tbuckley/cabot-search huggingface dataset:
Ischemic preconditioning attenuates calpain-mediated degradation of structural proteins through a protein kinase A-dependent mechanism*1
Authors: J INSERTE
Journal: Cardiovascular Research (2004)

It has been shown that sarcolemmal rupture can occur during reenergization in cardiomyocytes in which previous ischemia has induced sarcolemmal fragility by calpain-dependent hydrolysis of structural proteins. We tested the hypothesis that attenuated calpain activation contributes to the protection against reperfusion-induced cell death afforded by ischemic preconditioning (IPC), and investigated the involvement of protein kinase A (PKA) in this effect.Calpain activity and degradation of different structural proteins were studied along with the extent of necrosis in isolated rat hearts submitted to 60 min of ischemia and 30 min of reperfusion with or without previous IPC (two cycles of 5 min ischemia-5 min reperfusion), and the ability of different treatments to mimic or blunt the effects of IPC were analyzed.IPC accelerated ATP depletion and rigor onset during ischemia but reduced LDH release during reperfusion by 69% (P<0.001). At the end off reperfusion, calpain activity was reduced by 66% (P<0.001) in IPC, and calpain-dependent degradation of sarcolemmal proteins was attenuated. Addition of the calpain inhibitor MDL-28170 mimicked the effects of IPC on protein degradation and reduced LDH release by 48% (P<0.001). The effects of IPC on calpain, alpha-fodrin, and LDH release were blunted by the application of the PKA inhibitor H89 or alprenolol during IPC, while transient stimulation of PKA with CPT-cAMP or isoproterenol before ischemia attenuated calpain activation, alpha-fodrin degradation, and markedly reduced LDH release (P<0.001). In hearts exposed to Na(+)-free perfusion, IPC attenuated calpain activation by 67% (P<0.001) and reduced by 56% (P<0.001) LDH release associated to massive edema occurring during Na(+) readmission without modifying its magnitude.These results are consistent with PKA-dependent attenuation of calpain-mediated degradation of structural proteins being an end-effector mechanism of the protection afforded by IPC.
A critical analysis of mini peer assessment tool (mini-PAT)
Authors: Aza Abdulla
Journal: Journal of the Royal Society of Medicine (2008)

The structured evaluation of doctors’ performance through peer review is a relatively new phenomenon brought about by public demand for accountability to patients. Medical knowledge (as assessed by examination score) is no longer a good predictor of individual performance, humanistic qualities and communication skills. The process of peer review (or multi-source assessment) was developed over the last two decades in the USA and has started to pick up momentum in the UK through the introduction of Modernizing Medical Careers. However the concept is not new. Driven by market forces, it was initially developed by industrial organizations to improve leadership qualities with a view to increasing productivity through positive behaviour change and self-awareness. Multi-source feedback is not without its problems and may not always produce its desired outcomes. In this article we review the evidence for peer review and critically discuss the current process of mini peer assessment tool (mini-PAT) as the assessment tool for peer review employed in UK.
Mechanisms of Tubulointerstitial Fibrosis
Authors: Michael Zeisberg, Eric G. Neilson
Journal: Journal of the American Society of Nephrology (2010)

The pathologic paradigm for renal progression is advancing tubulointerstitial fibrosis. Whereas mechanisms underlying fibrogenesis have grown in scope and understanding in recent decades, effective human treatment to directly halt or even reverse fibrosis remains elusive. Here, we examine key features mediating the molecular and cellular basis of tubulointerstitial fibrosis and highlight new insights that may lead to novel therapies. How to prevent chronic kidney disease from progressing to renal failure awaits even deeper biochemical understanding.
PAI-1 is an essential component of the pulmonary host response during Pseudomonas aeruginosa pneumonia in mice
Authors: A. Goolaerts, M. Lafargue, Y. Song, B. Miyazawa, M. Arjomandi, M. Carles, J. Roux, M. Howard, D. A. Parks, K. E. Iles, J.-F. Pittet
Journal: Thorax (2011)

