tbuckley/cabot-search huggingface dataset:
Abstract 18325: Functional Relationship of the COL4A1/COL4A2 Locus on Chromosome 13q34 to Coronary Artery Disease (CAD)
Authors: Adam Turner, Majid Nikpay, Paulina Lau, Sebastien Soubeyrand, Ruth McPherson
Journal: Circulation (2013)

Background: The COL4A1/COL4A2 locus has been linked to CAD in recent large GWAS meta-analyses. The COL4A1 and COL4A2 proteins constitute the major structural component of basement membranes, have important functional roles in angiogenesis, and mutations have been associated with diverse vascular abnormalities. We performed epistasis analysis for CAD-associated SNPs at the COL4A1/COL4A2 locus; this revealed genetic interaction with members of the TGFβ/Smad signalling pathway. Furthermore, pathway analysis of GWAS has implicated TGFβ and Smad signaling as well as the extracellular matrix as enriched CAD pathways. Bioinformatic analysis also predicted binding of Smad3 and Smad4 to the promoter region of COL4A1/COL4A2 . We sought to address the hypothesis that the TGFβ-mediated regulation of COL4A1 and COL4A2 is via Smad3/Smad4 and that this pathway is relevant to the pathogenesis of CAD. Methods and Results: Under basal conditions, HT-1080 fibroblast cells treated with TGFβ1 for 16h produced 5 fold and 3 fold increases in COL4A1 and COL4A2 mRNA respectively as measured by qRT-PCR. In contrast, 16h treatment with TGFβ1 in the presence of the specific Smad pathway inhibitor SB431542 (10nM) abolished COL4A1/COL4A2 upregulation (p&lt;0.001). To rule out the possibility that TGFβ1 regulates COL4A1 and COL4A2 expression indirectly via a non-Smad pathway, we showed that inhibition of the JNK, p38 MAPK, and ERK pathways had no effect on COL4A1 and COL4A2 levels basally or in response to TGFβ1. siRNA knockdown (&gt;85%) of SMAD3 in HT-1080 cells diminished the TGFβ1 upregulation of both COL4A1 and COL4A2 mRNA levels in comparison to nontarget siRNA (p&lt;0.001). The effect of TGFβ1 on COL4A1 and COL4A2 mRNA expression was completely abolished when SMAD3 and SMAD4 were knocked-down in concert. These effects on COL4A1 and COL4A2 mRNA expression were recapitulated at the protein level by Western blotting. Conclusions: These data suggest that Smad3 and Smad4 are the downstream mediators by which TGFβ1 upregulates COL4A1 and COL4A2 expression in HT-1080 cells. This work further highlights the importance of the extracellular matrix and TGFβ/Smad signalling in the pathogenesis of CAD.
Morphine effects on striatal transcriptome in mice
Authors: Michal Korostynski, Marcin Piechota, Dorota Kaminska, Wojciech Solecki, Ryszard Przewlocki
Journal: Genome biology (2007)

Chronic opiate use produces molecular and cellular adaptations in the nervous system that lead to tolerance, physical dependence, and addiction. Genome-wide comparison of morphine-induced changes in brain transcription of mouse strains with different opioid-related phenotypes provides an opportunity to discover the relationship between gene expression and behavioral response to the drug.Here, we analyzed the effects of single and repeated morphine administrations in selected inbred mouse strains (129P3/J, DBA/2J, C57BL/6J, and SWR/J). Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts. Through ontologic classification, we linked particular sets of genes to biologic functions, including metabolism, transmission of nerve impulse, and cell-cell signaling. We identified numerous novel morphine-regulated genes (for instance, Olig2 and Camk1g), and a number of transcripts with strain-specific changes in expression (for instance, Hspa1a and Fzd2). Moreover, transcriptional activation of a pattern of co-expressed genes (for instance, Tsc22d3 and Nfkbia) was identified as being mediated via the glucocorticoid receptor (GR). Further studies revealed that blockade of the GR altered morphine-induced locomotor activity and development of physical dependence.Our results indicate that there are differences between strains in the magnitude of transcriptional response to acute morphine treatment and in the degree of tolerance in gene expression observed after chronic morphine treatment. Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait. The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine.
Pulmonary capillary blood flow studies in polycythaemia rubra vera
Authors: S. R. REUBEN, P. F. M. WRIGLEY, D. J. LANE, J. BUTLER
Journal: Cardiovascular Research (1973)

