tbuckley/cabot-search huggingface dataset:
Kinetics of Connective Tissue Growth Factor Expression during Experimental Proliferative Glomerulonephritis
Authors: YASUHIKO ITO, ROEL GOLDSCHMEDING, RICHARD J. BENDE, NIKE CLAESSEN, M. ANWAR CHAND, LIVIO KLEIJ, TON J. RABELINK, JAN J. WEENING, JAN ATEN
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Connective tissue growth factor (CTGF) is a member of the CCN family of immediate early genes, which are involved in cell proliferation, migration, and matrix production. Recently, CTGF was observed to be strongly upregulated in human proliferative and fibrogenic renal disease. By in situ hybridization and reverse transcriptase-PCR, the expression of CTGF was investigated in experimental proliferative glomerulonephritis induced by injection of anti—Thy-1.1 antibody in the rat. CTGF expression in cultured rat mesangial cells and glomerular visceral epithelial cells (GVEC) was studied in response to transforming growth factor β (TGF-β), an essential pathogenetic factor in this model. In normal rat kidneys, only some GVEC expressed CTGF mRNA. In anti—Thy-1.1 nephritis, CTGF mRNA expression was strongly increased in extracapillary and mesangial proliferative lesions and in areas of periglomerular fibrosis. Early glomerular CTGF overexpression in GVEC coincided with a striking upregulation of TGF-β2 and to a lesser extent of TGF-β3. Glomerular CTGF mRNA expression was maximal at day 7, in association with increased TGF-β1 mRNA and protein expression. CTGF mRNA overexpression by parietal epithelial cells preceded the periglomerular appearance of α-smooth muscle actin—positive fibroblasts. In cultured mesangial cells, TGF-β1, -β2, and -β3 transiently increased the CTGF/glyceraldehyde phosphate dehydrogenase mRNA ratio up to threefold versus control at 4 h. In GVEC, upregulation of CTGF mRNA by these TGF-β isoforms was more sustained, being 8- to 16-fold versus control at 24 h. The kinetics of CTGF expression strongly suggest a role in glomerular repair, possibly downstream of TGF-β, in this model of transient renal injury.
Nongenomic Effects of Aldosterone on Intracellular Ca <sup>2+</sup> in Vascular Smooth Muscle Cells
Authors: Martin Wehling, Craig B. Neylon, Meryl Fullerton, Alex Bobik, John W. Funder
Journal: Circulation Research (1995)

Abstract Genomic mechanisms of steroid action have been increasingly elucidated over the past four decades. In contrast, rapid steroid actions have been widely recognized only recently, and detailed analysis of the mechanisms involved are still lacking. The present article describes rapid effects of mineralocorticoid hormones on free intracellular calcium in vascular smooth muscle cells as determined by fura 2 spectrofluorometry in single cultured cells from rat aorta. These effects are almost immediate and reach a plateau after only 3 to 5 minutes and are characterized by high specificity for mineralocorticoids versus glucocorticoids. The potent mineralocorticoids aldosterone and fludrocortisone are agonists with estimated apparent EC 50 values of ≈0.1 to 0.5 nmol/L; deoxycorticosterone acetate is an agonist with an EC 50 of ≈5 nmol/L; and progesterone, cortisol, corticosterone, and estradiol have much lower potency (EC 50 values of ≈0.5 to 5 μmol/L). The effect of aldosterone is blocked by neomycin and short-term treatment with phorbol esters but augmented by staurosporine, indicating an involvement of phospholipase C and protein kinase C. The Ca 2+ effect appears to involve the release of intracellular Ca 2+ , as shown by the inhibitory effect of thapsigargin; intriguingly, a relatively small maximum effect (≈40 nmol/L increase) is consistently seen. This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to be a likely candidate for rapid fine tuning of cardiovascular responsivity. It may also contribute to known clinical features of mineralocorticoid action that are difficult to explain by the traditional genomic mechanism alone.
In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats
Authors: M Van de Casteele
Journal: Gut (2002)

