tbuckley/cabot-search huggingface dataset:
Improved Clinical Outcomes Associated With Metformin in Patients With Diabetes and Heart Failure
Authors: Dean T. Eurich, Sumit R. Majumdar, Finlay A. McAlister, Ross T. Tsuyuki, Jeffrey A. Johnson
Journal: Diabetes Care (2005)

OBJECTIVE—Metformin is considered contraindicated in patients with heart failure because of concerns over lactic acidosis, despite increasing evidence of potential benefit. The aim of this study was to evaluate the association between metformin and clinical outcomes in patients with heart failure and type 2 diabetes. RESEARCH DESIGN AND METHODS—Using the Saskatchewan Health databases, 12,272 new users of oral antidiabetic agents were identified between the years 1991 and 1996. Subjects with incident heart failure (n = 1,833) were identified through administrative records based on ICD-9 code 428 and grouped according to antidiabetic therapy: metformin monotherapy (n = 208), sulfonylurea monotherapy (n = 773), or combination therapy (n = 852). Multivariate Cox proportional hazards models were used to assess differences in all-cause mortality, all-cause hospitalization, and the combination (i.e., all-cause hospitalization or mortality). RESULTS—Average age of subjects was 72 years, 57% were male, and average follow-up was 2.5 ± 2.0 (SD) years. Compared with sulfonylurea therapy, fewer deaths occurred in subjects receiving metformin: 404 (52%) for sulfonylurea monotherapy versus 69 (33%) for metformin monotherapy (hazard ratio [HR] 0.70 [95% CI 0.54–0.91]) and 263 (31%) for combination therapy (0.61 [0.52–0.72]). A reduction in deaths or hospitalizations was also observed: 658 (85%) for sulfonylurea monotherapy versus 160 (77%) for metformin monotherapy (0.83 [0.70–0.99]) and 681 (80%) for combination therapy (0.86 [0.77–0.96]). There was no difference in time to first hospitalization between study groups. CONCLUSIONS—Metformin, alone or in combination, in subjects with heart failure and type 2 diabetes was associated with lower morbidity and mortality compared with sulfonylurea monotherapy.
Improving antibiotic prescribing in acute respiratory tract infections
Authors: Leanne Eddie
Journal: Thorax (2013)

Improving antibiotic prescribing in acute respiratory tract infectionsThis Norwegian cluster randomised controlled trial assessed the effects of multifaceted educational interventions on antibiotic prescribing for acute respiratory tract infections (RTI) in general practice.Authors of the study hoped to reduce prescription rates and use of broad spectrum antibiotics with their intervention.Seventy-nine medical education groups, totalling 382 general practitioners (GPs), were recruited in the study.The intervention consisted of two visits by specially trained GPs; one detailing national guidelines for antibiotic use and recent research on acute RTI, and the second to issue reports on individual antibiotic prescribing rates from the preceding year.Primary outcome measures were prescribing rates, and proportion of non-penicillin V (N-PV) prescription rates before and after intervention.The control arm received a different educational intervention regarding more appropriate prescribing in patients <70 years of age.An adjusted, multilevel model showed a reduction in prescribing rates of antibiotics for acute RTI (OR 0.72; 95% CI 0.61 to 0.84) compared with controls.Similarly, there was a reduction in the odds of prescribing a N-PV (OR 0.64; 95% CI 0.49 to 0.92).There was no indication of a stronger intervention effect on GPs with higher baseline prescription rates.The findings of this study are limited by the fact that educational interventions were delivered by 13 different specially trained GPs.Individual personalities may influence the effect of intervention.Furthermore, especially relevant for the acute RTI group, the data did not distinguish between primary contacts and follow-ups from hospital discharges; therefore prescription data in primary care may underestimate antibiotic rates for this specific group.
Prognostic Role of Myocardial Blood Flow Impairment in Idiopathic Left Ventricular Dysfunction
Authors: Danilo Neglia, Claudio Michelassi, Maria Giovanna Trivieri, Gianmario Sambuceti, Assuero Giorgetti, Lorenza Pratali, Michela Gallopin, Piero Salvadori, Oreste Sorace, Clara Carpeggiani, Rosa Poddighe, Antonio L’Abbate, Oberdan Parodi
Journal: Circulation (2002)

