tbuckley/cabot-search huggingface dataset:
Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies
Authors: Michael A Nalls, Vincent Plagnol, Dena G Hernandez, Manu Sharma, Una-Marie Sheerin, Mohamad Saad, J Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Kári Stefánsson, Maria Martinez, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B Singleton, Nicholas W Wood
Journal: The Lancet (2011)
Arrhythmogenic Cardiomyopathy: Etiology, Diagnosis, and Treatment
Authors: Srijita Sen-Chowdhry, Robert D. Morgan, John C. Chambers, William J. McKenna
Journal: Annual Review of Medicine (2010)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a prevalence of at least 1 in 1000, is a leading cause of sudden cardiac death in people aged ≤35 years, and accounts for up to 10% of deaths from undiagnosed cardiac disease in the &lt;65 age group. The classic form of the disease has an early predilection for the right ventricle, but recognition of left-dominant and biventricular subtypes has prompted proposal of the broader term arrhythmogenic cardiomyopathy. The clinical profile of the disease bridges the gap between the cardiomyopathies and inherited arrhythmia syndromes. The early “concealed” phase is characterized by propensity toward ventricular tachyarrhythmia in the setting of well-preserved morphology, histology, and ventricular function. As the disease progresses, however, myocyte loss, inflammation, and fibroadiposis become evident. Up to 40% of cases harbor rare variants in genes encoding components of the desmosome, specialized intercellular junctions that confer mechanical strength to cardiac and epithelial tissue, and may also participate in signaling networks. Phenotypic heterogeneity and the nonspecific nature of associated features complicate clinical diagnosis, which requires multipronged cardiovascular investigation rather than a single test. Development of a prospectively validated risk-stratification algorithm for the full disease spectrum remains the foremost clinical challenge.
Cigarette Smoking Impairs the Therapeutic Response to Oral Corticosteroids in Chronic Asthma
Authors: Rekha Chaudhuri, Eric Livingston, Alex D. McMahon, Lorna Thomson, William Borland, Neil C. Thomson
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The study was designed to assess the effect of cigarette smoking on the therapeutic response to oral corticosteroids in chronic stable asthma. We performed a randomized, placebo-controlled, crossover study with prednisolone (40 mg daily) or placebo for 2 weeks in smokers with asthma, ex-smokers with asthma, and never-smokers with asthma. All subjects had reversibility in FEV1 after nebulized albuterol of 15% or more and a mean postbronchodilator FEV1% predicted of more than 80%. Efficacy was assessed using FEV1, daily PEF, and an asthma control score. There was a significant improvement after oral prednisolone compared with placebo in FEV1, ml (mean difference, 237; 95% confidence intervals, 43, 231; p = 0.019), morning PEF L/m (mean difference, 36.8; 95% confidence intervals (CI), 11, 62; p = 0.006), and asthma control score (mean difference, −0.72; 95% CI, −1.2, −0.3; p = 0.004) in never-smokers with asthma but no change in smokers with asthma (mean differences of 47, 6.5, and −0.05 with p values of 0.605, 0.47, and 0.865, respectively). Ex-smokers with asthma had a significant improvement in morning and night PEF (mean difference, 29.1; CI, 2.3, 56; p = 0.04 and 52.4; CI, 26, 79; p = 0.003, respectively), but not in FEV1 or asthma control score. We conclude that active smoking impairs the efficacy of short-term oral corticosteroid treatment in chronic asthma.
Use of automated external defibrillator by first responders in out of hospital cardiac arrest: prospective controlled trial
Authors: A. P van Alem
Journal: BMJ (2003)

