tbuckley/cabot-search huggingface dataset:
Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis
Authors: A. Roy, M. Eisenhut, R. J. Harris, L. C. Rodrigues, S. Sridhar, S. Habermann, L. Snell, P. Mangtani, I. Adetifa, A. Lalvani, I. Abubakar
Journal: BMJ (2014)

<b>Objectives</b> To determine whether BCG vaccination protects against <i>Mycobacterium tuberculosis</i> infection as assessed by interferon γ release assays (IGRA) in children. <b>Design</b> Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. <b>Setting</b> Community congregate settings and households. <b>Inclusion criteria</b> Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with <i>M tuberculosis</i> with interferon γ release assays. <b>Data extraction </b>Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. <b>Results</b> The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). <b>Conclusions</b> BCG protects against <i>M tuberculosis</i> infection as well as progression from infection to disease. <b>Trial registration</b> PROSPERO registration No CRD42011001698 (www.crd.york.ac.uk/prospero/).
Nonantithrombotic Medical Options in Acute Coronary Syndromes
Authors: Victor Soukoulis, William E. Boden, Sidney C. Smith, Patrick T. O’Gara
Journal: Circulation Research (2014)

Acute coronary syndromes (ACS) constitute a spectrum of clinical presentations ranging from unstable angina and non-ST-segment elevation myocardial infarction to ST-segment myocardial infarction. Myocardial ischemia in this context occurs as a result of an abrupt decrease in coronary blood flow and resultant imbalance in the myocardial oxygen supply-demand relationship. Coronary blood flow is further compromised by other mechanisms that increase coronary vascular resistance or reduce coronary driving pressure. The goals of treatment are to decrease myocardial oxygen demand, increase coronary blood flow and oxygen supply, and limit myocardial injury. Treatments are generally divided into disease-modifying agents or interventions that improve hard clinical outcomes and other strategies that can reduce ischemia. In addition to traditional drugs such as β-blockers and inhibitors of the renin-angiotensin-aldosterone system, newer agents have expanded the number of molecular pathways targeted for treatment of ACS. Ranolazine, trimetazidine, nicorandil, and ivabradine are medications that have been shown to reduce myocardial ischemia through diverse mechanisms and have been tested in limited fashion in patients with ACS. Attenuating the no-reflow phenomenon and reducing the injury compounded by acute reperfusion after a period of coronary occlusion are active areas of research. Additionally, interventions aimed at ischemic pre- and postconditioning may be useful means by which to limit myocardial infarct size. Trials are also underway to examine altered metabolic and oxygen-related pathways in ACS. This review will discuss traditional and newer anti-ischemic therapies for patients with ACS, exclusive of revascularization, antithrombotic agents, and the use of high-intensity statins.
Identification of the primary collagen-binding surface on human glycoprotein VI by site-directed mutagenesis and by a blocking phage antibody
Authors: Peter A. Smethurst, Lotta Joutsi-Korhonen, Marie N. O'Connor, Erica Wilson, Nicola S. Jennings, Stephen F. Garner, Yanjun Zhang, C. Graham Knight, Timothy R. Dafforn, Ashley Buckle, Martin J. W. IJsseldijk, Philip G. de Groot, Nicholas A. Watkins, Richard W. Farndale, Willem H. Ouwehand
Journal: Blood (2003)
Transthyretin and the brain re-visited: Is neuronal synthesis of transthyretin protective in Alzheimer's disease?
Authors: Xinyi Li, Joel N Buxbaum
Journal: Molecular Neurodegeneration (2011)

