Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses. Copyright (C) 2005 S. Karger AG, Basel

Relevance of tissue Doppler in the quantification of stress echocardiography for the detection of myocardial ischemia in clinical practice

In the present article we review the main published data on the application of Tissue Doppler Imaging (TDI) to stress echocardiography for the detection of myocardial ischemia. TDI has been applied to stress echocardiography in order to overcome the limitations of visual analysis for myocardial ischemia. The introduction of a new technology for clinical routine use should pass through the different phases of scientific assessment from feasibility studies to large multicenter studies, from efficacy to effectiveness studies. Nonetheless the pro-technology bias plays a major role in medicine and expensive and sophisticated techniques are accepted before their real usefulness and incremental value to the available ones is assessed. Apparently, TDI is not exempted by this approach : its applications are not substantiated by strong and sound results. Nonetheless, conventional stress echocardiography for myocardial ischemia detection is heavily criticized on the basis of its subjectivity. Stress echocardiography has a long lasting history and the evidence collected over 20 years positioned it as an established tool for the detection and prognostication of coronary artery disease. The quantitative assessment of myocardial ischemia remains a scientific challenge and a clinical goal but time has not come for these newer ultrasonographic techniques which should be restricted to research laboratories

Positive Selection in East Asians for an EDAR Allele that Enhances NF-κB Activation

Genome-wide scans for positive selection in humans provide a promising approach to establish links between genetic variants and adaptive phenotypes. From this approach, lists of hundreds of candidate genomic regions for positive selection have been assembled. These candidate regions are expected to contain variants that contribute to adaptive phenotypes, but few of these regions have been associated with phenotypic effects. Here we present evidence that a derived nonsynonymous substitution (370A) in EDAR, a gene involved in ectodermal development, was driven to high frequency in East Asia by positive selection prior to 10,000 years ago. With an in vitro transfection assay, we demonstrate that 370A enhances NF-κB activity. Our results suggest that 370A is a positively selected functional genetic variant that underlies an adaptive human phenotype

Evaluating Research and Impact: A Bibliometric Analysis of Research by the NIH/NIAID HIV/AIDS Clinical Trials Networks

Evaluative bibliometrics uses advanced techniques to assess the impact of scholarly work in the context of other scientific work and usually compares the relative scientific contributions of research groups or institutions. Using publications from the National Institute of Allergy and Infectious Diseases (NIAID) HIV/AIDS extramural clinical trials networks, we assessed the presence, performance, and impact of papers published in 2006–2008. Through this approach, we sought to expand traditional bibliometric analyses beyond citation counts to include normative comparisons across journals and fields, visualization of co-authorship across the networks, and assess the inclusion of publications in reviews and syntheses. Specifically, we examined the research output of the networks in terms of the a) presence of papers in the scientific journal hierarchy ranked on the basis of journal influence measures, b) performance of publications on traditional bibliometric measures, and c) impact of publications in comparisons with similar publications worldwide, adjusted for journals and fields. We also examined collaboration and interdisciplinarity across the initiative, through network analysis and modeling of co-authorship patterns. Finally, we explored the uptake of network produced publications in research reviews and syntheses. Overall, the results suggest the networks are producing highly recognized work, engaging in extensive interdisciplinary collaborations, and having an impact across several areas of HIV-related science. The strengths and limitations of the approach for evaluation and monitoring research initiatives are discussed

Inositol 1,4,5-Trisphosphate Signalling Regulates the Avoidance Response to Nose Touch in Caenorhabditis elegans

When Caenorhabditis elegans encounters an unfavourable stimulus at its anterior, it responds by initiating an avoidance response, namely reversal of locomotion. The amphid neurons, ASHL and ASHR, are polymodal in function, with roles in the avoidance responses to high osmolarity, nose touch, and both volatile and non-volatile repellents. The mechanisms that underlie the ability of the ASH neurons to respond to such a wide range of stimuli are still unclear. We demonstrate that the inositol 1,4,5-trisphosphate receptor (IP3R), encoded by itr-1, functions in the reversal responses to nose touch and benzaldehyde, but not in other known ASH-mediated responses. We show that phospholipase Cβ (EGL-8) and phospholipase Cγ (PLC-3), which catalyse the production of IP3, both function upstream of ITR-1 in the response to nose touch. We use neuron-specific gene rescue and neuron-specific disruption of protein function to show that the site of ITR-1 function is the ASH neurons. By rescuing plc-3 and egl-8 in a neuron-specific manner, we show that both are acting in ASH. Imaging of nose touch–induced Ca2+ transients in ASH confirms these conclusions. In contrast, the response to benzaldehyde is independent of PLC function. Thus, we have identified distinct roles for the IP3R in two specific responses mediated by ASH

Expression of Odorant Receptor Family, Type 2 OR in the Aquatic Olfactory Cavity of Amphibian Frog Xenopus tropicalis

