tbuckley/cabot-search huggingface dataset:
Guidelines on anticoagulant treatment in atrial fibrillation in Great Britain: variation in content and implications for treatment
Authors: R. Thomson, H. McElroy, M. Sudlow
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objective:</b> To describe the content of guidelines on the use of anticoagulant treatment in patients with atrial fibrillation and the impact of variations in guidelines on treatment. <b>Design:</b> Postal survey of guidelines, semistructured interview with lead developers of guidelines, and application of guidelines to patient sample. <b>Subjects:</b> 15 lead developers of the 20 guidelines identified in the postal survey were interviewed. 100 patients over 65 with atrial fibrillation to whom the guidelines were applied. <b>Main outcome measures:</b> Evaluation of guidelines and the methods of dissemination, implementation, review, and evaluation; proportion of patients recommended for anticoagulant treatment by each guideline; and level of agreement between guidelines. <b>Results:</b> There was considerable variation in whether anticoagulant treatment was recommended for subjects (range 13% to 100%, κ=0.12). Guidelines varied greatly in advice on treatment by age, the use of echocardiography, and the target value or range of the international normalised ratio (8 of the 20 guidelines included values unlikely to be effective). Development was unsystematic; evidence based approaches were rarely used. 9 of the 15 lead developers had developed the guidelines themselves, and the 6 guidelines developed by groups relied on informal consensus. Methods to support effective dissemination, implementation, and evaluation were limited. <b>Conclusion:</b> The widespread non-systematic production of guidelines has led to considerable variation with implications for the quality of care and clinical decision making. There is a need for a central, well funded programme of guideline development to ensure that valid guidelines are produced and disseminated. <h3>Key messages</h3> Clinical practice guidelines improve the process and outcomes of health care, but these improvements are dependent on the validity of the advice the guidelines contain A survey of guidelines in Great Britain for the use of anticoagulant treatment to prevent stroke in patients with atrial fibrillation showed variation in their content and in the processes of development, dissemination, implementation, and evaluation Applying these guidelines produced variation in treatment This variation is most likely to be caused by non-systematic methods of development, which implies that some guidelines advocate management strategies that are less than optimal Such variation could have profound effects on the incidence of stroke and bleeding complications and would lead to substantial differences in the use of resources, particularly anticoagulation services
Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial
Authors: Marisa Hanney, Vee Prasher, Nicola Williams, Emma L Jones, Dag Aarsland, Anne Corbett, Dale Lawrence, Ly-Mee Yu, Stephen Tyrer, Paul T Francis, Tony Johnson, Roger Bullock, Clive Ballard
Journal: The Lancet (2012)
ESCMID Diagnostic and management guideline for Candida diseases 2012: Developing European guidelines in clinical microbiology and infectious diseases.
Authors: A.J. Ullman, O.A. Cornely, P. Donnelly, M. Akova, M.C. Arendrup, S. Arikan-Akdagli, M. Bassetti, J. Bille, T Calandra, E. Castagnola, J. Garbino, A. Groll, R. Herbrecht, W. Hope, H.E. Jensen, B.J. Kullberg, C. Lass-Flörl, O. Lortholary, W. Meersseman, G. Petrikkos, M. Richardson, E. Roilides, P.E. Verweij, C. Viscoli, M. Cuenca-Estrella
Journal: Clinical Microbiology and Infection (2012)
The effects of the 5-HT2C agonist m-chlorophenylpiperazine on elite athletes with unexplained underperformance syndrome (overtraining)
Authors: R Budgett, N Hiscock, R Arida, L M Castell
Journal: British Journal of Sports Medicine (2008)

A possible link between the neurotransmitter, 5-hydroxytryptamine (5-HT), plasma tryptophan, and branched chain amino acids concentration and exercise-induced fatigue is described by the central fatigue hypothesis. 5-HT receptors and neuroendocrine “challenge” tests, using prolactin release as an indirect measure of 5-HT activity were studied by recent investigations. In the present study, the original hypothesis about the role of amino acids in increasing brain 5-HT with a neuroendocrine challenge test on elite athletes diagnosed with unexplained, underperformance syndrome (UUPS) was combined. There was an apparent increased sensitivity of 5-HT receptors in athletes with UUPS compared with fit, well-trained controls, as measured via increased prolactin release following a bolus dose of m -chlorophenylpiperazine , a 5-HT agonist. No changes were observed in plasma amino acid concentrations in either group. There is evidence that well-trained athletes have a reduced sensitivity of 5-HT receptors. The present study suggests that this adaptation may be lost in athletes with UUPS: this might explain some of their observed symptoms.
The Psychiatric Day Center in the Treatment of the Chronic Schizophrenic
Authors: IRWIN GOOTNICK
Journal: American Journal of Psychiatry (1971)

