tbuckley/cabot-search huggingface dataset:
Selective peripheral dopamine-1 receptor stimulation with fenoldopam in human essential hypertension.
Authors: R M Carey, R M Stote, J W Dubb, L H Townsend, C E Rose, D L Kaiser
Journal: Journal of Clinical Investigation (1984)

SKF 82526-J, or fenoldopam, a benzazepine derivative, is a selective dopamine-1 (DA-1) agonist devoid of activity at dopamine-2, alpha- or beta-adrenergic receptors. We studied SKF 82526-J in 10 patients with essential hypertension and five normal control subjects on constant 150-meq sodium, 60 meq potassium intake. In the hypertensive patients, during a 6-d placebo period supine blood pressure and heart rate were stable at 156 +/- 6/105 +/- 4 mmHg and 76 +/- 5 beats/min, respectively. In response to a single oral dose of 100 mg of SKF 82526-J, supine blood pressure decreased to a nadir of 141 +/- 5/89 +/- 8 mmHg (P less than 0.0001) at 90 min and remained decreased at 145 +/- 6/99 +/- 3 mmHg (P less than 0.0001) at 4 h. Heart rate increased to 91 +/- 5 beats/min (P less than 0.002), but returned to control levels (82 +/- 5 beats/min) at 4 h. Renal blood flow increased from 371 +/- 57 to a peak of 659 +/- 104 ml/min and renal vascular resistance fell from 34 +/- 5 to 19 +/- 2 dyn sec cm-5 X 10(3) (P less than 0.01). Urine volume, sodium and fractional sodium excretion, and plasma renin activity were increased as a result of SKF 82526-J administration. During the ensuing 3 wk of SKF 82526-J, blood pressure remained decreased and returned to control levels after placebo administration. In contrast, in normal subjects SKF 82526-J administration was associated with a small transient reduction in diastolic pressure only. These results suggest that reduced dopaminergic activity expressed at the peripheral DA-1 receptor may contribute to the pathophysiology and/or maintenance of increased blood pressure in essential hypertension. In addition, the results suggest that peripheral DA-1 receptor stimulation with SKF 82526-J may be efficacious in the treatment of human essential hypertension.
Hidden Markov Models Incorporating Fuzzy Measures and Integrals for Protein Sequence Identification and Alignment
Authors: Niranjan P. Bidargaddi, Madhu Chetty, Joarder Kamruzzaman
Journal: Genomics Proteomics & Bioinformatics (2008)

Abstract Profile hidden Markov models (HMMs) based on classical HMMs have been widely applied for protein sequence identification. The formulation of the forward and backward variables in profile HMMs is made under statistical independence assumption of the probability theory. We propose a fuzzy profile HMM to overcome the limitations of that assumption and to achieve an improved alignment for protein sequences belonging to a given family. The proposed model fuzzifies the forward and backward variables by incorporating Sugeno fuzzy measures and Choquet integrals, thus further extends the generalized HMM. Based on the fuzzified forward and backward variables, we propose a fuzzy Baum-Welch parameter estimation algorithm for profiles. The strong correlations and the sequence preference involved in the protein structures make this fuzzy architecture based model as a suitable candidate for building profiles of a given family, since the fuzzy set can handle uncertainties better than classical methods.
Chronic respiratory disease in the elderly: A population study
Authors: F. I. Caird, A. J. Akhtar
Journal: Thorax (1972)

A study has been made of chronic respiratory disease among 83 men and 217 women aged 65 and over, randomly chosen from those living in their own homes. Twenty-six per cent of the men and 13% of the women had chronic bronchitis. The prevalence of chronic bronchitis was related to current cigarette smoking in both sexes, and to socio-economic status in men. Chronic bronchitis was a contributory cause of disabling dyspnoea and recurrent chest illness in half of the subjects with these symptoms. Significant radiological evidence of tuberculosis was found in 9% of men and in 4% of women, asthma in 2% of women, industrial lung disease in 4% of men, and bronchogenic carcinoma in three subjects.
Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering
Authors: Volker Spindler, Vera Rötzer, Carina Dehner, Bettina Kempf, Martin Gliem, Mariya Radeva, Eva Hartlieb, Gregory S. Harms, Enno Schmidt, Jens Waschke
Journal: Journal of Clinical Investigation (2013)

