tbuckley/cabot-search huggingface dataset:
Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation
Authors: A J Slooter, M X Tang, C M van Duijn, Y Stern, A Ott, K Bell, M M Breteler, C Van Broeckhoven, T K Tatemichi, B Tycko, A Hofman, R Mayeux
Journal: JAMA (1997)

To investigate the association between the apolipoprotein E (APOE) genotypes and dementia in patients with stroke, defined as either vascular dementia (VaD) or Alzheimer disease with cerebrovascular disease (AD with CVD).Population-based, case-control study from Rotterdam, the Netherlands, and New York City.A total of 187 patients with dementia and stroke were compared with 507 controls similar in age and ethnic group.The APOE allele frequencies in patients and controls; the odds ratio of dementia with stroke, VaD, and AD with CVD, adjusted for age, sex, residency, and education; and the percent attributable risk related to the APOE epsilon4 allele.Overall, patients with dementia and stroke had a higher APOE epsilon4 allele frequency than controls. Compared with APOE epsilon3 homozygote individuals, APOE epsilon4 homozygotes had a 7-fold increased risk of dementia with stroke (OR=6.9; 95% CI, 1.6-29.4), while APOE epsilon4 heterozygotes had nearly a 2-fold increase in risk (OR=1.8; 95% CI, 1.2-2.7). Risks associated with APOE epsilon4 were elevated regardless of the subtype of dementia with stroke or age or sex. The percent attributable risk related to the APOE epsilon4 allele among demented patients with stroke was 41% overall, 33% among those with VaD, and 44% among those with AD with CVD.The APOE epsilon4 allele is a genetic risk factor for dementia with stroke, including VaD and AD with CVD. This may imply shared genetic susceptibility to dementia associated with stroke and AD. Alternatively, the category of patients with dementia and stroke, including VaD as currently defined, may include patients with AD.
Community-acquired methicillin-resistant Staphylococcus aureus infections: an emerging threat in Spain
Authors: A. Manzur, A.M. Dominguez, M. Pujol, M.P.M. González, E. Limon, A. Hornero, R. Martín, F. Gudiol, J. Ariza
Journal: Clinical Microbiology and Infection (2008)
Natural history and predictors for progression of mild childhood obstructive sleep apnoea
Authors: A M Li, C T Au, S K Ng, V J Abdullah, C Ho, T F Fok, P C Ng, Y K Wing
Journal: Thorax (2009)

<h3>Aims:</h3> The natural history of mild childhood obstructive sleep apnoea (OSA) was examined and factors associated with disease progression were identified. <h3>Methods:</h3> Subjects were recruited from an epidemiological study which examined the prevalence of OSA in Chinese children aged 6–13 years. The first 56 consecutive children identified with mild OSA (apnoea-hypopnoea index 1–5) were invited for a repeat assessment 2 years after the diagnosis. <h3>Results:</h3> 45 children participated in the follow-up study, in 13 of whom (29%) the OSA was found to have worsened. Compared with those in whom OSA had not worsened, the worsened OSA group had a greater increase in waist circumference, a higher prevalence of large tonsils (occupying ⩾50% of the airway) at both baseline and follow-up, and a higher prevalence of habitual snoring at both baseline and follow-up. The presence of large tonsils had a positive predictive value of 53% and a negative predictive value of 83% for worsening OSA over a 2-year period. Multivariate linear regression analysis showed that the change in obstructive apnoea-hypopnoea index was associated with age at baseline (β (SE) = −0.92 (0.34), p = 0.009), gender (male = 1; female = 0) (β (SE) = 4.69 (1.29), p&lt;0.001), presence of large tonsils at baseline (β (SE) = 4.36 (1.24), p = 0.001), change in waist circumference (β (SE) = 0.30 (0.09), p = 0.002) and persistently large tonsils (β (SE) = 5.69 (1.36), p&lt;0.001) over the 2-year period. <h3>Conclusions:</h3> Mild OSA in the majority of children does not resolve spontaneously. Subjects with tonsillar hypertrophy, especially boys, should be closely monitored to allow early detection of worsening OSA. Weight control should be stressed in the management of childhood OSA.
Therapeutic Efficacy of a Novel Focal Adhesion Kinase Inhibitor TAE226 in Ovarian Carcinoma
Authors: Jyotsnabaran Halder, Yvonne G. Lin, William M. Merritt, Whitney A. Spannuth, Alpa M. Nick, Toshiyuki Honda, Aparna A. Kamat, Liz Y. Han, Tae Jin Kim, Chunhua Lu, Ana M. Tari, William Bornmann, Ariel Fernandez, Gabriel Lopez-Berestein, Anil K. Sood
Journal: Cancer Research (2007)

