tbuckley/cabot-search huggingface dataset:
Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure
Authors: Kiran K. Khush, David D. Waters, Vera Bittner, Prakash C. Deedwania, John J.P. Kastelein, Sandra J. Lewis, Nanette K. Wenger
Journal: Circulation (2007)

Statins reduce the rate of major cardiovascular events in high-risk patients, but their potential benefit as treatment for heart failure (HF) is less clear.Patients (n=10,001) with stable coronary disease were randomized to treatment with atorvastatin 80 or 10 mg/d and followed up for a median of 4.9 years. A history of HF was present in 7.8% of patients. A known ejection fraction <30% and advanced HF were exclusion criteria for the study. A predefined secondary end point of the study was hospitalization for HF. The incidence of hospitalization for HF was 2.4% in the 80-mg arm and 3.3% in the 10-mg arm (hazard ratio, 0.74; 95% confidence interval, 0.59 to 0.94; P=0.0116). The treatment effect of the higher dose was more marked in patients with a history of HF: 17.3% versus 10.6% in the 10- and 80-mg arms, respectively (hazard ratio, 0.59; 95% confidence interval, 0.4 to 0.88; P=0.009). Among patients without a history of HF, the rates of hospitalization for HF were much lower: 1.8% in the 80-mg group and 2.0% in the 10-mg group (hazard ratio, 0.87; 95% confidence interval, 0.64 to 1.16; P=0.34). Only one third of patients hospitalized for HF had evidence of preceding angina or myocardial infarction during the study period. Blood pressure was almost identical during follow-up in the treatment groups.Compared with a lower dose, intensive treatment with atorvastatin in patients with stable coronary disease significantly reduces hospitalizations for HF. In a post hoc analysis, this benefit was observed only in patients with a history of HF. The mechanism accounting for this benefit is unlikely to be due primarily to a reduction in interim coronary events or differences in blood pressure.
Evidence for protein oedema, neutrophil influx, and enhanced collagen production in lungs of patients with systemic sclerosis.
Authors: N K Harrison, R J McAnulty, P L Haslam, C M Black, G J Laurent
Journal: Thorax (1990)

Bronchoalveolar lavage fluid from patients with systemic sclerosis was analysed for evidence of pulmonary vascular leakage, inflammatory cell influx, and enhanced type III collagen synthesis. Eighteen patients with systemic sclerosis and computed tomographic evidence of fibrosing alveolitis were compared with 16 patients with a normal scan. The albumin concentration in lavage fluid was higher in all patients than in normal volunteers. Patients with an abnormal computed tomogram as a group had increased proportions of all inflammatory cell types, whereas those with a normal scan had increased neutrophils only. Increased lavage type III procollagen peptides were found in all patients with an abnormal computed tomogram and eight of those with a normal scan. These results suggest that pulmonary vascular leakage and neutrophil influx may be early pathological features of lung disease in systemic sclerosis and frequently associated with enhanced collagen production. Thus lavage of patients with systemic sclerosis may identify lung inflammation and altered collagen metabolism early in the evolution of fibrosing alveolitis.
Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men
Authors: Robert M. Grant, Javier R. Lama, Peter L. Anderson, Vanessa McMahan, Albert Y. Liu, Lorena Vargas, Pedro Goicochea, Martín Casapía, Juan Vicente Guanira-Carranza, Maria E. Ramirez-Cardich, Orlando Montoya-Herrera, Telmo Fernández, Valdilea G. Veloso, Susan P. Buchbinder, Suwat Chariyalertsak, Mauro Schechter, Linda-Gail Bekker, Kenneth H. Mayer, Esper Georges Kallás, K. Rivet Amico, Kathleen Mulligan, Lane R. Bushman, Robert J. Hance, Carmela Ganoza, Patricia Defechereux, Brian Postle, Furong Wang, J. Jeff McConnell, Jia-Hua Zheng, Jeanny Lee, James F. Rooney, Howard S. Jaffe, Ana I. Martinez, David N. Burns, David V. Glidden
Journal: New England Journal of Medicine (2010)

Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition.
Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer
Authors: Nora M. Hansen, Baiba Grube, Xing Ye, Roderick R. Turner, R. James Brenner, Myung-Shin Sim, Armando E. Giuliano
Journal: Journal of Clinical Oncology (2009)

Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria.Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i-), no evidence of tumor (n = 486); pN0(i+), tumor deposit < or = 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but < or = 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups.At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS.Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN.
Injectable Paromomycin for Visceral Leishmaniasis in India
Authors: Shyam Sundar, T.K. Jha, Chandreshwar P. Thakur, Prabhat K. Sinha, Sujit K. Bhattacharya
Journal: New England Journal of Medicine (2007)

Visceral leishmaniasis (kala-azar) affects large, rural, resource-poor populations in South Asia, Africa, and Brazil. Safe, effective, and affordable new therapies are needed. We conducted a randomized, controlled, phase 3 open-label study comparing paromomycin, an aminoglycoside, with amphotericin B, the present standard of care in Bihar, India.In four treatment centers for visceral leishmaniasis, 667 patients between 5 and 55 years of age who were negative for the human immunodeficiency virus and had parasitologically confirmed visceral leishmaniasis were randomly assigned in a 3:1 ratio to receive paromomycin (502 patients) at a dose of 11 mg per kilogram of body weight intramuscularly daily for 21 days or amphotericin B (165 patients) at a dose of 1 mg per kilogram intravenously every other day for 30 days. Final cure was assessed 6 months after the end of treatment; safety assessments included daily clinical evaluations and weekly laboratory and audiometric evaluations. Noninferiority testing was used to compare 6-month cure rates, with a chosen margin of noninferiority of 10 percentage points.Paromomycin was shown to be noninferior to amphotericin B (final cure rate, 94.6% vs. 98.8%; difference, 4.2 percentage points; upper bound of the 97.5% confidence interval, 6.9; P<0.001). Mortality rates in the two groups were less than 1%. Adverse events, which were more common among patients receiving paromomycin than among those receiving amphotericin B (6% vs. 2%, P=0.02), included transient elevation of aspartate aminotransferase levels (>3 times the upper limit of the normal range); transient reversible ototoxicity (2% vs. 0, P=0.20); and injection-site pain (55% vs. 0, P<0.001); and in patients receiving amphotericin B, as compared with those receiving paromomycin, nephrotoxicity (4% vs. 0, P<0.001), fevers (57% vs. 3%), rigors (24% vs. 0, P<0.001), and vomiting (10% vs. <1%, P<0.001).Paromomycin was shown to be noninferior to amphotericin B for the treatment of visceral leishmaniasis in India. (ClinicalTrials.gov number, NCT00216346.)
Genetic Information and the Prediction of Incident Type 2 Diabetes in a High-Risk Multiethnic Population
Authors: Sonia S. Anand, David Meyre, Guillaume Pare, Swneke D. Bailey, Changchun Xie, Xiaohe Zhang, Alexandre Montpetit, Dipika Desai, Jackie Bosch, Viswanathan Mohan, Rafael Diaz, Matthew J. McQueen, Heather J. Cordell, Bernard Keavney, Salim Yusuf, Daniel Gaudet, Hertzel Gerstein, James C. Engert
Journal: Diabetes Care (2013)

To determine if 16 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) in Europeans are also associated with T2DM in South Asians and Latinos and if they can add to the prediction of incident T2DM in a high-risk population.In the EpiDREAM prospective cohort study, physical measures, questionnaires, and blood samples were collected from 25,063 individuals at risk for dysglycemia. Sixteen SNPs that have been robustly associated with T2DM in Europeans were genotyped. Among 15,466 European, South Asian, and Latino subjects, we examined the association of these 16 SNPs alone and combined in a gene score with incident cases of T2DM (n = 1,016) that developed during 3.3 years of follow-up.Nine of the 16 SNPs were significantly associated with T2DM, and their direction of effect was consistent across the three ethnic groups. The gene score was significantly higher among subjects who developed incident T2DM (cases vs. noncases: 16.47 [2.50] vs. 15.99 [2.56]; P = 0.00001). The gene score remained an independent predictor of incident T2DM, with an odds ratio of 1.08 (95% CI 1.05-1.11) per additional risk allele after adjustment for T2DM risk factors. The gene score in those with no family history of T2DM was 16.02, whereas it was 16.19 in those with one parent with T2DM and it was 16.32 in those with two parents with T2DM (P trend = 0.0004). The C statistic of T2DM risk factors was 0.708 (0.691-0.725) and increased only marginally to 0.714 (0.698-0.731) with the addition of the gene score (P for C statistic change = 0.0052).T2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.
Loss of DNA Polymerase ζ Causes Chromosomal Instability in Mammalian Cells
Authors: John P. Wittschieben, Shalini C. Reshmi, Susanne M. Gollin, Richard D. Wood
Journal: Cancer Research (2006)