In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option.
Funding the NHS: A little local difficulty?
Authors: J. Dixon, A. Harrison
Journal: BMJ (1997)

The media have been full of reports of crisis in the NHS. Although national analyses suggest that the NHS should be able to cope within the increases in spending it has been given, local pressures can leave parts of the service struggling. Firstly, the change to allocation of funds on the basis of population needs has meant that some authorities and trusts have had effective cuts in their budgets, requiring them to trim services. Secondly, the government's insistence on an annual 3% increase in efficiency may have resulted in authorities taking short term measures that actually decrease efficiency in the long term. Thirdly, health authorities have had to bear the costs of national targets such as reducing waiting lists and junior doctors' hours as well as local problems such as higher numbers of mentally disordered offenders. However, all these factors can be controlled by national or local management and so their impact is not inevitable.
Hemoglobin D Ibadan‐β° thalassemia: Detection by neonatal screening and confirmation by electrospray‐ionization mass spectrometry
Authors: Peter A. Lane, H. Ewa Witkowska, Arnold M. Falick, Marva L. Houston, James D. McKinna
Journal: American Journal of Hematology (1993)

Abstract We describe an infant with hemoglobin D Ibadan‐β° thalassemia whose hemoglobinopathy was initially detected by neonatal screening. This previously undescribed condition was confirmed by family studies and by globin chain analysis by mass spectrometric techniques. The case illustrates the importance to neonatal screening programs of confirmatory testing and of linkage with reference laboratories capable of globin chain analysis. Hematologic studies at 36 months of age suggested that the presence of hemoglobin D Ibadan had no deleterious effect on this child with heterozygous β° thalassemia. © 1993 Wiley‐Liss, Inc.
IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells
Authors: Jonathan P Sherlock, Barbara Joyce-Shaikh, Scott P Turner, Cheng-Chi Chao, Manjiri Sathe, Jeff Grein, Daniel M Gorman, Edward P Bowman, Terrill K McClanahan, Jennifer H Yearley, Gérard Eberl, Christopher D Buckley, Robert A Kastelein, Robert H Pierce, Drake M LaFace, Daniel J Cua
Journal: Nature Medicine (2012)
Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils.
Authors: X F Niu, C W Smith, P Kubes
Journal: Circulation Research (1994)

The objective of the present study was to determine whether prolonged inhibition of nitric oxide synthesis in endothelial cells increased the surface adhesion of these cells for neutrophils. Human umbilical vein endothelial cells (HUVECs) were grown to confluence in 48-well microtiter plates. Exposure of HUVECs to the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) did not cause neutrophil adhesion at 1 hour but increased adhesion at 4 hours in a dose-dependent manner. The increased adhesion was prevented with L-arginine or nitric oxide donors but not an analogue of cGMP. The increased adhesion was inhibited by monoclonal antibodies directed against the beta 2-integrin CD18 and endothelial cell adhesion molecule ICAM-1. Platelet-activating factor (PAF) receptor antagonist WEB 2086 also prevented the L-NAME-induced neutrophil adhesion. Intracellular oxygen radical scavengers (dimethyl sulfoxide, butylated hydroxytoluene, and alpha, alpha'-dipyridyl), the iron chelator desferrioxamine, and the mitochondrial inhibitor azide inhibited the L-NAME-induced neutrophil adhesion, whereas extracellular oxygen radical scavengers (superoxide dismutase and catalase) had no effect. HUVECs were loaded with 2',7'-dichlorodihydrofluorescein diacetate, and oxidation to the fluorescent dichlorodihydrofluorescein (DCHF) was monitored. Fluorescence was enhanced in the L-NAME-treated HUVECs throughout the 4-hour incubation, an event inhibitable by an antioxidant and azide. The magnitude of the intracellular oxidation of DCHF was equivalent to approximately 0.8 mumol/L H2O2. These data suggest that prolonged nitric oxide synthesis inhibition in HUVECs causes an oxidant- and PAF-associated rise in adhesion on the surface of these endothelial cells for neutrophils.
Early Resolution of ST-Segment Elevation Correlates With Myocardial Salvage Assessed by Tc-99m Sestamibi Scintigraphy in Patients With Acute Myocardial Infarction After Mechanical or Thrombolytic Reperfusion Therapy
Authors: Jun Dong, Gjin Ndrepepa, Claus Schmitt, Julinda Mehilli, Sebastian Schmieder, Markus Schwaiger, Albert Schömig, Adnan Kastrati
Journal: Circulation (2002)

