tbuckley/cabot-search huggingface dataset:
Increased Expression of Mast Cell Chymase in the Lungs of Patients with Congenital Heart Disease Associated with Early Pulmonary Vascular Disease
Authors: HIROMICHI HAMADA, MASARU TERAI, HIROSHI KIMURA, KIYOMI HIRANO, SHINJI OANA, HIROO NIIMI
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The molecular mechanism involved in pulmonary vascular disease (PVD) associated with congenital heart disease (CHD) remains uncertain. Evidence suggesting that angiotensin converting enzyme plays an important role in pulmonary vascular pathology led us to hypothesize that mast cell chymase, another angiotensin I converting enzyme, also had the potential to contribute to the development of PVD in CHD. Twenty-three patients 3 mo to 45 yr of age with atrial or ventricular or both septal defects with increased pulmonary arterial blood flow and pressure, with pulmonary vascular resistance ranging from 1.3 to 8.1 units/m2, were studied. Mast cells and mast cell chymase were immunohistochemically identified in the lung biopsy tissues obtained during corrective surgery. There was a significant difference in numbers of total mast cells between patients (n = 23) and control subjects (n = 10) with normal pulmonary circulation (p < 0.01). Moreover, chymase-containing mast cells in the lung tissues of patients with CHD showed striking differences from those of control subjects. In the patients, 72% of lung mast cells contained chymase, compared with only 15% in control subjects (p < 0.0001). Chymase-containing mast cells predominantly appeared in the media and adventitia of vessel walls. Importantly, angiotensin II was immunohistochemically detected in perivascular lesions where chymase was present, but not in the lesions where chymase was sparsely seen. Furthermore, the number of chymase-containing mast cells was correlated with pulmonary vascular resistance (r = 0.64). These findings suggest a possible role of mast cell chymase in the development of early-stage PVD in patients with CHD.
Muscarinic Acetylcholine Receptor Knockout Mice: Novel Phenotypes and Clinical Implications
Authors: Jürgen Wess
Journal: The Annual Review of Pharmacology and Toxicology (2004)

Muscarinic acetylcholine receptors (mAChRs; M 1 –M 5 ) play key roles in regulating the activity of many important functions of the central and peripheral nervous system. Because of the lack of ligands endowed with a high degree of receptor subtype selectivity and the fact that most tissues or cell types express two or more mAChR subtypes, identification of the physiological and pathophysiological roles of the individual mAChR subtypes has proven a difficult task. To circumvent these difficulties, several laboratories recently employed gene-targeting techniques to generate mutant mouse strains deficient in each of the five mAChR subtypes. Phenotyping studies showed that each mutant mouse line displayed characteristic physiological, pharmacological, behavioral, biochemical, or neurochemical deficits. The novel insights gained from these studies should prove instrumental for the development of novel classes of muscarinic drugs.
Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial
Authors: Llifon Edwards, Philippa Shirtcliffe, Kirsten Wadsworth, Bridget Healy, Sarah Jefferies, Mark Weatherall, Richard Beasley
Journal: Thorax (2013)

<h3>Background</h3> Intravenous magnesium has been shown to cause bronchodilation in acute severe asthma and in small trials in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). There is also some evidence of benefit from nebulised magnesium in acute severe asthma. Our hypothesis was that adjuvant magnesium treatment administered via repeated nebulisation was effective in the management of AECOPD. <h3>Methods</h3> In this randomised double-blind placebo-controlled trial, we approached 161 patients with AECOPD presenting to the emergency departments at two New Zealand hospitals with a forced expiratory volume in 1 s (FEV<sub>1</sub>) &lt;50% predicted 20 min after initial administration of salbutamol 2.5 mg and ipratropium 500 µg via nebulisation. Patients received 2.5 mg salbutamol mixed with either 2.5 ml isotonic magnesium sulphate (151 mg per dose) or 2.5 ml isotonic saline (placebo) on three occasions at 30 min intervals via nebuliser. The primary outcome measure was FEV<sub>1</sub> at 90 min. <h3>Results</h3> 116 patients were randomised, 52 of whom were randomly allocated to the magnesium adjuvant group. At 90 min the mean (SD) FEV<sub>1</sub> in the magnesium group (N=47) was 0.78 (0.33) l compared with 0.81 (0.30) l in the saline group (N=61) (difference −0.026 l (95% CI −0.15 to 0.095, p=0.67). No patients required non-invasive ventilation. There were 43/48 admissions to hospital in the magnesium group and 56/61 in the saline group (RR 0.98, 95% CI 0.86 to 1.10, p=0.69). <h3>Conclusions</h3> Nebulised magnesium as an adjuvant to salbutamol treatment in the setting of AECOPD has no effect on FEV<sub>1</sub>. Australian New Zealand Clinical Trials Registry ACTRN12608000167369.
Diabetes is an independent risk factor for in-hospital mortality from acute spontaneous intracerebral hemorrhage.
Authors: A Arboix, J Massons, L García-Eroles, M Oliveres, C Targa
Journal: Diabetes Care (2000)

