Does Exercise Reduce the Risk of Falling in Parkinson’s Patients?

Objective: The objective of this selective EBM review is to determine whether or not exercise reduces the risk of falls in Parkinson’s patients Study Design: Review of three English language randomized control trials (RCTs) published in 2003, 2007 and 2010. Data Sources: 3 randomized controlled trials published after 1999 were obtained using Pubmed. Outcomes Measured: The Allen study used a Parkinson’s disease fall risk scoring. The Ashburn study used patient dairies to record incidence of falls. The Hirsch study used Sensory Orientation testing assessing the trials resulting in falls. Results: Allen et al and Ashburn et al found no significant reduce in the incidence in falls while Hirsch et al was able to show a significant reduction in the incidence of falls. Conclusion: Evidence supporting the role of exercise in reducing the incidence of falls in Parkinson’s patients in inconclusive and conflicting at this time. A more standard exercise program and method of collecting results is needed for studies that can last longer and represent a larger portion of the population of Parkinson’s patients

Enrichment of schizophrenia heritability in both neuronal and glia cell regulatory elements

Genome-wide association studies have identified over 100 robust risk loci for schizophrenia with thousands of variants mediating genetic heritability, the majority of which reside in non-coding regions. Analytical approaches have shown this heritability is strongly enriched at variants within regulatory elements identified from human post-mortem brain tissue. However, bulk post-mortem brain tissue has a heterogeneous cell composition, making biological interpretations difficult. We sought to refine the cell types mediating schizophrenia heritability by separating neuronal and glial signals using data from: (1) NeuN-sorted post-mortem brain and (2) cell culture systems. Schizophrenia heritability was partitioned using linkage disequilbrium (LD) score regression. Variants within genomic regions marked by H3K4me3 (marker of active promoters) from NeuN-positive (neuronal) and NeuN-negative (non-neuronal) cells explained a significant amount of schizophrenia heritability (P = 1.38 × 10−10 and P = 7.97 × 10−10). However, variants located in H3K4me3 sites specific to NeuN-positive (neuronal) cells were enriched (P = 3.13 × 10−4), while those specific to NeuN-negative (non-neuronal) cells were not (P = 0.470). Data from cell culture systems mimicked this pattern of association. We show the previously observed enrichment of heritability from variants at brain H3K4me3 sites is mediated by both neuronal and non-neuronal brain cell types. However, only neuronal cell populations showed a unique contribution driven by cell-type specific regulatory elements. Cell culture systems recapitulate disease relevant gene-regulatory landscapes, validating them as a tool for future investigation of genetic mechanisms underlying schizophrenia. Identifying the cell types in which risk variants operate will greatly increase our understanding of schizophrenia pathobiology and aid in the development of novel model systems and therapies

Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

Background/objectivesThe common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson's disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD.MethodsFor immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD.ResultsHomozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses.ConclusionsIn sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression

Manual vs. Mechanical Chest Compressions in Out-of-Hospital Cardiac Arrest

Objective: The objective was to conduct an analysis of literature that examined whether the use of mechanical vs. manual chest compressions results in outcomes (e.g. quality of CPR, return of spontaneous circulation (ROSC), neurologic outcome, survival) that are significantly increased or decreased in adults that experienced out of hospital cardiac arrest (OHCA). Methods: Systematic searches were conducted through the James Madison University Library. The inclusion criteria included human adults that experienced out of hospital cardiac arrest that were treated by Emergency Medical Services (EMS) with and/or without a mechanical chest compression device. Results: A statistically significant difference was not found between the manual chest compression study arm and the automated chest compression study arm. Conclusion: Because P-values were not statistically significant, when comparing manual to automated chest compressions, the researchers were unable to confidently state recommendations. However, there was moderate clinical significance for improved outcome with manual chest compressions

Genetic risk for Alzheimer's disease is concentrated in specific macrophage and microglial transcriptional networks

Background: Genome-wide association studies of Alzheimer’s disease (AD) have identified a number of significant risk loci, the majority of which lie in non-coding regions of the genome. The lack of causal alleles and considerable polygenicity remains a significant barrier to translation into mechanistic understanding. This includes identifying causal variants and the cell/tissue types in which they operate. A fuller understanding of the cell types and transcriptional networks involved in AD genetic risk mechanisms will provide important insights into pathogenesis. Methods: We assessed the significance of the overlap between genome-wide significant AD risk variants and sites of open chromatin from data sets representing diverse tissue types. We then focussed on macrophages and microglia to investigate the role of open chromatin sites containing motifs for specific transcription factors. Partitioned heritability using LDscore regression was used to investigate the contribution of specific macrophage and microglia transcription factor motif-containing open chromatin sites to the heritability of AD. Results: AD risk single nucleotide polymorphisms (SNPs) are preferentially located at sites of open chromatin in immune cells, particularly monocytes (z score = 4.43; corrected P = 5.88 × 10− 3). Similar enrichments are observed for macrophages (z score = 4.10; corrected P < 2.40 × 10− 3) and microglia (z score = 4.34, corrected P = 0.011). In both macrophages and microglia, AD risk variants are enriched at a subset of open chromatin sites that contain DNA binding motifs for specific transcription factors, e.g. SPI1 and MEF2. Genetic variation at many of these motif-containing sites also mediate a substantial proportion of AD heritability, with SPI1-containing sites capturing the majority of the common variant SNP-chip heritability (microglia enrichment = 16.28, corrected enrichment P = 0.0044). Conclusions: AD risk alleles plausibly operate in immune cells, including microglia, and are concentrated in specific transcriptional networks. Combined with primary genetic association results, the SPI1 and MEF2 transcriptional networks appear central to AD risk mechanisms. Investigation of transcription factors targeting AD risk SNP associated regulatory elements could provide powerful insights into the molecular processes affected by AD polygenic risk. More broadly, our findings support a model of polygenic disease risk that arises from variants located in specific transcriptional networks