Abstract Rev3L encodes the catalytic subunit of DNA polymerase ζ (pol ζ) in mammalian cells. In yeast, pol ζ helps cells bypass sites of DNA damage that can block replication enzymes. Targeted disruption of the mouse Rev3L gene causes lethality midway through embryonic gestation, and Rev3L−/− mouse embryonic fibroblasts (MEFs) remain in a quiescent state in culture. This suggests that pol ζ may be necessary for tolerance of endogenous DNA damage during normal cell growth. We report the generation of mitotically active Rev3L−/− MEFs on a p53−/− genetic background. Rev3L null MEFs exhibited striking chromosomal instability, with a large increase in translocation frequency. Many complex genetic aberrations were found only in Rev3L null cells. Rev3L null cells had increased chromosome numbers, most commonly near pentaploid, and double minute chromosomes were frequently found. This chromosomal instability associated with loss of a DNA polymerase activity in mammalian cells is similar to the instability associated with loss of homologous recombination capacity. Rev3L null MEFs were also moderately sensitive to mitomycin C, methyl methanesulfonate, and UV and γ-radiation, indicating that mammalian pol ζ helps cells tolerate diverse types of DNA damage. The increased occurrence of chromosomal translocations in Rev3L−/− MEFs suggests that loss of Rev3L expression could contribute to genome instability during neoplastic transformation and progression. (Cancer Res 2006; 66(1): 134-42)
Reduced myocardial reflow and increased coronary vascular resistance following prolonged myocardial ischemia in the dog.
Authors: J T Willerson, J T Watson, I Hutton, G H Templeton, D E Fixler
Journal: Circulation Research (1975)

Studies were performed to determine whether an alteration in coronary vascular resistance and a reduction in the reflow phenomenon occurred in the blood-perfused, heparinized canine heart after various periods of myocaridal ischemia. Regional myocardial blood flow was measured with radioactive microspheres. Proximal left anterior descending coronary artery blood flow was measured with a periarterial flow transducer. Reduced reflow to the ischemic portion of the left ventricle and increased resistance in the left anterior descending coronary artery were present after 120 minutes of myocardial ischemia. The reduction in reflow was specific to the subendocardium of the ischemic area. Saline and isosorbide dinitrate (Isordi) did not prevent the increase in coronary vascular resistance or the significant reduction in reflow to the subendocardial portion of the ischemic area. Hypertonic mannitol given so as to increase serum osmolality 40 mosmoles/kg prevented the increase in coronary vascular resistance and modified the reduction in the reflow phenomenon to the subendocardial portion of the ischemic area. Thus, both an increase in coronary vascular resistance and a significant reduction in reflow to the subendocardial portion of the ischemic area occur in the canine heart after 120 minutes of myocardial ischemia. Moreover, the increase in coronary vascular resistance can be prevented and the reduction in reflow to the subendocardial portion of the ischemic area can be modified by the administration of hypertonic mannitol.
Adrenergic coronary tone during submaximal exercise in the dog is produced by circulating catecholamines. Evidence for adrenergic denervation supersensitivity in the myocardium but not in coronary vessels.
Authors: W M Chilian, D G Harrison, C W Haws, W D Snyder, M L Marcus
Journal: Circulation Research (1986)

