tbuckley/cabot-search huggingface dataset:
Pulmonary Valve Replacement in Tetralogy of Fallot
Authors: David M. Harrild, Charles I. Berul, Frank Cecchin, Tal Geva, Kimberlee Gauvreau, Frank Pigula, Edward P. Walsh
Journal: Circulation (2009)

Background— Pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (TOF) reduces pulmonary regurgitation and decreases right ventricular (RV) dilation, but its long-term impact on ventricular tachycardia (VT) and mortality is unknown. This study aimed to determine the incidence of death and VT in TOF after PVR and to test the hypothesis that PVR leads to improvement in these outcomes. Methods and Results— A total of 98 patients with TOF and late PVR for RV dilation were identified. Matched control subjects were identified for 77 of these patients; control subjects had TOF with RV dilation but no PVR. Matching was done by age (±2 years) and baseline QRS duration (±30 ms). No significant differences were found in age, QRS duration, type or decade of initial repair, age at TOF repair, or presence of pre-PVR VT between the 2 groups; limited echocardiographic and magnetic resonance imaging data showed no difference in left ventricular function but more RV dilation among PVR patients than control subjects. In the PVR group, 13 events occurred over 272 patient-years. No significant change in QRS duration was seen for any group. Overall 5- and 10-year freedom from death, VT, or both was 80% and 41%, respectively. In the matched comparison, no significant differences were seen in VT, death, or combined VT and/or death ( P =0.32, P =0.06 [nearly favoring controls], and P =0.21). Conclusions— This cohort experienced either VT or death every 20 patient-years. In a matched comparison with a similar TOF group, late PVR for symptomatic pulmonary regurgitation/RV dilation did not reduce the incidence of VT or death.
First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting
Authors: Andrea Molckovsky, Lillian L Siu
Journal: Journal of Hematology & Oncology (2008)

This review summarizes phase I trial results of 11 drugs presented at the American Society of Clinical Oncology meeting held in Chicago IL from May 30 to June 3rd 2008: BMS-663513, CT-322, CVX-045, GDC-0449, GRN163L, LY2181308, PF-00562271, RAV12, RTA 402, XL765, and the survivin vaccine.
Carotid Intima-Media Thickness Is Associated With Premature Parental Coronary Heart Disease
Authors: Thomas J. Wang, Byung-Ho Nam, Ralph B. D’Agostino, Philip A. Wolf, Donald M. Lloyd-Jones, Calum A. MacRae, Peter W. Wilson, Joseph F. Polak, Christopher J. O’Donnell
Journal: Circulation (2003)

Background— A family history of coronary heart disease (CHD) is an independent risk factor for cardiovascular events. However, the mechanisms underlying this susceptibility have not been fully elucidated. We hypothesized that an important mediator of the familial predisposition to CHD is subclinical atherosclerosis, which is detectable by noninvasive imaging. Methods and Results— We studied 1662 subjects (mean age 57, 51% women) in the Framingham Offspring Study who underwent carotid ultrasonography and had both biological parents in the original (parental) cohort. Parental CHD events were validated prospectively by a physician endpoint committee. The associations of carotid intima-media thickness (IMT) with premature parental CHD (occurring before age 60) and any parental CHD (no age restriction) were examined in age- and multivariable-adjusted analyses. Age-adjusted mean internal carotid IMT was higher in subjects who had at least one parent with premature CHD than in those without a validated parental history of premature CHD (men 1.13 versus 1.04 mm, P &lt;0.01; women 0.92 versus 0.85 mm, P =0.03). In both sexes, these differences remained significant after adjustment for cardiovascular risk factors. In analyses without a restriction on parental age of CHD onset, the association between carotid IMT and parental CHD was not statistically significant. There was also no significant association of common carotid IMT with premature or any parental CHD. Conclusions— These findings suggest that subclinical atherosclerosis, assessed in the carotid arteries, is more prevalent in individuals with a family history of CHD. Early-onset parental CHD, in particular, identifies offspring with a strong familial predisposition to atherosclerosis.
Antibodies to alcohol altered liver cell determinants in patients with alcoholic liver disease.
Authors: J Neuberger, I R Crossley, J B Saunders, M Davis, B Portmann, A L Eddleston, R Williams
Journal: Gut (1984)