We tested the hypothesis that diabetes is an independent determinant of outcome after intracerebral hemorrhage (ICH).This was a hospital-based prospective study The setting was an acute care 350-bed hospital in the city of Barcelona, Spain. Spontaneous ICH was diagnosed in 229 (11%) of 2,000 consecutive stroke patients included in a prospective stroke registry during a 10-year period. Main outcome measures were frequency of demographic variables, risk factors, clinical events, neuroimaging data, and outcome in ICH patients with and without diabetes. Variables related to vital status at discharge (alive or dead) in the univariate analysis plus age were studied in 4 logistical regression models.A total of 35 patients (15.3%) had diabetes. The overall in-hospital mortality rate was 54.3% in the diabetic group and 26.3% in the nondiabetic group (P < 0.001). Previous cerebral infarction, altered consciousness, sensory symptoms, cranial nerve palsy, multiple topography of the hematoma, intraventricular hemorrhage, and infectious complications were significantly more frequent in diabetic patients than in nondiabetic patients. The presence of diabetes was a significant predictive variable in the model based on demographic variables and cardiovascular risk factors (odds ratio 2.98 [95% CI 1.37-6.46]) and in the models based on these variables plus clinical variables (5.76 [2.01-16.51]), neuroimaging variables (5.59 [1.87-16.691), and outcome data (6.10 [2.04-18.291).Diabetes is an independent determinant of death after ICH. ICH in diabetic individuals presents some different clinical features compared with ICH in nondiabetic patients.
Bromelain protects piglets from diarrhoea caused by oral challenge with K88 positive enterotoxigenic<i>Escherichia coli</i>
Authors: D S Chandler, T L Mynott
Journal: Gut (1998)

Background—K88 positive enterotoxigenic Escherichia coli (K88 + ETEC) is an important cause of diarrhoea in young piglets. K88 + ETEC pathogenesis relies on attachment to specific glycoprotein receptors located on the intestinal mucosa. Proteolytic treatment of these receptors in vitro and in vivo prevents attachment of K88 + ETEC to piglet small intestines and may be of clinical use to prevent K88 + ETEC pathogenesis. Aims —To determine whether bromelain, a proteolytic extract obtained from pineapple stems, would protect piglets against K88 + ETEC diarrhoea and to confirm and extend earlier findings on the effects of bromelain on K88 + ETEC receptors in vivo. Methods —Bromelain (0, 12.5, or 125 mg) was orally administered to just weaned piglets for 10 days. One day following commencement of bromelain treatment, piglets were challenged with K88 + ETEC (5 × 10 10 K88ac:0149) for seven days. Intestinal contents from unchallenged piglets were obtained via an intestinal fistula, and tested for their ability to bind K88 + ETEC before and after bromelain treatment. Results —Both doses of bromelain were successful in reducing the incidence of K88 + ETEC diarrhoea and protected piglets from life threatening disease. Bromelain treated pigs also had significantly increased weight gain compared with untreated pigs. Bromelain only temporarily inhibited K88 + ETEC receptor activity, with receptor activity being regenerated 30 hours following treatment, consistent with the regeneration of new enterocytes. Conclusion —Results show that bromelain can temporarily inactivate ETEC receptors in vivo and protect against ETEC induced diarrhoea. Bromelain may therefore be an effective prophylaxis against ETEC infection.
PDGF-Receptor Tyrosine Kinase Blocker AG1295 Selectively Attenuates Smooth Muscle Cell Growth In Vitro and Reduces Neointimal Formation After Balloon Angioplasty in Swine
Authors: Shmuel Banai, Yehuda Wolf, Gershon Golomb, Andrew Pearle, Johannes Waltenberger, Ilia Fishbein, Aviva Schneider, Aviv Gazit, Louise Perez, Rita Huber, Galila Lazarovichi, Laura Rabinovich, Alexander Levitzki, S. David Gertz
Journal: Circulation (1998)