Cardiopulmonary studies were performed in 12 patients with longstanding polycythaemia rubra vera. Lung function tests indicated an increase in physiological deadspace and evidence of mismatched ventilation/perfusion relationships. Pulmonary capillary blood flow was measured by the nitrous oxide-body plethysmograph technique and a high frequency phonocardiogram was recorded from the pulmonary area to indicate pulmonary valve opening. In 10 patients the lung blood flow studies were repeated 24 hr after a 11. venesection. In the pre-venesection studies the pulsatility index of capillary flow, expressed as the ratio of peak to mean flow rates, averaged 1·6:1. The pulmonary artery to capillary flow conduction time, measured from the time of pulmonary valve opening to the foot of the capillary flow pulse, averaged 94 msec. These values were markedly reduced from normal (2·0:1 and 160 msec respectively) and indicated elevated pulmonary vascular resistance and pulmonary artery pressure. Venesection produced no significant change in the flow conduction time (mean 107 msec; P>0·10) suggesting the presence of irreversibly stiffened pulmonary arterial walls. Venesection did, however, restore the pulsatility of the capillary flow pulse to a normal level (mean 2·0:1), suggesting that there is an additional reversible component to the elevated pulmonary vascular resistance.
The Complete Gene Sequence of Titin, Expression of an Unusual ≈700-kDa Titin Isoform, and Its Interaction With Obscurin Identify a Novel Z-Line to I-Band Linking System
Authors: Marie-Louise Bang, Thomas Centner, Friderike Fornoff, Adam J. Geach, Michael Gotthardt, Mark McNabb, Christian C. Witt, Dietmar Labeit, Carol C. Gregorio, Henk Granzier, Siegfried Labeit
Journal: Circulation Research (2001)

Titin is a giant vertebrate striated muscle protein with critical importance for myofibril elasticity and structural integrity. We show here that the complete sequence of the human titin gene contains 363 exons, which together code for 38 138 residues (4200 kDa). In its central I-band region, 47 novel PEVK exons were found, which contribute to titin’s extensible spring properties. Additionally, 3 unique I-band titin exons were identified (named novex-1 to -3). Novex-3 functions as an alternative titin C-terminus. The novex-3 titin isoform is ≈700 kDa in size and spans from Z1-Z2 (titin’s N-terminus) to novex-3 (C-terminal exon). Novex-3 titin specifically interacts with obscurin, a 721-kDa myofibrillar protein composed of 57 Ig/FN3 domains, followed by one IQ, SH3, DH, and a PH domain at its C-terminus. The obscurin domains Ig48/Ig49 bind to novex-3 titin and target to the Z-line region when expressed as a GFP fusion protein in live cardiac myocytes. Immunoelectron microscopy detected the C-terminal Ig48/Ig49 obscurin epitope near the Z-line edge. The distance from the Z-line varied with sarcomere length, suggesting that the novex-3 titin/obscurin complex forms an elastic Z-disc to I-band linking system. This system could link together calcium-dependent, SH3-, and GTPase-regulated signaling pathways in close proximity to the Z-disc, a structure increasingly implicated in the restructuring of sarcomeres during cardiomyopathies.
Ordered rearrangement of variable region genes of the T cell receptor gamma locus correlates with transcription of the unrearranged genes.
Authors: J P Goldman, D M Spencer, D H Raulet
Journal: The Journal of Experimental Medicine (1993)

T cell receptor V gamma genes rearrange to the J gamma 1 gene segment in a highly ordered fashion during development. We demonstrate a striking correlation between the pattern of expression of unrearranged V gamma genes and the timing of their rearrangement. Thus, the increases in V gamma 2 rearrangements, and decreases in V gamma 3 and V gamma 4 rearrangements observed during development are paralleled by increasing or decreasing levels of the corresponding unrearranged V gene transcript. We also provide evidence that both the V gamma 3 and V gamma 4 genes are accessible in mature V gamma 3+ cells, but that the V gamma 4 gene may be inaccessible in the progenitors of V gamma 3 cells. The results suggest that regulated local accessibility of the chromatin surrounding V gamma genes is responsible for ordered V gamma gene rearrangement during development.
Validation of predictive rules and indices of severity for community acquired pneumonia
Authors: S Ewig
Journal: Thorax (2004)

