tbuckley/cabot-search huggingface dataset:
ENVIRONMENTAL TOBACCO SMOKE:Health Effects and Policies to Reduce Exposure
Authors: Ross C. Brownson, Michael P. Eriksen, Ronald M. Davis, Kenneth E. Warner
Journal: Annual Review of Public Health (1997)

▪ Abstract The health hazards due to exposure to environmental tobacco smoke (ETS) are increasingly established. ETS contains thousands of chemicals including 43 known carcinogens. Known health effects of ETS exposure are lung cancer in nonsmokers, childhood disorders such as bronchitis, and perhaps, heart disease. Workplace exposure to ETS is widespread and is influenced strongly by the type of smoking policy in the workplace. To decrease ETS exposure, efforts to restrict public smoking have proliferated over the past decade. These restrictions have emanated from government as well as voluntary measures by various private industries. Bans on public smoking are effective in reducing nonsmokers' exposure to ETS. Workplace smoking bans also influence the intensity of smoking among employees and may increase quit smoking rates. In addition to the health benefits from smoke-free workplaces, there are likely cost savings to employers who implement such policies.
Genome-Wide Transcriptional Profiling Reveals Connective Tissue Mast Cell Accumulation in Bronchopulmonary Dysplasia
Authors: Soumyaroop Bhattacharya, Diana Go, Daria L. Krenitsky, Heidi L. Huyck, Siva Kumar Solleti, Valerie A. Lunger, Leon Metlay, Sorachai Srisuma, Susan E. Wert, Thomas J. Mariani, Gloria S. Pryhuber
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Bronchopulmonary dysplasia (BPD) is a major complication of premature birth. Risk factors for BPD are complex and include prenatal infection and O(2) toxicity. BPD pathology is equally complex and characterized by inflammation and dysmorphic airspaces and vasculature. Due to the limited availability of clinical samples, an understanding of the molecular pathogenesis of this disease and its causal mechanisms and associated biomarkers is limited.Apply genome-wide expression profiling to define pathways affected in BPD lungs.Lung tissue was obtained at autopsy from 11 BPD cases and 17 age-matched control subjects without BPD. RNA isolated from these tissue samples was interrogated using microarrays. Standard gene selection and pathway analysis methods were applied to the data set. Abnormal expression patterns were validated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry.We identified 159 genes differentially expressed in BPD tissues. Pathway analysis indicated previously appreciated (e.g., DNA damage regulation of cell cycle) as well as novel (e.g., B-cell development) biological functions were affected. Three of the five most highly induced genes were mast cell (MC)-specific markers. We confirmed an increased accumulation of connective tissue MC(TC) (chymase expressing) mast cells in BPD tissues. Increased expression of MC(TC) markers was also demonstrated in an animal model of BPD-like pathology.We present a unique genome-wide expression data set from human BPD lung tissue. Our data provide information on gene expression patterns associated with BPD and facilitated the discovery that MC(TC) accumulation is a prominent feature of this disease. These observations have significant clinical and mechanistic implications.
Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B-Cell Lymphoma
Authors: Thomas Clozel, ShaoNing Yang, Rebecca L. Elstrom, Wayne Tam, Peter Martin, Matthias Kormaksson, Samprit Banerjee, Aparna Vasanthakumar, Biljana Culjkovic, David W. Scott, Sarah Wyman, Micheal Leser, Rita Shaknovich, Amy Chadburn, Fabrizio Tabbo, Lucy A. Godley, Randy D. Gascoyne, Katherine L. Borden, Giorgio Inghirami, John P. Leonard, Ari Melnick, Leandro Cerchietti
Journal: Cancer Discovery (2013)

Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.
Physiological Alterations in the Pulmonary Capillary Bed at Rest and During Exercise
Authors: RICHARD A. KRUMHOLZ, RICHARD E. BRASHEAR, WALTER J. DALY, JOSEPH C. ROSS
Journal: Circulation (1966)