Recent genome wide in silico analyses discovered a new family (type 2 or family H) of odorant receptors (ORs) in teleost fish and frogs. However, since there is no evidence of the expression of these novel OR genes in olfactory sensory neurons (OSN), it remains unknown if type 2 ORs (OR2) function as odorant receptors. In this study, we examined expression of OR2 genes in the frog Xenopus tropicalis. The overall gene expression pattern is highly complex and differs depending on the gene and developmental stage. RT-PCR analysis in larvae showed that all of the OR2η genes we identified were expressed in the peripheral olfactory system and some were detected in the brain and skin. Whole mount in situ hybridization of the larval olfactory cavity confirmed that at least two OR2η genes so far tested are expressed in the OSN. Because tadpoles are aquatic animals, OR2η genes are probably involved in aquatic olfaction. In adults, OR2η genes are expressed in the nose, brain, and testes to different degrees depending on the genes. OR2η expression in the olfactory system is restricted to the medium cavity, which participates in the detection of water-soluble odorants, suggesting that OR2ηs function as receptors for water-soluble odorants. Moreover, the fact that several OR2ηs are significantly expressed in non-olfactory organs suggests unknown roles in a range of biological processes other than putative odorant receptor functions

Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82

G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments

Rigorous and thorough bioinformatic analyses of olfactory receptor promoters confirm enrichment of O/E and homeodomain binding sites but reveal no new common motifs

<p>Abstract</p> <p>Background</p> <p>Mammalian olfactory receptors (ORs) are subject to a remarkable but poorly understood regime of transcriptional regulation, whereby individual olfactory neurons each express only one allele of a single member of the large OR gene family.</p> <p>Results</p> <p>We performed a rigorous search for enriched sequence motifs in the largest dataset of OR promoter regions analyzed to date. We combined measures of cross-species conservation with databases of known transcription factor binding sites and <it>ab initio </it>motif-finding algorithms. We found strong enrichment of binding sites for the O/E family of transcription factors and for homeodomain factors, both already known to be involved in the transcriptional control of ORs, but did not identify any novel enriched sequences. We also found that TATA-boxes are present in at least a subset of OR promoters.</p> <p>Conclusions</p> <p>Our rigorous approach provides a template for the analysis of the regulation of large gene families and demonstrates some of the difficulties and pitfalls of such analyses. Although currently available bioinformatics methods cannot detect all transcriptional regulatory elements, our thorough analysis of OR promoters shows that in the case of this gene family, experimental approaches have probably already identified all the binding factors common to large fractions of OR promoters.</p

Functional Evidence of Multidrug Resistance Transporters (MDR) in Rodent Olfactory Epithelium

Background: P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP1) are membrane transporter proteins which function as efflux pumps at cell membranes and are considered to exert a protective function against the entry of xenobiotics. While evidence for Pgp and MRP transporter activity is reported for olfactory tissue, their possible interaction and participation in the olfactory response has not been investigated. Principal Findings: Functional activity of putative MDR transporters was assessed by means of the fluorometric calcein acetoxymethyl ester (calcein-AM) accumulation assay on acute rat and mouse olfactory tissue slices. Calcein-AM uptake was measured as fluorescence intensity changes in the presence of Pgp or MRP specific inhibitors. Epifluorescence microscopy measured time course analysis in the olfactory epithelium revealed significant inhibitor-dependent calcein uptake in the presence of each of the selected inhibitors. Furthermore, intracellular calcein accumulation in olfactory receptor neurons was also significantly increased in the presence of either one of the Pgp or MRP inhibitors. The presence of Pgp or MRP1 encoding genes in the olfactory mucosa of rat and mouse was confirmed by RT-PCR with appropriate pairs of speciesspecific primers. Both transporters were expressed in both newborn and adult olfactory mucosa of both species. To assess a possible involvement of MDR transporters in the olfactory response, we examined the electrophysiological response to odorants in the presence of the selected MDR inhibitors by recording electroolfactograms (EOG). In both animal species

Co-regulation of a large and rapidly evolving repertoire of odorant receptor genes

The olfactory system meets niche- and species-specific demands by an accelerated evolution of its odorant receptor repertoires. In this review, we describe evolutionary processes that have shaped olfactory and vomeronasal receptor gene families in vertebrate genomes. We emphasize three important periods in the evolution of the olfactory system evident by comparative genomics: the adaptation to land in amphibian ancestors, the decline of olfaction in primates, and the delineation of putative pheromone receptors concurrent with rodent speciation. The rapid evolution of odorant receptor genes, the sheer size of the repertoire, as well as their wide distribution in the genome, presents a developmental challenge: how are these ever-changing odorant receptor repertoires coordinated within the olfactory system? A central organizing principle in olfaction is the specialization of sensory neurons resulting from each sensory neuron expressing only ~one odorant receptor allele. In this review, we also discuss this mutually exclusive expression of odorant receptor genes. We have considered several models to account for co-regulation of odorant receptor repertoires, as well as discussed a new hypothesis that invokes important epigenetic properties of the system