98 research outputs found
Reversal of Misfolding: Prion Disease Behavioral and Physiological Impairments Recover following Postnatal Neuronal Deletion of the PrP Gene
The prionoses are fatal neurodegenerative diseases caused by a pathogenic protein, PrP scrapie, that derives from misfolding of a normal form, PrPc. These diseases progress through stages. A new study by Mallucci et al. in this issue of Neuron shows that prion disease may be reversed in mice by selective removal of the gene in neurons after early physiological, cognitive, and pathological features have developed
The Impact of a Dedicated Research Education Month for Anesthesiology Residents
An educational intervention was implemented at the University of Michigan starting in 2008, in which anesthesiology interns complete a dedicated month-long didactic rotation in evidence-based medicine (EBM) and research methodology. We sought to assess its utility. Scores on a validated EBM test before and after the rotation were compared and assessed for significance of improvement. A survey was also given to gauge satisfaction with the quality of the rotation and self-reported improvement in understanding of EBM topics. Fourteen consecutive interns completed the research rotation during the study period. One hundred percent completed both the pre- and postrotation test. The mean pretest score was 7.78 ± 2.46 (median = 7.5, 0–15 scale, and interquartile range 7.0–10.0) and the mean posttest score was 10.00 ± 2.35 (median = 9.5, interquartile range 8.0–12.3), which represented a statistically significant increase (P=0.011, Wilcoxon signed-rank test). All fourteen of the residents “agreed” or “strongly agreed” that they would recommend the course to future interns and that the course increased their ability to critically review the literature. Our findings demonstrate that this can be an effective means of improving understanding of EBM topics and anesthesiology research
Effect of changes in climate and emissions on future sulfate-nitrate-ammonium aerosol levels in the United States
Global simulations of sulfate, nitrate, and ammonium aerosols are performed for the present day and 2050 using the chemical transport model GEOS-Chem. Changes in climate and emissions projected by the IPCC A1B scenario are imposed separately and together, with the primary focus of the work on future inorganic aerosol levels over the United States. Climate change alone is predicted to lead to decreases in levels of sulfate and ammonium in the southeast U.S. but increases in the Midwest and northeast U.S. Nitrate concentrations are projected to decrease across the U.S. as a result of climate change alone. In the U.S., climate change alone can cause changes in annually averaged sulfate-nitrate-ammonium of up to 0.61 μg/m^3, with seasonal changes often being much larger in magnitude. When changes in anthropogenic emissions are considered (with or without changes in climate), domestic sulfate concentrations are projected to decrease because of sulfur dioxide emission reductions, and nitrate concentrations are predicted to generally increase because of higher ammonia emissions combined with decreases in sulfate despite reductions in emissions of nitrogen oxides. The ammonium burden is projected to increase from 0.24 to 0.36 Tg, and the sulfate burden to increase from 0.28 to 0.40 Tg S as a result of globally higher ammonia and sulfate emissions in the future. The global nitrate burden is predicted to remain essentially constant at 0.35 Tg, with changes in both emissions and climate as a result of the competing effects of higher precursor emissions and increased temperature
Improved Control of Tuberculosis and Activation of Macrophages in Mice Lacking Protein Kinase R
Host factors that microbial pathogens exploit for their propagation are potential targets for therapeuic countermeasures. No host enzyme has been identified whose genetic absence benefits the intact mammalian host in vivo during infection with Mycobacterium tuberculosis (Mtb), the leading cause of death from bacterial infection. Here, we report that the dsRNA-dependent protein kinase (PKR) is such an enzyme. PKR-deficient mice contained fewer viable Mtb and showed less pulmonary pathology than wild type mice. We identified two potential mechanisms for the protective effect of PKR deficiency: increased apoptosis of macrophages in response to Mtb and enhanced activation of macrophages in response to IFN-gamma. The restraining effect of PKR on macrophage activation was explained by its mediation of a previously unrecognized ability of IFN-gamma to induce low levels of the macrophage deactivating factor interleukin 10 (IL10). These observations suggest that PKR inhibitors may prove useful as an adjunctive treatment for tuberculosis
Effect of changes in climate and emissions on future sulfate-nitrate-ammonium aerosol levels in the United States
In Silico Whole Genome Association Scan for Murine Prepulse Inhibition
Background
The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups. Methodology/Principal Findings
We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI. Conclusions/Significance
These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans
Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells
Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on oestrogen-dependent tumours. Recently, it has been described that melatonin, on the basis of its antioxidant properties, inhibits the growth of glioma cells. Glioma cells express oestrogen receptors and have the ability to synthesise oestrogens from androgens. In the present study, we demonstrate that pharmacological concentrations of melatonin decreases the growth of C6 glioma cells and reduces the local biosynthesis of oestrogens, through the inhibition of aromatase, the enzyme that catalyses the conversion of androgens into oestrogens. These results are supported by three types of evidence. Firstly, melatonin counteracts the growth stimulatory effects of testosterone on glioma cells, which is dependent on the local synthesis of oestrogens from testosterone. Secondly, we found that melatonin reduces the aromatase activity of C6 cells, measured by the tritiated water release assay. Finally, by (RT)–PCR, we found that melatonin downregulates aromatase mRNA steady-state levels in these glioma cells. We conclude that melatonin inhibits the local production of oestrogens decreasing aromatase activity and expression. By analogy to the implications of aromatase in other forms of oestrogen-sensitive tumours, it is conceivable that the modulation of the aromatase by pharmacological melatonin may play a role in the growth of glioblastomas