Background —Signaling through protein tyrosine kinases (PTKs) is a major contributor to the transmission of mitogenic stimuli to the interior of the cell and nucleus. The present study was designed to determine the effect of the tyrphostin AG1295, a selective blocker of PDGF-receptor PTK, on the growth of porcine and human smooth muscle cells (SMCs) in culture, on the outgrowth kinetics of SMCs from porcine and human arterial explants, and on neointimal formation after balloon injury in pigs. Methods and Results —SMCs for culture were obtained from porcine abdominal aortas, human internal mammary arteries, and endarterectomy tissue from a single human carotid artery. Addition of AG1295 to SMCs before PDGF stimulation completely inhibited PDGF-β-receptor tyrosine phosphorylation without affecting the level of PDGF-β-receptor. AG1295 resulted in a selective, reversible inhibition of SMC proliferation in culture (76%) with only mild (13.5%) inhibition of endothelial cell proliferation. The number of SMCs accumulating around explants of porcine carotid arteries and human endarterectomy specimens 12, 15, 19, 22, and 24 days after plating was reduced by 82% to 92% in AG1295-treated compared with nontreated specimens, and initiation of SMC outgrowth was markedly delayed. The numbers of cells accumulated 10 days after initiation of outgrowth were significantly lower in treated versus control explants. Local intravascular delivery of AG1295-impregnated polylactic acid–based nanoparticles (130±25 nm) to the site of balloon injury to porcine femoral arteries resulted in significant reductions in intima/media area ratio and luminal cross-sectional area narrowing by neointima compared with contralateral control arteries to which empty nanoparticles were applied (0.15±0.07 versus 0.09±0.03, P =.046 and 20±4% versus 10±4%, P =.0009, n=6 for both). Conclusions —The tyrphostin AG1295, a selective blocker of PDGF-receptor kinase, exerts a marked inhibitory effect on the activation, migration, and proliferation of porcine and human SMCs in vitro and an ≈50% inhibitory effect on neointimal formation after balloon injury in porcine femoral arteries when delivered via biodegradable nanoparticles. Further studies appear to be warranted to evaluate the applicability of this novel approach to the interventional setting.
PTU-032 Management of autoimmune hepatitis: a UK-wide survey
Authors: H Dhaliwal, C Facey, D Gleeson
Journal: Gut (2012)

<h3>Introduction</h3> Most hepatologists and many gastroenterologists manage patients with autoimmune hepatitis (AIH). There are no data regarding management of AIH in the UK as a whole. We aimed to conduct a survey of UK clinicians9 practice in regard to managing AIH. <h3>Methods</h3> An anonymised online questionnaire was e-mailed to 952 UK gastroenterology and hepatology consultant physicians, identified via the Directory of Gastroenterology.<sup>1</sup> Responses were collected via surveymonkey, an online questionnaire tool. We included only responders who indicated that they managed patients with liver disease. We defined responders as hepatologists if liver disease made up &gt;70% of their workload. <h3>Results</h3> 228 (24%) responded, 222 of whom managed patients with liver disease (38 (17%) hepatologists and 184 (83%) gastroenterologists). 26% managed ≤5 patients with AIH, 25% 6–10, 30% 11–25, 10% 26–50 and 8% &gt;50 patients. Half the responders indicated that all gastroenterologists in their hospital managed AIH; the remainder indicated that AIH was managed by hepatologists or gastroenterologists with a "liver" interest. Diagnostic liver biopsy (in absence of serious contraindication) was performed always by 62%, usually by 27% and only if the diagnosis was in doubt by 11%. Hepatologists were more likely than gastroenterologists to perform diagnostic liver biopsy always (82% vs 58%; p=0.02). As routine initial therapy, 80% of respondents used prednisolone+azathioprine (PRED+AZA) combined, 12% used PRED alone and 3% used budesonide+AZA. 65% continued PRED only until serum ALT normalised or for up to 6 months. 20% did so for &gt;12 months and 15% did so until confirmation of histological remission. Gastroenterologists were more likely than hepatologists to continue PRED only until ALT normalised or for up to 6 months (68 vs 50%) and were less likely to do so until confirmation of histological remission (12 vs 29%; p=0.02). 17% of respondents repeated liver biopsy routinely to confirm histological remission, 67% did so in selected cases and 16% never did. 63% routinely used maintenance therapy and 30% did so only after first relapse. Preferred maintenance therapy was AZA monotherapy in 74% and AZA+PRED in 21%. 34% of respondents continued maintenance therapy indefinitely, 59% attempted withdrawal (6% after 2–5 years; 50% after 5–10 years and 3% after 10–20 years) and 7% had a personalised approach. There were no differences between hepatologists and gastroenterologists regarding repeat liver biopsy policy or maintenance therapy. <h3>Conclusion</h3> In the UK, there is much variation in the approach to managing AIH, specifically in regard to: role of liver biopsy, initial therapy (particularly duration of steroids) and use of maintenance therapy. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. <i>Directory of Gastroenterology 2011</i>. 5th edn. Mediahuset.
Applying the results of randomised control trials on asthma
Authors: I. Town
Journal: Thorax (2007)