The reactivity of the pulmonary capillary bed during exercise as estimated by change in the pulmonary diffusing capacity (D l co ) has been shown to be dependent upon at least two separate mechanisms. The initial (0 to 10 second) D l co rise with exercise appears to be volume-pressure dependent and may be altered by mechanisms influencing these factors in the lungs. The later elevation of D l co with exercise was demonstrated to be primarily independent of the initial rise and uninfluenced by factors affecting peripheral venous return, that is body position and ganglionic blockade.
Nrf2 Regulates Antioxidant Gene Expression Evoked by Oxidized Phospholipids in Endothelial Cells and Murine Arteries In Vivo
Authors: Henna-Kaisa Jyrkkänen, Emilia Kansanen, Matias Inkala, Annukka M. Kivelä, Hanna Hurttila, Suvi E. Heinonen, Gundars Goldsteins, Suvi Jauhiainen, Satu Tiainen, Harri Makkonen, Olga Oskolkova, Taras Afonyushkin, Jari Koistinaho, Masayuki Yamamoto, Valery N. Bochkov, Seppo Ylä-Herttuala, Anna-Liisa Levonen
Journal: Circulation Research (2008)

Besides their well-characterized proinflammatory and proatherogenic effects, oxidized phospholipids, such as oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphocholine) have been shown to have beneficial responses in vascular cells via induction of antioxidant enzymes such as heme oxygenase-1. We therefore hypothesized that oxPAPC could evoke a general cytoprotective response via activation of antioxidative transcription factor Nrf2. Here, we show that oxPAPC increases nuclear accumulation of Nrf2. Using the small interfering RNA approach, we demonstrate that Nrf2 is critical in mediating the induction of glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H quinone oxidoreductase-1 (NQO1) by oxPAPC in human endothelial cells, whereas the contribution to the induction of heme oxygenase-1 was less significant. The induction of GCLM and NQO1 was attenuated by reduction of electrophilic groups with sodium borohydrate, as well as treatment with thiol antioxidant N-acetylcysteine, suggesting that the thiol reactivity of oxPAPC is largely mediating its effect on Nrf2-responsive genes. Moreover, we show that oxidized phospholipid having a highly electrophilic isoprostane ring in its sn-2 position is a potent inducer of Nrf2 target genes. Finally, we demonstrate that the oxPAPC-inducible expression of heme oxygenase-1, GCLM, and NQO1 is lower in Nrf2-null than wild-type mouse carotid arteries in vivo. We suggest that the activation of Nrf2 by oxidized phospholipids provides a mechanism by which their deleterious effects are limited in the vasculature.
Portal hypertension and bleeding ileal varices after colectomy and ileostomy for chronic ulcerative colitis
Authors: A. D. Cameron, D. J. Fone
Journal: Gut (1970)

Two patients are described with chronic liver disease and portal hypertension in association with ulcerative colitis for which colectomy and ileostomy had been performed. Both patients developed bleeding from the varices situated around the ileostomy stoma and one also bled from the oesophageal varices. Each had a successful portacaval shunt performed because of this bleeding. The occurrence of such ileal varices is uncommon, but is important as a manifestation of portal hypertension. Although it can usually be easily controlled by local measures, portal-systemic shunt should always be considered, particularly as such patients are also very likely to bleed from oesophageal varices.
Two subsets of HLA-DQA1 alleles mark phenotypic variation in levels of insulin autoantibodies in first degree relatives at risk for insulin-dependent diabetes.
Authors: A Pugliese, T Bugawan, R Moromisato, Z L Awdeh, C A Alper, R A Jackson, H A Erlich, G S Eisenbarth
Journal: Journal of Clinical Investigation (1994)