Circulating antibodies reacting specifically with hepatocytes isolated from ethanol pretreated rabbits have been demonstrated by two techniques - induced cytotoxicity and immunofluorescence. In the cytotoxicity assay antibodies were found in seven of 19 (39%) of patients with alcoholic fatty liver (with or without fibrosis), six of 13 (46%) of those with alcoholic hepatitis, 15 of 36 (43%) of those with cirrhosis, and seven of 14 patients (50%) of those with hepatitis and cirrhosis. In the immunofluorescence studies, nine of 15 sera induced a granular pattern of fluorescence on the ethanol pretreated hepatocytes; two sera which induced significant cytotoxicity did not induce immunofluorescence. No ethanol related antibodies were found in normal individuals or in patients with other types of acute or chronic liver disease. These results show that antibodies directed against ethanol altered liver cell determinants are present in the serum of 43% of patients with alcoholic liver disease, and suggest a mechanism whereby chronic alcohol consumption may, by inducing antigenic changes in hepatocyte membranes, trigger a cell damaging immune reaction.
Association Between Competitive Food and Beverage Policies in Elementary Schools and Childhood Overweight/Obesity Trends
Authors: Emma V. Sanchez-Vaznaugh, Brisa N. Sánchez, Patricia B. Crawford, Susan Egerter
Journal: JAMA Pediatrics (2015)

IMPORTANCETo our knowledge, few published studies have examined the influence of competitive food and beverage (CF&B) policies on student weight outcomes; none have investigated disparities in the influence of CF&B policies on children's body weight by school neighborhood socioeconomic resources.OBJECTIVE To investigate whether the association between CF&B policies and population-level trends in childhood overweight/obesity differed by school neighborhood income and education levels.DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study, from July 2013 to October 2014, compared overweight/obesity prevalence trends before (2001-2005) and after (2006-2010) implementation of CF&B policies in public elementary schools in California.The study included 2 700 880 fifth-grade students in 5362 public schools from 2001 to 2010.EXPOSURES California CF&B policies (effective July 1, 2004, and July 1, 2007) and school neighborhood income and education levels.MAIN OUTCOMES AND MEASURES Overweight/obesity defined as a body mass index at or greater than the 85th percentile for age and sex. RESULTSOverall rates of overweight/obesity ranged from 43.5% in 2001 to 45.8% in 2010.Compared with the period before the introduction of CF&B policies, overweight/obesity trends changed in a favorable direction after the policies took effect (2005-2010); these changes occurred for all children across all school neighborhood socioeconomic levels.In the postpolicy period, these trends differed by school neighborhood socioeconomic advantage.From 2005-2010, trends in overweight/obesity prevalence leveled off among students at schools in socioeconomically disadvantaged neighborhoods but declined in socioeconomically advantaged neighborhoods.Students in the lowest-income neighborhoods experienced zero or near zero change in the odds of overweight/obesity over time: the annual percentage change in overweight/obesity odds was 0.1% for females (95% CI, -0.7 to 0.9) and -0.3% for males (95% CI, -1.1 to 0.5).In contrast, in the highest-income neighborhoods, the annual percentage decline in the odds of overweight was 1.2% for females (95% CI, 0.4 to 1.9) and 1.0% for males (95% CI, 0.3 to 1.8).Findings were similar for school neighborhood education.CONCLUSIONS AND RELEVANCE Our study found population-level improvements in the prevalence of childhood overweight/obesity that coincided with the period following implementation of statewide CF&B policies (2005-2010).However, these improvements were greatest at schools in the most advantaged neighborhoods.This suggests that CF&B policies may help prevent child obesity; however, the degree of their effectiveness is likely to depend on socioeconomic and other contextual factors in school neighborhoods.To reduce disparities and prevent obesity, school policies and environmental interventions must address relevant contextual factors in school neighborhoods.
Establishment and characterization of a diethylnitrosamine-initiated woodchuck hepatocyte cell line
Authors: Gang-Hong Lee, Tokuichi Kawaguchi, Kimie Nomura, Tomoyuki Kitagawa
Journal: Hepatology (1987)