To test the hypothesis that the use of an automated external defibrillator by police and fire fighters results in higher discharge rates for out of hospital cardiac arrest.Controlled clinical trial with initial random allocation of automated external defibrillators to first responders in four of the eight participating regions; each region switched from control to experimental, and vice versa, every four months.Amsterdam and surroundings, the Netherlands.Patients with witnessed out of hospital cardiac arrests, identified by the emergency medical system between January 2000 and January 2002.Survival to hospital discharge; return of spontaneous circulation; admission to hospital.243 patients (65% in ventricular fibrillation) were included in the experimental area and 226 patients (67% in ventricular fibrillation) in the control area. The median time interval between collapse and first shock was 668 seconds in the experimental area and 769 seconds in the control area (P < 0.001). 44 (18%) patients in the experimental area versus 33 (15%) patients in the control area were discharged (odds ratio 1.3 (95% confidence interval 0.8 to 2.2), P = 0.33), 139 (57%) experimental versus 108 (48%) control patients had return of spontaneous circulation (1.5 (1.0 to 2.2), P = 0.05), and 103 (42%) experimental versus 74 (33%) control patients were admitted (1.5 (1.1 to 1.6), P = 0.02). The median delay from receipt of call to dispatch of the ambulance was 120 seconds, and the delay to dispatch of the first responder was 180 seconds.Use of automated external defibrillators by first responders did not significantly increase survival to discharge from hospital, although it did improve return of spontaneous circulation and admission to hospital. Improved dispatch procedures should increase the success of programmes of first responders using external defibrillators.
Lattice Corneal Dystrophy Type II Associated with Familial Amyloid Polyneuropathy Type IV
Authors: Shinobu Akiya, Youko Nishio, Kenji Ibi, Hiroshiko Uozumi, Hiroshi Takahashi, Tsunekazu Hamada, Akio Onishi, Hiroshi Ishiguchi, Yoshinobu Hoshii, Masamitsu Nakazato
Journal: Ophthalmology (1996)
Temsirolimus Activates Autophagy and Ameliorates Cardiomyopathy Caused by Lamin A/C Gene Mutation
Authors: Jason C. Choi, Antoine Muchir, Wei Wu, Shinichi Iwata, Shunichi Homma, John P. Morrow, Howard J. Worman
Journal: Science Translational Medicine (2012)

Cardiomyopathy arising from lamin A/C mutations in mice can be corrected by enhancing autophagy through blockade of mTOR with temsirolimus.
TRANSPORT OF GLOBIN BY THE RENAL GLOMERULUS
Authors: Max G. Menefee, C. Barber Mueller, Allen L. Bell, Joseph K. Myers
Journal: The Journal of Experimental Medicine (1964)

Purified human globin injected into rats forms aggregates which are identifiable by their characteristic appearance in thin sections in the electron microscope and by their positive autoradiographs when the globin is tritiated before injection. Globin is taken up by endothelial cells of glomerular capillaries and is transported across the cell within the limits of a surrounding membrane. Globin is rarely seen to pass through fenestrations. Globin is also taken into the stalk region where it is seen usually within the sponge fibers and only occasionally within stalk cells. Globin is seen in all stages of passage through the basement membranes and sponge fibers, which are not deformed by its passage. On the basis of the findings presented here and by others, it is postulated that the basement membrane and sponge fibers consist of a thixotrophic gel. After traversing the basement membrane, the globin passes between foot processes of the epithelial cells. The slit membranes are deformed by this passage and thus appear to be distinctive structures. The globin is next found free in Bowman's space; the earliest aggregates are seen there within 1 minute after injection. Globin taken up in the stalk region is slowly discharged and very little is found there 6 hours postinjection.
Leukotrienes in Rhinitis
Authors: PETER H. HOWARTH
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Allergic rhinitis is characterized by the symptoms of nasal itch, sneezing, rhinorrhea, and nasal stuffiness with, in addition, in more severe and chronic disease the development of mucosal swelling that results in impaired sinus drainage, loss of sense of smell, and alteration in eustachian tube function (1). These symptoms and disruption of normal function are consequent on the local release of mediators from activated cells within the nasal mucosa, through interactions with end-organ receptors (2). In this respect the nose differs from the lower respiratory tract in that symptom expression and disordered function are secondary to stimulation of neural, glandular, and vascular components and does not involve airway smooth muscle constriction.
Targeted Deletion of the Lipopolysaccharide (LPS)-binding Protein Gene Leads to Profound Suppression of LPS Responses Ex Vivo, whereas In Vivo Responses Remain Intact
Authors: Mark M. Wurfel, Brian G. Monks, Robin R. Ingalls, Russell L. Dedrick, Russell Delude, Dahua Zhou, Norbert Lamping, Ralf R. Schumann, Rolf Thieringer, Matthew J. Fenton, Samuel D. Wright, Douglas Golenbock
Journal: The Journal of Experimental Medicine (1997)

Gram-negative bacterial lipopolysaccharide (LPS) stimulates phagocytic leukocytes by interacting with the cell surface protein CD14. Cellular responses to LPS are markedly potentiated by the LPS-binding protein (LBP), a lipid-transfer protein that binds LPS aggregates and transfers LPS monomers to CD14. LBP also transfers LPS to lipoproteins, thereby promoting the neutralization of LPS. LBP present in normal plasma has been shown to enhance the LPS responsiveness of cells in vitro. The role of LBP in promoting LPS responsiveness in vivo was tested in LBP-deficient mice produced by gene targeting in embryonic stem cells. Whole blood from LBP-deficient animals was 1,000-fold less responsive to LPS as assessed by the release of tumor necrosis factor (TNF)-α. Blood from gene-targeted mice was devoid of immunoreactive LBP, essentially incapable of transferring LPS to CD14 in vitro, and failed to support cellular responses to LPS. These activities were restored by the addition of exogenous recombinant murine LBP to the plasma. Despite these striking in vitro findings, no significant differences in TNF-α levels were observed in plasma from wild-type and LBP-deficient mice injected with LPS. These data suggest the presence of an LBP-independent mechanism for responding to LPS. These LBP knockout mice may provide a tool for discovering the nature of the presumed second mechanism for transferring LPS to responsive cells.
Benefits and Risks of Tight Glucose Control in Critically Ill Adults
Authors: Renda Soylemez Wiener, Daniel C. Wiener, Robin J. Larson
Journal: JAMA (2008)

