291 research outputs found

    Inhibition of cPLA2 has neuroprotective effects on motoneuron and muscle atrophy following spinal cord injury

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    Surviving motoneurons undergo dendritic atrophy after spinal cord injury (SCI), suggesting an important therapeutic target for neuroprotective strategies to improve recovery of function after SCI. Our previous studies showed that phospholipase A2 (PLA2) may play an important role in the pathogenesis of SCI. In the present study, we investigated whether blocking cPLA2 pharmacologically with arachidonyl trifluoromethyl ketone (ATK) or genetically using cPLA2 knockout (KO) mice attenuates motoneuron atrophy following SCI. C57BL/6 mice received either sham or contusive SCI at the T10 level. At 30 min after SCI, mice were treated with ATK or vehicle. Four weeks later, motoneurons innervating the vastus lateralis muscle of the quadriceps were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Soma volume, motoneuron number, lesion volume, and tissue sparing were also assessed, as were muscle weight, fiber cross-sectional area, and motor endplate size and density. ATK administration reduced percent lesion volume and increased percent volume of spared white matter compared to the vehicle-treated control animals. SCI with or without ATK treatment had no effect on the number or soma volume of quadriceps motoneurons. However, SCI resulted in a decrease in dendritic length of quadriceps motoneurons in untreated animals, and this decrease was completely prevented by treatment with ATK. Similarly, the vastus lateralis muscle weights of untreated SCI animals were smaller than those of sham-surgery controls, and these reductions were prevented by ATK treatment. No effects on fiber cross-sectional areas, motor endplate area or density were observed across treatment groups. Remarkably, genetically deleting cPLA2 in cPLA2 KO mice attenuated dendritic atrophy after SCI. These findings suggest that after SCI, cord tissue damage and regressive changes in motoneuron and muscle morphology can be reduced by inhibition of cPLA2, further supporting a role for cPLA2 as a neurotherapeutic target for SCI treatment

    Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective

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    This Report has a number of inter-related general purposes. One is to explore the extent to which food, nutrition, physical activity, and body composition modify the risk of cancer, and to specify which factors are most important. To the extent that environmental factors such as food, nutrition, and physical activity influence the risk of cancer, it is a preventable disease. The Report specifies recommendations based on solid evidence which, when followed, will be expected to reduce the incidence of cancer

    Invasion Expansion: Time since introduction best predicts global ranges of marine invaders.

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    Strategies for managing biological invasions are often based on the premise that characteristics of invading species and the invaded environment are key predictors of the invader's distribution. Yet, for either biological traits or environmental characteristics to explain distribution, adequate time must have elapsed for species to spread to all potential habitats. We compiled and analyzed a database of natural history and ecological traits of 138 coastal marine invertebrate species, the environmental conditions at sites to which they have been introduced, and their date of first introduction. We found that time since introduction explained the largest fraction (20%) of the variability in non-native range size, while traits of the species and environmental variables had significant, but minimal, influence on non-native range size. The positive relationship between time since introduction and range size indicates that non-native marine invertebrate species are not at equilibrium and are still spreading, posing a major challenge for management of coastal ecosystems

    Colorectal cancer screening among African American church members: A qualitative and quantitative study of patient-provider communication

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    BACKGROUND: A healthcare provider's recommendation to undergo screening has been shown to be one of the strongest predictors of completing a colorectal cancer (CRC) screening test. We sought to determine the relationship between the general quality of self-rated patient-provider communication and the completion of CRC screening. METHODS: A formative study using qualitative data from focus groups and quantitative data from a cross-sectional survey of church members about the quality of their communication with their healthcare provider, their CRC risk knowledge, and whether they had completed CRC screening tests. Focus group participants were a convenience sample of African American church members. Participants for the survey were recruited by telephone from membership lists of 12 African American churches located in rural counties of North Carolina to participate in the WATCH (Wellness for African Americans Through Churches) Project. RESULTS: Focus Groups. Six focus groups (n = 45) were conducted prior to the baseline survey. Discussions focused on CRC knowledge, and perceived barriers/motivators to CRC screening. A theme that emerged during each groups' discussion about CRC screening was the quality of the participants' communication with their health care provider. Survey. Among the 397 participants over age 50, 31% reported CRC screening within the recommended guidelines. Participants who self-rated their communication as good were more likely to have been screened (36%) within the recommended guidelines than were participants with poor communication (17%) (OR = 2.8, 95% CI 1.2, 6.4; p = 0.013). Participants who had adequate CRC knowledge completed CRC screening at a higher rate than those with inadequate knowledge (p = 0.011). The percentage of participants with CRC screening in the recommended guidelines, stratified by communication and knowledge group were: 42% for good communication/adequate knowledge; 27% for good communication/inadequate knowledge; 29% for poor communication/adequate knowledge; and 5% for poor communication/inadequate knowledge. CONCLUSIONS: Participants who rated their patient-provider communication as good were more likely to have completed CRC screening tests than those reporting poor communication. Among participants reporting good communication, knowledge about colorectal cancer was also associated with test completion. Interventions to improve patient-provider communication may be important to increase low rates of CRC screening test completion among African Americans