<b>Background:</b> A study was undertaken to validate the modified American Thoracic Society (ATS) rule and two British Thoracic Society (BTS) rules for the prediction of ICU admission and mortality of community acquired pneumonia and to provide a validation of these predictions on the basis of the pneumonia severity index (PSI). <b>Method:</b> Six hundred and ninety six consecutive patients (457 men (66%), mean (SD) age 67.8 (17.1) years, range 18–101) admitted to a tertiary care hospital were studied prospectively. Of these, 116 (16.7%) were admitted to the ICU. <b>Results:</b> The modified ATS rule achieved a sensitivity of 69% (95% CI 50.7 to 77.2), specificity of 97% (95% CI 96.4 to 98.9), positive predictive value of 87% (95% CI 78.3 to 93.1), and negative predictive value of 94% (95% CI 91.8 to 95.8) in predicting admission to the ICU. The corresponding predictive indices for mortality were 94% (95% CI 82.5 to 98.7), 93% (95% CI 90.6 to 94.7), 49% (95% CI 38.2 to 59.7), and 99.5% (95% CI 98.5 to 99.9), respectively. These figures compared favourably with both the BTS rules. The BTS-CURB criteria achieved predictions of pneumonia severity and mortality comparable to the PSI. <b>Conclusions:</b> This study confirms the power of the modified ATS rule to predict severe pneumonia in individual patients. It may be incorporated into current guidelines for the assessment of pneumonia severity. The CURB criteria may be used as an alternative tool to PSI for the detection of low risk patients.
Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells.
Authors: G K Hansson, M Hellstrand, L Rymo, L Rubbia, G Gabbiani
Journal: The Journal of Experimental Medicine (1989)

Differentiation of muscle cells is characterized morphologically by the acquisition of contractile filaments and characteristic shape changes, and on the molecular level by induction of the expression of several genes, including those for the muscle-specific alpha-actin isoforms. IFN-gamma is an inhibitor of proliferation for several cells, including vascular smooth muscle, and is also an inducer of differentiated properties for several hematopoietic cells. We have therefore investigated whether IFN-gamma affects the expression of alpha-smooth muscle actin in cultured arterial smooth muscle cells. Cells exposed to IFN-gamma show a reduction of alpha-smooth muscle actin-containing stress fibers, as detected by immunofluorescence. The effect was observed in all phases of the cell cycle, and was caused by a reduction of the synthesis of alpha-smooth muscle actin protein as revealed by two-dimensional electrophoretic analysis of actin isoforms. RNA hybridization using a cRNA probe that hybridizes to all actin mRNAs showed that IFN-gamma-treated cells have a reduced content of the 1.7-kb mRNA that codes for alpha-smooth muscle actin, and to a lesser extent, also of the 2.1-kb mRNA encoding the beta and gamma-cytoplasmic actins. The reduction of alpha-smooth muscle actin mRNA was confirmed using an alpha-smooth muscle actin-specific cRNA probe. The reduction of alpha-smooth muscle actin mRNA occurs within 12 h, and is dependent on protein synthesis, since cycloheximide treatment reversed the effect. The inhibition of this mRNA species was dose dependent, and detectable by RNA hybridization at a dose of 50 U/ml IFN-gamma. These results suggest that the differentiation of arterial smooth muscle cells is not necessarily coupled to an inhibition of cellular proliferation. Instead, IFN-gamma may regulate the expression of several genes that control both proliferation and expression of differentiation markers.
Mechanisms of Ventricular Fibrillation Induction by 60-Hz Alternating Current in Isolated Swine Right Ventricle
Authors: Olga Voroshilovsky, Zhilin Qu, Moon-Hyoung Lee, Toshihiko Ohara, Gregory A. Fishbein, Hsun-Lun A. Huang, Charles D. Swerdlow, Shien-Fong Lin, Alan Garfinkel, James N. Weiss, Hrayr S. Karagueuzian, Peng-Sheng Chen
Journal: Circulation (2000)

