tbuckley/cabot-search huggingface dataset:
Hepatocyte polarization is essential for the productive entry of the hepatitis B virus
Authors: Andreas Schulze, Kerry Mills, Thomas S. Weiss, Stephan Urban
Journal: Hepatology (2011)

Abstract Human hepatitis B virus (HBV) is characterized by a high species specificity and a distinct liver tropism. Within the liver, HBV replication occurs in differentiated and polarized hepatocytes. Accordingly, the in vitro HBV infection of primary human hepatocytes (PHHs) and the human hepatoma cell line, HepaRG, is restricted to differentiated, hepatocyte-like cells. Though preparations of PHH contain up to 100% hepatic cells, cultures of differentiated HepaRG cells are a mixture of hepatocyte-like and biliary-like epithelial cells. We used PHH and HepaRG cells and compared the influence of virus inoculation dose, cell differentiation, and polarization on productive HBV infection. At multiplicities of genome equivalents (mge) &gt;8,000, almost 100% of PHHs could be infected. In contrast, only a subset of HepaRG cells stained positive for HBcAg at comparable or even higher mge. Infection predominantly occurred at the edges of islands of hepatocyte-like HepaRG cells. This indicates a limited accessibility of the HBV receptor, possibly as a result of its polar sorting. Multidrug resistance protein 2 (MRP2), a marker selectively transported to the apical (i.e., canalicular) cell membrane, revealed two polarization phenotypes of HepaRG cells. HBV infection within the islands of hepatocyte-like HepaRG cells preferentially occurred in cells that resemble PHH, exhibiting canalicular structures. However, disruption of cell-cell junctions allowed the additional infection of cells that do not display a PHH-like polarization. Conclusion: HBV enters hepatocytes via the basolateral membrane. This model, at least partially, explains the difference of PHH and HepaRG cells in infection efficacy, provides insights into natural HBV infection, and establishes a basis for optimization of the HepaRG infection system. (Hepatology 2012)
Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell Anemia
Authors: Martin H. Steinberg, Franca Barton, Oswaldo Castro, Charles H. Pegelow, Samir K. Ballas, Abdullah Kutlar, Eugene Orringer, Rita Bellevue, Nancy Olivieri, James Eckman, Mala Varma, Gloria Ramirez, Brian Adler, Wally Smith, Timothy Carlos, Kenneth Ataga, Laura DeCastro, Carolyn Bigelow, Yogen Saunthararajah, Margaret Telfer, Elliott Vichinsky, Susan Claster, Susan Shurin, Kenneth Bridges, Myron Waclawiw, Duane Bonds, Michael Terrin
Journal: JAMA (2003)

Hydroxyurea increases levels of fetal hemoglobin (HbF) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia (SCA). High HbF levels reduce morbidity and mortality.To determine whether hydroxyurea attenuates mortality in patients with SCA.Long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine if hydroxyurea reduces vaso-occlusive events. In the MSH Patients' Follow-up, conducted in 1996-2001, patients could continue, stop, or start hydroxyurea. Data were collected during the trial and in the follow-up period.Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada.Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients.In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147).Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality.Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P =.002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P =.03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P =.02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P =.06). Taking hydroxyurea was associated with a 40% reduction in mortality (P =.04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal.Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown.
Cardiovascular reflexes arising from the gallbladder of the cat. Effects of capsaicin, bradykinin, and distension.
Authors: G A Ordway, J C Longhurst
Journal: Circulation Research (1983)

We have studied the cardiovascular responses which can be evoked when the gallbladder is stimulated pharmacologically or mechanically. To determine the potential for reflex cardiovascular activation, we applied capsaicin, a selective thin-fiber agonist, to the serosal surface of the gallbladder. This algesic substance evoked cardiovascular responses which included increases in mean arterial pressure (MAP) by 14%, heart rate (HR) by 3%, left ventricular dP/dt at 40 mm Hg developed pressure (dP/dt DP40) by 14%, and systemic vascular resistance (SVR) by 19%. There were no demonstrable effects on the cardiovascular system when this same substance was applied to the surface of the liver. Bilateral vagotomy at the level of the diaphragm did not alter the responses to capsaicin. Right atrial overdrive pacing did not reduce the positive inotropic effect elicited when the gallbladder was stimulated. Removal of the celiac and superior mesenteric ganglia, or selective denervation of the gallbladder, abolished the cardiovascular responses which were evoked previously. beta-Adrenergic blockade, however, abolished only the reflex chronotropic and intropic responses. Thus, the potential for eliciting reflex cardiovascular alterations by stimulating gallbladder afferents with capsaicin was established. In subsequent studies, stimulating the gallbladder with bradykinin, an endogenous polypeptide, evoked a reflex activation of the cardiovascular system similar to that seen with capsaicin (MAP = 14%; HR = 4%; dP/dt DP40 = 18%; SVR = 14%). These reflex responses were dose dependent, were produced by mucosal as well as serosal application of this substance, and were eliminated by bilateral splanchnic nerve action. In contrast to capsaicin and bradykinin, distension of the gallbladder did not cause any cardiovascular alterations. We conclude that stimulation of gallbladder afferents by the algesic substance capsaicin or by bradykinin, an endogenous substance that under certain conditions may be formed in bile, can induce significant reflex activation of the cardiovascular system.
Screening for Colorectal Neoplasms With New Fecal Occult Blood Tests: Update on Performance Characteristics
Authors: J. E. Allison, L. C. Sakoda, T. R. Levin, J. P. Tucker, I. S. Tekawa, T. Cuff, M. P. Pauly, L. Shlager, A. M. Palitz, W. K. Zhao, J. S. Schwartz, D. F. Ransohoff, J. V. Selby
Journal: JNCI Journal of the National Cancer Institute (2007)

