tbuckley/cabot-search huggingface dataset:
Variation in the <i>GST mu</i> Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function
Authors: Carrie V. Breton, Hita Vora, Muhammad T. Salam, Talat Islam, Made Wenten, W. James Gauderman, David Van Den Berg, Kiros Berhane, John M. Peters, Frank D. Gilliland
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: The glutathione S-transferases (GSTs) are important detoxification enzymes.Objectives: To investigate effects of variants in GST mu genes on lung function and assess their interactions with tobacco smoke exposure.Methods: In this prospective study, 14,836 lung function measurements were collected from 2,108 children who participated in two Southern California cohorts. For each child, tagging single nucleotide polymorphisms in GSTM2, GSTM3, GSTM4, and GSTM5 loci were genotyped. Using principal components and haplotype analyses, the significance of each locus in relation to level and growth of FEV1, maximum midexpiratory flow rate (MMEF), and FVC was evaluated. Interactions between loci and tobacco smoke on lung function were also investigated.Measurements and Main Results: Variation in the GST mu family locus was associated with lower FEV1 (P = 0.01) and MMEF (0.04). Two haplotypes of GSTM2 were associated with FEV1 and MMEF, with effect estimates in opposite directions. One haplotype in GSTM3 showed a decrease in growth for MMEF (−164.9 ml/s) compared with individuals with other haplotypes. One haplotype in GSTM4 showed significantly decreased growth in FEV1 (−51.3 ml), MMEF (−69.1 ml/s), and FVC (−44.4 ml), compared with all other haplotypes. These results were consistent across two independent cohorts. Variation in GSTM2 was particularly important for FVC and FEV1 among children whose mothers smoked during pregnancy.Conclusions: Genetic variation across the GST mu locus is associated with 8-year lung function growth. Children of mothers who smoked during pregnancy and had variation in GSTM2 had lower lung function growth.
Effect of Captopril on Uterine Blood Flow and Prostaglandin E Synthesis in the Pregnant Rabbit
Authors: Thomas F. Ferris, Edward K. Weir
Journal: Journal of Clinical Investigation (1983)

Captopril, 5 mg/kg, administered to pregnant rabbits caused a reduction in mean arterial pressure (MAP) from 106±2 to 87±2 mmHg (P<0.01) without change in cardiac output or renal blood flow. Uterine blood flow fell from 31.9±2.5 to 21.3±3.4 ml/min (P<0.01) as uterine vein prostaglandin E series level (PGE) decreased from 127±23 ng/ml to 26±8 ng/ml (P<0.01). Saralasin also caused a reduction in MAP from 110±5 to 92±4.3 (P<0.01), a reduction in uterine blood flow from 28.8±1.6 to 21.8±1.7 ml/min (P<0.01) as uterine vein PGE decreased from 121.3±14.4 to 63.5±14.2 ng/ml (P<0.01). Plasma renin activity (PRA) was higher in the uterine vein, 11±3 ng/ml per h, than peripheral vein, 6±1.6 ng/ml per h, (P<0.05), before Captopril and rose in the uterine vein to 90±19 ng/ml per h (P<0.01) as peripheral vein PRA rose to 62±15 ng/ml per h (P<0.05) after Captopril. After saralasin uterine vein PRA rose from 4.6±1.5 to 14.8±6.3 ng/ml per h (P<0.05) and peripheral vein PRA rose from 3.7±1 to 6.5±2.1 (P<0.05).
Effects of calcium antagonists on beta-receptors of cultured cardiac myocytes isolated from neonatal rat ventricle.
Authors: H Yonemochi, T Saikawa, T Takakura, S Ito, R Takaki
Journal: Circulation (1990)