<h3>Rationale</h3> Elevated plasma and bronchoalveolar lavage fluid plasminogen activator inhibitor 1 (PAI-1) levels are associated with adverse clinical outcome in patients with pneumonia caused by <i>Pseudomonas aeruginosa</i>. However, whether PAI-1 plays a pathogenic role in the breakdown of the alveolar–capillary barrier caused by <i>P aeruginosa</i> is unknown. <h3>Objectives</h3> The role of PAI-1 in pulmonary host defence and survival during <i>P aeruginosa</i> pneumonia in mice was tested. The in vitro mechanisms by which <i>P aeruginosa</i> causes PAI-1 gene and protein expression in lung endothelial and epithelial cells were also examined. <h3>Methods and results</h3> PAI-1 null and wild-type mice that were pretreated with the PAI-1 inhibitor Tiplaxtinin had a significantly lower increase in lung vascular permeability than wild-type littermates after the airspace instillation of 1×10<sup>7</sup> colony-forming units (CFU) of <i>P aeruginosa</i> bacteria. Furthermore, <i>P aeruginosa</i> in vitro induced the expression of the PAI-1 gene and protein in a TLR4/p38/RhoA/NF-κB (Toll-like receptor 4/p38/RhoA/nuclear factor-κB) manner in lung endothelial and alveolar epithelial cells. However, in vivo disruption of PAI-1 signalling was associated with higher mortality at 24 h (p&lt;0.03) and higher bacterial burden in the lungs secondary to decreased neutrophil migration into the distal airspace in response to <i>P aeruginosa</i>. <h3>Conclusions</h3> The results indicate that PAI-1 is a critical mediator that controls the development of the early lung inflammation that is required for the activation of the later innate immune response necessary for the eradication of <i>P aeruginosa</i> from the distal airspaces of the lung.
Validation of automated sleep analysis in normal children
Authors: MP Villa, S Piro, A Dotta, E Bonci, P Scola, B Paggi, MG Paglietti, F Midulla, R Ronchetti
Journal: European Respiratory Journal (1998)

With the aim of determining normal reference values for our sleep laboratory and evaluating the reliability of automated analysis for scoring polysomnographic studies in children, we recorded polysomnograms in 16 healthy boarding-school children. Sleep recordings were obtained with a computer system (Medilog SAC, Oxford Instruments). Polysomnographic variables were monitored continuously on a 16-channel recorder equipped with a video. Data were acquired on optical disk for computer-assisted data interpretation. Sleep stages and respiratory events were also scored visually by operator. Comparison with visual scores showed that the computer system significantly overscored wakefulness (W) (p<0.02) and stage IV (p<0.001) and underscored stage II (p<0.001) and rapid eye movement (REM) sleep (p<0.001). It also assigned respiratory events a higher score than did visual scoring, as shown by the higher apnoea index (AI) and hypopnoea index (HI) (AI p<0.03; HI p<0.001). Regression analysis showed a significant correlation between visual and automated scores for central (r=0.679; p<0.004) and obstructive apnoea (r=0.631; p<0.008). Computer apnoea scores did not correlate with visual scores. Much remains to be done before computer-based scoring systems can be relied upon, without visual scoring, for polysomnographic sleep studies in children. Their main advantage at present is that they offer a convenient means of saving paper, space and time.
Ligand-dependent Notch Signaling Is Involved in Tumor Initiation and Tumor Maintenance in Pancreatic Cancer
Authors: Michael E. Mullendore, Jan-Bart Koorstra, Yue-Ming Li, G. Johan Offerhaus, Xing Fan, Clark M. Henderson, William Matsui, Charles G. Eberhart, Anirban Maitra, Georg Feldmann
Journal: Clinical Cancer Research (2009)

Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has not been elucidated.A panel of 20 human pancreatic cancer cell lines was profiled for the expression of Notch pathway-related ligands, receptors, and target genes. Disruption of intracellular Notch signaling, either genetically by RNA interference targeting NOTCH1 or pharmacologically by means of the gamma-secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance.Striking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently JAGGED2 (18 of 20 cases, 90%) and DLL4 (10 of 20 cases, 50%). In two cell lines, genomic amplification of the DLL3 locus was observed, mirrored by overexpression of DLL3 transcripts. In contrast, coding region mutations of NOTCH1 or NOTCH2 were not observed. Genetic and pharmacologic inhibition of Notch signaling mitigated anchorage-independent growth in pancreatic cancer cells, confirming that sustained Notch activation is a requirement for pancreatic cancer maintenance. Further, transient pretreatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase-expressing subpopulation and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase-expressing cells in pancreatic cancer initiation.Our studies confirm that Notch activation is almost always ligand dependent in pancreatic cancer, and inhibition of Notch signaling is a promising therapeutic strategy in this malignancy.
Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43
Authors: Harold V.M. van Rijen, Dominik Eckardt, Joachim Degen, Martin Theis, Thomas Ott, Klaus Willecke, Habo J. Jongsma, Tobias Opthof, Jacques M.T. de Bakker
Journal: Circulation (2004)

