tbuckley/cabot-search huggingface dataset:
Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial
Authors: Eric Lawitz, Jay P Lalezari, Tarek Hassanein, Kris V Kowdley, Fred F Poordad, Aasim M Sheikh, Nezam H Afdhal, David E Bernstein, Edwin DeJesus, Bradley Freilich, David R Nelson, Douglas T Dieterich, Ira M Jacobson, Donald Jensen, Gary A Abrams, Jama M Darling, Maribel Rodriguez-Torres, K Rajender Reddy, Mark S Sulkowski, Natalie H Bzowej, Robert H Hyland, Hongmei Mo, Ming Lin, Michael Mader, Robert Hindes, Efsevia Albanis, William T Symonds, Michelle M Berrey, Andrew Muir
Journal: The Lancet Infectious Diseases (2013)
Development of Chronic Bronchitis and Emphysema in β-Epithelial Na<sup>+</sup> Channel–Overexpressing Mice
Authors: Marcus A. Mall, Jack R. Harkema, Joanna B. Trojanek, Diana Treis, Alessandra Livraghi, Susanne Schubert, Zhe Zhou, Silvia M. Kreda, Stephen L. Tilley, Elizabeth J. Hudson, Wanda K. O'Neal, Richard C. Boucher
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in β-epithelial Na+ channel (βENaC)–overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors.Objectives: The aim of this study was to identify the initiating lesions and investigate the natural progression of lung disease caused by airway surface dehydration.Methods: Lung morphology, gene expression, bronchoalveolar lavage, and lung mechanics were studied at different ages in βENaC-overexpressing mice.Measurements and Main Results: Mucus obstruction in βENaC-overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving βENaC-overexpressing mice, mucus obstruction extended into the lungs and was accompanied by goblet cell metaplasia, increased mucin expression, and airway inflammation with transient perinatal increases in tumor necrosis factor-α and macrophages, IL-13 and eosinophils, and persistent increases in keratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. βENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance.Conclusions: Our studies demonstrate that airway surface dehydration is sufficient to initiate persistent neutrophilic airway inflammation with chronic airways mucus obstruction and to cause transient eosinophilic airway inflammation and emphysema. These results suggest that deficient airway surface hydration may play a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and serve as a target for novel therapies.
5'-Nucleotidase activity of mouse peritoneal macrophages. II. Cellular distribution and effects of endocytosis.
Authors: P J Edelson, Z A Cohn
Journal: The Journal of Experimental Medicine (1976)

The diazonium salt of sulfanilic acid (DASA) can inactivate about 80% of the total 5'-nucleotidase of viable macrophages. The remaining 20% can be inactivated if the cells are first lysed in detergent, and presumably represents an intracellular pool of 5'-nucleotidase. The bulk of this pool may represent cytoplasmic vesicles derived from plasma membrane by endocytosis. This internal compartment is expanded up to threefold immediately after the cells have ingested a large latex load. This is consistent with previous observations on the internalization of 5'-nucleotidase in latex phagosomes. In latex-filled cells this intracellular pool of enzyme is inactivated over a few hours, and the cells then slowly increase their enzyme activity to nearly normal levels. However, 24 h after latex ingestion the metabolism of 5'-nucleotidase in these recovered cells is abnormal, as the rate of enzyme degradation is about twice the normal rate, and the DASA-insensitive enzyme pool in these cells is strikingly diminished. This may reflect effects of the accumulated indigestible particles on the fate of incoming pinocytic vesicles or on newly synthesized plasma membrane precursor. Another endocytic stimulus, concanavalin A, also reduces the total cell 5'-nucleotidase activity. This effect, which is time and temperature dependent, can be prevented by the competitive sugar alpha-methyl mannose. The concanavalin A inhibition can be reversed in the absence of new protein synthesis or in cells cultivated in serum-free conditions. It is not known whether the effect of concanavalin A on 5'-nucleotidase depends upon the interiorizaiton of plasma membrane or is strictly associated with events at the cell surface.
Human Cardiac Inwardly-Rectifying K <sup>+</sup> Channel Kir <sub>2.1b</sub> Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System
Authors: Christoph A. Karle, Edgar Zitron, Wei Zhang, Gunnar Wendt-Nordahl, Sven Kathöfer, Dierk Thomas, Bernd Gut, Eberhard Scholz, Christian-Friedrich Vahl, Hugo A. Katus, Johann Kiehn
Journal: Circulation (2002)