Woodchucks free from woodchuck hepatitis virus were treated with diethylnitrosamine in vivo for 2 months, and then hepatocytes obtained by enzymatic perfusion were cultured with the hepatopromoter phenobarbital. This in vivo-in vitro procedure gave rise to proliferating epithelial cell foci, from one of which the presently described hepatocyte cell line (WLC-3) was established and characterized. WLC-3 cells possess morphological and biochemical features of differentiated hepatocytes, including glucose-6-phosphatase activity and albumin production. Histopathological analysis of the tumor which developed transitorily in nude mouse subcutis after inoculation of the cell line revealed glandular structures comprising cells of hepatocellular-like morphology. This is the first established woodchuck hepatocyte cell line free from woodchuck hepatitis virus and is therefore expected to be useful for studying the mode of gene expression and viral proliferation of woodchuck hepatitis virus and the mechanisms underlying woodchuck hepatitis virus-related hepatocarcinogenesis.
Differential effects of hyperinsulinemia and hyperaminoacidemia on leucine-carbon metabolism in vivo. Evidence for distinct mechanisms in regulation of net amino acid deposition.
Authors: P Tessari, S Inchiostro, G Biolo, R Trevisan, G Fantin, M C Marescotti, E Iori, A Tiengo, G Crepaldi
Journal: Journal of Clinical Investigation (1987)

The effects of physiologic hyperinsulinemia and hyperaminoacidemia, alone or in combination, on leucine kinetics in vivo were studied in postabsorptive healthy subjects with primed-constant infusions of L-[4,5-3H]leucine and [1-14C]alpha-ketoisocaproate (KIC) under euglycemic conditions. Hyperinsulinemia (approximately 100 microU/ml) decreased (P less than 0.05 vs. baseline) steady state Leucine + KIC rates of appearance (Ra) from proteolysis, KIC (approximately leucine-carbon) oxidation, and nonoxidized leucine-carbon flux (leucine----protein). Hyperaminoacidemia (plasma leucine, 210 mumol/liter), with either basal hormone replacement or combined to hyperinsulinemia, resulted in comparable increases in leucine + KIC Ra, KIC oxidation, and leucine----protein (P less than 0.05 vs. baseline). However, endogenous leucine + KIC Ra was suppressed only with the combined infusion. Therefore, on the basis of leucine kinetic data, hyperinsulinemia and hyperaminoacidemia stimulated net protein anabolism in vivo by different mechanisms. Hyperinsulinemia decreased proteolysis but did not stimulate leucine----protein. Hyperaminoacidemia per se stimulated leucine----protein but did not suppress endogenous proteolysis. When combined, they had a cumulative effect on net leucine deposition into body protein.
An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype
Authors: John W Whitaker, Robert Shoemaker, David L Boyle, Josh Hillman, David Anderson, Wei Wang, Gary S Firestein
Journal: Genome Medicine (2013)

Abstract Background A DNA methylation signature has been characterized that distinguishes rheumatoid arthritis (RA) fibroblast like synoviocytes (FLS) from osteoarthritis (OA) FLS. The presence of epigenetic changes in long-term cultured cells suggest that rheumatoid FLS imprinting might contribute to pathogenic behavior. To understand how differentially methylated genes (DMGs) might participate in the pathogenesis of RA, we evaluated the stability of the RA signature and whether DMGs are enriched in specific pathways and ontology categories. Methods To assess the RA methylation signatures the Illumina HumanMethylation450 chip was used to compare methylation levels in RA, OA, and normal (NL) FLS at passage 3, 5, and 7. Then methylation frequencies at CpGs within the signature were compared between passages. To assess the enrichment of DMGs in specific pathways, DMGs were identified as genes that possess significantly differential methylated loci within their promoter regions. These sets of DMGs were then compared to pathway and ontology databases to establish enrichment in specific categories. Results Initial studies compared passage 3, 5, and 7 FLS from RA, OA, and NL. The patterns of differential methylation of each individual FLS line were very similar regardless of passage number. Using the most robust analysis, 20 out of 272 KEGG pathways and 43 out of 34,400 GO pathways were significantly altered for RA compared with OA and NL FLS. Most interestingly, we found that the KEGG 'Rheumatoid Arthritis' pathway was consistently the most significantly enriched with differentially methylated loci. Additional pathways involved with innate immunity (Complement and Coagulation, Toll-like Receptors, NOD-like Receptors, and Cytosolic DNA-sensing), cell adhesion (Focal Adhesion, Cell Adhesion Molecule), and cytokines (Cytokine-cytokine Receptor). Taken together, KEGG and GO pathway analysis demonstrates non-random epigenetic imprinting of RA FLS. Conclusions The DNA methylation patterns include anomalies in key genes implicated in the pathogenesis of RA and are stable for multiple cell passages. Persistent epigenetic alterations could contribute to the aggressive phenotype of RA synoviocytes and identify potential therapeutic targets that could modulate the pathogenic behavior.
Tamoxifen for the Prevention of Breast Cancer: Late Results of the Italian Randomized Tamoxifen Prevention Trial Among Women With Hysterectomy
Authors: U. Veronesi, P. Maisonneuve, N. Rotmensz, B. Bonanni, P. Boyle, G. Viale, A. Costa, V. Sacchini, R. Travaglini, G. D'Aiuto, P. Oliviero, F. Lovison, G. Gucciardo, M. R. del Turco, M. G. Muraca, M. A. Pizzichetta, S. Conforti, A. Decensi
Journal: JNCI Journal of the National Cancer Institute (2007)