Background — Early resolution of ST-segment elevation is an indicator of final infarct size and clinical outcomes. Whether this correlation is an expression of initial infarct characteristics or degree of myocardial salvage achieved with reperfusion therapy is unclear. Methods and Results — We prospectively included 243 patients with acute myocardial infarction (AMI) treated with either coronary stenting (122 patients) or thrombolysis (121 patients). Serial 12-lead electrocardiograms (ECG) were performed at baseline and 90 minutes after initiation of therapy. ST-segment resolution was defined as complete (≥70%), partial (&lt;70% to 30%), or no resolution (&lt;30%). Paired technetium-99m sestamibi scintigraphic studies were performed to calculate the initial perfusion defect, final infarct size, and the proportion of initial defect salvaged with reperfusion (salvage index). ST-segment resolution correlated significantly with salvage index ( P =0.008), final infarct size ( P &lt;0.001), and 6-month mortality ( P =0.03). In the groups with complete, partial, and no resolution, salvage index was 0.54±0.32, 0.39±0.36, and 0.33±0.60; final infarct size was 12.5±12.0%, 20.0±13.9%, and 22.7±19.4% of the left ventricle; 6-month mortality was 2.4%, 6.2%, and 12.8%, respectively. After adjustment for baseline characteristics, ST-segment resolution was the second strongest predictor of salvage index ( P =0.007) after the type of reperfusion, stenting, or thrombolysis ( P =0.001); it was greater after stenting than after thrombolysis ( P &lt;0.001). Conclusion — Early resolution of ST-segment elevation in surface ECG correlates with myocardial salvage as assessed by scintigraphy in patients with AMI after reperfusion therapy. These data provide an explanation for the favorable prognostic value of the ST-segment resolution and support the use of this parameter to compare the efficacy of different reperfusion strategies.
Involving patients in setting the research agenda in drug addiction
Authors: M. Ferri, M. Davoli, R. D'Amico
Journal: BMJ (2013)

The involvement of patients and other stakeholders in decision making is crucial in daily medical practice and priority setting for research.1

After the inheritance left by Alessandro Liberati (1954-2012) some members of the Cochrane Collaboration led by the Italian Cochrane Network decided to …
Aetiology of mitral regurgitation differentially affects 2‐year adverse outcomes after MitraClip therapy in high‐risk patients
Authors: Volker Rudolph, Edith Lubos, Michael Schlüter, Daniel Lubs, Britta Goldmann, Malgorzata Knap, Tjark de Vries, Hendrik Treede, Johannes Schirmer, Lenard Conradi, Karl Wegscheider, Hermann Reichenspurner, Stefan Blankenberg, Stephan Baldus
Journal: European Journal of Heart Failure (2013)
Control of Adrenal Secretion of Electrolyte-active Steroids--I
Authors: D. A. Denton, R. D. Wright
Journal: BMJ (1959)