The effects of calcium antagonists (verapamil, diltiazem, and nicardipine) on beta-adrenergic receptors of cultured cardiac myocytes isolated from neonatal rat ventricle were studied with the hydrophilic ligand [3H]CGP-12177, which identifies cell surface-bound beta-receptors. The three calcium antagonists suppressed spontaneous beating of the myocytes, increased the number of beta-receptors, but did not alter the affinity (Kd). These effects were dose and time dependent. Verapamil (10(-6) M) increased the beta-receptor density by about 13% after 6 hours of incubation, and this increase in density reached a plateau of about 45% after 24 hours of incubation. beta-Receptor density increased by 15% with 5 x 10(-7) M and by 37% with 10(-6) M verapamil. The increased beta-receptors appeared to retain their normal function, as assessed by the increased spontaneous beating of the myocytes in response to applied isoproterenol. The increase in beta-receptors was abolished by colchicine but not by cycloheximide. When the calcium ion concentration of the medium was lowered to 0.1 mM, no significant change occurred in the density of beta-receptors compared with that in 1.8-mM Ca2+ medium. The results suggest that calcium antagonists increase beta-receptors by accelerating recycling by microtubules but not by decreasing the inward calcium current. Such effects of calcium antagonists may be clinically important and promise insight into the mechanism of the withdrawal phenomenon of calcium antagonists.
Is there freedom of speech in the medical profession?
Authors: C. Hilton
Journal: BMJ (2011)

Although the BMJ briefly and objectively mentioned the ombudsman’s report,1 2 the medical profession is all too muted. Geriatric nurses seem afraid to support the critics, and some doctors report feeling powerless to change things. I would have expected far more anger and outrage. But the truth is unpalatable and people recoil …
Continuous positive airway pressure in bronchiolitis.
Authors: J M Beasley, S E Jones
Journal: BMJ (1981)

Over five years 23 infants with evidence of respiratory insufficiency due to bronchiolitis were managed with continuous positive airway pressure (CPAP). This was applied through either a short nasal cannula (14 patients) or an endotracheal tube (nine patients). Clinical improvement was seen in all patients, and there were significant falls in mean respiratory and pulse rates and pressure of carbon dioxide (PCO2). Seven infants with PCO2 values exceeding 8.0 KPa (60.2 mm Hg) responded particularly well. CPAP is effective in bronchiolitis, and when applied by the nasal route it is relatively free from complications.
Virologic Response Following Combined Ledipasvir and Sofosbuvir Administration in Patients With HCV Genotype 1 and HIV Co-infection
Authors: Anu Osinusi, Kerry Townsend, Anita Kohli, Amy Nelson, Cassie Seamon, Eric G. Meissner, Dimitra Bon, Rachel Silk, Chloe Gross, Angie Price, Mohammad Sajadi, Sreetha Sidharthan, Zayani Sims, Eva Herrmann, John Hogan, Gebeyehu Teferi, Rohit Talwani, Michael Proschan, Veronica Jenkins, David E. Kleiner, Brad J. Wood, G. Mani Subramanian, Phillip S. Pang, John G. McHutchison, Michael A. Polis, Anthony S. Fauci, Henry Masur, Shyam Kottilil
Journal: JAMA (2015)

There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV).
361. Radiation-Induced Lung Apoptosis Is Mediated by TNF-alpha Action
Authors: Ming Zhang, Jun Qian, Ming Chen, Spring Kong, Theodore S. Lawrence
Journal: Molecular Therapy (2005)