Guidelines for management of common medical conditions are just guidelines—to be used and interpreted by health practitioners

An important article by Peter Rothwell1 published in the Lancet in 2005 eloquently summarised issues concerning the external validity of randomised controlled trials (RCTs). The issue underlying the question “to whom do the results of this trial apply?” is sometimes referred to as generalisability and reporting on this is now a standard requirement for articles published by many journals directed at a general audience.

Rothwell summarises several factors that must be taken into account when considering generalisability, including the trial setting, patient selection, the characteristics of the patients randomised, the type of outcome measures employed, the nature and duration of follow-up, and the completeness of adverse event reporting. Further, differences between the trial protocol and routine local practice must be taken into account, especially the possibility, given the likely time elapsed between the trial design and reporting, that considerable therapeutic or diagnostic advances have occurred in the interim.1

A further important development in respect of clinical practice is the emergence of widely disseminated guidelines for the management of common medical conditions. Something of an industry has developed in this regard, with national and international agencies taking a leadership role.2 …
Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study
Authors: Gudrun Leidig-Bruckner, Stefanie Hosch, Petroula Dodidou, Dorothea Ritschel, Christian Conradt, Christina Klose, Gerd Otto, Rüdiger Lange, Lorenz Theilmann, Rainer Zimmerman, Maria Pritsch, Reinhard Ziegler
Journal: The Lancet (2001)
Functional Up-regulation of Human Leukocyte Antigen Class I Antigens Expression by 5-aza-2′-deoxycytidine in Cutaneous Melanoma: Immunotherapeutic Implications
Authors: Ester Fonsatti, Hugues J.M. Nicolay, Luca Sigalotti, Luana Calabrò, Laura Pezzani, Francesca Colizzi, Maresa Altomonte, Massimo Guidoboni, Francesco M. Marincola, Michele Maio
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To investigate the potential of the DNA hypomethylating agent 5-aza-2′-deoxycytidine (5-aza-CdR) to improve the effectiveness of immunotherapeutic approaches against melanocyte differentiation antigens. Experimental Design: The effect of 5-aza-CdR on the constitutive expression of gp100 was investigated in 11 human melanoma cell lines by real-time reverse transcription-PCR and indirect immunofluorescence (IIF) analyses. 5-aza-CdR–mediated changes in the levels of expression of human leukocyte antigen (HLA) class I antigens and HLA-A2 allospecificity, intercellular adhesion molecule-1 (ICAM-1), and leukocyte-function–associated antigen-3 were investigated by IIF analysis on melanoma cells under study. The recognition of gp100-positive Mel 275 melanoma cells, treated or not with 5-aza-CdR, by HLA-A2–restricted gp100(209–217)-specific CTL was investigated by 51Cr-release assays, IFN-γ release and IFN-γ ELISPOT assays. Results: The constitutive expression of gp100 was not affected by 5-aza-CdR on all melanoma cells investigated. Compared with untreated cells, the exposure of Mel 275 melanoma cells to 5-aza-CdR significantly (P &amp;lt; 0.05) up-regulated their expression of HLA class I antigens and of ICAM-1. These phenotypic changes significantly (P &amp;lt; 0.05) increased the lysis of 5-aza-CdR–treated Mel 275 melanoma cells by gp100-specific CTL and increased their IFN-γ release. 5-aza-CdR treatment of Mel 275 cells also induced a higher number of gp100-specific CTL to secrete IFN-γ. Conclusions: Treatment with 5-aza-CdR improves the recognition of melanoma cells by gp100-specific CTL through the up-regulation of HLA class I antigens expression; ICAM-1 also contributes to this phenomenon. These findings highlight a broader range of therapeutic implications of 5-aza-CdR when used in association with active or adoptive immunotherapeutic approaches against a variety of melanoma-associated antigens.
Altered lipid raft–associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus
Authors: Elizabeth C. Jury, Panagiotis S. Kabouridis, Fabian Flores-Borja, Rizgar A. Mageed, David A. Isenberg
Journal: Journal of Clinical Investigation (2004)