Protein kinases A (PKA) and C (PKC) are activated in ischemic preconditioning and heart failure, conditions in which patients develop arrhythmias. The native inward rectifier potassium current (IK1) plays a central role in the stabilization of the resting membrane potential and the process of arrhythmogenesis. This study investigates the functional relationship between PKC and IK1.In whole-cell patch-clamp experiments with isolated human atrial cardiomyocytes, the IK1 was reduced by 41% when the nonspecific activator of PKC phorbol 12 myristate 13-acetate (PMA; 100 nmol/L) was applied. To investigate the effects of PKC on cloned channel underlying parts of the native IK1, we expressed Kir(2.1b) heterologously in Xenopus oocytes and measured currents with the double-electrode voltage-clamp technique. PMA decreased the current by an average of 68%, with an IC50 of 0.68 nmol/L. The inactive compound 4-alpha-PMA was ineffective. Thymeleatoxin and 1-oleolyl-2-acetyl-sn-glycerol, 2 specific activators of PKC, produced effects similar to those of PMA. Inhibitors of PKC, ie, staurosporine and chelerytrine, could inhibit the PMA effect (1 nmol/L) significantly. After mutation of the PKC phosphorylation sites (especially S64A and T353A), PMA became ineffective.The human IK1 in atrial cardiomyocytes and one of its underlying ion channels, the Kir(2.1b) channel, is inhibited by PKC-dependent signal transduction pathways, possibly contributing to arrhythmogenesis in patients with structural heart disease in which PKC is activated.
Statin Use in Outpatients With Obstructive Coronary Artery Disease
Authors: Suzanne V. Arnold, John A. Spertus, Fengming Tang, Harlan M. Krumholz, William B. Borden, Steven A. Farmer, Henry H. Ting, Paul S. Chan
Journal: Circulation (2011)

Clinical trials have shown that statin therapy reduces cardiovascular morbidity and mortality in patients with coronary artery disease (CAD), even among patients with low-density lipoprotein cholesterol levels <100 mg/dL. We sought to determine the extent to which patients with obstructive CAD in routine outpatient care are treated with statins, nonstatins, or no lipid-lowering therapy.Within the American College of Cardiology's Practice Innovation and Clinical Excellence (PINNACLE) outpatient registry, we examined rates of treatment with statin and nonstatin medications in 38 775 outpatients with obstructive CAD (history of myocardial infarction or coronary revascularization) and without documented contraindications to statin therapy. Among these patients, 30 160 (77.8%) were prescribed statins, 2042 (5.3%) were treated only with nonstatin lipid-lowering medications, and 6573 (17.0%) were untreated. Lack of medical insurance was associated with no statin treatment, and male sex, coexisting hypertension, and a recent coronary revascularization were associated with statin treatment. Among those not on any lipid-lowering therapy, low-density lipoprotein cholesterol levels were available for 51.2% (3365/6573). Among these untreated patients, low-density lipoprotein cholesterol levels were <100 mg/dL in 1794 patients (53.3%) and ≥ 100 mg/dL in 1571 patients (46.7%).Despite robust clinical trial evidence, a substantial number of patients with obstructive CAD remain untreated with statins. A small proportion were treated with nonstatin therapy, and 1 in 6 patients was simply untreated; half of the untreated patients had low-density lipoprotein cholesterol values <100 mg/dL. These findings illustrate important opportunities to improve lipid management in outpatients with obstructive CAD.
International Union of Pharmacology. LX. Retinoic Acid Receptors
Authors: Pierre Germain, Pierre Chambon, Gregor Eichele, Ronald M. Evans, Mitchell A. Lazar, Mark Leid, Angel R. De Lera, Reuben Lotan, David J. Mangelsdorf, Hinrich Gronemeyer
Journal: Pharmacological Reviews (2006)

Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RARα, RARβ, and RARγ), members of the nuclear hormone receptor superfamily. The most important endogenous retinoid is all-<i>trans</i>-retinoic acid. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis, as well as their disorders. This review summarizes the considerable amount of knowledge generated on these receptors.
Molecular Scores to Predict Ovarian Cancer Outcomes: A Worthy Goal, but Not Ready for Prime Time
Authors: E. M. Swisher, T. Taniguchi, B. Y. Karlan
Journal: JNCI Journal of the National Cancer Institute (2012)