Ask Me About It: The Role of Inferencing Questions in Fostering Students' Reading Comprehension

Children’s reading comprehension has primarily been measured through scores on literal and inferential questions of texts. However, few studies have assessed whether the process of answering questions influences children’s level of comprehension. Moreover, no studies have explored the impact of ‘embedded’ inference questions, which are questions that contain inferences themselves. Here, a sample of 25 fifth and sixth grade students (10-12 years old) were given one short story to be read independently in class, each week, over the course of one month. After each story, students were asked six questions from one of four conditions: literal detail questions, causal inference questions, embedded inference questions, or were given no questions. After a one-day delay, students were then asked to retell the story. Performance on the questions and retell accuracy were measured. Children scored significantly higher on questions asking about literal details compared to the two inferencing conditions. However, in the retell task, children recalled an equal amount of story propositions in the literal detail and causal inference question conditions. The lowest retell scores were observed when students were either asked embedded inference questions or no questions at all. Furthermore, only literal detail questions were found to predict variance in students’ retell scores. Directions for future research and educational implications are discussed

Infarct size and free fatty acids in the early phase of acute myocardial infarction

The management of acute myocardial infarction (AMI) has been improved by the realisation that the size of infarction can influence mortality (Sobel et al, 1972) and that the infarct size can be altered by subsequent therapy (Maroko et al, 1972). The identification of any factor which may have adverse effects on the ischaemic myocardium and which is amenable to treatment would therefore have important prognostic implications. Elevation of circulating free fatty acid (FFA) concentrations is a consistent feature (Kurien and Oliver, 1966; Oliver et al, 1968) of the profound, non-specific metabolic reaction associated with the onset of AMI (Opie, 1975). The FFA rise has been correlated with the development of arrhythmias (Oliver et al, 1968) after AMI, and with the severity of ischaemic damage (Oliver et al, 1968; Gupta et al, 1969; Russell & Oliver, 1978) on clinical grounds. The method of quantifying infarct size developed by Shell et al (1972) has provided a means of correlating the degree of metabolic disturbance with extent of myocardial damage, and of assessing the benefits of metabolic interventions. The purpose of the studies reported in this thesis was to examine in detail the FFA rise in the early phase of AMI and to correlate this rise with the development of arrhythmias and other complications of AMI and with enzymatically estimated infarct size, thus leading to a more rational approach to therapeutic interventions

Combined chemical and genetic approach to inhibit proteolysis by the proteasome

Regulated protein destruction by the proteasome is crucial for the maintenance of normal cellular homeostasis. Much of our understanding of proteasome function stems from the use of drugs that inhibit its activity. Curiously, despite the importance of proteasomal proteolysis, previous studies have found that proliferation of the yeast Saccharomyces cerevisiae is relatively resistant to the effects of proteasome inhibitors such as MG132, even in the presence of mutations that increase inhibitor levels in cells. We reasoned that part of the resistance of S. cerevisiae to proteasome inhibitors stems from the fact that most proteasome inhibitors preferentially target the chymotryptic activity of the proteasome, and that the caspase-like and tryptic sites within the 20S core could compensate for proteasome function under these conditions. To test this hypothesis, we generated a strain of yeast in which the gene encoding the drug efflux pump Pdr5 is deleted, and the tryptic and caspase-like proteasome activities are inactivated by mutation. We find that this strain has dramatically increased sensitivity to the proteasome inhibitor MG132. Under these conditions, treatment of yeast with MG132 blocks progression through the cell cycle, increases the accumulation of polyubiquitylated proteins and decreases the ability to induce transcription of certain genes. These results highlight the contribution of the caspase-like and tryptic activities of the proteasome to its function, and provide a strategy to potently block proteasomal proteolysis in yeast that has practical applications

Longitudinal evaluation of cognitive functioning in young children with type 1 diabetes over 18 months

OBJECTIVE: Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D. METHODS: 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 yrs; mean age of onset 4.1 yrs) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes. RESULTS: Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function. CONCLUSIONS: The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (VIQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism

<p>Abstract</p> <p>Background</p> <p>Arginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (<it>AVPR1A</it>) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at <it>AVPR1A </it>has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of <it>AVPR1A </it>in variable gene expression and social behaviour.</p> <p>Methods</p> <p>We examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the <it>AVPR1A </it>gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human <it>AVPR1A</it>, RS3 and RS1, were also tested for their effect on relative promoter activity.</p> <p>Results</p> <p>The short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (<it>P </it>= 0.036 and <it>P </it>= 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y.</p> <p>Conclusions</p> <p>These aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased <it>AVPR1A </it>transcription, which may proffer increased susceptibility to the autism phenotype.</p