Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons.

Disrupting particular mitochondrial fission and fusion proteins leads to the death of specific neuronal populations; however, the normal functions of mitochondrial fission in neurons are poorly understood, especially in vivo, which limits the understanding of mitochondrial changes in disease. Altered activity of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) may contribute to the pathophysiology of several neurologic diseases. To study Drp1 in a neuronal population affected by Alzheimer's disease (AD), stroke, and seizure disorders, we postnatally deleted Drp1 from CA1 and other forebrain neurons in mice (CamKII-Cre, Drp1lox/lox (Drp1cKO)). Although most CA1 neurons survived for more than 1 year, their synaptic transmission was impaired, and Drp1cKO mice had impaired memory. In Drp1cKO cell bodies, we observed marked mitochondrial swelling but no change in the number of mitochondria in individual synaptic terminals. Using ATP FRET sensors, we found that cultured neurons lacking Drp1 (Drp1KO) could not maintain normal levels of mitochondrial-derived ATP when energy consumption was increased by neural activity. These deficits occurred specifically at the nerve terminal, but not the cell body, and were sufficient to impair synaptic vesicle cycling. Although Drp1KO increased the distance between axonal mitochondria, mitochondrial-derived ATP still decreased similarly in Drp1KO boutons with and without mitochondria. This indicates that mitochondrial-derived ATP is rapidly dispersed in Drp1KO axons, and that the deficits in axonal bioenergetics and function are not caused by regional energy gradients. Instead, loss of Drp1 compromises the intrinsic bioenergetic function of axonal mitochondria, thus revealing a mechanism by which disrupting mitochondrial dynamics can cause dysfunction of axons

Lung Cancer in Pulmonary Fibrosis: Tales of Epithelial Cell Plasticity

Lung epithelial cells exhibit a high degree of plasticity. Alterations to lung epithelial cell function are critically involved in several chronic lung diseases such as pulmonary fibrosis. Pulmonary fibrosis is characterized by repetitive injury and subsequent impaired repair of epithelial cells, which leads to aberrant growth factor activation and fibroblast accumulation. Increased proliferation and hyper- and metaplasia of epithelial cells upon injury have also been observed in pulmonary fibrosis; this epithelial cell activation might represent the basis for lung cancer development. Indeed, several studies have provided histopathological evidence of an increased incidence of lung cancer in pulmonary fibrosis. The mechanisms involved in the development of cancer in pulmonary fibrosis, however, remain poorly understood. This review highlights recently uncovered molecular mechanisms shared between lung cancer and fibrosis, which extend the current evidence of a common trait of cancer and fibrosis, as provided by histopathological observations. Copyright (C) 2011 S. Karger AG, Base

Surgical management of low grade isthmic spondylolisthesis; a randomized controlled study of the surgical fixation with and without reduction

<p>Abstract</p> <p>Background</p> <p>spondylolisthesis is a condition in which a vertebra slips out of the proper position onto the bone below it as a result of pars interarticularis defect. The slipped segment produces abnormal positioning of the vertebrae in relation to each other along the spinal column and causes mechanical back pain and neural breach.</p> <p>Materials and methods</p> <p>A randomized and double blinded study consisted of 41 patients aged 36-69 years (18 females and 28 males) treated for symptomatic spondylolisthesis between December,2006 and December, 2009. All patients were randomly distributed into two groups I and II. Twenty patients were in Group I; they underwent reduction of the slipped vertebrae by using Reduction-Screw Technique and posterior lumbar interbody fixation (PLIF). Group II consisted of twenty one patients who underwent only surgical fixation (PLIF) without reduction. All patients in this study had same pre and post operative management.</p> <p>Results</p> <p>only one case had broken rod in group I that required revision. Superficial wound infection was experienced in two patients and one patient, from group II, developed wound hematoma. The outcome in both groups was variable on the short term but was almost the same on the long term follow up.</p> <p>Conclusion</p> <p>surgical management of symptomatic low grade spondylolisthesis should include neural decompression and surgical fixation. Reduction of slipped vertebral bodies is unnecessary as the ultimate outcome will be likely similar.</p

Estimating cumulative pathway effects on risk for age-related macular degeneration using mixed linear models