Levels of insulin autoantibodies (IAA) vary among different first degree relatives of insulin-dependent diabetes mellitus patients, suggesting genetic regulation. We previously reported elevated IAA among DR4-positive at risk relatives. In this study, 72/82 at risk relatives were IAA positive, of whom 75% (54/72) carried DR4 versus 20% (2/10) of IAA-negative relatives (P = 0.0004). However, 69% (18/26) of DR4-negative relatives were IAA positive. Since DR4 did not account for all IAA positivity, we analyzed DQA1 and DQB1 alleles. Homozygosity for DQA1 alleles deriving from the evolutionary lineage 4 (*0401, *0501, *0601) was associated with low IAA levels, while lineage 1-3 alleles (*0101, *0102, *0103, *0201, *0301) correlated with higher levels. Most (93%, 65/70) relatives with lineage 1-3 alleles were IAA positive (mean = 360 +/- 63 SEM nU/ml). Only 7/12 relatives homozygous for lineage 4 alleles were IAA-positive, with lower levels than relatives with lineage 1-3 alleles (mean = 55 +/- 15 SEM nU/ml, P < 0.0001; 7/12 vs 65/70, P = 0.004). The amino acid sequences of lineage 1-3 alleles uniquely share glutamic acid (E) and phenylalanine (F) at positions 40 and 51 (EF alleles). Lineage 4 alleles have glycine (G) and leucine (L) at those positions (GL alleles). 90% (65/72) of IAA-positive relatives had an EF allele, while only 75% (54/72) had DR4 (P = 0.01). Homozygosity for GL alleles (often DQA1 *0501 on DR3 haplotypes) correlated with little or no humoral response to insulin. Thus, HLA-DQB1 GL alleles, or other genes on haplotypes (e.g., DR3) that carry these DQA1 alleles, may confer recessive low responsiveness to insulin.
Serum Vitamin D Concentration and Prostate Cancer Risk: A Nested Case-Control Study
Authors: J. Ahn, U. Peters, D. Albanes, M. P. Purdue, C. C. Abnet, N. Chatterjee, R. L. Horst, B. W. Hollis, W.-Y. Huang, J. M. Shikany, R. B. Hayes
Journal: JNCI Journal of the National Cancer Institute (2008)

Epidemiological studies have yielded inconsistent associations between vitamin D status and prostate cancer risk, and few studies have evaluated whether the associations vary by disease aggressiveness. We investigated the association between vitamin D status, as determined by serum 25-hydroxyvitamin D [25(OH)D] level, and risk of prostate cancer in a case–control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The study included 749 case patients with incident prostate cancer who were diagnosed 1–8 years after blood draw and 781 control subjects who were frequency matched by age at cohort entry, time since initial screening, and calendar year of cohort entry. All study participants were selected from the trial screening arm (which includes annual standardized prostate cancer screening). Conditional logistic regression was used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) by quintile of season-standardized serum 25(OH)D concentration. Statistical tests were two-sided. No statistically significant trend in overall prostate cancer risk was observed with increasing season-standardized serum 25(OH)D level. However, serum 25(OH)D concentrations greater than the lowest quintile (Q1) were associated with increased risk of aggressive (Gleason sum ≥7 or clinical stage III or IV) disease (in a model adjusting for matching factors, study center, and history of diabetes, ORs for Q2 vs Q1 = 1.20, 95% CI = 0.80 to 1.81, for Q3 vs Q1 =1.96, 95% CI = 1.34 to 2.87, for Q4 vs Q1 = 1.61, 95% CI = 1.09 to 2.38, and for Q5 vs Q1 = 1.37, 95% CI = 0.92 to 2.05; Ptrend = .05). The rates of aggressive prostate cancer for increasing quintiles of serum 25(OH)D were 406, 479, 780, 633, and 544 per 100 000 person-years. In exploratory analyses, these associations with aggressive disease were consistent across subgroups defined by age, family history of prostate cancer, diabetes, body mass index, vigorous physical activity, calcium intake, study center, season of blood collection, and assay batch. The findings of this large prospective study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; indeed, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.
Wnt Antagonist Gene <i>DKK2</i> Is Epigenetically Silenced and Inhibits Renal Cancer Progression through Apoptotic and Cell Cycle Pathways
Authors: Hiroshi Hirata, Yuji Hinoda, Koichi Nakajima, Ken Kawamoto, Nobuyuki Kikuno, Kazumori Kawakami, Soichiro Yamamura, Koji Ueno, Shahana Majid, Sharanjot Saini, Nobuhisa Ishii, Rajvir Dahiya
Journal: Clinical Cancer Research (2009)