Background— Connexin 43 (Cx43) is a major determinant of conduction in the ventricular working myocardium of mammals. We investigated the effect of decreased Cx43 expression on conduction velocity and arrhythmogenesis using adult mice with inducible deletion of Cx43. Methods and Results— Cx43 Cre-ER(T)/+ mice, in which 1 coding region of the Cx43 gene was replaced by Cre-ER(T), were mated to Cx43 fl/fl mice, generating Cx43 Cre-ER(T)/fl mice. Application of 4-hydroxytamoxifen (4-OHT) induced Cre-ER(T)–mediated deletion of the floxed Cx43 allele. Epicardial ventricular mapping using a 13×19 multiterminal electrode grid (300-μm spacing) was performed on Langendorff-perfused hearts from Cx43 fl/fl plus carrier (n=10), Cx43 fl/fl plus 4-OHT (n=10), Cx43 Cre-ER(T)/fl plus carrier (n=9), and Cx43 Cre-ER(T)/fl plus 4-OHT (n=10). Cx43 protein amount in group 3 hearts was decreased by ≈50% compared with group 1. 4-OHT did not affect cardiac protein amounts in group 2 but decreased Cx43 expression up to 95% in group 4 compared with group 3. Epicardial activation of both left ventricle (LV) and right ventricle (RV) during sinus rhythm was similar in all groups. Conduction velocity (CV) changed only in group 4 animals. For RV (LV), longitudinal CV decreased from 38 (35) to 31.6 (33.6) and transverse CV from 24.4 (16.8) to 10.1 (11.3) cm/s. Dispersion of conduction in RV (LV) was increased by 91% (38%). Programmed stimulation resulted in ventricular arrhythmias in group 4 (7 of 10 mice) but never in groups 1 through 3. Conclusions— Heterozygous expression of Cx43 did not affect ventricular conduction velocity. Up to 95% decrease of Cx43 protein in 4-OHT–treated Cx43 Cre-ER(T)/fl mice reduced conduction velocity and increased dispersion of conduction and propensity for ventricular arrhythmias.
Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis
Authors: Takehiko Dohi, Elena Beltrami, Nathan R. Wall, Janet Plescia, Dario C. Altieri
Journal: Journal of Clinical Investigation (2004)

Evasion of apoptosis is a hallmark of cancer, but the molecular circuitries of this process are not understood. Here we show that survivin, a member of the inhibitor of apoptosis gene family that is overexpressed in cancer, exists in a novel mitochondrial pool in tumor cells. In response to cell death stimulation, mitochondrial survivin is rapidly discharged in the cytosol, where it prevents caspase activation and inhibits apoptosis. Selective targeting of survivin to mitochondria enhances colony formation in soft agar, accelerates tumor growth in immunocompromised animals, and abolishes tumor cell apoptosis in vivo. Therefore, mitochondrial survivin orchestrates a novel pathway of apoptosis inhibition, which contributes to tumor progression.
Variation of Dihydrofolate Reductase Activity During &lt;italic&gt;In Vitro&lt;/italic&gt; and &lt;italic&gt;In Vivo&lt;/italic&gt; Growth of Sublines of L1210 Lymphoma&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Brian L. Hillcoat
Journal: JNCI Journal of the National Cancer Institute (1971)

Three cloned strains of L1210 lymphoma were isolated and studied in suspension culture and mice. All lines doubled more slowly in vivo (24 hr) than in vitro (19 hr) and differed in their lethal effect on mice, in their chromosomes, and their sensitivity to growth inhibition by methotrexate. However, no significant difference occurred in enzyme behavior in any one cell during in vitro and in vivo growth. The transfer of cells from culture to mice can be used to increase significantly the yield of cells available for enzyme studies.
Management of stroke in childhood
Authors: Lewis Rosenbloom
Journal: BMJ (2005)