Background — Depressed myocardial blood flow (MBF) has been reported in dilated cardiomyopathy. The aim of this study was to investigate whether MBF impairment is an independent predictor of prognosis in patients with idiopathic left ventricular (LV) dysfunction. Methods and Results — Sixty-seven patients (52 male, mean age 52±12 years) with different degrees of idiopathic LV systolic dysfunction (average LV ejection fraction, 0.34±0.10; range, 0.07 to 0.49) were prospectively enrolled. Thirty-four subjects (51%) had no history of heart failure symptoms at enrollment (NYHA class I). All patients underwent clinical and functional evaluation and a PET study to measure absolute MBF at rest and after intravenous dipyridamole. During a mean follow-up of 45±37 months, 24 patients had major cardiac events, including cardiac death in 8 and development or progression of heart failure in 16 patients. Multivariate regression analysis (Cox proportional hazards model) revealed heart rate (χ 2 11.06, P &lt;0.001), LV end-diastolic dimension (χ 2 11.73, P &lt;0.001), and dipyridamole MBF (χ 2 11.04, P &lt;0.001) as independent predictors of subsequent cardiac events. Dipyridamole MBF ≤1.36 mL · min −1 · g −1 was associated with an increase in the relative risk of death, development, or progression of heart failure of 3.5 times over other more common clinical and functional variables. Conclusions — The present study demonstrates that severely depressed MBF is a predictor of poor prognosis in patients with idiopathic LV dysfunction independently of the degree of LV functional impairment and of the presence of overt heart failure.
Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma
Authors: Wen Xue, Etienne Meylan, Trudy G. Oliver, David M. Feldser, Monte M. Winslow, Roderick Bronson, Tyler Jacks
Journal: Cancer Discovery (2011)

Lung adenocarcinoma is a leading cause of cancer death worldwide. We recently showed that genetic inhibition of the NF-κB pathway affects both the initiation and the maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this investigation, we tested the efficacy of small-molecule NF-κB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-κB activity, the proteasome inhibitor bortezomib efficiently reduced nuclear p65, repressed NF-κB target genes, and rapidly induced apoptosis. Bortezomib also induced lung tumor regression and prolonged survival in tumor-bearing Kras(LSL-G12D/wt);p53(flox/flox) mice but not in Kras(LSL-G12D/wt) mice. After repeated treatment, initially sensitive lung tumors became resistant to bortezomib. A second NF-κB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired resistance in mice. Our results using preclinical mouse models support the NF-κB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma.Using small-molecule compounds that inhibit NF-κB activity, we provide evidence that NF-κB inhibition has therapeutic efficacy in the treatment of lung cancer. Our results also illustrate the value of mouse models in validating new drug targets in vivo and indicate that acquired chemoresistance may later influence bortezomib treatment in lung cancer.
<i>EGFR</i> Mutations in Non–Small-Cell Lung Cancer: Analysis of a Large Series of Cases and Development of a Rapid and Sensitive Method for Diagnostic Screening With Potential Implications on Pharmacologic Treatment
Authors: Antonio Marchetti, Carla Martella, Lara Felicioni, Fabio Barassi, Simona Salvatore, Antonio Chella, Pier P. Camplese, Teodorico Iarussi, Felice Mucilli, Andrea Mezzetti, Franco Cuccurullo, Rocco Sacco, Fiamma Buttitta
Journal: Journal of Clinical Oncology (2005)

Purpose It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non–small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method. Patients and Methods We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach—direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations. Results There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing. Conclusion Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.
Progesterone Inhibition of Wnt/β-Catenin Signaling in Normal Endometrium and Endometrial Cancer
Authors: Yongyi Wang, Payman Hanifi-Moghaddam, Eline E. Hanekamp, Helenius J. Kloosterboer, Patrick Franken, Jos Veldscholte, Helena C. van Doorn, Patricia C. Ewing, J. Julie Kim, J. Anton Grootegoed, Curt W. Burger, Riccardo Fodde, Leen J. Blok
Journal: Clinical Cancer Research (2009)