The mechanisms by which 60-Hz alternating current (AC) can induce ventricular fibrillation (VF) are unknown.We studied 7 isolated perfused swine right ventricles in vitro. The action potential duration restitution curve was determined. Optical mapping techniques were used to determine the patterns of activation on the epicardium during 5-second 60-Hz AC stimulation (10 to 999 microA). AC captured the right ventricles at 100+/-65 microA, which is significantly lower than the direct current pacing threshold (0.77+/-0.45 mA, P:<0.05). AC induced ventricular tachycardia or VF at 477+/-266 microA, when the stimulated responses to AC had (1) short activation CLs (128+/-14 ms), (2) short diastolic intervals (16+/-9 ms), and (3) short diastolic intervals associated with a steep action potential duration restitution curve. Optical mapping studies showed that during rapid ventricular stimulation by AC, a wave front might encounter the refractory tail of an earlier wave front, resulting in the formation of a wave break and VF. Computer simulations reproduced these results.AC at strengths less than the regular pacing threshold can capture the ventricle at fast rates. Accidental AC leak to the ventricles could precipitate VF and sudden death if AC results in a fast ventricular rate coupled with a steep restitution curve and a nonuniform recovery of excitability of the myocardium.
Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion
Authors: Guocan Wang, Andrea Lunardi, Jiangwen Zhang, Zhenbang Chen, Ugo Ala, Kaitlyn A Webster, Yvonne Tay, Enrique Gonzalez-Billalabeitia, Ainara Egia, David R Shaffer, Brett Carver, Xue-Song Liu, Riccardo Taulli, Winston Patrick Kuo, Caterina Nardella, Sabina Signoretti, Carlos Cordon-Cardo, William L Gerald, Pier Paolo Pandolfi
Journal: Nature Genetics (2013)
Intestinal permeability and inflammation in patients on NSAIDs
Authors: G Sigthorsson, J Tibble, J Hayllar, I Menzies, A Macpherson, R Moots, D Scott, M J Gumpel, I Bjarnason
Journal: Gut (1998)

Background —The frequency with which non-steroidal anti-inflammatory drugs (NSAIDs) increase small intestinal permeability and cause inflammation is uncertain. Aims —To examine small intestinal permeability and inflammation in a large number of patients on long term NSAIDs. Methods —Sixty eight patients receiving six different NSAIDs for over six months underwent combined absorption-permeability tests at three different test dose osmolarities (iso-, hypo-, and hyperosmolar). Two hundred and eighty six patients on 12 different NSAIDs underwent indium-111 white cell faecal excretion studies to assess the prevalence and severity of intestinal inflammation. Results —The iso- and hyperosmolar tests showed significant malabsorption of 3–0-methyl- d -glucose, d -xylose, and l -rhamnose. Intestinal permeability changes were significantly more pronounced and frequent with the hypo- and hyperosmolar as opposed to the iso-osmolar test. Sequential studies showed that four and nine patients (of 13) developed inflammation after three and six months treatment with NSAIDs, respectively. There was no significant difference (p&gt;0.1) in the prevalence (54–72%) or severity of intestinal inflammation in the 286 patients taking the various NSAIDs apart from those on aspirin and nabumetone, these having no evidence of intestinal inflammation. There was no significant correlation between the inflammatory changes and age, sex, dose of NSAID, length of disease, or NSAID ingestion. Conclusions —Intestinal permeability test dose composition is an important factor when assessing the effects of NSAIDs on intestinal integrity. All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel.
Republished research: Effectiveness of physical activity promotion based in primary care: systematic review and meta-analysis of randomised controlled trials
Authors: Gillian Orrow, Ann-Louise Kinmonth, Simon Sanderson, Stephen Sutton
Journal: British Journal of Sports Medicine (2012)

Study question Do trials of physical activity promotion based in primary care show sustained effects on physical activity or fitness in sedentary adults, and are exercise referral interventions more effective than other interventions?Summary answer Trials of physical activity promotion based in primary care show positive effects on physical activity levels, but not on fitness, over at least 12 months; however, not enough evidence exists to indicate whether exercise referral is more effective than other primary care interventions.What is known and what this paper adds Physical activity promotion in primary care, including exercise referral, is reported to improve physical activity levels in the short term but its longer term effect was unclear. Our review found that promotion of physical activity to sedentary adults identified through primary care significantly improves self reported physical activity levels over at least 12 months; we found few trials of exercise referral interventions with 12 months’ follow-up and more trials are needed to determine their relative effectiveness.
Primary diffuse tracheo-bronchial amyloidosis
Authors: M. L. Antunes, J. M. V. Da Luz
Journal: Thorax (1969)