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the elderly in developed countries and typically affects more than 10 % of individuals over age 80. AMD has a large genetic component, with heritability estimated to be between 45 % and 70 %. Numerous variants have been identified and implicate various molecular mechanisms and pathways for AMD pathogenesis but those variants only explain a portion of AMD’s heritability. The goal of our study was to estimate the cumulative genetic contribution of common variants on AMD risk for multiple pathways related to the etiology of AMD, including angiogenesis, antioxidant activity, apoptotic signaling, complement activation, inflammatory response, response to nicotine, oxidative phosphorylation, and the tricarboxylic acid cycle. While these mechanisms have been associated with AMD in literature, the overall extent of the contribution to AMD risk for each is unknown. METHODS: In a case–control dataset with 1,813 individuals genotyped for over 600,000 SNPs we used Genome-wide Complex Trait Analysis (GCTA) to estimate the proportion of AMD risk explained by SNPs in genes associated with each pathway. SNPs within a 50 kb region flanking each gene were also assessed, as well as more distant, putatively regulatory SNPs, based on DNaseI hypersensitivity data from ocular tissue in the ENCODE project. RESULTS: We found that 19 previously associated AMD risk SNPs contributed to 13.3 % of the risk for AMD in our dataset, while the remaining genotyped SNPs contributed to 36.7 % of AMD risk. Adjusting for the 19 risk SNPs, the complement activation and inflammatory response pathways still explained a statistically significant proportion of additional risk for AMD (9.8 % and 17.9 %, respectively), with other pathways showing no significant effects (0.3 % – 4.4 %). DISCUSSION: Our results show that SNPs associated with complement activation and inflammation significantly contribute to AMD risk, separately from the risk explained by the 19 known risk SNPs. We found that SNPs within 50 kb regions flanking genes explained additional risk beyond genic SNPs, suggesting a potential regulatory role, but that more distant SNPs explained less than 0.5 % additional risk for each pathway. CONCLUSIONS: From these analyses we find that the impact of complement SNPs on risk for AMD extends beyond the established genome-wide significant SNPs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-015-0760-4) contains supplementary material, which is available to authorized users

Can an Integrated Approach Reduce Child Vulnerability to Anaemia? Evidence from Three African Countries.

Addressing the complex, multi-factorial causes of childhood anaemia is best done through integrated packages of interventions. We hypothesized that due to reduced child vulnerability, a "buffering" of risk associated with known causes of anaemia would be observed among children living in areas benefiting from a community-based health and nutrition program intervention. Cross-sectional data on the nutrition and health status of children 24-59 mo (N = 2405) were obtained in 2000 and 2004 from program evaluation surveys in Ghana, Malawi and Tanzania. Linear regression models estimated the association between haemoglobin and immediate, underlying and basic causes of child anaemia and variation in this association between years. Lower haemoglobin levels were observed in children assessed in 2000 compared to 2004 (difference -3.30 g/L), children from Tanzania (-9.15 g/L) and Malawi (-2.96 g/L) compared to Ghana, and the youngest (24-35 mo) compared to oldest age group (48-59 mo; -5.43 g/L). Children who were stunted, malaria positive and recently ill also had lower haemoglobin, independent of age, sex and other underlying and basic causes of anaemia. Despite ongoing morbidity, risk of lower haemoglobin decreased for children with malaria and recent illness, suggesting decreased vulnerability to their anaemia-producing effects. Stunting remained an independent and unbuffered risk factor. Reducing chronic undernutrition is required in order to further reduce child vulnerability and ensure maximum impact of anaemia control programs. Buffering the impact of child morbidity on haemoglobin levels, including malaria, may be achieved in certain settings

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis

Background Patients with resected colorectal liver metastasis (CRLM) who display only the desmoplastic histopathological growth pattern (dHGP) exhibit superior survival compared to patients with any non-desmoplastic growth (non-dHGP). The aim of this study was to compare the tumour microenvironment between dHGP and non-dHGP. Methods The tumour microenvironment was investigated in three cohorts of chemo-naive patients surgically treated for CRLM. In cohort A semi-quantitative immunohistochemistry was performed, in cohort B intratumoural and peritumoural T cells were counted using immunohistochemistry and digital image analysis, and in cohort C the relative proportions of individual T cell subsets were determined by flow cytometry. Results One hundred and seventeen, 34, and 79 patients were included in cohorts A, B, and C, with dHGP being observed in 27%, 29%, and 15% of patients, respectively. Cohorts A and B independently demonstrated peritumoural and intratumoural enrichment of cytotoxic CD8+ T cells in dHGP, as well as a higher CD8+/CD4+ ratio (cohort A). Flow cytometric analysis of fresh tumour tissues in cohort C confirmed these results; dHGP was associated with higher CD8+ and lower CD4+ T cell subsets, resulting in a higher CD8+/CD4+ ratio. Conclusion The tumour microenvironment of patients with dHGP is characterised by an increased and distinctly cytotoxic immune infiltrate, providing a potential explanation for their superior survival