Wnt signaling regulates the fine balance between stemness and differentiation. Here, the role of Wnt signaling to maintain the balance between estrogen-induced proliferation and progesterone-induced differentiation during the menstrual cycle, as well as during the induction of hyperplasia and carcinogenesis of the endometrium, was investigated.Endometrial gene expression profiles from estradiol (E(2)) and E(2) + medroxyprogesterone acetate-treated postmenopausal patients were combined with profiles obtained during the menstrual cycle (PubMed; GEO DataSets). Ishikawa cells were transfected with progesterone receptors and Wnt inhibitors dickkopf homologue 1 (DKK1) and forkhead box O1 (FOXO1), measuring Wnt activation. Expression of DKK1 and FOXO1 was inhibited by use of sequence-specific short hairpins. Furthermore, patient samples (hormone-treated endometria, hyperplasia, and endometrial cancer) were stained for Wnt activation using nuclear beta-catenin and CD44.In vivo, targets and components of the Wnt signaling pathway (among them DKK1 and FOXO1) are regulated by E(2) and progesterone. In Wnt-activated Ishikawa cells, progesterone inhibits Wnt signaling by induction of DKK1 and FOXO1. Furthermore, using siRNA-mediated knockdown of both DKK1 and FOXO1, progesterone inhibition of Wnt signaling was partly circumvented. Subsequently, immunohistochemical analysis of the Wnt target gene CD44 showed that progesterone acted as an inhibitor of Wnt signaling in hyperplasia and in well-differentiated endometrial cancer.Progesterone induction of DKK1 and FOXO1 results in inhibition of Wnt signaling in the human endometrium. This Wnt inhibitory effect of progesterone is likely to play a rate-limiting role in the maintenance of endometrial homeostasis and, on its loss, in tumor onset and progression toward malignancy.
Hipocondrie a 7 Concertanti
Authors: D. O'Neill
Journal: BMJ (2011)

Fans of the US detective series Columbo (and of its recently deceased star, Peter Falk) will recognise the scenario immediately. The interview seems to be over without a satisfactory resolution, when, with his hand on the door handle, he turns and says, “Just one more thing . . .” As in medicine, it is this last question that is the key to the story, and astute doctors have learnt to temper natural impatience at late running consultations and to pay particular attention to the “doorknob question” (see Int J Clin Pract 2005;59:869, doi:10.1111/j.1368-5031.2005.0599a.x).

What is …
KR-POK Interacts with p53 and Represses Its Ability to Activate Transcription of p21WAF1/CDKN1A
Authors: Bu-Nam Jeon, Min-Kyeong Kim, Won-Il Choi, Dong-In Koh, Sung-Yi Hong, Kyung-Sup Kim, Minjung Kim, Chae-Ok Yun, Juyong Yoon, Kang-Yell Choi, Kyung-Ryul Lee, Kenneth P. Nephew, Man-Wook Hur
Journal: Cancer Research (2012)

Transcriptional regulation by p53 is thought to play a role in its ability to suppress tumorigenesis. However, there remain gaps in understanding about how p53 regulates transcription and how disrupting this function may promote cancer. Here we report a role in these processes for the kidney cancer-related gene KR-POK (ZBTB7C), a POZ domain and Krüppel-like zinc finger transcription factor that we found to physically interact with p53. Murine embryonic fibroblasts isolated from genetically deficient mice (Kr-pok(-/-) MEFs) exhibited a proliferative defect relative to wild-type mouse embryonic fibroblasts (MEF). The zinc finger domain of Kr-pok interacted directly with the DNA binding and oligomerization domains of p53. This interaction was essential for Kr-pok to bind the distal promoter region of the CDKN1A gene, an important p53 target gene encoding the cell-cycle regulator p21WAF1, and to inhibit p53-mediated transcriptional activation of CDKN1A. Kr-pok also interacted with the transcriptional corepressors NCoR and BCoR, acting to repress histone H3 and H4 deacetylation at the proximal promoter region of the CDKN1A gene. Importantly, Kr-pok(-/-) MEFs displayed an enhancement in CDKN1A transactivation by p53 during the DNA damage response, without any parallel changes in transcription of either the p53 or Kr-pok genes themselves. Furthermore, Kr-pok promoted cell proliferation in vitro and in vivo, and its expression was increased in more than 50% of the malignant human kidney cancer cases analyzed. Together, our findings define KR-POK as a transcriptional repressor with a pro-oncogenic role that relies upon binding to p53 and inhibition of its transactivation function.
Prolonged defibrination syndrome after bite by the carpet viper Echis carinatus.
Authors: H A Reid
Journal: BMJ (1977)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Prolonged defibrination syndrome after bite by the carpet viper Echis carinatus. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
A Neural Signature of Anorexia Nervosa in the Ventral Striatal Reward System
Authors: Anne-Katharina Fladung, Georg Grön, Karl Grammer, Bärbel Herrnberger, Edgar Schilly, Sabine Grasteit, Robert Christian Wolf, Henrik Walter, Jörn von Wietersheim
Journal: American Journal of Psychiatry (2009)