Portal hypertension in cirrhosis results from enhanced intrahepatic resistance to an augmented inflow. The former is partly due to an imbalance between intrahepatic vasoconstriction and vasodilatation. Enhanced endothelin-1 and decreased activity of hepatic constitutive endothelial nitric oxide synthase (NOS 3) was reported in carbon tetrachloride (CCl(4)) cirrhotic rat liver.To study whether an increase in hepatic NOS 3 could be obtained in the CCl(4) cirrhotic rat liver by in vivo cDNA transfer and to investigate a possible effect on portal pressure.Hepatic NOS 3 immunohistochemistry and western blotting were used to measure the amount of NOS 3 protein. Recombinant adenovirus, carrying cDNA encoding human NOS 3, was injected into the portal vein of CCl(4) cirrhotic rats. Cirrhotic controls received carrier buffer, naked adenovirus, or adenovirus carrying the lac Z gene.NOS 3 immunoreactivity and amount of protein (western blotting) were significantly decreased in CCl(4) cirrhotic livers. Following cDNA transfer, NOS 3 expression and the amount of protein were partially restored. Portal pressure was 11.4 (1.6) mm Hg in untreated cirrhotic (n=9) and 11.8 (0.6) in lac Z transfected (n=4) cirrhotic rats but was reduced to 7.8 (1.0) mm Hg (n=9) five days after NOS 3 cDNA transfer. No changes were observed in systemic haemodynamics, in liver tests or urinary nitrates, or in NOS 3 expression in lung or kidney, indicating a highly selective transfer.NOS 3 cDNA transfer to cirrhotic rat liver is feasible and the increase in hepatic NOS 3 leads to a marked decrease in portal hypertension without systemic effects. These data indicate a major haemodynamic role of intrahepatic NOS 3 in the pathogenesis of portal hypertension in CCl(4) cirrhosis.
Preserved Working Memory and Altered Brain Activation in Persons at Risk for Psychosis
Authors: Siti N. Yaakub, Kavitha Dorairaj, Joann S. Poh, Christopher L. Asplund, Ranga Krishnan, Jimmy Lee, Richard S.E. Keefe, R. Alison Adcock, Stephen J. Wood, Michael W.L. Chee
Journal: American Journal of Psychiatry (2013)

Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters.Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance.The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters.Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.
Should labeled lines and pattern models be either-or? Issues of scope and definition
Authors: Jennifer A. Stillman
Journal: Behavioral and Brain Sciences (2008)

Abstract Erickson's conclusion that if basic tastes are not appropriate at one level, reference to labeled lines is inappropriate at any level, depends on matters of definition and scope. His population model mirrors Young's theory of color perception. However, there is evidence for distinct pathways to the cortex for two cone-opponent and one achromatic channel. Depending on the use made of key terms, sensory systems may display both across-fiber and labeled-line features.
infections in mouse models: relevance for atherosclerosis research
Authors: M DEKRUIF, E VANGORP, T KELLER, J OSSEWAARDE, H TENCATE
Journal: Cardiovascular Research (2004)

Mouse models have been frequently used in the study of Chlamydia pneumoniae (also known as Chlamydophila pneumoniae) infections. This gram-negative obligate intracellular bacterium causes respiratory infections, followed by dissemination of the bacterium to various organs throughout the body, including cardiovascular tissues, supporting the current hypothesis of a relationship between C. pneumoniae and atherosclerosis. Recently, clinical trials evaluated the effect of antichlamydial antibiotics on secondary cardiovascular events. Although small studies showed some effect, the large WIZARD study did not confirm these results, and the role of antichlamydial antibiotics in prevention of secondary events was questioned. To address these issues, data obtained from mouse models were systematically reviewed here. C. pneumoniae infections showed atherogenic properties in mice that were reproducible and confirmed by different research groups. However, antibiotic therapy was of limited value in these mouse models. Antibiotic therapy effectively cleared the acute infection, but did not influence the atherogenic properties of C. pneumoniae unless the therapy was started early during the acute infection. The results summarized here may help to better understand the results of the clinical antibiotic trials.
Fatal and Near-Fatal Asthma
Authors: E.R. McFadden
Journal: New England Journal of Medicine (1991)