Ovarian carcinoma has the highest mortality of all gynecological cancers. The American Cancer Society estimates that in 2012, about 22 280 new cases of ovarian cancer will be diagnosed, and 15 500 women will die of ovarian cancer in the United States (1). Despite achieving high rates of remission following radical surgery and platinum-based chemotherapy, most women relapse and ultimately die of chemoresistant disease. Advances in chemotherapy lengthen survival for women with advanced-stage (stages III and IV) disease but have not changed the likelihood of cure. Biomarkers, such as the rate of decline of serum cancer antigen 125 (CA-125, also known as mucin-16) level or the absolute CA-125 nadir, can be predictors of progression-free and overall survivals (2–4); however, when faced with a slowly declining level of CA-125 during primary treatment, the oncologist has few effective alternatives. With almost 80% of primary ovarian cancers initially responding to platinum-based therapy, a prospective biomarker would need to be highly predictive of treatment failure because alternative treatments would be purely experimental.
High serum acid phosphatase values in a case of lymphoblastic leukaemia.
Authors: J. Klastersky, A. Coune
Journal: BMJ (1970)

In a patient with acute lymphoblastic leukaemia and a greatly increased serum acid nitrophenylphosphatase activity, as measured with the Sigma procedure (Sigma Technical Bulletin No. 104, revised August 1961), disappearance of blast cells from the bone marrow and the blood after chemotherapy was followed by the return of serum acid phosphatase levels to normal. Relapse was again accompanied by a rise in enzyme levels. © 1970, British Medical Journal Publishing Group. All rights reserved.
Carcinogenicity and Acute Toxicity of Dimethylnitrosamine in Rainbow Trout (Salmo gairdneri)23
Authors: M. P. Grieco, J. D. Hendricks, R. A. Scanlan, R. O. Sinnhuber, D. A. Pierce
Journal: JNCI Journal of the National Cancer Institute (1978)

Four-week-old rainbow trout (Salmo gairdneri) were fed diets containing 0, 3, 50, 200, 400, and 800 ppm dimethylnitrosamine (DMN) for 52 weeks. At the end of 52 weeks, the fish were fed a control diet without DMN for an additional 26 weeks. Samples were taken at 26, 52, and 78 weeks to determine tumor incidence. A dose-related carcinogenic response was established from these results, and an equation was derived to relate the level of the carcinogen to the hepatocellular carcinoma incidence. From a published dose-response study that used outbred Porton rats, a second equation was derived for comparison. Rats and trout were approximately equal in their sensitivity to DMN carcinogenesis. The median lethal dose after ip injection of DMN was 1,770 mg/kg body weight in rainbow trout. Relative to the range of 15-50 mg/kg body weight reported for .several mammalian species, trout were resistant to the acute toxicity of DMN.
Use of Medroxyprogesterone Acetate as a Contraceptive in conjunction with Early Postpartum Rubella Vaccination
Authors: D. S. Sharp, H. Macdonald
Journal: BMJ (1973)

During a 12-month period 170 women received early postpartum rubella vaccination. An injectable "depot" progestogen was given to each of these patients for contraceptive purposes at the same time as the vaccine was administered. Subsequent observations showed that the progestogen was effective as a contraceptive in this context and that it did not appear to affect the immune response of the patients to the vaccine.
Geographic Sampling Scheme as a Determinant of the Major Axis of Genetic Variation in Principal Components Analysis
Authors: M. DeGiorgio, N. A. Rosenberg
Journal: Molecular Biology and Evolution (2012)

Principal component (PC) maps, which plot the values of a given PC estimated on the basis of allele frequency variation at the geographic sampling locations of a set of populations, are often used to investigate the properties of past range expansions. Some studies have argued that in a range expansion, the axis of greatest variation (i.e., the first PC) is parallel to the axis of expansion. In contrast, others have identified a pattern in which the axis of greatest variation is perpendicular to the axis of expansion. Here, we seek to understand this difference in outcomes by investigating the effect of the geographic sampling scheme on the direction of the axis of greatest variation under a two-dimensional range expansion model. From datasets simulated using each of two different schemes for the geographic sampling of populations under the model, we create PC maps for the first PC. We find that depending on the geographic sampling scheme, the axis of greatest variation can be either parallel or perpendicular to the axis of expansion. We provide an explanation for this result in terms of intra- and interpopulation coalescence times.
Factors influencing bromsulphalein retention and its evaluation in bilharzial hepatic fibrosis
Authors: H. S. Badawi, A. M. Nomeir, R. A. Zaher
Journal: Gut (1962)