The goal of this study was to test the hypothesis that circulating catecholamines are primarily responsible for alpha-adrenergic coronary vasoconstriction during submaximal exercise. The experimental series consisted of chronic studies in which a regional left ventricular sympathectomy was performed with phenol. Myocardial perfusion to the innervated and sympathectomized left ventricular regions was measured in these animals during (1) a control period, (2) treadmill exercise, (3) exercise during beta-adrenergic blockade, and (4) exercise during combined alpha- + beta-adrenergic blockade. We found no differences in myocardial perfusion between the innervated and sympathectomized regions or the transmural distribution of perfusion during any of these interventions. Thus, there is no evidence for neurogenic alpha-adrenergic coronary vasoconstriction. However, during exercise in the presence of alpha- and beta-blockade, coronary resistance (mmHg X min X 100 g/ml) was significantly less in both the innervated (0.65 +/- 0.07) and sympathectomized (0.68 +/- 0.07) regions than during beta-blockade, 0.90 +/- 0.17 and 0.89 +/- 0.16, respectively. This suggests that coronary alpha-adrenergic constriction was produced by circulating catecholamines. This concept of humorally mediated, alpha-adrenergic coronary vasoconstriction was strengthened by in vivo and in vitro studies that demonstrated that alpha-adrenergic supersensitivity of the coronary vasculature was not present. Myocardial beta-adrenergic supersensitivity was observed in the phenol regional sympathectomy model; however, this effect was blocked by propranolol (1 mg/kg). This indicates that alpha-adrenergic vasoconstriction in both myocardial regions during submaximal exercise is produced by circulating catecholamines. The major conclusion of this study is that, during submaximal exercise in the canine, alpha-adrenergic coronary vasoconstrictor tone is predominantly due to circulating catecholamines rather than direct neural effects.
Transcriptional Profiling of the Heart Reveals Chamber-Specific Gene Expression Patterns
Authors: Raymond Tabibiazar, Roger A. Wagner, Arnold Liao, Thomas Quertermous
Journal: Circulation Research (2003)

Cardiac chamber-specific gene expression is critical for the normal development and function of the heart. To investigate the genetic basis of cardiac anatomical specialization, we have undertaken a nearly genome-wide transcriptional profiling of the four heart chambers and the interventricular septum. Rigorous statistical analysis has allowed the identification of known and novel members of gene families that are felt to be important in cardiac development and function, including LIM proteins, homeobox proteins, wnt and T-box pathway proteins, as well as structural proteins like actins and myosins. In addition, these studies have allowed the identification of thousands of additional differentially expressed genes, for which there is little structural or functional information. Clustering of genes with known and unknown functions provides insights into signaling pathways that are essential for development and maintenance of chamber-specific features. To facilitate future research in this area, a searchable internet database has been constructed that allows study of the chamber-specific expression of any gene represented on this comprehensive microarray. It is anticipated that further study of genes identified through this effort will provide insights into the specialization of heart chamber tissues, and their specific roles in cardiac development, aging, and disease.
Renal Net Glucose Release In Vivo and Its Contribution to Blood Glucose in Rats
Authors: Kaichi Kida, Shinjiro Nakajo, Fumitada Kamiya, Yoshiko Toyama, Takashi Nishio, Hachiro Nakagawa
Journal: Journal of Clinical Investigation (1978)

This study describes the contribution of de novo glucose synthesis by the kidney to blood glucose homeostasis in rats. The net glucose release by the kidney in vivo was measured by an isotope-dilution method, which calculated the extent of dilution of injected [(14)C]glucose by glucose newly synthesized in the kidney. The extent of dilution was determined from the difference between the decrease of the actual blood glucose concentration and that of the radioactivity of [(14)C]glucose, after injecting [(14)C]glucose into functionally hepatectomized rats. The results indicate that the net glucose release by the kidney in vivo in normal fed rats was 0.75+/-0.13 mg/dl per min, and that its contribution to blood glucose was 25.9+/-5.0%. When unilateral nephrectomy was performed, under the same conditions, renal net glucose release was one-half of that in rats with two intact kidneys, which indicates the quantitative accuracy of the isotope-dilution method employed in this study. In rats starved for 24 h, the renal net glucose release increased to 0.99+/-0.08 mg/dl per min. Diabetic rats showed a remarkably higher renal net glucose of 2.28+/-0.33 mg/dl per min, which was 360% of the normal level. Treatment of diabetic rats with insulin, restored the renal net glucose release to the normal level. In acidotic rats, renal net glucose release was as great as 1.03+/-0.15 mg/dl per min, which suggests that the acid-base balance participates in control of renal glucose output. Measurements every 6 h throughout the day showed that glucose was supplied from the kidney at a constant rate without any circadian rhythm. These data suggest that renal gluconeogenesis is of physiological importance in the maintenance of homeostasis of blood glucose.
Role of Fibroblast Growth Factor-2 Isoforms in the Effect of Estradiol on Endothelial Cell Migration and Proliferation
Authors: B. Garmy-Susini, E. Delmas, P. Gourdy, M. Zhou, C. Bossard, B. Bugler, F. Bayard, A. Krust, A.C. Prats, T. Doetschman, H. Prats, J.F. Arnal
Journal: Circulation Research (2004)