Wnt/beta-catenin signaling is involved in renal cancer. DKK2, a Wnt antagonist, is silenced in some cancers, although its function has not been investigated. We hypothesized that DKK2 may be epigenetically silenced and inhibits progression of renal cell carcinoma (RCC).RCC cell lines and a normal kidney cell line were used for methylation and chromatin immunoprecipitation assays. To assess various functions of DKK2, we established stable DKK2-transfected cells and examined them with regard to cell viability, colony formation, apoptosis, cell cycle, and invasive capability. A total of 52 patients with confirmed conventional RCC were enrolled in this study.RCC cell lines had decreased levels of DKK2, which were significantly increased after treatment with 5-Aza-2'-deoxycytidine alone or 5-Aza-2'-deoxycytidine and trichostatin A. In chromatin immunoprecipitation assay, the levels of acetyl H3, acetyl H4, and dimethylated H3K4 were decreased, whereas the level of dimethylated H3K9 was increased in RCC cell lines compared with HK2 cells. Increased methylation in RCC tissues was associated with higher grades, pathologic stages, and pathologic tumor in RCC. Functional analysis showed that the numbers of viable A498 cells were significantly decreased in DKK2-transfected cells compared with mock cells. The number of apoptotic cells and S/G(2)-M phase cells was significantly increased and decreased after DKK2 transfection, respectively. Corresponding to these results, Bcl2 and cyclin D1 expression were also decreased in DKK2-overexpressing cells.DKK2 is epigenetically silenced by methylation in higher grades and stages of RCC. These results suggest that DKK2 inhibits renal cancer progression through apoptotic and cell cycle pathways.
S41 Screening for latent TB in HIV: are NICE &amp; BHIVA guidance effective?
Authors: S. Capocci, C. Smith, I. Cropley, S. Bhagani, M. A. Johnson, M. C. I. Lipman
Journal: Thorax (2011)

<h3></h3> HIV infection is the strongest single risk factor for the development of active TB in latently infected individuals. NICE and BHIVA 2011 guidelines both recommend screening for latent TB in HIV positive subjects in the UK. NICE bases this on blood CD4 count; and recommends testing all patients with CD4&lt;500 cells/μl (if CD4&lt;200, this is with an Interferon Gamma Release Assay (IGRA) and tuberculin skin test (TST), and if CD4 200–500, then IGRA ± TST is proposed). BHIVA test-stratify on CD4 count, country of origin and use of antiretroviral therapy (ART). They recommend IGRA in the following populations: all subjects from Sub Saharan Africa, irrespective of CD4 if on ART &lt;2 years; medium TB incidence countries if on ART &lt;2 years and CD4 &lt;500; and low TB incidence countries if on ART &lt;6 months and CD4 &lt;350. To our knowledge, neither strategy has been formally tested in a UK HIV population. Here, using data on all subjects over a 10-year period (2000–2010) within our large HIV service (n=3306), we determine the impact of applying both strategies to detect cases of latent TB infection who subsequently developed active TB during this time period (n=72). Subjects who developed active TB &lt;3 months from HIV diagnosis were excluded from analysis, as it was felt that the time interval was too short for them to be screened for TB. Abstract S41 table 1 illustrates the differences between NICE and BHIVA strategies over the 10-year period. Neither screening method had optimal sensitivity and specificity. Both guidelines9 eligible groups were only twice as likely to develop active TB compared to those ineligible for screening. NICE guidelines were poorly specific while the BHIVA strategy missed 42% of cases (largely as they were either UK born or on ART). Using data from our UK HIV population, we find that new TB screening guidance does not appear to discriminate those at risk of active TB.
Biventricular Cineangiography in the Evaluation of Patients with Asymmetric Septal Hypertrophy
Authors: DAVID R. REDWOOD, JAMES L. SCHERER, STEPHEN E. EPSTEIN
Journal: Circulation (1974)