Thirty-six patients with bilharzial hepatic fibrosis were investigated, and five other patients were studied before and after portacaval shunt operation. The liver parenchyma is well preserved in bilharzial hepatic fibrosis and this is reflected in the almost normal results of liver function tests. In 40% of the patients bromsulphalein was retained to an abnormal degree and retention was increased post-operatively in the patients studied before and after portacaval shunt operations. The increased retention of bromsulphalein was found to be the result of prehepatic factors, namely, diminished hepatic blood flow and increased systemic portal collateral circulation either singly or in combination.
Bronchoalveolar mastocytosis and lymphocytosis after nitrogen dioxide exposure in man: a time-kinetic study
Authors: T Sandstrom, MC Andersson, B Kolmodin-Hedman, N Stjernberg, T Angstrom
Journal: European Respiratory Journal (1990)

The combination of environmental chamber exposure and bronchoalveolar lavage (BAL) was used to study the time-course of the cell response in the human lung to nitrogen dioxide (NO2). Healthy subjects were exposed for 20 min to 7 mg NO2.m-3 (4 ppm), a concentration which occurs indoors in industries and is below the peak exposure limit for work places in most countries, 10 mg.m-3 (5.5 ppm). BAL was performed in all subjects several weeks before exposure and 4, 8, 24 and 72 h after exposure, in eight subjects at each time. Mastocytosis and lymphocytosis were found in BAL fluid 4-24 h after exposure, with normalization after 72 h. A mild increase in lysozyme positive macrophages was found 24-72 h after exposure. The time-course of the human pulmonary cell response to NO2, demonstrated in BAL fluid, represents a new and previously not reported finding after exposure to this common air pollutant. Our findings are diverging from results obtained in animal studies, using approximately the same NO2 concentrations, indicating that the results from the animal studies may not be transferable to man.
Inhibition of Metastases by Anticoagulants
Authors: M. Hejna, M. Raderer, C. C. Zielinski
Journal: JNCI Journal of the National Cancer Institute (1999)

Metastasis involves several distinct steps, including one in which the tumor cell, after entry into the bloodstream, comes to rest in a capillary located at the distant site where a metastatic tumor will ultimately form. Components of the blood-clotting pathway may contribute to metastasis by trapping cells in capillaries or by facilitating adherence of cells to capillary walls. Conceivably, anticoagulants could interfere with this step in the metastatic process. In this review, we have summarized current knowledge on the interaction of malignant cells, clotting factors, and anticoagulants. We used computerized (MEDLINE®) and manual searches to identify studies done in humans, in animals, and in in vitro systems that were published in English between 1952 and 1998. We found many reports that the formation of metastatic tumors could be inhibited by heparin, a vitamin K antagonist (warfarin), and inhibitors of platelet aggregation (prostacyclin and dipyridamole). Despite these encouraging preliminary results and a compelling biochemical rationale, only limited information exists on the clinical use of anticoagulants for the prevention or treatment of metastatic cancer because there have been so few controlled and prospectively randomized studies on this topic. In view of the preliminary results, anticoagulants may hold promise for the prevention and treatment of metastases. We believe that larger controlled investigations are strongly warranted to evaluate the clinical potential of anticoagulants for the prevention and treatment of metastases in humans.
Cancer Incidence in Blood Transfusion Recipients
Authors: H. Hjalgrim, G. Edgren, K. Rostgaard, M. Reilly, T. N. Tran, K. E. Titlestad, A. Shanwell, C. Jersild, J. Adami, A. Wikman, G. Gridley, L. Wideroff, O. Nyren, M. Melbye
Journal: JNCI Journal of the National Cancer Institute (2007)