Guidelines are welcome, but have some gaps—such as perinatal stroke 

Stroke care for adults has been revolutionised in recent years, possibly in association with the publication of national clinical guidelines for stroke.1 In consequence, rehabilitative care after stroke for adults is now considered the norm. Stroke is less common in children, and clinical experience and anecdotal evidence indicate that children may receive a variable quality of care. A welcome development therefore has been the publication last year of guidelines by the UK Royal College of Physicians paediatric stroke working group.2

The guidelines deal mainly with the diagnosis, investigation, and management of acute arterial ischaemic stroke in children beyond the neonatal period, covering acute presentation, management, rehabilitation, and longer term care. …
Vascular Cell Adhesion Molecule 1 Predicts Cancer-Free Survival in Clear Cell Renal Carcinoma Patients
Authors: Ko-ichi Shioi, Atsushi Komiya, Keiko Hattori, Ying Huang, Futoshi Sano, Takayuki Murakami, Noboru Nakaigawa, Takeshi Kishida, Yoshinobu Kubota, Yoji Nagashima, Masahiro Yao
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Vascular cell adhesion molecule 1 (VCAM1) is a cell surface glycoprotein implicated in various pathophysiologic conditions. We measured VCAM1 expression levels in tumor tissues and evaluated its significance and prognostic use in renal cell carcinoma (RCC). Experimental Design: We used real-time quantitative PCR to examine the VCAM1 expression levels of a total of 485 sporadic renal tumors, including 429 clear cell, 21 papillary, 17 chromophobe, 11 oncocytomas, and 7 collecting duct carcinomas. We retrospectively examined the relationship of this expression to various clinicopathologic variables and the von Hippel-Lindau alteration status. We evaluated its significance with respect to patient survival rates using the Cox regression model combined with the split-sample method. Results: Compared with normal kidney samples (n = 43), VCAM1 was significantly up-regulated in clear cell RCC and papillary RCC, whereas it was down-regulated in chromophobe RCC and oncocytoma. In clear cell RCC, VCAM1 expression levels were apparently high in patients asymptomatic at presentation and in patients with small tumor size, low-stage, low-grade, microvascular invasion–negative, and von Hippel-Lindau alteration-positive tumors. Univariate analyses showed that VCAM1 high expression is strongly associated with better outcomes in clear cell and papillary RCCs. Further, Cox multivariate analysis models combined with the split-sample method revealed that this association is significant only in cancer-free survival for patients with clear cell RCC after curative surgical resection. Conclusions: VCAM1 expression levels were found to be histologically subtype specific in renal tumors. Determination of the VCAM1 expression level as a biomarker can provide useful prognostic information for patients with clear cell RCC.
Disruption of Inducible Nitric Oxide Synthase Improves β-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced Cardiomyopathy
Authors: Hajime Funakoshi, Toru Kubota, Natsumi Kawamura, Yoji Machida, Arthur M. Feldman, Hiroyuki Tsutsui, Hiroaki Shimokawa, Akira Takeshita
Journal: Circulation Research (2002)

Abstract— Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-α develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates β-adrenergic hyporesponsiveness in TG mice. To examine whether long-term inhibition of iNOS may rescue TG mice from developing congestive heart failure, we disrupted iNOS gene by crossing TG mice with iNOS knockout mice. Myocardial levels of iNOS protein were significantly increased in TG mice compared with age- and sex-matched wild-type (WT) mice. No iNOS protein was detected in TG mice with the disruption of iNOS. Myocardial levels of endothelial NOS were not different among these mice. To examine the effects of iNOS disruption on myocardial contractility, left ventricular pressure was measured. In TG mice, +dP/dt max was significantly suppressed, and its β-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved β-adrenergic inotropic responsiveness in TG mice but not in WT mice. However, the iNOS disruption did not alter myocardial inflammation, ventricular hypertrophy, or the survival of these mice. These results indicate that although myocardial expression of iNOS plays a key role in the attenuation of β-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.
Respiratory function and self-reported functional health: EPIC-Norfolk population study
Authors: P. K. Myint, R. N. Luben, P. G. Surtees, N. W. J. Wainwright, A. A. Welch, S. A. Bingham, N. J. Wareham, N. E. Day, K-T. Khaw
Journal: European Respiratory Journal (2005)