Initial findings of the Italian Randomized Tamoxifen Prevention Trial found no reduction in risk of breast cancer with tamoxifen use, whereas the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial showed that tamoxifen treatment reduces risk of estrogen receptor–positive breast cancer. Here we present an extended follow-up of the Italian trial. From October 1, 1992, to December 31, 1997, 5408 otherwise healthy women who had undergone hysterectomy were randomly assigned in a double-blind manner to tamoxifen (20 mg daily) or placebo for 5 years. Rates of breast cancer and other events in the two groups were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). After 11 years of follow-up, 136 women (74 placebo, 62 tamoxifen) developed breast cancer (RR = 0.84, 95% CI = 0.60 to 1.17; annual rates were 2.48 and 2.07 per 1000 women-years, respectively). The rates of breast cancer in the two study groups were similar among women who had had bilateral oophorectomy and among women at low risk for hormone receptor–positive (HR+) disease but were much lower in the tamoxifen group among women at high risk (placebo, 6.26 per 1000 women-years, tamoxifen, 1.50 per 1000 women-years; RR = 0.24, 95% CI = 0.10 to 0.59). During the treatment period, women in the tamoxifen group reported more hot flashes (RR = 1.78, 95% CI = 1.57 to 2.00), vaginal discharge (RR = 3.44, 95% CI = 2.90 to 4.09), and urinary disturbances (RR = 1.52, 95% CI = 1.23 to 1.89) but fewer headaches (RR = 0.68, 95% CI = 0.50 to 0.94) than women in the placebo group. Hypertriglyceridemia (RR = 4.33, 95% CI = 1.96 to 9.53), thromboembolic events (RR = 1.63, 95% CI = 1.02 to 2.62), and cardiac arrhythmia or atrial fibrillation (RR = 1.73, 95% CI = 1.01 to 2.98) were also more frequent in the tamoxifen group than in the placebo group. Appropriate selection of women at high risk for HR+ disease may improve the risk–benefit ratio of tamoxifen intervention.
National Trends in US Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare Beneficiaries, 1999 to 2011
Authors: Kasia J. Lipska, Joseph S. Ross, Yun Wang, Silvio E. Inzucchi, Karl Minges, Andrew J. Karter, Elbert S. Huang, Mayur M. Desai, Thomas M. Gill, Harlan M. Krumholz
Journal: JAMA Internal Medicine (2014)