The treatment needs of the posthospitalized chronic schizophrenic have not been successfully met by one-to-one psychotherapy, mostly due to the transference problems in the patient-therapist relationship. The author believes that the group therapy and social experience provided in a psychiatric day center better meet the needs of these patients, leading to a marked decrease in rehospitalization rates and to significant functional improvement.
Functional Divergence of the miRNA Transcriptome at the Onset of Drosophila Metamorphosis
Authors: Shu-Dan Yeh, Marcin von Grotthuss, Kania A. Gandasetiawan, Suvini Jayasekera, Xiao-Qin Xia, Carolus Chan, Vivek Jayaswal, José M. Ranz
Journal: Molecular Biology and Evolution (2014)

MicroRNAs (miRNAs) are endogenous RNA molecules that regulate gene expression posttranscriptionally. To date, the emergence of miRNAs and their patterns of sequence evolution have been analyzed in great detail. However, the extent to which miRNA expression levels have evolved over time, the role different evolutionary forces play in shaping these changes, and whether this variation in miRNA expression can reveal the interplay between miRNAs and mRNAs remain poorly understood. This is especially true for miRNA expressed during key developmental transitions. Here, we assayed miRNA expression levels immediately before (≥18BPF [18 h before puparium formation]) and after (PF) the increase in the hormone ecdysone responsible for triggering metamorphosis. We did so in four strains of Drosophila melanogaster and two closely related species. In contrast to their sequence conservation, approximately 25% of miRNAs analyzed showed significant within-species variation in male expression levels at ≥18BPF and/or PF. Additionally, approximately 33% showed modifications in their pattern of expression bias between developmental timepoints. A separate analysis of the ≥18BPF and PF stages revealed that changes in miRNA abundance accumulate linearly over evolutionary time at PF but not at ≥18BPF. Importantly, ≥18BPF-enriched miRNAs showed the greatest variation in expression levels both within and between species, so are the less likely to evolve under stabilizing selection. Functional attributes, such as expression ubiquity, appeared more tightly associated with lower levels of miRNA expression polymorphism at PF than at ≥18BPF. Furthermore, ≥18BPF- and PF-enriched miRNAs showed opposite patterns of covariation in expression with mRNAs, which denoted the type of regulatory relationship between miRNAs and mRNAs. Collectively, our results show contrasting patterns of functional divergence associated with miRNA expression levels during Drosophila ontogeny.
T <sub>H</sub> 2 and T <sub>H</sub> 17 inflammatory pathways are reciprocally regulated in asthma
Authors: David F. Choy, Kevin M. Hart, Lee A. Borthwick, Aarti Shikotra, Deepti R. Nagarkar, Salman Siddiqui, Guiquan Jia, Chandra M. Ohri, Emma Doran, Kevin M. Vannella, Claire A. Butler, Beverley Hargadon, Joshua C. Sciurba, Richard L. Gieseck, Robert W. Thompson, Sandra White, Alexander R. Abbas, Janet Jackman, Lawren C. Wu, Jackson G. Egen, Liam G. Heaney, Thirumalai R. Ramalingam, Joseph R. Arron, Thomas A. Wynn, Peter Bradding
Journal: Science Translational Medicine (2015)

Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Time course of functional deterioration after coronary artery ligation in rats
Authors: O. M BECH, O. KAHR, B. DIAMANT, E. STEINESS
Journal: Cardiovascular Research (1989)

The aim of this study was to investigate the time course of deterioration of functional capacity in the rat after ligation of the left coronary artery. Functional capacity was evaluated from the increase in blood lactate concentrations in 109 rats during a standardised treadmill test. Animals with myocardial infarction were compared with sham operated and normal controls. Functional capacity was followed during a 13 week period and estimations of the functional capacity were performed 1, 3, 7, 9 and 13 weeks after infarction. Coronary artery ligation produced a significant reduction in functional capacity, averaging 47% (p<0.01) over the first 3 weeks after myocardial infarction, irrespective of infarct size. In rats with large infarcts, functional capacity remained essentially unchanged throughout the observation period, but rats with small infarcts improved gradually until their measured exercise response was completely normal at the end of the 13 week period.
Patterns of Care for Patients with Chronic Kidney Disease in the United States
Authors: William F. Owen
Journal: Journal of the American Society of Nephrology (2003)