PUBlished a randomized controlled trial of critically ill surgical patients showing that tight glucose control reduced hospital mortality by onethird.Since the greatest decrease in deaths occurred in the subgroup of patients with sepsis and multisystem organ failure, some speculated that the benefits of tight glucose control might extend to medical intensive care unit (ICU) patients as well. 2 Because few interventions in critically ill adult patients reduce mortality to this extent, the results of this trial were enthusiastically received and rapidly incorporated into guidelines.In 2004, the Surviving Sepsis Campaign 3 recommended glucose control for all patients with sepsis and explicitly stated, "There is no reason to think that these data are not generalizable to all severely septic patients."This recommendation persists in the 2008 update, now endorsed internationally by 16 professional societies. 4In addition, the Institute for Healthcare Improvement, 5 the Volunteer Hospital Association, 6 the Michigan Health and Safety Coalition, 7 the American Association of Clinical Endo-
Preparing the U.S. Health Community for Climate Change
Authors: Richard Jackson, Kyra Naumoff Shields
Journal: Annual Review of Public Health (2008)

In society's effort to address and prepare for climate change, the health community itself must ensure that it is prepared. Health personnel will require flexible and iterative action plans to address climate change at the individual, hospital, local health department, state, and national levels. This requires that health workers analyze the impact of climate change with a view to human health, and then formulate robust policy and demonstrate authentic leadership. In this review, we summarize the status of the health community's preparation for climate change and provide specific recommendations for action at each level. Although preparation status and recommendations vary, our observation is that it is not enough for public health and medical care agencies and departments to develop policies and advocate change. They have a direct responsibility to demonstrate substantive leadership.
AT-57 * LONG-TERM CLINICAL RESULTS OF EXTENSIVE TUMOR REMOVAL FOLLOWED BY ACNU-BASED CHEMORADIOTHERAPY FOR 147 ANAPLASTIC GLIOMAS
Authors: Y. Takayuki, N. Masayuki, M. Takashi, S. Taichi, I. Satoko, O. Yoshikazu, I. Hiroshi, M. Yoshihiro
Journal: Neuro-Oncology (2014)

INTRODUCTION: Recent randomized trials showed that highly extent of resection (EOR) and PCV chemoradiotherapy had therapeutic long-term efficacy to anaplastic glioma (AG). From 2000, we have consistently enforced extensive removal and ACNU-based chemoradiotherapy for AG. We report retrospective clinical results of a single institution. METHODS: We reviewed 147 cases of primary AG between 2000 and 2011 (Male : Female = 94:53, average age; 43.9 year-old). 69 were anaplastic astrocytoma (41%), 43 were anaplastic oligoastrocytoma (29%), and 44 were anaplastic oligodendroglioma (30%). The intraoperative MRI was performed in 133 cases (90%), and awake surgery was performed in 58 cases (39%). Gross-total removal was 46 (31%), partial removal was 89 (61%), and biopsy was 12 (8%) (average; 83%, median; 95%). After resection, 60 Gy radiotherapy and ACNU or PAV chemotherapy were performed. The average Mib-1 index was 15%. The mean observation periods were 57 months and 95% follow-up rate. RESULTS: Overall survival (OS) wasn't reached median. The 3y-OS was 82%, 5y-OSs was 72%, and 10y-OS was 66%. There was no statistical significance among AA, AOA, AO (5y-OS; 64%, 79%, 77%). The each 5 years survival rate of gross-total resection, partial resection, and biopsy were 83%, 70%, 39%, and there was statistical significance (P = 0.0024). Extent of resection (EOR) correlated OS in AA (P = 0.02) but not in oligodendroglial subtypes (P = 0.6). Statistical significant factors were EOR (P = 0.0024) and Mib-1 index (P = 0.013). The significant factors in multi variable analysis were EOR (more than 95% or not, HR 2.5) and Mib-1 index (more than 13% or not, HR 2.3). The median PFS was 8.3, and 5y-PFS was 59%,and 10y-PFS was 45%. CONCLUSION: Our long-term clinical results of AG treated with extensive resection and ACNU-based chemoradiotherapy were better than previous reports. The EOR contributed better prognosis especially for AA.
A Profound Role for the Expansion of Trypsin-Like Serine Protease Family in the Evolution of Hematophagy in Mosquito
Authors: Dong-Dong Wu, Guo-Dong Wang, David M Irwin, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2009)