OF all of the medical emergencies that confront practicing physicians, asthma is the one most often dealt with in accordance with the adage "familiarity breeds contempt." Because asthma is such a common disease and is so readily reversed with treatment, many health care professionals, and even some patients, tend to view acute exacerbations of this illness as annoyances that will pass rather than as potentially life-threatening events. Unfortunately, as shown by Molfino et al.1 and by O'Hollaren and associates2 in this issue of the Journal, this disease, for reasons not yet understood, can place the lives of affected persons . . .
The effects of hypoxia on the cells of the pulmonary vasculature
Authors: O. Pak, A. Aldashev, D. Welsh, A. Peacock
Journal: European Respiratory Journal (2007)

Pulmonary hypertension is associated with remodelling of pulmonary vessels. Chronic hypoxia is a common cause of pulmonary hypertension and pulmonary vascular remodelling. Vascular remodelling is characterised largely by fibroblast, smooth muscle and endothelial cell proliferation, which results in lumen obliteration. Chronic hypoxia elicits expression of mitogens, growth factors and cytokines by fibroblasts and endothelial cells, and also the suppression of endothelial nitric oxide synthase. Although hypoxic pulmonary vascular remodelling is associated with medial hypertrophy, many in vitro studies have found that hypoxia does not lead to a direct increase in smooth muscle cell proliferation. This paradox is not well understood and this review aims to examine the various reasons why this might be so. The present authors reviewed data from in vitro studies and also considered whether hypoxia could act on adjacent cells such as fibroblasts and endothelial cells to trigger smooth muscle cell proliferation. It is possible that hypoxia is sensed by fibroblasts, endothelial cells, or both, and relayed to adjacent pulmonary artery smooth muscle cells by intercellular signalling, causing proliferation. The present article reviews the data from in vitro studies of hypoxia on the three cellular components of the pulmonary vascular wall, namely endothelial cells, smooth muscle cells and fibroblasts.
Clinical development of demethylating agents in hematology
Authors: Shyamala C. Navada, Juliane Steinmann, Michael Lübbert, Lewis R. Silverman
Journal: Journal of Clinical Investigation (2014)

The term epigenetics refers to the heritable changes in gene expression that are not associated with a change in the actual DNA sequence. Epigenetic dysregulation is linked to the pathogenesis of a number of malignancies and has been studied extensively in myelodysplastic syndromes and acute myeloid leukemia. DNA methylation is frequently altered in cancerous cells and likely results in transcriptional silencing of tumor suppressor genes. Re-expression of these genes by inhibition of the DNA methyltransferases has been successful in the treatment of benign and malignant disease. In this Review, we discuss the clinical development of demethylating agents in hematology, with a focus on azacitidine and decitabine.
Peak expiratory flow (PEF) monitoring
Authors: R Ruffin
Journal: Thorax (2004)

The role of PEF monitoring in the diagnosis and monitoring of asthma The Wright peak expiratory flow meter was introduced in 19591 and provided a portable piece of equipment for assessing some aspects of lung function in the ambulatory care setting. The original device has been supplanted by the mini Wright peak flow meter (and a range of other devices) which have become relatively cheap but are reasonably reliable for home monitoring.2 So, with an available device for measuring peak expiratory flow (PEF), what is its role in the 21st century? PEF reflects a range of physiological characteristics of the lungs, airways, and neuromuscular characteristics of individuals. These include lung elastic recoil, large airway calibre, lung volume, effort, and neuromuscular integrity.3 The reflection of airway calibre makes the PEF meter suitable for measuring variation in PEF over time to provide support for:
The Intrinsic Mitochondrial Membrane Potential of Colonic Carcinoma Cells Is Linked to the Probability of Tumor Progression
Authors: Barbara G. Heerdt, Michele A. Houston, Leonard H. Augenlicht
Journal: Cancer Research (2005)