Echocardiographic studies have demonstrated that the characteristic anatomic defect in idiopathic hypertrophic subaortic stenosis (IHSS) is asymmetric septal hypertrophy (ASH). Although echocardiographic diagnosis of ASH is extremely sensitive, occasionally adequate echocardiograms cannot be obtained. Moreover, echocardiographic assessment of the extent of the underlying cardiomyopathic process, known to be distributed nonuniformly, is limited to evaluation of the upper part of the ventricular septum and the posterobasal left ventricular (LV) free wall. To determine if a specific angiographic marker of ASH can be identified even in the absence of LV outflow obstruction, and to delineate the extent and degree of cardiomyopathic involvement of the ventricular septum and LV free wall in patients with ASH, septal and LV wall configuration and thickness were measured using simultaneous biventricular cineangiography. The ventricular septum was thicker in 16 patients with ASH (avg. 15.2 ± 1.5 mm) and in six patients with concentric left ventricular hypertrophy (LVH) due to aortic valve disease (avg. 12.8 ± 1.1 mm) than in seven normal subjects (avg. 6.7 ± 0.4 mm, P &lt; 0.001). In normal subjects and in patients with concentric LV hypertrophy, the walls of the ventricular septum were parallel. In contrast, the walls diverged in ASH so that septal width increased significantly inferiorly. Thus, the ratio of upper to lower septal width was greater than 0.8 (avg. 1.04 ± 0.06 mm) in normals and LVH patients but less than 0.77 (avg. 0.70 ± 0.01 mm, P &lt; 0.001) in ASH patients. Furthermore, upper septal width and the ratio of upper to lower septal width in ASH were significantly greater in seven patients with LV outflow obstruction than in six patients without obstruction, suggesting that the upper septum bulges into the LV outflow tract to a greater extent in obstructive ASH. In addition, the LV free wall in ASH was nonuniformly thickened, whereas in LVH the hypertrophy was uniform. We conclude that angiographic delineation of the septum and LV free wall 1) demonstrates abnormalities that distinguish ASH from normal and concentrically hypertrophied hearts, 2) demonstrates abnormalities that distinguish obstructive from nonobstructive ASH, and 3) aids in characterizing the distribution of myopathic involvement in patients with ASH.
Evaluation of standard and active compression-decompression CPR in an acute human model of ventricular fibrillation.
Authors: J J Shultz, P Coffeen, M Sweeney, B Detloff, C Kehler, E Pineda, P Yakshe, S W Adler, M Chang, K G Lurie
Journal: Circulation (1994)

BACKGROUND The mechanisms that underlie cardiopulmonary resuscitation (CPR) in humans remain controversial and difficult to study. This report describes a new human model to evaluate CPR during the first 1 to 2 minutes after the onset of ventricular fibrillation (VF). With this model, standard CPR was compared with active compression-decompression (ACD) CPR, a method that uses a handheld suction device to actively compress and actively decompress the chest. METHODS AND RESULTS During routine inductions of VF as part of a transvenous lead cardioverter/defibrillator implantation procedure, CPR was performed in 21 patients if the first defibrillation shock failed and until a successful rescue shock was delivered. Compressions during CPR were performed according to American Heart Association guidelines. For ACD CPR, decompression was performed with up to -30 lbs. Radial arterial and right atrial pressures were measured in all patients. Esophageal pressures, intratracheal pressures, or minute ventilation was measured in the last 13 patients. Application of both CPR techniques increased arterial and right atrial pressures. The mean coronary perfusion pressure was increased throughout the entire CPR cycle with ACD CPR (compression, 21.5 +/- 9.0 mm Hg; decompression, 21.9 +/- 8.7 mm Hg) compared with standard CPR (compression, 17.9 +/- 8.2 mm Hg; decompression, 18.5 +/- 6.9 mm Hg; P &lt; .02 and P &lt; .02, respectively). Ventilation per compression-decompression cycle was 97.3 +/- 65.6 mL with standard CPR and 168.4 +/- 68.6 mL with ACD CPR (n = 7, P &lt; .001). Negative inspiratory pressure was -0.8 +/- 4.8 mm Hg with standard CPR and -11.4 +/- 6.3 mm Hg with ACD CPR (n = 6, P &lt; .04). CONCLUSIONS Patients undergoing multiple inductions of VF during cardioverter/defibrillator implantation with transvenous leads provide a well-controlled and reproducible model to study the mechanisms of CPR. Using this model, ACD CPR significantly increased arterial blood pressure, coronary perfusion pressure, minute ventilation, and negative inspiratory pressure compared with standard CPR.