The trypsin-like serine protease (Tryp_SPc) family is ubiquitous in animals and plays diverse roles, especially in the digestive system, in different phyla. In the mosquito, some Tryp_SPc proteases make important contributions to the digestion of the blood meal. Here, we have defined the complete Tryp_SPc gene repertoire in the genome of the malaria mosquito, a repertoire that has expanded remarkably compared with that of Drosophila. Phylogenetic analysis also indicates that the large-scale lineage-specific expansion occurred leading to mosquitoes. Expression of Tryp_SPc genes elevates after a blood meal, and the expression level of genes that belong to subfamilies that specifically expanded on the mosquito lineage increased significantly more than genes that belong to subfamilies that did not expand in number, suggesting a profound role for the Tryp_SPc genes, especially the expanded subfamilies, in the hematophagous trait of the mosquito. The mosquito Tryp_SPc genes are mostly distributed in a tandem manner on chromosomes, suggesting a role for tandem duplication in the expansion of the subfamilies. Furthermore, evidence for positive selection was found for some genes. Structural modeling indicates that the positively selected sites locate to the surface that is conjugated by protein inhibitors. Our results suggest that the expansion and diversification of the Tryp_SPc domain family in mosquito was driven by positive selection and helps to explain the adaptive hematophagy of the mosquito.
Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of <i>TWIST</i> Gene Expression
Authors: Hui-Wen Lo, Sheng-Chieh Hsu, Weiya Xia, Xinyu Cao, Jin-Yuan Shih, Yongkun Wei, James L. Abbruzzese, Gabriel N. Hortobagyi, Mien-Chie Hung
Journal: Cancer Research (2007)

Abstract Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression. [Cancer Res 2007;67(19):9066–76]
Improving vascular health: are pills the answer?
Authors: L. Smeeth, H. Hemingway
Journal: BMJ (2012)

Lowering the statin treatment threshold raises important questions



C & M WERNER, VISUALS UNLIMITED/SPL

Guidelines from the National Institute for Health and Clinical Excellence,1 the United States,2 and Europe3 recommend statins for people with cardiovascular disease and for those at high risk of developing disease on the basis of an individual risk assessment. Although there has been much debate about the optimal risk assessment tool, surprisingly, the risk threshold above which statins are recommended has been less hotly debated. A risk of developing cardiovascular disease of greater than 20% over 10 years—or greater than 10% over five years—is widely used as the cut-off point for prescribing statins. The results of a recent meta-analysis of data from the Cholesterol Treatment Trialists Collaborators directly challenges the consensus over this threshold.4

Statins reduce the relative risk of major vascular events by around 20% per 1 mmol/L reduction in low density lipoprotein-cholesterol—the typical effect on lipids produced by a low to moderate dose of statin. The striking finding from the new meta-analysis is that the established beneficial effects were seen across a broad spectrum of vascular risk, including people with a five year risk of vascular disease of less than 5%, well below the current threshold …
Comparison of three methods for estimating rates of adverse events and rates of preventable adverse events in acute care hospitals
Authors: P. Michel
Journal: BMJ (2004)

To compare the effectiveness, reliability, and acceptability of estimating rates of adverse events and rates of preventable adverse events using three methods: cross sectional (data gathered in one day), prospective (data gathered during hospital stay), and retrospective (review of medical records).Independent assessment of three methods applied to one sample.37 wards in seven hospitals (three public, four private) in southwestern France.778 patients: medical (n = 278), surgical (n = 263), and obstetric (n = 237).The main outcome measures were the proportion of cases (patients with at least one adverse event) identified by each method compared with a reference list of cases confirmed by ward staff and the proportion of preventable cases (patients with at least one preventable adverse event). Secondary outcome measures were inter-rater reliability of screening and identification, perceived workload, and face validity of results.The prospective and retrospective methods identified similar numbers of medical and surgical cases (70% and 66% of the total, respectively) but the prospective method identified more preventable cases (64% and 40%, respectively), had good reliability for identification (kappa = 0.83), represented an acceptable workload, and had higher face validity. The cross sectional method showed a large number of false positives and identified none of the most serious adverse events. None of the methods was appropriate for obstetrics.The prospective method of data collection may be more appropriate for epidemiological studies that aim to convince clinical teams that their errors contribute significantly to adverse events, to study organisational and human factors, and to assess the impact of risk reduction programmes.