Both 17β-estradiol (E 2 ) and fibroblast growth factor-2 (FGF2) stimulate angiogenesis and endothelial cell migration and proliferation. The first goal of this study was to explore the potential link between this hormone and this growth factor. E 2 -stimulated angiogenesis in SC Matrigel plugs in Fgf2 +/+ mice, but not in Fgf2 −/− mice. Cell cultures from subcutaneous Matrigel plugs demonstrated that E 2 increased both migration and proliferation in endothelial cells from Fgf2 +/+ mice, but not from in Fgf2 −/− mice. Several isoforms of fibroblast growth factor-2 (FGF2) are expressed: the low molecular weight 18-kDa protein (FGF2 lmw ) is secreted and activates tyrosine kinase receptors (FGFRs), whereas the high molecular weight (21 and 22 kDa) isoforms (FGF2 hmw ) remains intranuclear, but their role is mainly unknown. The second goal of this study was to explore the respective roles of FGF2 isoforms in the effects of E 2 . We thus generated mice deficient only in the FGF2 lmw ( Fgf2 lmw−/− ). E 2 stimulated in vivo angiogenesis and in vitro migration in endothelial cells from Fgf2 lmw−/− as it did in Fgf2 +/+ mice. E 2 increased FGF2 hmw protein abundance in endothelial cell cultures from Fgf2 +/+ and Fgf2 lmw−/− mice. As shown using siRNA transfection, these effects were FGFR independent but involved FGF2-Interacting Factor, an intracellular FGF2 hmw partner. This is the first report for a physiological role for the intracellular FGF2 hmw found to mediate the effect of E 2 on endothelial cell migration via an intracrine action.
Neural Correlates of Error Processing in Young People With a History of Severe Childhood Abuse: An fMRI Study
Authors: Lena Lim, Heledd Hart, Mitul A Mehta, Andrew Simmons, Kah Mirza, Katya Rubia
Journal: American Journal of Psychiatry (2015)

Objective: Childhood maltreatment is associated with various cognitive deficits, including inhibitory deficits and hypersensitivity to negative feedback. The authors used a stop-signal task to investigate the association between severe childhood abuse and inhibitory and error processing brain activation in medication-naive, drug-free young people with and without severe childhood abuse, controlling for psychiatric comorbidities by including a psychiatric control group. Method: Using functional MRI, the authors compared brain activation in 22 age- and gender-matched young people exposed to severe childhood abuse, 17 psychiatric comparison subjects matched for psychiatric diagnoses with the abused group, and 27 healthy comparison subjects during an individually adjusted tracking stop-signal task designed to elicit 50% inhibition failures. Results: During failed inhibition, the childhood abuse group showed increased brain activation relative to the healthy comparison group in typical error processing regions of the dorsomedial frontal cortex, including the left and right presupplementary and supplementary motor area and anterior cingulate cortex. The increased activation in a smaller cluster in the supplementary motor area survived comparison with the psychiatric comparison group. No group differences in activation were observed for successful inhibition. Conclusions: The findings suggest that severe childhood abuse is associated with abnormally increased activation in classical dorsomedial frontal error-processing regions; furthermore, the increased activation in the supplementary motor area was abuse specific. However, childhood abuse was not associated with inhibitory dysfunction. Increased sensitivity of error-detection networks in participants in the childhood abuse group may be due to the constant need to monitor their own actions in order to avoid painful mistakes, which are often associated with harsh punishment in abusive settings.