Gesellschaft fur Okologie. Published by Elsevier GmbH. All rights reserved.

Electrical neuroimaging in the time domain

A publication entitled “A default mode of brain function” initiated a new way of looking at functional imaging data. In this PET study the authors discussed the often-observed consistent decrease of brain activation in a variety of tasks as compared with the baseline. They suggested that this deactivation is due to a task-induced suspension of a default mode of brain function that is active during rest, i.e. that there exists intrinsic well-organized brain activity during rest in several distinct brain regions. This suggestion led to a large number of imaging studies on the resting state of the brain and to the conclusion that the study of this intrinsic activity is crucial for understanding how the brain works. The fact that the brain is active during rest has been well known from a variety of EEG recordings for a very long time. Different states of the brain in the sleep–wake continuum are characterized by typical patterns of spontaneous oscillations in different frequency ranges and in different brain regions. Best studied are the evolving states during the different sleep stages, but characteristic EEG oscillation patterns have also been well described during awake periods (see Chapter 1 for details). A highly recommended comprehensive review on the brain's default state defined by oscillatory electrical brain activities is provided in the recent book by György Buzsaki, showing how these states can be measured by electrophysiological procedures at the global brain level as well as at the local cellular level.

Changes in skill variety predict job satisfaction and psychosomatic complaints

Purpose Skill variety in terms of opportunities for utilizing different skills is an important element of job design; it is associated with well-being and health, but most pertinent research is cross-sectional. Positive associations with well-being, and with intellectual flexibility, have been shown longitudinally, but these studies focus on levels of skill variety at time 1 and do not use changes in skill variety as a predictor. We expect changes in skill variety to be associated with well-being in terms of higher job satisfaction and fewer psychosomatic complaints. Design/Methodology Skill variety, job satisfaction, and psychosomatic complaints were assessed in 2005, 2006, 2007, and 2010 (N = 317 young employees). Data were analyzed using latent growth modeling. Results Skill variety decreased over the first three years after labor market entry. Initial levels of skill variety predicted higher job satisfaction in 2010. Steeper decreases in skill variety from 2005 to 2007 predicted lower levels of job satisfaction and more psychosomatic complaints three years later. Limitations This longitudinal study used only self-report. Research/Practical Implications Our results extend the often found association between challenging work content and job satisfaction in terms of a) showing it for young employees, b) longitudinally, c) not only for initial level but also for changes, and d) for psychosomatic complaints; they underscore the importance of maintaining a high level of challenging work content beyond the initial phase by enriching work as routine increases. Originality/Value Compared to the few existing longitudinal studies, we focus on changes and their relations with well-being.

Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC)

BACKGROUND Raf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human cancers and is known to inhibit Ras/Raf/MEK/ERK signaling. By suppressing the activation of the NFkB/SNAIL circuit, RKIP can regulate the induction of epithelial-mesenchymal transition (EMT). The aim of this study was to evaluate RKIP expression and to determine its association with clinicopathological features, including EMT in form of tumor budding in pancreatic ductal adenocarcinoma (PDAC). METHODS Staining for RKIP was performed on a multipunch Tissue Microarray (TMA) of 114 well-characterized PDACs with clinico-pathological, follow-up and adjuvant therapy information. RKIP-expression was assessed separately in the main tumor body and in the tumor buds. Another 3 TMAs containing normal pancreatic tissue, precursor lesions (Pancreatic Intraepithelial Neoplasia, PanINs) and matched lymph node metastases were stained in parallel. Cut-off values were calculated by receiver operating characteristic (ROC) curve analysis. RESULTS We found a significant progressive loss of RKIP expression between normal pancreatic ductal epithelia (average: 74%), precursor lesions (PanINs; average: 37%), PDAC (average 20%) and lymph node metastases (average 8%, p<0.0001). RKIP expression was significantly lower in tumor buds (average: 6%) compared to the main tumor body (average 20%; p<0.005). RKIP loss in the tumor body was marginally associated with advanced T-stage (p=0.0599) as well as high-grade peritumoral (p=0.0048) and intratumoral budding (p=0.0373). RKIP loss in the buds showed a clear association with advanced T stage (p=0.0089). CONCLUSIONS The progressive loss of RKIP seems to play a major role in the neoplastic transformation of pancreas, correlates with aggressive features in PDAC and is associated with the presence of EMT in form of tumor budding.