Since the mid-1990's a trickle of publications from scattered independent laboratories have presented data suggesting that the systemic amyloid precursor transthyretin (TTR) could interact with the amyloidogenic β-amyloid (Aβ) peptide of Alzheimer's disease (AD). The notion that one amyloid precursor could actually inhibit amyloid fibril formation by another seemed quite far-fetched. Further it seemed clear that within the CNS, TTR was only produced in choroid plexus epithelial cells, not in neurons. The most enthusiastic of the authors proclaimed that TTR sequestered Aβ in vivo resulting in a lowered TTR level in the cerebrospinal fluid (CSF) of AD patients and that the relationship was salutary. More circumspect investigators merely showed in vitro interaction between the two molecules. A single in vivo study in Caenorhabditis elegans suggested that wild type human TTR could suppress the abnormalities seen when Aβ was expressed in the muscle cells of the worm. Subsequent studies in human Aβ transgenic mice, including those from our laboratory, also suggested that the interaction reduced the Aβ deposition phenotype. We have reviewed the literature analyzing the relationship including recent data examining potential mechanisms that could explain the effect. We have proposed a model which is consistent with most of the published data and current notions of AD pathogenesis and can serve as a hypothesis which can be tested.
Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma
Authors: Tim F Cloughesy, Koji Yoshimoto, Phioanh Nghiemphu, Kevin Brown, Julie Dang, Shaojun Zhu, Teli Hsueh, Yinan Chen, Wei Wang, David Youngkin, Linda Liau, Neil Martin, Don Becker, Marvin Bergsneider, Albert Lai, Richard Green, Tom Oglesby, Michael Koleto, Jeff Trent, Steve Horvath, Paul S Mischel, Ingo K Mellinghoff, Charles L Sawyers
Journal: PLoS Medicine (2008)

Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. Methods and Findings Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. Trial registration: http://www.ClinicalTrials.gov (#NCT00047073).
Idiopathic Pulmonary Alveolar Proteinosis as an Autoimmune Disease with Neutralizing Antibody against Granulocyte/Macrophage Colony-Stimulating Factor
Authors: Takayuki Kitamura, Naohiko Tanaka, Junichi Watanabe, None Uchida, Shiro Kanegasaki, Yoshitsugu Yamada, Koh Nakata
Journal: The Journal of Experimental Medicine (1999)

Idiopathic pulmonary alveolar proteinosis (I-PAP) is a rare disease of unknown etiology in which the alveoli fill with lipoproteinaceous material. We report here that I-PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against granulocyte/macrophage colony-stimulating factor (GM-CSF). The antibody was found to be present in all specimens of bronchoalveolar lavage fluid obtained from 11 I-PAP patients but not in samples from 2 secondary PAP patients, 53 normal subjects, and 14 patients with other lung diseases. It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro. The antibody was also found in sera from all I-PAP patients examined but not in sera from a secondary PAP patient or normal subjects, indicating that it exists systemically in I-PAP patients. As lack of GM-CSF signaling causes PAP in congenital cases and PAP-like disease in murine models, our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance.
A Mutation in the <i>SDHC</i> Gene of Complex II Increases Oxidative Stress, Resulting in Apoptosis and Tumorigenesis
Authors: Takamasa Ishii, Kayo Yasuda, Akira Akatsuka, Okio Hino, Philip S. Hartman, Naoaki Ishii
Journal: Cancer Research (2005)

Intracellular oxidative stress from mitochondria is thought to be important in carcinogenesis and tumorigenesis, but direct experimental proof is limited. In this study, a transgenic mouse cell line (SDHC E69) with a mutated SDHC gene (a subunit of complex II in the electron transport chain) was constructed to test this question. The SDHC E69 cells overproduced superoxide anion (O(2)(-)) from mitochondria, had elevated cytoplasmic carbonyl proteins and 8-OH-deoxyguanine in their DNA as well as significantly higher mutation frequencies than wild type. There were many apoptotic cells in this cell line, as predicted by the observed increase in caspase 3 activity, decrease in mitochondrial membrane potential, and structural changes in their mitochondria. In addition, some cells that escaped from apoptosis underwent transformation, as evidenced by the fact that SDHC E69 cells caused benign tumors when injected under the epithelium of nude mice. These results underscore the notion that mitochondrially generated oxidative stress can contribute to nuclear DNA damage, mutagenesis, and ultimately, tumorigenesis.
Clinical Management of Metabolic Syndrome
Authors: Scott M. Grundy, Barbara Hansen, Sidney C. Smith, James I. Cleeman, Richard A. Kahn
Journal: Circulation (2004)

Characteristics of the metabolic syndrome occur in some children and adolescents, but prevalence of the metabolic The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
Bayesian Inference of Infectious Disease Transmission from Whole-Genome Sequence Data
Authors: Xavier Didelot, Jennifer Gardy, Caroline Colijn
Journal: Molecular Biology and Evolution (2014)

