Soluble Epoxide Hydrolase and Diabetes Complications

Type 2 diabetes mellitus (T2DM) can result in microvascular complications such as neuropathy, retinopathy, nephropathy, and cerebral small vessel disease, and contribute to macrovascular complications, such as heart failure, peripheral arterial disease, and large vessel stroke. T2DM also increases the risks of depression and dementia for reasons that remain largely unclear. Perturbations in the cytochrome P450-soluble epoxide hydrolase (CYP-sEH) pathway have been implicated in each of these diabetes complications. Here we review evidence from the clinical and animal literature suggesting the involvement of the CYP-sEH pathway in T2DM complications across organ systems, and highlight possible mechanisms (e.g., inflammation, fibrosis, mitochondrial function, endoplasmic reticulum stress, the unfolded protein response and autophagy) that may be relevant to the therapeutic potential of the pathway. These mechanisms may be broadly relevant to understanding, preventing and treating microvascular complications affecting the brain and other organ systems in T2DM.     

Developments in Mannose-Based Treatments for Uropathogenic Escherichia coli-Induced Urinary Tract Infections

During their lifetime almost half of women will experience a symptomatic urinary tract infection (UTI) with a further half experiencing a relapse within six months. Currently UTIs are treated with antibiotics, but increasing antibiotic resistance rates highlight the need for new treatments. Uropathogenic Escherichia coli (UPEC) is responsible for the majority of symptomatic UTI cases and thus has become a key pathological target. Adhesion of type one pilus subunit FimH at the surface of UPEC strains to mannose-saturated oligosaccharides located on the urothelium is critical to pathogenesis. Since the identification of FimH as a therapeutic target in the late 1980s, a substantial body of research has been generated focusing on the development of FimH-targeting mannose-based anti-adhesion therapies. In this review we will discuss the design of different classes of these mannose-based compounds and their utility and potential as UPEC therapeutics.     

A Cubic Silsesquioxane Chemically Modified with a PAMAM Dendrimer G0: an Application in Electro-Oxidation of Ascorbic Acid

Silicon - Octa-(3-chloropropyl) octasilsesquioxane (SS) was functionalized with a PAMAM dendrimer (SP) and characterized by some spectroscopic techniques such as Fourier Transform Infrared, Nuclear...     

Mothers' attributions regarding their children's social behavior and personality characteristics.

Sixty mothers of four 12-yr-old children described their children's positive and negative characteristics and specific instances of their children's desirable and undesirable social behavior. They rated (a) the environmental versus dispositional basis of their child's behavior, (b) the behavior's probable origins, cross-situational consistency, and temporal stability, (c) the child's controllability, and (d) personal responsibility for engaging in each behavior. As predicted from attribution theory, mothers perceived desirable child behaviors as dispositional and undesirable ones as unstable and situationally caused. Positive personal characteristics were seen as stable and inborn, but negative ones as transitory. Children perceived as difficult to manage, however, were also seen as dispositionally and stably oppositional. Older children were considered more difficult to manage than younger ones, but only their misbehavior was seen as more innately determined. Girls' conduct of all types was considered more dispositional, and sons' characteristics were seen as more stable, especially during adolescence. The results suggest a positive bias in mothers' perceptions of their children, except when they are considered difficult to control. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential expression of CD40 ligand on T cell subsets. Implications for different roles of CD45RA+ and CD45RO+ cells in IgE production

Physical contact between human T lymphocytes and B lymphocytes is required for the induction of IgE production. In the present study, we examined the abilities of CD45RA+ and CD45RO+ human T cell subsets to provide help for IgE production by human peripheral blood B cells in the presence of IL-4. Purified peripheral CD45RA+ T cells are much better inducers of IgE synthesis than are CD45RO+ T cells. Activation of CD45RA+ T cells, but not CD45RO+ T cells, via the TCR/CD3 complex is sufficient to confer the ability to provide IgE help, suggesting that an inducible T cell surface molecule plays an important role in this system. The CD40 ligand, an inducible T cell surface molecule, is expressed at higher levels on CD45RA+ T cells as compared with CD45RO+ T cells following CD3-stimulation. Blocking of the CD40-CD40 ligand interaction in vitro by the addition of a soluble form of B cell CD40 Ag completely blocks IgE production induced by CD45RA+ T cells. Finally, the in vitro conversion of CD45RA+ T cells to the CD45RO+ phenotype is accompanied by a loss in the ability of these cells to express the CD40 ligand in response to anti-CD3 stimulation as well as a loss in their ability to provide IgE help. These results suggest that both CD45 subsets may play significant and distinct roles in the induction of IgE production under physiologic conditions: CD45RO+ T cells provide IL-4 and the CD45RA+ subset provides the second signal via the CD40 ligand.     

The immune response to trauma

The response to trauma begins in the immune system at the moment of injury. The loci are the wound, with activation of macrophages and production of proinflammatory mediators, and the microcirculation with activation of endothelial cells, blood elements, and a capillary leak. These processes are potentiated by ischemia and impaired oxygen delivery and by the presence of necrotic tissue, each exacerbating the inflammatory response. Hemorrhage alone may be a sufficient stimulus. Inflammation once was considered to be a host reaction to bacteria or other irritants. This concept was expanded by the discovery of autoimmune diseases, and we are now aware that some illnesses are the result of the body's response to an invader rather than the direct effect of the invader itself. The discoveries about the response to trauma described here add another dimension, showing inflammation to be a fundamental life process that begins at the molecular level at the moment of injury and that, depending on the severity of the stimulus and the effectiveness of initial treatment, may spread to include every cell, tissue, and organ in the body, for good or ill. An important part of these expanding concepts is the notion that all noxious stimuli activate the cytokine system as a final common pathway. Sepsis, hemorrhage, ischemia, ischemia-reperfusion, and soft tissue trauma all share an ability to activate macrophages and produce proinflammatory cytokines that may initiate the SIRS. Second-message compounds and effector molecules mediate the observed clinical phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)     

A simulation-intensive approach for checking hierarchical models

Recent computational advances have made it feasible to fit hierarchical models in a wide range of serious applications. In the process, the question of model adequacy arises. While model checking usually addresses the entire model specification, model failures can occur at each hierarchical stage. Such failures include outliers, mean structures errors, dispersion misspecification, and inappropriate exchangeabilities. We propose an approach which is entirely simulation based. Given a model specification and a dataset, we need only be able to simulate draws from the resultant posterior. By replicating a posterior of interest using data obtained under the model we can “see” the extent of variability in such a posterior. Then, we can compare the posterior obtained under the observed data with this medley of posterior replicates to ascertain whether the former is in agreement with them and accordingly, whether it is plausible that the observed data came from the proposed model. Many such comparisons can be run, each focusing on a different potential model failure. Focusing on generalized linear mixed models, we explore the questions of when hierarchical model stages are separable and checkable and illustrate the approach with both real and simulated data. Research supported in part by NSF SCREMS grant DMS-9506557, NSF grant DMS-9301316 and by the Natural Sciences and Engineering Research Council of Canada