A case of diffuse tracheo-bronchial amyloidosis in a 62-year-old woman thought to have chronic bronchitis is reported. The immunological mechanism in the pathogenesis of this condition is considered and the need for bronchological investigation in chronic bronchial disorders is stressed.
Study of Helicobacter pullorum proinflammatory properties on human epithelial cells in vitro
Authors: C Varon, A Duriez, P Lehours, A Menard, S Laye, F Zerbib, F Megraud, D Laharie
Journal: Gut (2008)

<h3>Background and aims:</h3> <i>Helicobacter pullorum</i> is an enterohepatic <i>Helicobacter</i> species of avian origin detected in patients with acute diarrhoea and inflammatory bowel disease. The aim of the present study was to determine whether <i>H pullorum</i> exerts a direct effect on human intestinal epithelial cells in vitro and to characterise the bacterial mechanisms and the signalling pathways involved. <h3>Materials and methods:</h3> The proinflammatory properties of <i>H pullorum</i> from human and avian origins were measured on human gastric (AGS) and intestinal (CaCo-2 and HT-29) epithelial cell lines after co-culture with different <i>H pullorum</i> strains, and the extent of nuclear factor-κB (NF-κB) involvement was determined. <h3>Results:</h3> All of the <i>H pullorum</i> strains tested stimulated interleukin 8 (IL8) secretion by the three cell lines. Similar results were obtained with heat-killed <i>H pullorum</i>. Incubation of cells with filtered <i>H pullorum</i> culture supernatants did not stimulate IL8 secretion. The same observation was made when bacterial adherence was inhibited by Transwell inserts. <i>H pullorum</i> induced NF-κB activation and rapid nuclear translocation as demonstrated by immunofluorescent staining and cellular fractionation. NF-κB involvement was confirmed by using the specific inhibitor SN50 and small interfering RNA (siRNA) which abolished <i>H pullorum</i>-induced IL8 production. <h3>Conclusions:</h3> <i>H pullorum</i> strains stimulate IL8 secretion by human gastric and intestinal epithelial cell lines. This effect requires bacterial adherence and probably lipopolysaccharides, and is mediated by NF-κB signalling. The present study strengthens the argument that <i>H pullorum</i> is a potent human pathogen and highlights its putative role in acute and chronic digestive diseases such as inflammatory bowel disease.
Exercise capacity as a predictor of postoperative complications in lung resection candidates.
Authors: C T Bolliger, P Jordan, M Solèr, P Stulz, E Grädel, K Skarvan, S Elsasser, M Gonon, C Wyser, M Tamm
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Exercise testing with measurement of maximal oxygen uptake (VO2max) is increasingly used in the assessment of lung resection candidates, but its predictive value for postoperative complications remains controversial. We therefore sought to determine the prognostic value of VO2max compared with other pulmonary function tests. A consecutive group of 80 patients (mean age 61 yr; 57 males and 23 females) scheduled for lung resection (62 malignancies, 12 benign disorders, and 6 carcinoids) underwent pulmonary function tests and symptom-limited cycle ergometry. All patients underwent lung resections: 21 pneumonectomies, 45 lobectomies, and 14 segmental or wedge resections. Group A (64 patients, 80%) had an uneventful postoperative course, whereas Group B (16 patients, 20%) had complications; 3 of them died (4% overall mortality rate). In a stepwise logistic regression analysis used to determine independent risk factors for postoperative complications (within 30 d), VO2max expressed as a percentage of predicted (84 +/- 19 for Group A versus 61 +/- 11 for Group B) proved to be the best predictor (predictive value 85.5%). Although VO2max expressed in absolute values (ml/kg/min) was also highly predictive (79.5%), a ROC curve analysis proved the percentage predicted values to be significantly more sensitive. Of 9 patients with a VO2max < 60% of predicted, 8 had complications, including all 3 patients who died after resections of more than one lobe (sensitivity 50%, specificity 98%). The estimated probability (probit model SAS software package) of suffering no complication was 0.9 for VO2max > 75% of predicted and 0.1 for a VO2max < 43%.(ABSTRACT TRUNCATED AT 250 WORDS)