Increased Number of Cerebellar Granule Cells and Astrocytes in the Internal Granule Layer in Sheep Following Prenatal Intra-amniotic Injection of Lipopolysaccharide
Chorioamnionitis is an important problem in perinatology today, leading to brain injury and neurological handicaps. However, there are almost no data available regarding chorioamnionitis and a specific damage of the cerebellum. Therefore, this study aimed at determining if chorioamnionitis causes cerebellar morphological alterations. Chorioamnionitis was induced in sheep by the intra-amniotic injection of lipopolysaccharide (LPS) at a gestational age (GA) of 110 days. At a GA of 140 days, we assessed the mean total and layer-specific volume and the mean total granule cell (GCs) and Purkinje cell (PC) number in the cerebelli of LPS-exposed and control animals using high-precision design-based stereology. Astrogliosis was assessed in the gray and white matter (WM) using a glial fibrillary acidic protein staining combined with gray value image analysis. The present study showed an unchanged volume of the total cerebellum as well as the molecular layer, outer and inner granular cell layers (OGL and IGL, respectively), and WM. Interestingly, compared with controls, the LPS-exposed brains showed a statistically significant increase (+20.4%) in the mean total number of GCs, whereas the number of PCs did not show any difference between the two groups. In addition, LPS-exposed animals showed signs of astrogliosis specifically affecting the IGL. Intra-amniotic injection of LPS causes morphological changes in the cerebellum of fetal sheep still detectable at full-term birth. In this study, changes were restricted to the inner granule layer. These cerebellar changes might correspond to some of the motor or non-motor deficits seen in neonates from compromised pregnancies
Women's Education Level, Maternal Health Facilities, Abortion Legislation and Maternal Deaths: A Natural Experiment in Chile from 1957 to 2007
The aim of this study was to assess the main factors related to maternal mortality reduction in large time series available in Chile in context of the United Nations' Millennium Development Goals (MDGs).Time series of maternal mortality ratio (MMR) from official data (National Institute of Statistics, 1957-2007) along with parallel time series of education years, income per capita, fertility rate (TFR), birth order, clean water, sanitary sewer, and delivery by skilled attendants were analysed using autoregressive models (ARIMA). Historical changes on the mortality trend including the effect of different educational and maternal health policies implemented in 1965, and legislation that prohibited abortion in 1989 were assessed utilizing segmented regression techniques.During the 50-year study period, the MMR decreased from 293.7 to 18.2/100,000 live births, a decrease of 93.8%. Women's education level modulated the effects of TFR, birth order, delivery by skilled attendants, clean water, and sanitary sewer access. In the fully adjusted model, for every additional year of maternal education there was a corresponding decrease in the MMR of 29.3/100,000 live births. A rapid phase of decline between 1965 and 1981 (-13.29/100,000 live births each year) and a slow phase between 1981 and 2007 (-1.59/100,000 live births each year) were identified. After abortion was prohibited, the MMR decreased from 41.3 to 12.7 per 100,000 live births (-69.2%). The slope of the MMR did not appear to be altered by the change in abortion law.Increasing education level appears to favourably impact the downward trend in the MMR, modulating other key factors such as access and utilization of maternal health facilities, changes in women's reproductive behaviour and improvements of the sanitary system. Consequently, different MDGs can act synergistically to improve maternal health. The reduction in the MMR is not related to the legal status of abortion
Phenotypic Characterization of a Genetically Diverse Panel of Mice for Behavioral Despair and Anxiety
Animal models of human behavioral endophenotypes, such as the Tail Suspension Test (TST) and the Open Field assay (OF), have proven to be essential tools in revealing the genetics and mechanisms of psychiatric diseases. As in the human disorders they model, the measurements generated in these behavioral assays are significantly impacted by the genetic background of the animals tested. In order to better understand the strain-dependent phenotypic variability endemic to this type of work, and better inform future studies that rely on the data generated by these models, we phenotyped 33 inbred mouse strains for immobility in the TST, a mouse model of behavioral despair, and for activity in the OF, a model of general anxiety and locomotor activity.We identified significant strain-dependent differences in TST immobility, and in thigmotaxis and distance traveled in the OF. These results were replicable over multiple testing sessions and exhibited high heritability. We exploited the heritability of these behavioral traits by using in silico haplotype-based association mapping to identify candidate genes for regulating TST behavior. Two significant loci (-logp >7.0, gFWER adjusted p value <0.05) of approximately 300 kb each on MMU9 and MMU10 were identified. The MMU10 locus is syntenic to a major human depressive disorder QTL on human chromosome 12 and contains several genes that are expressed in brain regions associated with behavioral despair.We report the results of phenotyping a large panel of inbred mouse strains for depression and anxiety-associated behaviors. These results show significant, heritable strain-specific differences in behavior, and should prove to be a valuable resource for the behavioral and genetics communities. Additionally, we used haplotype mapping to identify several loci that may contain genes that regulate behavioral despair
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