The burden of chronic kidney disease can be assessed by multiple criteria that underscore the need for improved detection, treatment, and outcome monitoring. Several process measures for the care of advanced CKD patients are examined herein. Twenty seven and 11% of patients with CKD in National Health and Nutrition Examination Surveys (NHANES) III had BP <140/90 and 130/85, respectively. In addition to inadequate prescription of antihypertensive drugs, another confounder is poor diagnostic recognition of CKD. Recent surveys of incident Medicare-eligible ESRD patients observed severe anemia in a preponderance of patients; mean and median hematocrit values were 27.7% +/- 5.9 and 27.8%, respectively. Only 23 to 28% of these patients were prescribed epoetin alfa. Clinical practice guidelines recommend that <10% of maintenance hemodialysis patients should be chronically dialyzed using percutaneous catheters. A recent national survey of vascular access types among incident American hemodialysis patients found that 30%, 41%, and 29% were dialyzing through a catheter, prosthetic graft, and autologous fistula, respectively. Tunneled catheters are associated with a 39% annual increased risk of death. Based on pharmacokinetic assumptions about the minimum amount of solute clearance by hemodialysis needed for patient survival in ESRD, a GFR of 10.5 ml/min per 1.73 m(2) is needed. The mean GFR of incident ESRD patients in the United States was 9.5 ml/min per 1.73 m(2) in 2000. In addition to the wide international variability in modality treatment selection, geographic variability exists within the United States; <7 to >15% of the prevalent patients are treated by peritoneal dialysis across the country. Despite survival and quality-of-life benefits with transplantation, most eligible recipients in the United States have not been placed on a transplant waiting list 6 mo after beginning dialysis. Last, <40% of incident ESRD patients in the United States have received the recommended frequency of mammography, PAP examinations, or prostate-specific antigen (PSA) or HbA1c measurements. These deficiencies in care for patients with advanced CKD likely adversely influence the survival of US ESRD patients. Contemporary outcome information supports this contention. CKD patients referred to a nephrologist for the first time within 90 d of the start of dialysis have an approximately 40% to 60% increased risk of death during their first year of renal replacement therapy (RRT). Thirty-five percent of CKD patients are seen within 90 d of receiving RRT. In addition, if fewer than five nephrology visits occur, death risks are increased by 15%. These findings confirm the urgent need for improvement in healthcare delivery for CKD patient in the United States.
Excisional surgery with ileostomy for Crohn's colitis with particular reference to factors affecting recurrence
Authors: D. M. Steinberg, R. N. Allan, H. Thompson, B. N. Brooke, J. Alexander-Williams, W. T. Cooke
Journal: Gut (1974)

This paper reports the indications for, and results of, excision of the large intestine with ileostomy in 73 patients with Crohn9s colitis who have been followed for a mean of nine years since resection. Sixty-four of them are still alive and all but two of the survivors are now in good health. However, 23 (33%) have developed recurrent Crohn9s disease since resection. This is higher than that reported in many other series and may be due to differences in the length of follow up, the site and extent of colonic disease, the age of the patient at the time of excision with ileostomy, and differences in the pathological interpretation of the diagnosis of Crohn9s disease. The high recurrence rate in this series lends caution to the view that the prognosis after excisional surgery and ileostomy for Crohn9s colitis is as good as after the same operation for ulcerative colitis and should influence the decision when the alternative of medical or surgical management are being considered for patients with Crohn9s colitis.
Oral BCG vaccine in Crohn's disease.
Authors: W R Burnham, J E Lennard-Jones, P Hecketsweiler, R Colin, Y Geffroy
Journal: Gut (1979)

In a randomised double-blind trial over one year oral BCG has been compared with a control preparation in the treatment of chronic Crohn9s disease. Overall assessment scores deteriorated in nine of 22 patients taking BCG, and 11 of 26 in the control group (P = 0.25); this deterioration was great enough to be regarded as a clinical relapse in three patients taking BCG and in seven taking the control preparation (P greater than 0.1). No significant benefit from oral BCG treatment has been demonstrated.
Targeting protease activated receptor-1 with P1pal-12 limits bleomycin-induced pulmonary fibrosis
Authors: Cong Lin, JanWillem Duitman, Joost Daalhuisen, Marieke ten Brink, Jan von der Thüsen, Tom van der Poll, Keren Borensztajn, C Arnold Spek
Journal: Thorax (2013)

