Limited Systemic Sclerosis Patients with Pulmonary Arterial Hypertension Show Biomarkers of Inflammation and Vascular Injury

Pulmonary arterial hypertension (PAH) is a common complication for individuals with limited systemic sclerosis (lSSc). The identification and characterization of biomarkers for lSSc-PAH should lead to less invasive screening, a better understanding of pathogenesis, and improved treatment.Forty-nine PBMC samples were obtained from 21 lSSc subjects without PAH (lSSc-noPAH), 15 lSSc subjects with PAH (lSSc-PAH), and 10 healthy controls; three subjects provided PBMCs one year later. Genome-wide gene expression was measured for each sample. The levels of 89 cytokines were measured in serum from a subset of subjects by Multi-Analyte Profiling (MAP) immunoassays. Gene expression clearly distinguished lSSc samples from healthy controls, and separated lSSc-PAH from lSSc-NoPAH patients. Real-time quantitative PCR confirmed increased expression of 9 genes (ICAM1, IFNGR1, IL1B, IL13Ra1, JAK2, AIF1, CCR1, ALAS2, TIMP2) in lSSc-PAH patients. Increased circulating cytokine levels of inflammatory mediators such as TNF-alpha, IL1-beta, ICAM-1, and IL-6, and markers of vascular injury such as VCAM-1, VEGF, and von Willebrand Factor were found in lSSc-PAH subjects.The gene expression and cytokine profiles of lSSc-PAH patients suggest the presence of activated monocytes, and show markers of vascular injury and inflammation. These genes and factors could serve as biomarkers of PAH involvement in lSSc

Apathy Is Associated With Ventral Striatum Volume in Schizophrenia Spectrum Disorder

Apathy is prevalent in schizophrenia, but its etiology has received little investigation. The ventral striatum (VS), a key brain region involved in motivated behavior, has been implicated in studies of apathy. We therefore evaluated whether apathy is associated with volume of the VS on MRI in 23 patients with schizophrenia using voxel-based morphometry. Results indicated that greater self-reported apathy severity was associated with smaller volume of the right VS even when controlling for age, gender, depression, and total gray matter volume. The finding suggests that apathy is related to abnormality of brain circuitry subserving motivated behavior in patients with schizophrenia

A thin layer angiogenesis assay: a modified basement matrix assay for assessment of endothelial cell differentiation

BACKGROUND: Basement matrices such as Matrigel™ and Geltrex™ are used in a variety of cell culture assays of anchorage-dependent differentiation including endothelial cell tube formation assays. The volumes of matrix recommended for these assays (approximately 150 μl/cm(2)) are costly, limit working distances for microscopy, and require cell detachment for subsequent molecular analysis. Here we describe the development and validation of a thin-layer angiogenesis (TLA) assay for assessing the angiogenic potential of endothelial cells that overcomes these limitations. RESULTS: Geltrex™ basement matrix at 5 μl/cm(2) in 24-well (10 μl) or 96-well (2 μl) plates supports endothelial cell differentiation into tube-like structures in a comparable manner to the standard larger volumes of matrix. Since working distances are reduced, high-resolution single cell microscopy, including DIC and confocal imaging, can be used readily. Using MitoTracker dye we now demonstrate, for the first time, live mitochondrial dynamics and visualise the 3-dimensional network of mitochondria present in differentiated endothelial cells. Using a standard commercial total RNA extraction kit (Qiagen) we also show direct RNA extraction and RT-qPCR from differentiated endothelial cells without the need to initially detach cells from their supporting matrix. CONCLUSIONS: We present here a new thin-layer assay (TLA) for measuring the anchorage-dependent differentiation of endothelial cells into tube-like structures which retains all the characteristics of the traditional approach but with the added benefit of a greatly lowered cost and better compatibility with other techniques, including RT-qPCR and high-resolution microscopy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12860-014-0041-5) contains supplementary material, which is available to authorized users

First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring

In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.Peer reviewe

ASPEN computer simulations of the mixed waste treatment project baseline flowsheet