Abstract Focal adhesion kinase (FAK) overexpression is frequently found in ovarian and other cancers and is predictive of poor clinical outcome. In the current study, we characterized the biological and therapeutic effects of a novel FAK inhibitor, TAE226. Taxane-sensitive (SKOV3ip1 and HeyA8) and taxane-resistant (HeyA8-MDR) cell lines were used for in vitro and in vivo therapy experiments using TAE226 alone and in combination with docetaxel. Assessment of cytotoxicity, cell proliferation [proliferating cell nuclear antigen (PCNA)], angiogenesis (CD31), and apoptosis (terminal nucleotidyl transferase–mediated nick end labeling) were done by immunohistochemistry and immunofluorescence. In vitro, TAE226 inhibited the phosphorylation of FAK at both Y397 and Y861 sites, inhibited cell growth in a time- and dose-dependent manner, and enhanced docetaxel-mediated growth inhibition by 10- and 20-fold in the taxane-sensitive and taxane-resistant cell lines, respectively. In vivo, FAK inhibition by TAE226 significantly reduced tumor burden in the HeyA8, SKOV3ip1, and HeyA8-MDR models (46–64%) compared with vehicle-treated controls. However, the greatest efficacy was observed with concomitant administration of TAE226 and docetaxel in all three models (85–97% reduction, all P values &amp;lt;0.01). In addition, TAE226 alone and in combination with chemotherapy significantly prolonged survival in tumor-bearing mice. Even in larger tumors, combination therapy with TAE226 and docetaxel resulted in tumor regression. The therapeutic efficacy was related to reduced pericyte coverage, induction of apoptosis of tumor-associated endothelial cells, and reduced microvessel density and tumor cell proliferation. The novel FAK inhibitor, TAE226, offers an attractive therapeutic approach in ovarian carcinoma. [Cancer Res 2007;67(22):10976–83]
Effects of experimental phosphate deficiency on action potential characteristics and contractile performance of rat myocardium
Authors: J. M CAPASSO, R. S ARONSON, J. E STROBECK, E. H SONNENBLICK
Journal: Cardiovascular Research (1982)

Chronic hypophosphataemia is associated with reversible depression in myocardial performance of the intact heart. To define the basis for this, we studied the mechanical and electrical properties of isolated left ventricular papillary muscles from rats with 6 weeks of phosphorus depletion (P6), 6 weeks of phosphorus repletion and age-matched controls (C). Muscles were perfused with Tyrode's solution (Ca2+ = 2.4 mmol·litre−1, K+ = 4.0 mmol·litre−1, dextrose = 5.5 mmol·litre−1) and driven at 0.1 Hz. P6 muscles had slowed isometric relaxation (T1/2R), depressed velocity of shortening and relaxation and prolongation of the transmembrane action potential to 75% of complete repolarisation. These results suggest that the slow relaxation phase may be the result of the prolonged APD75 and that the depressed myocardial performance in the intact heart may be based on impaired relaxation and reduced the velocity of shortening associated with hypophosphataemia. This view is supported by our finding that these alterations are reversible with phosphate repletion.
Analysis of long repeats in bacterial genomes reveals alternative evolutionary mechanisms in Bacillus subtilis and other competent prokaryotes
Authors: E. P. Rocha, A. Danchin, A. Viari
Journal: Molecular Biology and Evolution (1999)

Prokaryotic genomes seem to be optimized toward compactness and have therefore been thought to lack long redundant DNA sequences. However, we identified a large number of long strict repeats in eight prokaryotic complete genomes and found that their density is negatively correlated with genome size. A detailed analysis of the long repeats present in the genome of Bacillus subtilis revealed a very strict constraint on the spatial distribution of repeats in this genome. We interpret this as the hallmark of selection processes leading to the addition of new genetic information. Such addition is independent of insertion sequences and relies on the nonspecific DNA uptake by the competent cell and its subsequent integration in the chromosome in a circular form through a Campbell-like mechanism. Similar patterns are found in other competent genomes of Gram-negative bacteria and Archaea, suggesting a similar evolutionary mechanism. The correlation of the spatial distribution of repeats and the absence of insertion sequences in a genome may indicate, in the framework of our model, that mechanisms aiming at their avoidance/elimination have been developed.
Disease Course Patterns After Discontinuation of Bevacizumab: Pooled Analysis of Randomized Phase III Trials
Authors: David Miles, Nadia Harbeck, Bernard Escudier, Herbert Hurwitz, Leonard Saltz, Eric Van Cutsem, Jim Cassidy, Barbara Mueller, Florin Sirzén
Journal: Journal of Clinical Oncology (2010)