Respiratory function is known to be associated with mortality. However, its association with health related quality of life (HRQoL) has not yet been examined. A population-based cross sectional study was conducted in 16,738 subjects aged 40–79 yrs and resident in Norfolk, to examine the association between forced expiratory volume in one second (FEV 1 ) and HRQoL measured by the 36-item short form questionnaire. Individuals who were in the highest quintiles of FEV 1 were more likely to report good physical functional health (odds ratio (OR) 1.60; 95% confidence interval (CI) 1.28–2.01 and OR 1.71; 95% CI 1.40–2.10 for males and females, respectively) controlling for age, height, weight or body mass index, smoking, physical activity, prevalent illness and social class. Being in the highest quintile for FEV 1 was associated with significantly lower likelihood of poor self-reported mental functional health status in males (OR 0.78; 95% CI 0.61–0.99), but not in females (OR 1.00; 95% CI 0.82–1.22). In conclusion, forced expiratory volume in one second independently predicts self perceived physical well being in a general population across the whole normal distribution of respiratory function.
Residential Dampness Problems and Symptoms and Signs of Bronchial Obstruction in Young Norwegian Children
Authors: PER NAFSTAD, LEIF ØIE, REIDAR MEHL, PER I. GAARDER, KARIN C.L ØDRUP-CARLSEN, GRETE BOTTEN, PER MAGNUS, JOUNI J. K. JAAKKOLA
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

To assess the role of dampness problems and house dust mite exposure in the development of bronchial obstruction in early life, a cohort of 3,754 children born in Oslo during 1992 and 1993 was followed for 2 yr. Bronchial obstruction was defined as two or more episodes with symptoms and signs of obstruction or one lasting 1 mo or more. A matched case-control study was carried out in 251 cases of bronchial obstruction (response rate: 98%) and their 251 paired controls. Information on home dampness problem(s), house dust mite exposure, and potential confounders was collected during home visits and by questionnaires. Dampness problems were confirmed in the homes of 27% of the cases and 14% of the controls, while a concentration of Dermatophagoides pteronyssinus allergens > 2 microg/g dust was found in the beds of 11 (4.5%) cases and three (1.2%) controls. In conditional logistic regression analysis controlling for potential confounders, confirmed dampness problems increased the risk of bronchial obstruction (adjusted odds ratio: 3.8; 95% confidence interval: 2.0-7.2). Exposure to D. pteronyssinus allergens > 2 microg/g dust increased the risk of bronchial obstruction (adjusted odds ratio: 2.8; 95% confidence interval: 0.7-11.7). Residential dampness problems in Oslo dwellings seem to increase symptoms and signs of bronchial obstruction in young children, apparently without increasing their exposure to house dust mites.
Barriers to Physical Activity Among Predominantly Low-Income African- American Patients With Type 2 Diabetes
Authors: Gareth R. Dutton, Jolene Johnson, Dori Whitehead, Jamie S. Bodenlos, Phillip J. Brantley
Journal: Diabetes Care (2005)

Physical activity is one of the most neglected aspects of the type 2 diabetes treatment regimen (1). Environmental barriers may play a role (2), particularly among African-American patients who report more physical activity barriers than Caucasians (3,4). African-American focus groups reported numerous barriers, including unsafe walking areas, transportation problems, lack of child care, peripheral neuropathy, and degenerative joint disease, some of which are not assessed by existing questionnaires (5,6). Despite these initial qualitative findings from focus groups, there is limited quantitative research addressing physical activity barriers specific to African-American or low-income diabetic samples. The current objective was to examine barriers reported by this population. The relationships between barriers and medical outcomes, demographic variables, and attitudes about exercise were examined.

Participants included 105 adult patients with type 2 diabetes attending primary care appointments. The clinic was affiliated with a public teaching hospital providing care to predominantly low-income African-American patients. Patients were approached in the waiting room before appointments. After obtaining informed consent, study personnel administered demographic and diabetes history questionnaires. They assessed 35 perceived barriers to physical activity, which were taken from several …