    Coral Colonisation of an Artificial Reef in a Turbid Nearshore Environment, Dampier Harbour, Western Australia

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    A 0.6 hectare artificial reef of local rock and recycled concrete sleepers was constructed in December 2006 at Parker Point in the industrial port of Dampier, western Australia, with the aim of providing an environmental offset for a nearshore coral community lost to land reclamation. Corals successfully colonised the artificial reef, despite the relatively harsh environmental conditions at the site (annual water temperature range 18-32Β°C, intermittent high turbidity, frequent cyclones, frequent nearby ship movements). Coral settlement to the artificial reef was examined by terracotta tile deployments, and later stages of coral community development were examined by in-situ visual surveys within fixed 25 x 25 cm quadrats on the rock and concrete substrates. Mean coral density on the tiles varied from 113 Β± 17 SE to 909 Β± 85 SE per m2 over five deployments, whereas mean coral density in the quadrats was only 6.0 Β± 1.0 SE per m2 at eight months post construction, increasing to 24.0 Β± 2.1 SE per m2 at 62 months post construction. Coral taxa colonising the artificial reef were a subset of those on the surrounding natural reef, but occurred in different proportions-Pseudosiderastrea tayami, Mycedium elephantotus and Leptastrea purpurea being disproportionately abundant on the artificial reef. Coral cover increased rapidly in the later stages of the study, reaching 2.3 Β± 0.7 SE % at 62 months post construction. This study indicates that simple materials of opportunity can provide a suitable substrate for coral recruitment in Dampier Harbour, and that natural colonisation at the study site remains sufficient to initiate a coral community on artificial substrate despite ongoing natural and anthropogenic perturbations. Β© 2013 Blakeway et al

    Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

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    The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genomeΒ sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants’ pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine

    Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

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    This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

    Functional Characterization of CLPTM1L as a Lung Cancer Risk Candidate Gene in the 5p15.33 Locus

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    Cleft Lip and Palate Transmembrane Protein 1-Like (CLPTM1L), resides in a region of chromosome 5 for which copy number gain has been found to be the most frequent genetic event in the early stages of non-small cell lung cancer (NSCLC). This locus has been found by multiple genome wide association studies to be associated with lung cancer in both smokers and non-smokers. CLPTM1L has been identified as an overexpressed protein in human ovarian tumor cell lines that are resistant to cisplatin, which is the only insight thus far into the function of CLPTM1L. Here we find CLPTM1L expression to be increased in lung adenocarcinomas compared to matched normal lung tissues and in lung tumor cell lines by mechanisms not exclusive to copy number gain. Upon loss of CLPTM1L accumulation in lung tumor cells, cisplatin and camptothecin induced apoptosis were increased in direct proportion to the level of CLPTM1L knockdown. Bcl-xL accumulation was significantly decreased upon loss of CLPTM1L. Expression of exogenous Bcl-xL abolished sensitization to apoptotic killing with CLPTM1L knockdown. These results demonstrate that CLPTM1L, an overexpressed protein in lung tumor cells, protects from genotoxic stress induced apoptosis through regulation of Bcl-xL. Thus, this study implicates anti-apoptotic CLPTM1L function as a potential mechanism of susceptibility to lung tumorigenesis and resistance to chemotherapy

    Interferon Regulatory Factor-1 (IRF-1) Shapes Both Innate and CD8+ T Cell Immune Responses against West Nile Virus Infection

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    Interferon regulatory factor (IRF)-1 is an immunomodulatory transcription factor that functions downstream of pathogen recognition receptor signaling and has been implicated as a regulator of type I interferon (IFN)-Ξ±Ξ² expression and the immune response to virus infections. However, this role for IRF-1 remains controversial because altered type I IFN responses have not been systemically observed in IRF-1-/- mice. To evaluate the relationship of IRF-1 and immune regulation, we assessed West Nile virus (WNV) infectivity and the host response in IRF-1-/- cells and mice. IRF-1-/- mice were highly vulnerable to WNV infection with enhanced viral replication in peripheral tissues and rapid dissemination into the central nervous system. Ex vivo analysis revealed a cell-type specific antiviral role as IRF-1-/- macrophages supported enhanced WNV replication but infection was unaltered in IRF-1-/- fibroblasts. IRF-1 also had an independent and paradoxical effect on CD8+ T cell expansion. Although markedly fewer CD8+ T cells were observed in naΓ―ve animals as described previously, remarkably, IRF-1-/- mice rapidly expanded their pool of WNV-specific cytolytic CD8+ T cells. Adoptive transfer and in vitro proliferation experiments established both cell-intrinsic and cell-extrinsic effects of IRF-1 on the expansion of CD8+ T cells. Thus, IRF-1 restricts WNV infection by modulating the expression of innate antiviral effector molecules while shaping the antigen-specific CD8+ T cell response
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