Preclinical studies have suggested accelerated tumor growth, local invasion, and distant metastasis after withdrawal of treatment with some antiangiogenic agents. To investigate whether discontinuation of bevacizumab treatment is associated with accelerated disease progression or increased mortality, we retrospectively analyzed five randomized, placebo-controlled phase III studies in 4,205 patients with breast, colorectal, renal, and pancreatic cancer.Time from treatment discontinuation to progressive disease or death was analyzed in patients discontinuing bevacizumab/placebo as a result of adverse events (AEs). Mortality rates were assessed at 30, 60, 90, 120, 150, 180, and 210 days after the last bevacizumab/placebo dose in the following two groups: patients discontinuing bevacizumab/placebo as a result of AEs and patients discontinuing bevacizumab/placebo for any reason. In the same groups, time from treatment discontinuation to death was analyzed. Data on disease progression pattern were available and analyzed in four of the five studies.In the pooled analysis, median time from discontinuation as a result of AEs to progression/death was 3.0 months (95% CI, 2.6 to 3.8 months) for placebo and 4.0 months (95% CI, 3.4 to 4.6 months) for bevacizumab (hazard ratio, 0.93; 95% CI, 0.79 to 1.10). Mortality rates from 30 days to 210 days after treatment discontinuation and time from discontinuation to death were similar in bevacizumab- and placebo-treated patients. In addition, similar patterns of disease progression were seen in bevacizumab- and placebo-treated patients.This retrospective analysis of five placebo-controlled clinical trials does not support a decreased time to disease progression, increased mortality, or altered disease progression pattern after cessation of bevacizumab therapy.
Interleukin 1 receptor antagonist mediates the beneficial effects of systemic interferon beta in mice: implications for rheumatoid arthritis
Authors: M. Corr, D. L. Boyle, L. M. Ronacher, B. R. Lew, L. G. van Baarsen, P. P. Tak, G. S. Firestein
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> Interferon beta (IFNβ) therapy is effective in multiple sclerosis and murine models of arthritis. Surprisingly, systemic IFNβ treatment induces only minimal improvement in rheumatoid arthritis (RA). To explain this paradox, the authors evaluated the mechanism of IFNβ benefit in passive K/BxN arthritis and the effect of IFNβ treatment on RA synovium. <h3>Methods</h3> Interleukin 10 (IL-10) null, IL-1 receptor antagonist (IL-1Ra) null, IL-1Ra transgenic and wild-type mice were administered K/BxN serum and in some cases treated with IFNβ or normal saline. Clinical response and histological scores were assessed. Gene expression was measured by quantitative PCR. Serum IL-1Ra and IL-6 were measured by ELISA. Paired synovial biopsy specimens from RA patients pre-IFNβ and post-IFNβ treatment (purified natural fibroblast IFNβ (Frone) subcutaneously three times weekly 6 million IU, 12 million IU or 18 million IU) were immunostained for IL-1Ra and IL-10. <h3>Results</h3> <i>Il1rn</i> transgenic mice had an attenuated course of arthritis, whereas <i>Il1rn</i><sup>−/−</sup> and <i>Il10</i><sup>−/−</sup> mice had more severe serum transfer arthritis than wild-type mice. Daily IFNβ treatment significantly decreased arthritis severity in <i>Il10</i><sup>−/−</sup> but not <i>Il1rn</i><sup>−/−</sup> mice. IFNβ treatment did not reduce the histological scores in <i>Il1rn</i><sup>−/−</sup> mice or gene expression of articular cytokines and chemokines. Paired synovial biopsy specimens from RA patients treated with IFNβ demonstrated a trend towards increased IL-1Ra and reduced IL-10 expression on day 85 levels compared with pretreatment specimens. <h3>Conclusions</h3> The anti-inflammatory effects of IFNβ in passive K/BxN arthritis are dependent on IL-1Ra, but not IL-10. Systemic IFNβ treatment in RA increases synovial IL-1Ra production, but also decreases IL-10 production.
Toward Alzheimer Therapies Based on Genetic Knowledge
Authors: John Hardy
Journal: Annual Review of Medicine (2004)