Genomics is increasingly being used to investigate disease outbreaks, but an important question remains unansweredhow well do genomic data capture known transmission events, particularly for pathogens with long carriage periods or large within-host population sizes?Here we present a novel Bayesian approach to reconstruct densely sampled outbreaks from genomic data while considering within-host diversity.We infer a time-labeled phylogeny using Bayesian evolutionary analysis by sampling trees (BEAST), and then infer a transmission network via a Monte Carlo Markov chain.We find that under a realistic model of within-host evolution, reconstructions of simulated outbreaks contain substantial uncertainty even when genomic data reflect a high substitution rate.Reconstruction of a real-world tuberculosis outbreak displayed similar uncertainty, although the correct source case and several clusters of epidemiologically linked cases were identified.We conclude that genomics cannot wholly replace traditional epidemiology but that Bayesian reconstructions derived from sequence data may form a useful starting point for a genomic epidemiology investigation.
Spectrum of Mutations in the Gene for Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1)
Authors: Carsten Bergmann, Jan Senderek, Beate Sedlacek, Ioannis Pegiazoglou, Patricia Puglia, Thomas Eggermann, Sabine Rudnik-Schneborn, Laszlo Furu, Luiz F. Onuchic, Monica de Baca, Gregory G. Germino, Lisa Guay-Woodford, Stefan Somlo, Markus Moser, Reinhard Bu[Combining Diaeresis]ttner, Klaus Zerres
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Autosomal recessive polycystic kidney disease (ARPKD/PKHD1) is an important cause of renal-related and liver-related morbidity and mortality in childhood. Recently mutations in the PKHD1 gene on chromosome 6p21.1-p12 have been identified as the molecular cause of ARPKD. The longest continuous open reading frame (ORF) is encoded by a 67-exon transcript and predicted to yield a 4074–amino acid protein ("polyductin") of thus far unknown function. By now, a total of 29 different PKHD1 mutations have been described. This study reports mutation screening in 90 ARPKD patients and identifies mutations in 110 alleles making up a detection rate of 61%. Thirty-four of the detected mutations have not been reported previously. Two underlying mutations in 40 patients and one mutation in 30 cases are disclosed, and no mutation was detected on the remaining chromosomes. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. About 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin orthologue. One recurrent missense mutation (T36M) likely represents a mutational hotspot and occurs in a variety of populations. Two founder mutations (R496X and V3471G) make up about 60% of PKHD1 mutations in the Finnish population. Preliminary genotype-phenotype correlations could be established for the type of mutation rather than for the site of the individual mutation. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise. PKHD1 mutation analysis is a powerful tool to establish the molecular cause of ARPKD in a given family. Direct identification of mutations allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges. E-mail: [email protected]
Eccentric activation and muscle damage: biomechanical and physiological considerations during downhill running.
Authors: R G Eston, J Mickleborough, V Baltzopoulos
Journal: British Journal of Sports Medicine (1995)

An eccentric muscle activation is the controlled lengthening of the muscle under tension. Functionally, most leg muscles work eccentrically for some part of a normal gait cycle, to support the weight of the body against gravity and to absorb shock. During downhill running the role of eccentric work of the 'anti-gravity' muscles--knee extensors, muscles of the anterior and posterior tibial compartments and hip extensors--is accentuated. The purpose of this paper is to review the relationship between eccentric muscle activation and muscle damage, particularly as it relates to running, and specifically, downhill running.
Food‐restriction in obese dyslipidaemic diabetic mice partially restores basal contractility but not contractile reserve
Authors: An Van den Bergh, Peter Vangheluwe, Annelies Vanderper, Peter Carmeliet, Frank Wuytack, Stefan Janssens, Willem Flameng, Paul Holvoet, Paul Herijgers
Journal: European Journal of Heart Failure (2009)
Regional Expansion of Oleic Acid–Injured Lungs
Authors: MAREK A. MARTYNOWICZ, THOMAS A. MINOR, BRUCE J. WALTERS, ROLF D. HUBMAYR
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