One type of fecal occult blood test (FOBT), the unrehydrated guaiac fecal occult blood test (GT), is recommended by the United States Preventive Services Task Force and the Institute of Medicine for use in screening programs, but it has relatively low sensitivity as a single test for detecting advanced colonic neoplasms (cancer and adenomatous polyps > or = 1 cm in diameter). Thus, improving the sensitivity of FOBT should make colon cancer screening programs that use these tests more effective.We assessed prospectively the performance characteristics of two newer FOBTs in 5841 subjects at average risk for colorectal cancer in a large group-model managed care organization. The tests evaluated included a sensitive GT, a fecal immunochemical test (FIT), and the combination of both tests. Patients with positive and negative test results were advised to have colonoscopy and sigmoidoscopy, respectively. Sensitivity and specificity for detecting advanced neoplasms in the left colon within 2 years after the FOBT screening were evaluated for the two tests administered separately and in combination.A total of 139 patients were diagnosed with advanced colorectal neoplasms (n = 14 cancers, n = 128 adenomas) within the 2 years following their initial FOBT screening. Sensitivity for detecting cancer was 81.8% (95% confidence interval [CI] = 47.8% to 96.8%) for the FIT alone and 64.3% (95% CI = 35.6% to 86.0%) for the sensitive GT and the combination test. Sensitivity for detecting advanced colorectal adenomas was 41.3% (95% CI = 32.7% to 50.4%) for the sensitive GT, 29.5% (95% CI = 21.4% to 38.9%) for the FIT, and 22.8% (95% CI =16.1% to 31.3%) for the combination test. Specificity for detecting cancer and adenomas was 98.1% (95% CI = 97.7% to 98.4%) and 98.4% (95% CI = 98.0% to 98.7%), respectively, for the combination test; 96.9% (95% CI = 96.4% to 97.4%) and 97.3% (95% CI = 96.8% to 97.7%), respectively, for the FIT; and 90.1% (95% CI = 89.3% to 90.8%) and 90.6% (95% CI = 89.8% to 91.4%), respectively, for the sensitive GT.The FIT has high sensitivity and specificity for detecting left-sided colorectal cancer, and it may be a useful replacement for the GT.
Lidocaine and Sinus Standstill
Authors: Tsung O. Cheng
Journal: JAMA (1983)

<h3>To the Editor.—</h3> I read the recent letter entitled "Sinus Standstill Following Lidocaine Administration" by Antonelli and Bloch (1982;248:827). Although the authors stated that "lidocaine does not depress the sinus node at the conventional therapeutic dose," we reported in 1973 the first instance of sinus standstill after intravenous lidocaine administration inThe Journal.<sup>1</sup>Our patient received the conventional therapeutic doses of lidocaine, experienced sinus standstill, and died. She did not have sick sinus syndrome or receive either quinidine or phenytoin at the time. Therefore, we advocate great care in administering this drug, even at doses within the recommended therapeutic ranges.
Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the San Francisco Bay Area
Authors: Gayle C. Windham, Lixia Zhang, Robert Gunier, Lisa A. Croen, Judith K. Grether
Journal: Environmental Health Perspectives (2006)

ObjectiveTo explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency.MethodsSubjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors.ResultsThe adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs), 1.1–2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7; 95% CI, 1.0–3.0; third quartile = 1.95; 95% CI, 1.2–3.1). The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride.ConclusionsOur results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies.
Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial
Authors: Lorenz von Seidlein, Paul Milligan, Margaret Pinder, Kalifa Bojang, Chukwudi Anyalebechi, Roland Gosling, Rosalind Coleman, Justin Ifeanyichukwu Ude, Abubakar Sadiq, Manoj Duraisingh, David Warhurst, Ali Alloueche, Geoffrey Targett, Keith McAdam, Brian Greenwood, Gijs Walraven, Piero Olliaro, Tom Doherty
Journal: The Lancet (2000)
Dietary Sugar and Body Weight: Have We Reached a Crisis in the Epidemic of Obesity and Diabetes?
Authors: Richard Kahn, John L. Sievenpiper
Journal: Diabetes Care (2014)