Genetic analysis has allowed the dissection of the pathogenic pathway that leads to Alzheimer's disease. It has also been integral to the development of earlier and more accurate diagnostic practices. This analysis has identified many potential therapeutic targets, and clinical trials aimed at these targets are now under way. If these approaches are successful, it will be a spectacular validation of genetic-knowledge-based treatment strategies; if they are not, researchers will need to re-evaluate this approach toward understanding and developing strategies for treating complex diseases.
Appraising Pulmonary Edema Using Supine Chest Roentgenograms in Ventilated Patients
Authors: JASON W. W. THOMASON, E. WESLEY ELY, CAROLINE CHILES, GILBERT FERRETTI, RITA I. FREIMANIS, EDWARD F. HAPONIK
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The role of portable, anteroposterior, supine chest X-rays (CXRs) in distinguishing hydrostatic pulmonary edema (HPE) from permeability pulmonary edema (PPE) in mechanically ventilated patients is controversial. We prospectively obtained and evaluated such CXRs in 33 supine, mechanically ventilated intensive-care-unit patients with pulmonary artery catheters. Three chest radiologists independently reviewed CXRs without clinical information and recorded the cardiothoracic (CT) ratio, vascular pedicle width (VPW), and other radiographic features commonly used to evaluate pulmonary edema. Hydrostatic pulmonary edema was associated with a larger CT ratio (p < 0.001), subjective impressions of cardiomegaly (p < 0.01), and increased VPW (p = 0.02). There was a significant correlation between the pulmonary artery occlusion pressure and the VPW (r = 0.45, p = 0.0076) and CT ratio (r = 0.52, p = 0.0016), as well as between the VPW and CT ratio (r = 0.49, p = 0.0032). Despite this detailed evaluation of the CXRs, the mean accuracy of the radiologists' clinical diagnosis of HPE versus PPE was 41%, and 15 of 19 (79%) of PPE patients showed one or more roentgenographic signs of volume overload. Receiver-operating-characteristic curves were constructed to determine optimum cut-off values of VPW and CT ratio associated with HPE. Hydrostatic pulmonary edema was found to correlate best using a VPW > 63 mm coupled to a CT ratio > 0.52 (p = 0.027). With this combination of objective criteria, radiologists' diagnostic accuracy could have been increased to 73%. We therefore conclude that measurements of CT ratio and VPW correlate with pulmonary artery occlusion pressure in supine, mechanically ventilated patients. Distinction of hydrostatic from permeability pulmonary edema is difficult using portable, supine CXRs, but readily assessed radiologic signs may contribute to the correct diagnosis.
The Role of Cyclooxygenase-2 in Mediating the Effects of Histamine on Cell Proliferation and Vascular Endothelial Growth Factor Production in Colorectal Cancer
Authors: Fabio Cianchi, Camillo Cortesini, Nicola Schiavone, Federico Perna, Lucia Magnelli, Elena Fanti, Daniele Bani, Luca Messerini, Valentina Fabbroni, Giuliano Perigli, Sergio Capaccioli, Emanuela Masini
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Activity of histidine decarboxylase, the key enzyme in the synthesis of histamine, has been shown to be increased in several types of human tumors. We attempted to establish whether the possible involvement of histidine decarboxylase and histamine in colorectal carcinogenesis might be mediated by the activation of the cyclooxygenase-2 (COX-2) pathway. Experimental Design: Expression/activity of histidine decarboxylase, histamine content, and prostaglandin E2 (PGE2) production were analyzed in 33 colorectal cancer samples and in the HT29, Caco-2, and HCT116 colon cancer cell lines. The effects of histamine, celecoxib, and H1, H2, and H4 receptor antagonists on COX-2 expression/activity, cell proliferation, and vascular endothelial growth factor (VEGF) production were assessed in the three colon cancer lines that showed different constitutive COX-2 expression. Results: We showed the up-regulation of histidine decarboxylase protein expression and activity in the tumor specimens when compared with normal colonic mucosa. Histidine decarboxylase activity and histamine content were also significantly higher in metastatic tumors than in nonmetastatic ones. These variables significantly correlated with tumor PGE2 production. The administration of histamine increased COX-2 expression/activity, cell proliferation, and VEGF production in the COX-2-positive HT29 and Caco-2 cells. Treatment with either H2/H4 receptor antagonists or celecoxib prevented these effects. Histamine had no effect on both the COX-2 pathway and VEGF production in the COX-2-negative HCT116 cells. Conclusions: Our data showed that histamine exerts both a proproliferative and a proangiogenic effect via H2/H4 receptor activation. These effects are likely to be mediated by increasing COX-2-related PGE2 production in COX-2-expressing colon cancer cells.
Germline Genetic Variation, Cancer Outcome, and Pharmacogenetics
Authors: Linda Coate, Sinead Cuffe, Anne Horgan, Rayjean J. Hung, David Christiani, Geoffrey Liu
Journal: Journal of Clinical Oncology (2010)