<h3>Background</h3> Idiopathic pulmonary fibrosis is the most devastating fibrotic diffuse parenchymal lung disease which remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. Protease-activated receptor (PAR)-1 is a G-protein-coupled receptor that mediates critical signalling pathways in pathology and physiology. Bleomycin-induced lung fibrosis has been shown to be diminished in PAR-1-deficient mice. The purpose of this study is to investigate whether pharmacological PAR-1 inhibition is a potential therapeutic option to combat pulmonary fibrosis. <h3>Methods</h3> Pulmonary fibrosis was induced by intranasal instillation of bleomycin into wild-type mice with or without a specific PAR-1 antagonist (ie, P1pal-12, a pepducin that blocks the PAR-1/G-protein interaction). Fibrosis was assessed by hydroxyproline analysis, immunohistochemistry, quantitative PCR and western blot for fibrotic markers expression. <h3>Results</h3> We first show that P1pal-12 effectively inhibits PAR-1-induced profibrotic responses in fibroblasts. Next, we show that once daily treatment with 0.5, 2.5 or 10 mg/kg P1pal-12 reduced the severity and extent of fibrotic lesions in a dose-dependent manner. These findings correlated with significant decreases in fibronectin, collagen and α smooth muscle actin expression at the mRNA and protein level in treated mice. To further establish the potential clinical applicability of PAR-1 inhibition, we analysed fibrosis in mice treated with P1pal-12 1 or 7 days after bleomycin instillation. Interestingly, when administered 7 days after the induction of fibrosis, P1pal-12 was as effective in limiting the development of pulmonary fibrosis as when administration was started before bleomycin instillation. <h3>Conclusions</h3> Overall, targeting PAR-1 may be a promising treatment for pulmonary fibrosis.
NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis
Authors: Suzanne A. Eccles, Andy Massey, Florence I. Raynaud, Swee Y. Sharp, Gary Box, Melanie Valenti, Lisa Patterson, Alexis de Haven Brandon, Sharon Gowan, Frances Boxall, Wynne Aherne, Martin Rowlands, Angela Hayes, Vanessa Martins, Frederique Urban, Kathy Boxall, Chrisostomos Prodromou, Laurence Pearl, Karen James, Thomas P. Matthews, Kwai-Ming Cheung, Andrew Kalusa, Keith Jones, Edward McDonald, Xavier Barril, Paul A. Brough, Julie E. Cansfield, Brian Dymock, Martin J. Drysdale, Harry Finch, Rob Howes, Roderick E. Hubbard, Alan Surgenor, Paul Webb, Mike Wood, Lisa Wright, Paul Workman
Journal: Cancer Research (2008)

Abstract We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nmol/L, inducing G1-G2 arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI50. This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1α, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials. [Cancer Res 2008;68(8):2850–60]
SWI/SNF Chromatin-Remodeling Factors Induce Changes in DNA Methylation to Promote Transcriptional Activation
Authors: Fatima Banine, Christopher Bartlett, Ranjaka Gunawardena, Christian Muchardt, Moshe Yaniv, Erik S. Knudsen, Bernard E. Weissman, Larry S. Sherman
Journal: Cancer Research (2005)

Abstract Brahma (Brm) and brahma-related gene-1 (Brg1) are mammalian homologues of SWI/SNF chromatin-remodeling factor subunits that can regulate both transcriptional activation and repression. Both Brg1 and Brm are mutated or deleted in numerous cancer cell lines, leading to the altered expression of genes that influence cell proliferation and metastasis. Here, we find that the promoters of two such genes, CD44 and E-cadherin, are hypermethylated in cells that have lost Brg1 or Brm. In two carcinoma cell lines that lack functional Brg1 and Brm, CD44 and E-cadherin expression are induced by the demethylating agent 5-aza-2′-deoxycytidine. Transfection with either Brg1 or Brm also induces CD44 and E-cadherin transcription and protein expression in these cells, as well as loss of methylation at sequences in the promoters of both genes. Chromatin immunoprecipitation assays show that Brg1 and Brm associate with these regions of the CD44 and E-cadherin promoters, suggesting that SWI/SNF protein complexes may directly influence the loss of DNA methylation. In vivo, Brm-deficient mice also show methylation and silencing of the CD44 promoter. Collectively, these data implicate loss of SWI/SNF-mediated transcriptional activation as a novel mechanism to increase DNA methylation in cancer cells and provide insight into the mechanisms underlying aberrant gene induction and repression during tumor progression.