<h3>Background</h3> Urokinase-type plasminogen activator receptor (uPAR), is a multi-functional receptor on cell surface, widely present in endothelial cells, fibroblasts, and a variety of malignant cells. Our previous studies have suggested that expression of uPAR is higher in patients with rheumatoid arthritis (RA) compared to osteoarthritis (OA) and the traumatic patients. <h3>Objectives</h3> Our objective was to investigate the promoting-angiogenesis effects of uPAR in fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLSs). <h3>Methods</h3> Chemically synthesized small interference RNA (siRNA) specifically targeting the uPAR gene was transfected into RA-FLSs by cationic liposome and the cell supernatants from uPAR gene-silenced RA-FLSs were extracted to cultivate the EA.hy926 (a human endothelial cell line). Transwell and tubule formation assays were used to explore the influence of RA-FLSs uPAR on EA.hy926 angiogenesis. <h3>Results</h3> EA.hy926 cells treated with conditioned medium of uPAR-siRNA RA-FLSs had a worse migrating ability and tubule formation effects, for they had only about 38% transmembrane cells and the average number of complete tubular structures decreased to 38.2%,relative to the transfection reagent control group (*P&lt;0.05). <h3>Conclusions</h3> uPAR in RA-FLSs affects neoangiogenesis of synovial tissues in patients with RA, which imply that targeting uPAR and its downstream signal pathway may provide beneficial therapeutic effects on RA. <h3>References</h3> Noh H, Hong S, Huang S. Role of urokinase receptor in tumor progression and development. Theranostics. 2013;3(7):487–95. Ferraris GM, Sidenius N. Urokinase plasminogen activator receptor: a functional integrator of extracellular proteolysis, cell adhesion, and signal transduction. Seminars in thrombosis and hemostasis. 2013;39(4):347–55. Yoo SA, Kwok SK, Kim WU. Proinflammatory role of vascular endothelial growth factor inthe pathogenesis of rheumatoid arthritis: prospects for therapeutic intervention. Mediators of inflammation. 2008;2008:129873. <h3>Disclosure of Interest</h3> None declared
Cotton dust-mediated lung epithelial injury.
Authors: G H Ayars, L C Altman, C E O'Neil, B T Butcher, E Y Chi
Journal: Journal of Clinical Investigation (1986)

To determine if constituents of cotton plants might play a role in byssinosis by injuring pulmonary epithelium, we added extracts of cotton dust, green bract, and field-dried bract to human A549 and rat type II pneumocytes. Injury was measured as pneumocyte lysis and detachment, and inhibition of protein synthesis. Extracts of cotton dust and field-dried bract produced significant dose- and time-dependent lysis and detachment of both target cells, while green bract extract was less damaging. Extracts treated with polyvinylpolypyrrolidone to remove tannins produced significantly less injury. In contrast, purified 5,7,3',4'-tetrahydroxy-flavan 3,4-diol (THF), a tannin in cotton dust and bract, caused substantial cell damage. Field-dried bract extract and THF also produced dose-dependent inhibition of pneumocyte protein synthesis. Endotoxin levels did not correlate with observed injury. THF added to rat tracheal explants caused epithelial disruption and desquamation, whereas endotoxin did not. Instillation of cotton dust and field-dried bract extract in rat lungs produced disruption of bronchial epithelium and smooth muscle constriction, while polyvinylpolypyrrolidone-treated cotton dust extract produced no injury. These findings suggest that extracts of cotton plants are toxic to alveolar, tracheal, and bronchial epithelium and that THF or other tannins may be the responsible agents.
Stopping smokeless tobacco with varenicline: randomised double blind placebo controlled trial
Authors: K. Fagerstrom, H. Gilljam, M. Metcalfe, S. Tonstad, M. Messig
Journal: BMJ (2010)