Blood transfusions may influence the recipients' cancer risks both through transmission of biologic agents and by modulation of the immune system. However, cancer occurrence in transfusion recipients remains poorly characterized. We used computerized files from Scandinavian blood banks to identify a cohort of 888843 cancer-free recipients transfused after 1968. The recipients were followed from first registered transfusion until the date of death, emigration, cancer diagnosis, or December 31, 2002, whichever came first. Relative risks were expressed as ratios of the observed to the expected numbers of cancers, that is, standardized incidence ratios (SIRs), using incidence rates for the general Danish and Swedish populations as a reference. All statistical tests were two-sided. During 5652918 person-years of follow-up, 80990 cancers occurred in the transfusion recipients, corresponding to a SIR of 1.45 (95% confidence interval [CI] = 1.44 to 1.46). The SIR for cancer overall decreased from 5.36 (95% CI = 5.29 to 5.43) during the first 6 months after transfusion to 1.10 or less for follow-up periods more than 2 years after the transfusion. However, the standardized incidence ratios for cancers of the tongue, mouth, pharynx, esophagus, liver, and respiratory and urinary tracts and for squamous cell skin carcinoma remained elevated beyond 10 years after the transfusion. The marked increase in cancer risk shortly after a blood transfusion may reflect the presence of undiagnosed occult cancers with symptoms that necessitated the blood transfusion. The continued increased risk of tobacco- and alcohol-related cancers suggests that lifestyle and other risk factors related to conditions prompting transfusion rather than transfusion-related exposures per se are important to the observed cancer occurrence in the recipients.
Air-Quality Standards
Authors: Max Bader
Journal: JAMA (1980)

<h3>To the Editor.—</h3> In discussing "Health Effects of Urban Air Pollution," Mitchell et al (242:1163, 1979) seem to take the view that current national ambient air quality standards, as adopted by the Environmental Protection Agency, for carbon monoxide (CO) are justified for sea level, but that an eight-hour CO standard of 6 ppm should be substituted in high-altitude areas. Adjustment of the basic CO standard to accommodate for high-altitude effects is reasonable, but, for sea level areas, the present 9 ppm, eight-hour CO standard, which may be exceeded only once a year, is already more stringent than can be justified by cost-benefit analysis. The difference between using a 15 ppm, eight-hour CO standard and a 9 ppm, eight-hour CO standard is an increase of 1% in COHb concentration. Can one truly argue that this makes any real difference to a person's health if it happens five to ten times a year
THE CUTANEOUS TRICHOPHYTIN REACTION
Authors: Samuel Amberg
Journal: The Journal of Experimental Medicine (1910)

There exists a far-reaching analogy between the cutaneous trichophytin reaction and the cutaneous tuberculin reaction. Both indicate that the organism is the seat of a definite infection or that it has passed through such an infection. Both may persist for a long time after the active disease has come to rest, indicating that the infection has left the organism in a state of altered reactivity-allergy. Under certain conditions both may be of diagnostic value, but since the reaction persists for a long time after the infection has passed, the negative reaction may be of greater value, excluding the existence of a specific infection. The analogy of the trichophytin reaction with the tuberculin reaction is not only limited to the obvious clinical manifestations, but, as in the tuberculin reaction, it can be shown that with uniform concentration of antibody, the intensity of the reaction is dependent on the concentration of the trichophytin. A tentative explanation of the halo formation is offered, based on a rapidly renewed formation of antibody stimulated probably by the entrance of a small amount of allergen into the general circulation.
Atypical Measles in Adolescents: Evaluation of Clinical and Pulmonary Function
Authors: WILLIAM J. HALL
Journal: Annals of Internal Medicine (1979)

During a community outbreak of measles, 10 patients aged 11 through 19 were hospitalized with prominent pulmonary infiltrates and clinical manifestations of high fever and rash. Diagnoses of atypical measles were confirmed by hemagglutination-inhibition and complement-fixation antibody studies. Patients were followed with pulmonary function studies for 12 weeks. The most common admitting diagnoses were varicella, scarlet fever, meningococcemia, and Rocky Mountain spotted fever, due largely to the protean cutaneous manifestations. Roentgenographic studies showed diffuse, segmental, and nodular chest lesions. Hypoxemia (mean arterial Po2, 58 mm Hg) and markedly reduced lung volumes were noted. Gradual resolution of physiologic abnormalities was noted during 12 weeks, but two children had persistent nodular densities seen on chest roentgenograms. Atypical measles in the older child and young adult has a wide spectrum of pulmonary manifestations ranging from acute respiratory failure to isolated nodular lesions. Proper recognition of this syndrome will prevent unnecessary invasive diagnostic procedures.