Lung damage by radiation limits the efficacy of radiotherapy for lung cancer. This damage correlates with lung apoptosis that can be initiated by various cytokines. In this study, we investigated the role of TNF-alpha in radiation-induced lung apoptosis and the potential protective effect of inhibiting TNF-alpha action by using antisense oligonucleotide (ASO) gene therapy. We demonstrated that regional ionizing radiation induced lung apoptosis in mice in a time-and dose-dependent manner. TUNEL staining and caspase-3 activation in lung were increased maximally at 3 h after 15 Gy of radiation by approximately 5-and 3-fold. These inductions were correlated with the increases in TNF-alpha production (|[sim]|2-fold) and gene transcripts (|[sim]|30%), and moderate induction of TNFR1 mRNA levels (|[sim]|20%) in irradiated lung. Pre-treatment of mice using specific ASO significantly inhibited TNFR1 gene transcription by 50% in lung but had no effect on the induction of TNF-alpha transcription by radiation. The reduction of TNFR1 by ASO pre-treatment, and thus, the inhibition of TNF-alpha action, prevented lung from radiation-induced apoptosis. Moreover, we demonstrated that radiation stimulated TNF-alpha production in cultured lung macrophages (|[sim]|2-fold) but not microvascular endothelial cells, although increased caspase-3 activation was observed in both cell types after radiation treatment. Radiation-induced caspase-3 activation in co-cultured cells was diminished in the presence of TNF-alpha antibody, suggesting that radiation-induced TNF-alpha secretion mediated cell apoptosis. These findings support the idea that radiation induces lung apoptosis through upregulation of TNF-alpha, providing us the rationale for TNF-alpha targeted strategies for lung protection.
Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor
Authors: Carl Atkinson, Susan Stewart, Paul D. Upton, Rajiv Machado, Jennifer R. Thomson, Richard C. Trembath, Nicholas W. Morrell
Journal: Circulation (2002)

Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH).Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31.The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.
Cross-talk between CD8+ T cells and natural killers: the role of mitochondrial Aa2+ transport
Authors: Roman Uzhachenko, Shawn Goodwin, Menaka Thounaojam, William Hofmeister, Anil Shanker
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Unraveling complex interactions between immune cells is a key to the development of new strategies for immunotherapy. In the present study, we investigated functional outcome of bidirectional interaction between activated CD8+T and naive natural killer (NK) cells. We found that
Lectures on the Diagnosis and Treatment of Diseases of Women
Authors: G. Hewitt
Journal: BMJ (1861)

GENTLEMEN,-We have now considered the diagnosis and treatment of cases in which the menstrual dis- charge is less than usual, or in which it is absent altogether.We have now to consider cases in which the discharge is greater than usual.But, in order to deal with this subject clinically and practically, and therefore usefully, it will be convenient to group together cases in which the menstrual discharge is excessive in quantity, and those in which there is hcemorrhage from the genera-
Metabolic Disease of Bone
Authors: Leonard F. Peltier
Journal: JAMA (1978)

This small monograph on metabolic diseases of bone is an auspicious beginning for a new series of monographs in clinical orthopedics. The author, Dr Jowsey, is a recognized authority in this aspect of metabolic diseases. She has assembled and organized the material effectively and writes clearly and concisely. There is no redundancy or padding in the text. The monograph is divided into three parts, the first of which deals with the basic processes of mineral metabolism and bone morphology; the second, with methods of evaluation; and the third, with specific metabolic bone diseases. This book is essential for the education of every orthopedic house officer. Its contents should not be neglected by those in practice. While the monograph is directed primarily to orthopedic surgeons, family practitioners, pediatricians, internists, and radiologists will find this book to be a mine of useful information also.
Abstract 4384: Differential expression and function of peroxiredoxin genes in normal vs. cancerous breast epithelial cell lines
Authors: Kevin Gongalves, Katie Sullivan, Shelley A. Phelan
Journal: Cancer Research (2010)