Animal studies assessing mechanisms of self-starvation under conditions of stress and diet suggest a pivotal role for the mesolimbic reward system in the maintenance of core symptoms in anorexia nervosa, which is corroborated by initial empirical evidence in human studies. The authors examined activity in the ventral striatal system in response to disease-specific stimuli in women with acute anorexia nervosa.Participants were 14 women with acute anorexia nervosa and 14 matched healthy comparison women who underwent functional magnetic resonance imaging (fMRI) during evaluation of visual stimuli depicting a female body with underweight, normal weight, and overweight canonical whole-body features according to standardized body mass indices. Participants were required to process each stimulus in a self-referring way. Ratings for each weight category were used as the control task.Behaviorally, women with anorexia nervosa provided significantly higher positive ratings in response to underweight stimuli than in response to normal-weight stimuli, while healthy comparison women showed greater preference for normal-weight stimuli relative to underweight stimuli. Functionally, ventral striatal activity demonstrated a highly significant group-by-stimulus interaction for underweight and normal-weight stimuli. In women with anorexia nervosa, activation was higher during processing of underweight stimuli compared with normal-weight stimuli. The reverse pattern was observed in healthy comparison women.These findings are consistent with predictions in animal studies of the pivotal role of the human reward system in anorexia nervosa and thus support theories of starvation dependence in maintenance of the disorder.
Occupational and nonoccupational factors associated with high grade bronchial pre-invasive lesions
Authors: C. Paris, J. Benichou, S. Bota, S. Sagnier, J. Metayer, S. Eloy, J-B. Auliac, G. Nouvet, L. Thiberville
Journal: European Respiratory Journal (2003)

Besides tobacco exposure, factors associated with the development of pre-invasive bronchial lesions are not known. Autofluorescence bronchoscopy was used to assess the prevalence of severe dysplasia and carcinoma in situ (SD/CIS) of the proximal bronchial tree in relation to occupational or nonoccupational carcinogen exposure. Among the 241 individuals in this study, the overall prevalence of at least one SD/CIS was 9% (21 subjects). Multivariable analysis revealed significant and independent associations between presence of SD/CIS and: 1) active smoking, relative to former smokers; 2) presence of synchronous invasive lung cancer; 3) duration of asbestos exposure and; 4) exposure to other occupational carcinogens. The independent associations of synchronous lung cancer with severe dysplasia and carcinoma, after adjusting for both occupational and nonoccupational carcinogen exposures, suggest other mechanisms than a field cancerisation may be involved in the carcinogenesis of these pre-invasive lesions. Moreover, active smokers, patients with recently resected invasive lung cancer and workers occupationally exposed to bronchial carcinogens may represent a population of choice for early cancer endoscopic detection programmes in view of their high severe dysplasia and carcinoma prevalence.
Is C-Reactive Protein a Useful Predictor of Outcome in Peritoneal Dialysis Patients?
Authors: KAREN ANN HERZIG, DAVID MICHAEL PURDIE, WENDY CHANG, ALLISON MARGARET BROWN, CARMEL MARY HAWLEY, SCOTT BRYAN CAMPBELL, JOANNA MARY STURTEVANT, NICOLE MAREE ISBEL, DAVID LAWRENCE NICOL, DAVID WAYNE JOHNSON
Journal: Journal of the American Society of Nephrology (2001)