The increasing intensity of diabetes mellitus management over the past decade may have resulted in lower rates of hyperglycemic emergencies but higher rates of hospital admissions for hypoglycemia among older adults. Trends in these hospitalizations and subsequent outcomes are not known.To characterize changes in hyperglycemia and hypoglycemia hospitalization rates and subsequent mortality and readmission rates among older adults in the United States over a 12-year period, and to compare these results according to age, sex, and race.Retrospective observational study using data from 33,952,331 Medicare fee-for-service beneficiaries 65 years or older from 1999 to 2011.Hospitalization rates for hyperglycemia and hypoglycemia, 30-day and 1-year mortality rates, and 30-day readmission rates.A total of 279,937 patients experienced 302,095 hospitalizations for hyperglycemia, and 404,467 patients experienced 429,850 hospitalizations for hypoglycemia between 1999 and 2011. During this time, rates of admissions for hyperglycemia declined by 38.6% (from 114 to 70 admissions per 100,000 person-years), while admissions for hypoglycemia increased by 11.7% (from 94 to 105 admissions per 100,000 person-years). In analyses designed to account for changing diabetes mellitus prevalence, admissions for hyperglycemia and hypoglycemia declined by 55.2% and 9.5%, respectively. Trends were similar across age, sex, and racial subgroups, but hypoglycemia rates were 2-fold higher for older patients (≥75 years) when compared with younger patients (65-74 years), and admission rates for both hyperglycemia and hypoglycemia were 4-fold higher for black patients compared with white patients. The 30-day and 1-year mortality and 30-day readmission rates improved during the study period and were similar after an index hospitalization for either hyperglycemia or hypoglycemia (5.4%, 17.1%, and 15.3%, respectively, after hyperglycemia hospitalizations in 2010; 4.4%, 19.9%, and 16.3% after hypoglycemia hospitalizations).Hospital admission rates for hypoglycemia now exceed those for hyperglycemia among older adults. Although admissions for hypoglycemia have declined modestly since 2007, rates among black Medicare beneficiaries and those older than 75 years remain high. Hospital admissions for severe hypoglycemia seem to pose a greater health threat than those for hyperglycemia, suggesting new opportunities for improvement in care of persons with diabetes mellitus.
β3 integrin modulates transforming growth factor beta induced (TGFBI) function and paclitaxel response in ovarian cancer cells
Authors: David A Tumbarello, Jillian Temple, James D Brenton
Journal: Molecular Cancer (2012)

Abstract Background The extracellular matrix (ECM) has a key role in facilitating the progression of ovarian cancer and we have shown recently that the secreted ECM protein TGFBI modulates the response of ovarian cancer to paclitaxel-induced cell death. Results We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface αvβ3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a β1 integrin-mediated pathway. We demonstrate that suppression of β1 integrin expression, in β3 integrin-expressing ovarian cancer cells, increases adhesion to rTGFBI. In addition, Syndecan-1 and −4 expression is dispensable for adhesion to rTGFBI and loss of Syndecan-1 cooperates with the loss of β1 integrin to further enhance adhesion to rTGFBI. The RGD motif present in the carboxy-terminus of TGFBI is necessary, but not sufficient, for SKOV3 cell adhesion and is dispensable for adhesion of ovarian cancer cells lacking β3 integrin expression. In contrast to TGFBI, the carboxy-terminus of periostin, lacking a RGD motif, is unable to support adhesion of ovarian cancer cells. Suppression of β3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of β1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a β1 integrin-mediated pathway, increases paclitaxel sensitivity. Conclusions Therefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a β3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.
The Attributable Morbidity and Mortality of Ventilator-Associated Pneumonia in the Critically Ill Patient
Authors: DAREN K. HEYLAND, DEBORAH J. COOK, LAUREN GRIFFITH, SEAN P. KEENAN, CHRISTIAN BRUN-BUISSON
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

To evaluate the attributable morbidity and mortality of ventilator-associated pneumonia (VAP) in intensive care unit (ICU) patients, we conducted a prospective, matched cohort study. Patients expected to be ventilated for > 48 h were prospectively followed for the development of VAP. To determine the excess ICU stay and mortality attributable to VAP, we matched patients with VAP to patients who did not develop clinically suspected pneumonia. We also conducted sensitivity analyses to examine the effect of different populations, onset of pneumonia, diagnostic criteria, causative organisms, and adequacy of empiric treatment on the outcome of VAP. One hundred and seventy-seven patients developed VAP. As compared with matched patients who did not develop VAP, patients with VAP stayed in the ICU for 4.3 d (95% confidence interval [CI]: 1.5 to 7. 0 d) longer and had a trend toward an increase in risk of death (absolute risk increase: 5.8%; 95% CI: -2.4 to 14.0 d; relative risk (RR) increase: 32.3%; 95% CI: -20.6 to 85.1%). The attributable ICU length of stay was longer for medical than for surgical patients (6. 5 versus 0.7 d, p < 0.004), and for patients infected with "high risk" organisms as compared with "low risk" organisms (9.1 d versus 2.9 d). The attributable mortality was higher for medical patients than for surgical patients (RR increase of 65% versus -27.3%, p = 0. 04). Results were similar for three different VAP diagnostic criteria. We conclude that VAP prolongs ICU length of stay and may increase the risk of death in critically ill patients. The attributable risk of VAP appears to vary with patient population and infecting organism.