Abstract Peroxiredoxins are thiol-specific antioxidants that reduce a wide variety of cellular peroxides and protect cells from oxidative stress-induced damage and death. These proteins have been implicated in numerous disease processes associated with increased oxidative stress, including cancer. We sought to compare peroxiredoxin expression between the normal MCF10A and cancerous MCF7 breast epithelial cell lines and examine the effect of Prdx1 and Prdx6 suppression in each line. Prdx1 and Prdx6 suppression was achieved through transient transfection of siRNA, and the relative expression of all six mammalian peroxiredoxin genes was determined by real time PCR and western blotting. We also examined the effect on peroxide-induced reactive oxygen species (ROS) accumulation and cytotoxicity. We demonstrated that MCF7 cells express significantly higher levels of Prdxs 1-5, while Prdx6 levels are comparable in the two lines. We achieved approximately 90% mRNA suppression of Prdx1 and Prdx6 in both lines using siRNA. Interestingly, Prdx1 suppression in both lines led to a marked reduction in Prdx2 expression and significant induction of Prdx4 expression. In addition, several Prdx genes were upregulated in MCF10 cells when either Prdx1 or Prdx6 were suppressed. We further demonstrated that Prdx1 and Prdx6 suppression caused a differential increase in peroxide-induced ROS levels and cytotoxicity in the two lines, and that simultaneous knock-down of both genes in MCF10 cells leads to a much more pronounced effect than in MCF7 cells. Together, these data suggest coordinated and complex regulatory interactions between the peroxiredoxin genes, and implicate a potentially different function for these proteins in transformed vs. untransformed cells. The elevated expression of peroxiredoxins in MCF7 cells may also represent a cellular adaptation to the cancerous state. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4384.
Toxicity of Indomethacin
Authors: Manuel Guerra
Journal: JAMA (1967)

SINCE its recent introduction, the nonsteroidal chemical called indomethacin (1-[<i>p</i>-chlorobenzoyl]-5-methoxy-2-methylindole-3-acetic acid) has been used extensively as a new "antirheumatic"<sup>1</sup>drug that has anti-inflammatory,<sup>2</sup>analgesic, and antipyretic<sup>3</sup>activity. The side effects have been described by various authors. These were usually limited to the central nervous system, with symptoms of headache, vertigo, light-headedness, and disturbed sensorium; and to the gastrointestinal system, with the symptoms of cramping, epigastric pain, and peptic ulceration.<sup>4</sup> We found no mention of pancreatic involvement recorded in the literature. In the case being reported, the patient's condition was not associated with biliary tract disease, alcoholism, or any of the other conditions usually considered important in the cause of pancreatitis. We believe this case gives evidence that indomethacin does have a direct and toxic effect on the pancreas. <h3>Report of a Case</h3> A 69-year-old Negro man was admitted to the hospital on Aug 21,
Impact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies
Authors: Karsten Bruins Slot, Eivind Berge, Paul Dorman, Steff Lewis, Martin Dennis, Peter Sandercock
Journal: BMJ (2008)

To estimate the impact on long term survival of functional status at six months after ischaemic stroke.Prospective cohort study. Settings Three cohorts: Oxfordshire community stroke project, Lothian stroke register, and the first international stroke trial (in the United Kingdom).7710 patients with ischaemic stroke registered between 1981 and 2000 and followed up for a maximum of 19 years.Functional status at six months after stroke assessed with modified Rankin scale or "two simple questions." Mortality during follow-up. Survival analysis with Kaplan-Meier curves, log rank test, and Cox's regression model.In a combined analysis of all three cohorts, among patients who survived to assessment six months after the index stroke, the subsequent median length of survival among those independent in daily living and those dependent was 9.7 years (95% confidence interval 8.9 to 10.6) and 6.0 years (5.7 to 6.4), respectively. In a combined analysis of the Oxfordshire and Lothian cohorts, subsequent median survival fell progressively from 12.9 years (10.0 to 15.9) for patients with a Rankin score of 0-1 at six months after the stroke to 2.5 years (1.4 to 3.5) for patients with a Rankin score of 5. All previously stated differences in median survival were significant (log rank test P<0.001). The influence of functional outcome on survival remained significant (P<0.05) in each cohort after adjustment for relevant covariates (such as age, presence of atrial fibrillation, visible infarct on computed tomography, subtype of stroke) in a Cox's regression model.Functional status six months after an ischaemic stroke is associated with long term survival. Early interventions that reduce dependency at six months might have positive effects on long term survival.
Abstract P157: Does Physical Activity Modify the Association of 15 Well-established Obesity Loci with BMI: The ARIC Study
Authors: Kristin L Young, Keri L Monda, Ellen W Demerath, W.H. Linda Kao, Eric Boerwinkle, Kari E North
Journal: Circulation (2013)