Abstract. An elevated C-reactive protein (CRP) has recently been shown to be strongly predictive of mortality in hemodialysis patients. However, its predictive value in peritoneal dialysis (PD) patients has not been assessed. A cohort of 50 PD patients was followed prospectively for a 3-yr period, after initial determination of CRP. Patients with an elevated CRP (&gt;6 mg/L; n = 29) had significantly reduced plasma prealbumin (0.36 ± 0.02 versus 0.44 ± 0.03 g/L; P &lt; 0.05), decreased total weekly creatinine clearance (C Cr ; 52.5 ± 2.3 versus 63.1 ± 3.2 L/1.73 m 2 ; P &lt; 0.01), and increased left ventricular thickness (1.24 ± 0.05 versus 1.08 ± 0.06 cm; P &lt; 0.05) at baseline compared with those who had a normal CRP (≤6 mg/L; n = 21). Baseline CRP (log-transformed) correlated weakly with baseline Kt/V, C Cr , and pre-albumin. With the use of a multivariate Cox's proportional hazards model to adjust for potential confounding factors, an elevated CRP was predictive of myocardial infarction (adjusted hazard ratio, 4.8; 95% confidence interval [CI], 1.0 to 23; P = 0.048) and tended to be predictive of fatal myocardial infarction (adjusted hazard ratio, 6.0; 95% CI, 0.8 to 43; P = 0.07). However, CRP was not significantly associated with all-cause mortality (adjusted hazard ratio, 2.1; 95% CI,0.8 to 5.4; P = 0.15). In conclusion, CRP elevation occurs in a substantial proportion of PD patients and is independently predictive of future myocardial infarction. Such patients may warrant closer monitoring and attention to modifiable cardiovascular risk factors.
Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia
Authors: Vincent Cottin, Henri Plauchu, Jean-Yves Bayle, Martine Barthelet, Didier Revel, Jean-François Cordier
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Pulmonary arteriovenous malformations (PAVMs) associated with hereditary hemorrhagic telangiectasia may cause severe cerebral complications that may be prevented by embolization therapy. We retrospectively compared the diagnostic value of noninvasive tests for the screening of treatable (amenable to embolization) PAVMs in a series of 105 patients, using chest computerized tomography (CT) and/or pulmonary angiography as a "gold standard." Patients had assessment of dyspnea, chest radiograph, alveolar–arterial PO2 gradient under 100% oxygen (AaPO2), contrast echocardiography, and radionuclide perfusion lung scanning. Contrast echocardiography in the supine position was the most sensitive test (93%). The sensitivity of self-reported dyspnea (59%), chest radiograph alone (70%), measurement of AaPO2 by the 100% oxygen method (62%), or radionuclide lung scanning (71%), was not suitable for efficient screening. A 100% sensitivity and negative predictive value could be obtained when combining anteroposterior chest radiograph and contrast echocardiography. Our data support a screening algorithm based on the combined use of contrast echocardiography and anteroposterior chest radiograph, followed by chest CT if either test is positive. An alternative is to screen directly by chest CT. However, this algorithm may obviate the need for chest CT in patients without PAVM, who represent a majority of patients with hereditary hemorrhagic telangiectasia.
Fibers From Disposable Gowns and Drapes
Authors: D. Murray Angevine
Journal: JAMA (1979)

<h3>To the Editor.—</h3> In a brief CLINICAL NOTE, Myroslaw J. Dragan, MD (241:2297, 1979), described the presence of wood fibers in surgical specimens, presumably from disposable surgical gowns and drapes. The article raises several questions that need to be clarified. The report "was prompted by a rise in postoperative morbidity [22 per 1,000 cases] during the 18-month use of disposable paper gowns and drapes." What is meant by a rise? How many more surgical complications occurred during this 18-month period than during other periods of similar duration? How does the reported incidence compare with that of other similar hospitals? The author next listed the complications that occured in a total of 22 cases, but no indication was given of the number of cases in which wood fibers were observed. Furthermore, he made no attempt to evaluate their significance in relation to the etiology of the complications described. A single case
Rose's homeodynamic perspective is not an alternative to neo-Darwinism
Authors: A. J. Wells
Journal: Behavioral and Brain Sciences (1999)

Lifelines discusses two approaches to biology, “ultra-Darwinism” which Rose criticises, and the “homeodynamic perspective,” which he offers as an alternative. This review suggests that ultra-Darwinism is a caricature of the theoretical positions Rose wishes to oppose and that the homeodynamic perspective is not an alternative, but is complementary to so-called ultra-Darwinism.