Abstract We subcloned cell lines from SW620 cells establishing that, despite the dynamic nature of the mitochondrial membrane potential (Δψm), there are significant and stable differences in the intrinsic Δψm among cells within an in vitro population of human colonic carcinoma cells. Whereas more dramatic differences in Δψm would likely perturb essential mitochondrial functions, the differences in Δψm of the subclones did not affect steady-state reactive oxygen species levels, electron transport activity, or cellular viability and growth rates. However, the differences in intrinsic Δψm had a significant effect on the tumorigenic behavior of the cells. Subcloned cell lines with higher Δψm were more likely to exhibit elevated steady-state levels of vascular endothelial growth factor and matrix metalloproteinase 7, and increased invasive behavior (properties associated with tumor progression), than cells with lower intrinsic Δψm, whereas cells with lower Δψm were more likely to respond to the chemopreventive activities of butyrate, including Δψm dissipation, growth arrest, and apoptosis, than cells with higher Δψm. Therefore, these data establish that the probability for tumor development and progression is linked to stable differences in the intrinsic Δψm of colonic epithelial cells.
Molecular Characterization of the Pediatric Preclinical Testing Panel
Authors: Geoffrey Neale, Xiaoping Su, Christopher L. Morton, Doris Phelps, Richard Gorlick, Richard B. Lock, C. Patrick Reynolds, John M. Maris, Henry S. Friedman, Jeffrey Dome, Joseph Khoury, Timothy J. Triche, Robert C. Seeger, Richard Gilbertson, Javed Khan, Malcolm A. Smith, Peter J. Houghton
Journal: Clinical Cancer Research (2008)

Identifying novel therapeutic agents for the treatment of childhood cancers requires preclinical models that recapitulate the molecular characteristics of their respective clinical histotypes.Here, we have applied Affymetrix HG-U133Plus2 profiling to an expanded panel of models in the Pediatric Preclinical Testing Program. Profiling led to exclusion of two tumor lines that were of mouse origin and five osteosarcoma lines that did not cluster with human or xenograft osteosarcoma samples. We compared expression profiles of the remaining 87 models with profiles from 112 clinical samples representing the same histologies and show that model tumors cluster with the appropriate clinical histotype, once "immunosurveillance" genes (contributed by infiltrating immune cells in clinical samples) are eliminated from the analysis. Analysis of copy number alterations using the Affymetrix 100K single nucleotide polymorphism GeneChip showed that the models have similar copy number alterations to their clinical counterparts. Several consistent copy number changes not reported previously were found (e.g., gain at 22q11.21 that was observed in 5 of 7 glioblastoma samples, loss at 16q22.3 that was observed in 5 of 9 Ewing's sarcoma and 4 of 12 rhabdomyosarcoma models, and amplification of 21q22.3 that was observed in 5 of 7 osteosarcoma models). We then asked whether changes in copy number were reflected by coordinate changes in gene expression. We identified 493 copy number-altered genes that are nonrandom and appear to identify histotype-specific programs of genetic alterations.These data indicate that the preclinical models accurately recapitulate expression profiles and genetic alterations common to childhood cancer, supporting their value in drug development.
S34 Effects of the cyclin-dependent kinase inhibitor R-roscovitine on eosinophil survival and clearance
Authors: N. Farahi, L. Uller, J. K. Juss, A. J. Langton, A. S. Cowburn, A. Gibson, M. R. Foster, S. N. Farrow, A. Sobolewski, A. M. Condliffe, E. R. Chilvers
Journal: Thorax (2010)