It has been suggested that dependent regions of an injured lung are collapsed and subject to cyclic reopening and collapse during mechanical ventilation. To test this hypothesis, we measured both temporal and spatial heterogeneity of lobar expansion in oleic acid (OA)–injured dogs. Regional volumes were measured in nine dogs (seven supine and two prone) during closed loop sinusoidal oscillations of the lungs before and after OA injury using the parenchymal marker technique. In contrast to computer tomography, the parenchymal marker technique provides absolute measures of regional tissue dimensions as opposed to relative measures of regional air to liquid content. The experiments generated three major findings: (1) OA injury did not lead to the collapse of dependent lung units at FRC, (2) OA injury did not steepen the vertical gradient in regional lung volumes at FRC, and (3) during sinusoidal oscillation of the OA-injured lungs from FRC, dependent regions did not undergo cyclic reopening and collapse. On the basis of these results, we propose an alternative mechanism for the topographic variability in regional impedances and lung expansion after injury, namely liquid and foam in conducting airways.
Sarcoplasmic reticulum Ca2+ release channel complex and automatism: A matter of fine tuning
Authors: J BASSANI, R BASSANI
Journal: Cardiovascular Research (2007)

See article by Dirksen et al.  [10]  (pages 69–78) and Faber and Rudy  [15]  (pages 79–88) in this issue. 

In heart muscle, excitation contraction coupling (ECC) relies on proper release of Ca2+ from the sarcoplasmic reticulum (SR), which is accomplished by the activation of SR Ca2+ release channels (also known as ryanodine receptors, RyR) upon Ca2+ binding, a process termed calcium-induced calcium release [1]. The spontaneous activation of a cluster of RyRs produces local Ca2+ release seen under confocal fluorescence microscopy as minuscule flashes of light called Ca2+ sparks, the elementary Ca2+ release events [2].

SR release units are never totally quiescent. They keep on releasing Ca2+ randomly even during diastole, when sparks are rare in time and spatially separable [3]. During ECC, thousands of intracellular release events are synchronized by Ca2+ influx during the action potential, which causes both spatial and temporal overlap of elementary events in a way to produce a global intracellular transient increase in Ca2+ concentration ([Ca2+] i ) that initiates cell contraction. For relaxation to occur, [Ca2+] i must be reduced to the resting levels. This is accomplished by a number of transport systems that compete for Ca2+, mainly the SR Ca2+-ATPase and the Na+/Ca2+exchanger (NCX) [3].

The amount of Ca2+ released is strongly regulated by the SR Ca2+ content, both during systole [4] and diastole [5], so that release ceases at critically low SR loads, a condition in which a significant amount of Ca2+ (more than 40% of maximum load) can still be found in the organelle [4]. SR Ca2+ content, in turn, is regulated under normal physiological conditions by … 

*Centro de Engenharia Biomedica/UNICAMP, Caixa Postal 6040, 13084-971 Campinas, SP, Brazil. Tel.: +55 19 3521 9287; fax: +55 19 3289 3346. bassani{at}ceb.unicamp.br
Head and neck soft tissue sarcomas: prognostic factors and outcome in a series of patients treated at a single institution
Authors: D. Mattavelli, R. Miceli, S. Radaelli, F. Mattavelli, G. Cantù, M. Barisella, P. Quattrone, S. Stacchiotti, C. Sangalli, P.G. Casali, A. Gronchi, M. Fiore
Journal: Annals of Oncology (2013)
The Gly972Arg Polymorphism in Insulin Receptor Substrate-1 Is Associated With Decreased Birth Weight in a Population-Based Sample of Brazilian Newborns
Authors: Rosângela M.N. Bezerra, Vagner de Castro, Teresa Sales, Renato Passini, Sergio T.M. Marba, Sara T.O. Saad, Mario J.A. Saad
Journal: Diabetes Care (2002)

OBJECTIVE—We studied the association between the Gly972Arg polymorphism in insulin receptor substrate-1 (IRS-1) and birth weight in a population-based sample of Brazilian newborns. RESEARCH DESIGN AND METHODS—We studied 194 newborn children with adequate gestational age to identify the association between the Gly972Arg polymorphism and birth weight using PCR—restriction fragment length polymorphism analysis. RESULTS—The data showed that the birth weight was lower in the newborns with the Gly972Arg polymorphism in IRS-1 compared with control subjects (3,141 ±31.8 vs. 3,373 ±80.3 g, P &amp;lt; 0.008). The results also showed that the frequency of this polymorphism was increased in newborns with a birth weight &amp;lt;3,000 g (P=0.041). CONCLUSIONS—These results suggest that the genotype Gly972Arg may influence birth weight, reinforcing the hypothesis that genetically determined insulin resistance and/or reduced insulin secretion can result in impaired insulin-mediated growth in the fetus.