Systemic lupus erythematosus (SLE) is characterized by abnormalities in T lymphocyte receptor-mediated signal transduction pathways. Our previous studies have established that lymphocyte-specific protein tyrosine kinase (LCK) is reduced in T lymphocytes from patients with SLE and that this reduction is associated with disease activity and parallels an increase in LCK ubiquitination independent of T cell activation. This study investigated the expression of molecules that regulate LCK homeostasis, such as CD45, C-terminal Src kinase (CSK), and c-Cbl, in lipid raft domains from SLE T cells and investigated the localization of these proteins during T cell receptor (TCR) triggering. Our results indicate that the expression of raft-associated ganglioside, GM1, is increased in T cells from SLE patients and LCK may be differentially regulated due to an alteration in the association of CD45 with lipid raft domains. CD45 tyrosine phosphatase, which regulates LCK activity, was differentially expressed and its localization into lipid rafts was increased in T cells from patients with SLE. Furthermore, T cells allowed to "rest" in vitro showed a reversal of the changes in LCK, CD45, and GM1 expression. The results also revealed that alterations in the level of GM1 expression and lipid raft occupancy cannot be induced by serum factors from patients with SLE but indicated that cell-cell contact, activating aberrant proximal signaling pathways, may be important in influencing abnormalities in T cell signaling and, therefore, function in patients with SLE.
Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low-grade gliomas
Authors: Johan Pallud, Marie Blonski, Emmanuel Mandonnet, Etienne Audureau, Denys Fontaine, Nader Sanai, Luc Bauchet, Philippe Peruzzi, Marc Frénay, Philippe Colin, Rémy Guillevin, Valérie Bernier, Marie-Hélène Baron, Jacques Guyotat, Hugues Duffau, Luc Taillandier, Laurent Capelle
Journal: Neuro-Oncology (2013)

Supratentorial diffuse low-grade gliomas present a slow macroscopic tumor growth that can be quantified through the measurement of their velocity of diametric expansion. We assessed whether spontaneous velocity of diametric expansion can predict long-term outcomes as a categorical variable and as a continuous predictor.A total of 407 adult patients with newly diagnosed supratentorial diffuse low-grade gliomas in adults were studied.The mean spontaneous velocity of diametric expansion before first-line treatment was 5.8 ± 6.3 mm/year. During the follow-up (mean, 86.5 ± 59.4 months), 209 patients presented a malignant transformation, and 87 died. The malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (median, 103 and 249 months, respectively) than in cases of fast velocity of diametric expansion (median, 35 and 91 months, respectively; P < .001). In multivariate analyses, spontaneous velocity of diametric expansion as a categorical variable (<4, ≥4 and <8, ≥8 and <12, ≥12 mm/year) was an independent prognostic factor for malignant progression-free survival (P < .001; hazard ratio, 3.87; 95% confidence interval [CI], 2.67-5.52) and for overall survival (P < .001; hazard ratio, 4.62; 95% CI, 2.58-7.97). Velocity of diametric expansion was also an independent prognostic factor for overall survival as a continuous predictor, showing a linear relationship between overall survival and spontaneous velocity of diametric expansion (hazard ratio, 1.09 per one unit increase; 95% CI, 1.06-1.12; P < .001).Independent of the molecular status, the spontaneous velocity of diametric expansion allows the identification of rapidly growing diffuse low-grade gliomas (at higher risk of worsened evolution) during the pretherapeutic period and without delaying treatment.
Commitment: Beyond Rachlin's control?
Authors: N. E. Wetherick
Journal: Behavioral and Brain Sciences (1995)

Abstract Rachlin's view of self-control is rejected on the grounds that his arguments do not establish the possibility of “molar” abstract, external, stimulus patterns and that his experiments, although they show that pigeons and human beings do sometimes choose postponed rather than immediate gratification, do not challenge the commonly held view that internal factors are involved in the former choice.