This study investigates gene-by-physical activity interaction with 15 well-replicated body mass index (BMI) loci in the Atherosclerosis Risk in Communities (ARIC) Study, a prospective, multi-center, bi-racial population-based cohort of adults (N=15,792 at baseline (1987-1989), aged 45-64). Our analyses were restricted to subjects of self-reported European descent with complete genotype and phenotype data (n=8059, 53% female, mean age 54.3 (SD 5.7)). BMI was computed from measured height and weight. Physical activity (PA) was measured using a modified validated Baecke questionnaire, resulting in an ordinal score ranging from 1.00-10.00 for sport and leisure-time activity. Physical activity was dichotomized at the sex-specific median for high/low PA, with high PA as the referent. BMI was regressed on single nucleotide polymorphism (SNP), PA level, SNP*PA level, and study-specific covariates assuming an additive genetic model. To account for multiple testing, interaction p-values less than 0.006 (0.10/15) were considered statistically significant. Mean BMI was 27.0 (SD 4.8) kg/m2, and sports and leisure time physical activity was 5.00 (SD 1.13, range 1.75-9.25) units. We replicated the main effects of SNP on BMI for FTO (rs9939609, p=8.52E-11) and SEC16B/RASAL2 (rs10913469, p=0.001), and NEGR1 was borderline significant (rs2815752, p=0.006). MAF was the only SNP that displayed a directionally inconsistent effect estimate with earlier findings (Beta: -0.02, SE -0.16, 0.13). Four of the interactions had a p-value &lt;0.1, including SEC16B, PTER, NEGR1, and SH2B1. The largest magnitude effect estimates among the nominally significant interactions were observed for SNPs rs10913469 (locus SEC16B/RASAL2, frequency: 0.2024) and rs10508503 (locus PTER, frequency: 0.0871). For rs10913469, each additional copy of the risk allele resulted in an increased BMI of 0.58 kg/m2 for those in the low PA category, but an increase of only 0.07 kg/m2 for those in the high PA category (p-interaction=0.007). For rs10508503, each additional copy of the risk allele resulted in an increased BMI of 0.51 kg/m2 for those in the low PA category, and a decreased BMI of 0.14 kg/m2 for those in the high PA category (p-interaction=0.013). Mean BMIs for those in the low physical activity category increase with additional copies of the C (risk) allele (mean BMI for TT=25.6, TC=27.2, CC=27.6 kg/m2, p=0.04), while mean BMIs of those with high PA do not differ between genotypes (mean BMI for TT=26.7, TC=26.8, CC=26.6 kg/m2, p=0.51). While we found a significant main effect of the SEC16B/RASAL2 SNP on BMI (p=0.001), for the PTER SNP we did not (p=0.229). These novel findings demonstrate the importance of context specific genetic effects and contribute to the growing literature highlighting the possible importance of physical activity in the attenuation of underlying genetic risk.
Platelet Production and Destruction in Idiopathic Thrombocytopenic Purpura: A Controversial Issue
Authors: Mario G. Baldini
Journal: JAMA (1978)

Progress in the understanding of idiopathic thrombocytopenic purpura (ITP) has been slow through the years. When splenectomy was first performed in 1916 at the suggestion of Kaznelson, the mechanism of the thrombocytopenia was not known. In the preceding year, Frank had painstakingly demonstrated that the thrombocytopenia in ITP was the result of a "toxic" suppression of megakaryocyte activity. Young Kaznelson, who at the time was a medical student in Prague, challenged Frank's idea and formulated the hypothesis of the "thrombolytic" nature of ITP with the spleen as the graveyard for the platelets. The success of splenectomy in his single patient gave him fame and seemed to conclude the debate, but only for a few decades. The problem of thrombokinetics in ITP is still controversial today. During the past 20 years, pertinent experimental evidence has been accumulated to the effect that a shortened platelet life span has regularly been found in