The treatment and disposal of mixed waste (i.e., waste containing both hazardous and radioactive components) is a challenging waste- management problem of particular concern to Department of Energy (DOE) sites throughout the United States. Traditional technologies used for destroying hazardous wastes must be re- evaluated for their ability to handle mixed wastes, and, in some cases, new technologies must be developed. The Mixed Waste Treatment Project (MWTP), a collaborative effort between Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory, and Pacific Northwest Laboratory (PNL), was established by the DOE`s Waste Operations Program (EM-30) to develop and analyze alternative mixed waste treatment approaches. One of the MWTP`s initiatives, and the objective of this study, was to develop flowsheets for prototype, integrated, mixed-waste treatment facilities that can serve as models for sites developing their own treatment strategies. Evaluation of these flowsheets is being facilitated through the use of computer modeling. The objectives of the flowsheet simulations are to compare process effectiveness and costs of alternative flowsheets and to determine if commercial process-simulation software could be used on the large, complex process of an integrated mixed waste processing facility. Flowsheet modeling is needed to evaluate many aspects of proposed flowsheet designs. A major advantage of modeling the complete flowsheet is the ability to define the internal recycle streams, thereby making it possible to evaluate the impact of one operation on the whole plant. Many effects that can be seen only in this way. Modeling also can be used to evaluate sensitivity and range of operating conditions, radioactive criticality, and relative costs of different flowsheet designs. Further, the modeled flowsheets must be easily modified so that one can examine how alternative technologies and varying feed streams affect the overall integrated process

Communication in Diagnostic Radiology

Communication in the diagnostic radiology department in regard to the current work load has been discussed with certain recommendations being made to increase efficiency. The need for improvement in communication equipment and techniques is necessitated by problems facing diagnostic radiology today.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73519/1/j.1440-1673.1972.tb01316.x.pd

PDRMIP: a precipitation driver and response model intercomparison project - protocol and preliminary results

PDRMIP investigates the role of various drivers of climate change for mean and extreme precipitation changes, based on multiple climate model output and energy budget analyses. As the global temperature increases with changing climate, precipitation rates and patterns are affected through a wide range of physical mechanisms. The globally averaged intensity of extreme precipitation also changes more rapidly than the globally averaged precipitation rate. While some aspects of the regional variation in precipitation predicted by climate models appear robust, there is still a large degree of inter-model differences unaccounted for. Individual drivers of climate change initially alter the energy budget of the atmosphere leading to distinct rapid adjustments involving changes in precipitation. Differences in how these rapid adjustment processes manifest themselves within models are likely to explain a large fraction of the present model spread and needs better quantifications to improve precipitation predictions. Here, we introduce the Precipitation Driver and Response Model Intercomparison Project (PDRMIP), where a set of idealized experiments designed to understand the role of different climate forcing mechanisms were performed by a large set of climate models. PDRMIP focuses on understanding how precipitation changes relating to rapid adjustments and slower responses to climate forcings are represented across models. Initial results show that rapid adjustments account for large regional differences in hydrological sensitivity across multiple drivers. The PDRMIP results are expected to dramatically improve our understanding of the causes of the present diversity in future climate projections

A new family of covalent inhibitors block nucleotide binding to the active site of pyruvate kinase

PYK (pyruvate kinase) plays a central role in the metabolism of many organisms and cell types, but the elucidation of the details of its function in a systems biology context has been hampered by the lack of specific high-affinity small-molecule inhibitors. High-throughput screening has been used to identify a family of saccharin derivatives which inhibit LmPYK (Leishmania mexicana PYK) activity in a time- (and dose-) dependent manner, a characteristic of irreversible inhibition. The crystal structure of DBS {4-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfanyl]benzoic acid} complexed with LmPYK shows that the saccharin moiety reacts with an active-site lysine residue (Lys335), forming a covalent bond and sterically hindering the binding of ADP/ATP. Mutation of the lysine residue to an arginine residue eliminated the effect of the inhibitor molecule, providing confirmation of the proposed inhibitor mechanism. This lysine residue is conserved in the active sites of the four human PYK isoenzymes, which were also found to be irreversibly inhibited by DBS. X-ray structures of PYK isoforms show structural differences at the DBS-binding pocket, and this covalent inhibitor of PYK provides a chemical scaffold for the design of new families of potentially isoform-specific irreversible inhibitors