Studies of the role of germline or inherited genetic variation on cancer outcome can fall into three distinct categories. First, the impact of highly penetrant but lowly prevalent mutations of germline DNA on cancer prognosis has been studied extensively for BRCA1 and BRCA2 mutations as well as mutations related to hereditary nonpolyposis colorectal cancer syndrome. These mainly modest-sized analyses have produced conflicting results. Although some associations have been observed, they may not be independent of other known clinical or molecular prognostic factors. Second, the impact of germline polymorphisms on cancer prognosis is a burgeoning field of research. However, a deeper understanding of potentially confounding somatic changes and larger multi-institutional, multistage studies may be needed before consistent results are seen. Third, research examining the impact of germline genetic variation on differential treatment response or toxicity (pharmacogenetics) has produced some proof-of-principle results. Putative germline pharmacogenetic predictors of outcome include DPYD polymorphisms and fluorouracil toxicity, UGT1A1 variation and irinotecan toxicity, and CYP2D6 polymorphisms and tamoxifen efficacy, with emerging data on predictors of molecularly targeted or biologic drugs. Here we review data pertaining to these germline outcome and germline toxicity relationships.
Diagnosis of Obstructive Sleep Apnea in Adults: A Clinical Practice Guideline From the American College of Physicians
Authors: Amir Qaseem, Paul Dallas, Douglas K. Owens, Melissa Starkey, Jon-Erik C. Holty, Paul Shekelle
Journal: Annals of Internal Medicine (2014)

The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the diagnosis of obstructive sleep apnea in adults.This guideline is based on published literature on this topic that was identified by using MEDLINE (1966 through May 2013), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular mortality, nonfatal cardiovascular disease, stroke, hypertension, type 2 diabetes, postsurgical outcomes, and quality of life. Sensitivities, specificities, and likelihood ratios were also assessed as outcomes of diagnostic tests. This guideline grades the evidence and recommendations by using ACP's clinical practice guidelines grading system.ACP recommends a sleep study for patients with unexplained daytime sleepiness. (Grade: weak recommendation, low-quality evidence).ACP recommends polysomnography for diagnostic testing in patients suspected of obstructive sleep apnea. ACP recommends portable sleep monitors in patients without serious comorbidities as an alternative to polysomnography when polysomnography is not available for diagnostic testing. (Grade: weak recommendation, moderate-quality evidence).
Effect of school-based interventions on physical activity and fitness in children and adolescents: a review of reviews and systematic update
Authors: S Kriemler, U Meyer, E Martin, E M F van Sluijs, L B Andersen, B W Martin
Journal: British Journal of Sports Medicine (2011)

Background School-based interventions are thought to be the most universally applicable and effective way to counteract low physical activity (PA) and fitness although there is controversy about the optimal strategy to intervene. Objectives The objective of this review was to summarise recent reviews that aimed to increase PA or fitness in youth and carry out a systematic review of new intervention studies. Methods Relevant systematic reviews and original controlled and randomised controlled school-based trials with a PA or fitness outcome measure, a duration of ≥12 weeks, a sufficient quality and involvement of a healthy population aged 6–18 years that were published from 2007 to 2010 were included. Results In these reviews, 47–65% of trials were found to be effective. The effect was mostly seen in school-related PA while effects outside school were often not observed or assessed. Conclusions The school-based application of multicomponent intervention strategies was the most consistent, promising strategy, while controversy existed regarding the effectiveness of family involvement, focus on healthy populations at increased risk or duration and intensity of the intervention. All 20 trials in the review update showed a positive effect on in-school, out-of-school or overall PA, and 6 of 11 studies showed an increase in fitness. Taking into consideration both assessment quality and public health relevance, multicomponent approaches in children including family components showed the highest level of evidence for increasing overall PA. This review confirms the public health potential of high quality, school-based PA interventions for increasing PA and possibly fitness in healthy youth.