<b>Objective</b> To assess the efficacy and safety of varenicline (a licensed cigarette smoking cessation aid) in helping users of smokeless tobacco to quit. <b>Design</b> Double blind, placebo controlled, parallel group, multicentre, randomised controlled trial. <b>Setting</b> Medical clinics (mostly primary care) in Norway and Sweden. <b>Participants</b> Men and women aged ≥18 who used smokeless tobacco at least eight times a day, with no abstinence period over three months within one year before screening, who wanted to quit all tobacco use. Participants were excluded if they used any other form of tobacco (except smokeless tobacco) or medication to stop smoking within three months of screening or had any pre-existing medical or psychiatric condition. <b>Interventions</b> Varenicline 1 mg twice daily (titrated during the first week) or placebo for 12 weeks, with 14 weeks' follow-up after treatment. <b>Main outcome measures</b> The primary end point was the four week continuous abstinence rate at the end of treatment (weeks 9-12) confirmed with cotinine concentration. A secondary end point was continuous abstinence rate for weeks 9-26. Safety and tolerability were also evaluated. <b>Results</b> 431 participants (213 varenicline; 218 placebo) were randomised and received at least one dose of study drug. Participants' demographics and baseline use of smokeless tobacco were similar (89% (189) and 90% (196), respectively, were men; mean age in both groups was 43.9; participants used smokeless tobacco products about 15 times a day, and about 80% first used smokeless tobacco within 30 minutes after awakening). Continuous abstinence rate at week 9-12 was higher in the varenicline group than the placebo group (59% (125) <i>v</i> 39% (85); relative risk 1.60, 95% confidence interval 1.32 to 1.87, P&lt;0.001; risk difference 20%; number needed to treat 5). The advantage of varenicline over placebo persisted through 14 weeks of follow-up (continuous abstinence rate at week 9-26 was 45% (95) <i>v</i> 34% (73); relative risk 1.42, 1.08 to 1.79, P=0.012; risk difference 11%; number needed to treat 9). The most common adverse events in the varenicline group compared with the placebo group were nausea (35% (74) <i>v</i> 6% (14)), fatigue (10% (22) <i>v</i> 7% (15)), headache (10% (22) <i>v</i> 9% (20)), and sleep disorder (10% (22) <i>v</i> 7% (15)). Few adverse events led to discontinuation of treatment (9% (19) and 4% (9), respectively), and serious adverse events occurred in two (1%) and three (1%) participants, respectively. <b>Conclusion</b> Varenicline can help people to give up smokeless tobacco and has an acceptable safety profile. The response rate in the placebo group in this study was high, suggesting a population less resistant to treatment than smokers. <b>Trial Registration</b>NCT00717093.
Chemical Mediation of Hormone Action
Authors: M W Bitensky, R E Corman
Journal: Annual Review of Medicine (1972)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Magazines Without Tobacco Advertising
Authors: Marsha F. Goldsmith
Journal: JAMA (1991)

INQUIRIES from many physicians reveal that they've been watching for an update ofThe Journal'slist of publications that carry no cigarette or other tobacco advertisements. Here it is. Since its first list appeared (<i>JAMA</i>. 1989;262:1290-1291,1295), the length has more than doubled. Credit for the idea of having only "smoke-free magazines" in physicians' reception rooms goes to DOC (Doctors Ought to Care), a group of physicians devoted to educating people about the causes of preventable illness. Publication of such a list in<i>JAMA</i>follows a resolution adopted by the American Medical Association's House of Delegates 2 years ago. Of the making of magazines there is apparently no end. This list includes all that could be verified, but there are probably many more. The<i>JAMA</i>Medical News &amp; Perspectives Department will be pleased to hear about them—for the next list. Accent on Living PO Box 700 Bloomington, IL 61701 Adirondack Life
Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization
Authors: Yuji Ito, Steven L. Teitelbaum, Wei Zou, Yi Zheng, James F. Johnson, Jean Chappel, F. Patrick Ross, Haibo Zhao
Journal: Journal of Clinical Investigation (2010)

The modeling and remodeling of bone requires activation and polarization of osteoclasts, achieved by reorganization of the cytoskeleton. Members of the Rho subfamily of small GTPases, including Cdc42, are known regulators of cytoskeletal components, but the role of these proteins in bone physiology and pathophysiology remains unclear. Here, we examined loss-of-function mice in which Cdc42 was selectively ablated in differentiated osteoclasts and gain-of-function animals wherein Cdc42Gap, a protein that inactivates the small GTPase, was deleted globally. Cdc42 loss-of-function mice were osteopetrotic and resistant to ovariectomy-induced bone loss, while gain-of-function animals were osteoporotic. Isolated Cdc42-deficient osteoclasts displayed suppressed bone resorption, while osteoclasts with increased Cdc42 activity had enhanced resorptive capacity. We further demonstrated that Cdc42 modulated M-CSF-stimulated cyclin D expression and phosphorylation of Rb and induced caspase 3 and Bim, thus contributing to osteoclast proliferation and apoptosis rates. Furthermore, Cdc42 was required for multiple M-CSF- and RANKL-induced osteoclastogenic signals including activation and expression of the differentiation factors MITF and NFATc1 and was a component of the Par3/Par6/atypical PKC polarization complex in osteoclasts. These data suggest that Cdc42 regulates osteoclast formation and function and may represent a promising therapeutic target for prevention of pathological bone loss.