<h3>Background</h3> Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying the resolution of eosinophilic inflammation and studies have indicated the ability of interventions that induce human eosinophil apoptosis to promote the resolution of eosinophilic inflammation. Recently, the cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to enhance neutrophil apoptosis and promote the resolution of neutrophilic inflammation. <h3>Aim</h3> The purpose of this study was to examine the expression of CDKs in human blood eosinophils, the effects of R-roscovitine on eosinophil survival and phagocytosis <i>in vitro</i> and determine whether R-roscovitine could influence eosinophilic lung inflammation <i>in vivo</i>. <h3>Methods</h3> Eosinophils were isolated from human peripheral blood and the effects of R-roscovitine on apoptosis, degranulation and phagocytic uptake examined <i>in vitro</i>. The effects of R-roscovitine on eosinophilic lung inflammation <i>in vivo</i> were also assessed using an ovalbumin mouse model. <h3>Results</h3> Our data demonstrate that human eosinophils express five targets for R-roscovitine: CDK1, −2, −5, −7 and −9. R-roscovitine induced eosinophil apoptosis in a time- and concentration-dependent manner but also accelerated transition to secondary necrosis as assessed by light and electron microscopy, flow cytometry and caspase activation. In addition, we report that the pro-apoptotic effect of R-roscovitine is associated with suppression of Mcl-1L expression and that the apoptotic eosinophils are phagocytosed by human monocyte derived macrophages. R-roscovitine also induced apoptosis in mouse eosinophils purified from the bone-marrow, spleen and peripheral blood. Despite this, R-roscovitine did not modulate the tissue and lumen eosinophilia characteristic of the ovalbumin mouse model of airway eosinophilia. <h3>Conclusions</h3> These data demonstrate that R-roscovitine is capable of inducing rapid apoptosis and secondary necrosis in human eosinophils but does not affect the onset or resolution of eosinophilic airway inflammation <i>in vivo</i>.
Efficacy and safety of out-of-hospital self-administered single-dose oral drug treatment in the management of infrequent, well-tolerated paroxysmal supraventricular tachycardia
Authors: Paolo Alboni, Corrado Tomasi, Carlo Menozzi, Nicola Bottoni, Nelly Paparella, Giuseppe Fucà, Michele Brignole, Riccardo Cappato
Journal: Journal of the American College of Cardiology (2001)
Altered mouse cholinephosphotransferase gene expression in kidneys of type 2 diabetic KK/TA mouse
Authors: Tomohito Gohda, Mitsuo Tanimoto, Kenji Shiina, Takamichi Ito, Michimasa Kobayashi, Shinji Hagiwara, Shigeru Kaneko, Yuichiro Makita, Kazuhiko Funabiki, Satoshi Horikoshi, Yasuhiko Tomino
Journal: Metabolism (2004)
Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomised controlled trial
Authors: Nicola Dalbeth, Ruth Ames, Greg D Gamble, Anne Horne, Sumwai Wong, Barbara Kuhn-Sherlock, Alastair MacGibbon, Fiona M McQueen, Ian R Reid, Kate Palmano
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Previous laboratory studies have identified two dairy fractions, glycomacropeptide (GMP) and G600 milk fat extract (G600), with anti-inflammatory effects in models of acute gout. The aim of this proof-of-concept clinical trial was to test the hypothesis that daily intake of skim milk powder (SMP) enriched with GMP and G600 can prevent gout flares. <h3>Methods</h3> This was a 3-month randomised double-blind controlled trial of milk products for prevention of gout flares. One hundred and twenty patients with recurrent gout flares were randomised to one of three arms: lactose powder control, SMP control and SMP enriched with GMP and G600 (SMP/GMP/G600). The primary end point was change in the frequency of gout flares using a daily flare diary measured monthly for 3 months. <h3>Results</h3> The frequency of gout flares reduced in all three groups over the 3-month study period compared with baseline. Over the 3-month study period there was a significantly greater reduction in gout flares in the SMP/GMP/G600 group (analysis of covariance p<sub>group</sub>=0.031, Tukey post hoc test compared with lactose control, p=0.044). Following treatment with SMP/GMP/G600 over the 3-month period, greater improvements were also observed in pain and fractional excretion of uric acid, with trends to greater improvement in tender joint count. Similar adverse event rates and discontinuation rates were observed between the three groups. <h3>Conclusions</h3> This is the first reported controlled trial of dietary intervention in patients with gout, and suggests that SMP enriched with GMP and G600 may reduce the frequency of gout flares.