In the preceding point narrative, Drs. Bray and Popkin provide their opinion and review data that suggest to them that we need to reconsider the consumption of dietary sugar based on the growing concern of obesity and type 2 diabetes. In the counterpoint narrative below, we argue that there is no clear or convincing evidence that any dietary or added sugar has a unique or detrimental impact relative to any other source of calories on the development of obesity or diabetes. Sugar is purely a highly palatable source of energy; because it has no other property that appears to contribute to our nutritional well-being, it is not an essential food for most of us. For those who wish to reduce energy consumption, ingesting less sugar is a good place to start. However, doing so does not automatically portend any clinical benefit.
Small for Gestational Age: Short Stature and Beyond
Authors: Paul Saenger, Paul Czernichow, Ieuan Hughes, Edward O. Reiter
Journal: Endocrine Reviews (2007)

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.
INFLAMMATORY ANGIOMATOUS NODULES WITH ABNORMAL BLOOD VESSELS OCCURRING ABOUT THE EARS AND SCALP (PSEUDO OR ATYPICAL PYOGENIC GRANULOMA)
Authors: EDWARD WILSON JONES, STANLEY S. BLEEHEN
Journal: British Journal of Dermatology (1969)

SUMMARY.— Persistent angiomatous nodules and plaques about the ears and scalp with distinctive histological features are described. Of the 12 women and 2 men affected, 9 showed involvement of the external auditory meatus, the pinna or the retroauricular fold. Three patients presented with lesions in the occipital region and solitary nodules affecting the nasolabial fold and forehead occurred in 2 patients. Eight patients had multiple lesions with bleeding and pruritus as the main symptoms. Several recurred after removal. The characteristic histological features were the presence of abnormal hypertrophied capillaries with greatly swollen endothelial cells and an associated lympho-histiocytic and eosinophil infiltrate. The abnormal endothelial cells showed absent or greatly diminished alkaline phosphatase activity, but enhanced reactions were obtained to certain hydrolytic and oxidative enzymes as compared to normal capillary endothelium. Pseudopyogenic granuloma appears to be an entirely benign reactive condition. Its relationship to ordinary pyogenic granuloma and to subcutaneous angiolymphoid hyperplasia with eosinophilia is discussed.
Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial
Authors: Moses Laman, Brioni R. Moore, John M. Benjamin, Gumul Yadi, Cathy Bona, Jonathan Warrel, Johanna H. Kattenberg, Tamarah Koleala, Laurens Manning, Bernadine Kasian, Leanne J. Robinson, Naomi Sambale, Lina Lorry, Stephan Karl, Wendy A. Davis, Anna Rosanas-Urgell, Ivo Mueller, Peter M. Siba, Inoni Betuela, Timothy M. E. Davis
Journal: PLoS Medicine (2014)

In a randomized controlled trial Tim Davis and colleagues investigate Artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of P. falciparum and P. vivax malaria. Please see later in the article for the Editors' Summary
Randomized Phase II Trial of First-Line Treatment With Sorafenib Versus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma
Authors: Bernard Escudier, Cezary Szczylik, Thomas E. Hutson, Tomasz Demkow, Michael Staehler, Frédéric Rolland, Sylvie Negrier, Nicole Laferriere, Urban J. Scheuring, David Cella, Sonalee Shah, Ronald M. Bukowski
Journal: Journal of Clinical Oncology (2009)

An open-label, phase II study to evaluate progression-free survival (PFS), overall best response, adverse events (AEs), and patient-reported outcomes with sorafenib versus interferon alfa-2a (IFN-alpha-2a) in patients with untreated, advanced renal cancer.A total of 189 patients were randomly assigned to oral sorafenib 400 mg twice daily or to subcutaneous IFN-alpha-2a 9 million U three times weekly (period 1). Sorafenib patients who progressed were dose-escalated to 600 mg twice daily; IFN-alpha-2a patients who progressed were switched to sorafenib 400 mg twice daily (period 2).In period 1 PFS was similar for sorafenib-treated (n = 97; 5.7 months) and IFN-alpha-2a-treated patients (n = 92; 5.6 months); more sorafenib-treated patients had tumor shrinkage (68.2% v 39.0%). Common drug-related AEs (Grades > or = 3) for sorafenib were hand-foot skin reaction (11.3%), diarrhea (6.2%), and rash/desquamation (6.2%); for IFN-alpha-2a, these were fatigue (10.0%), nausea (3.3%), flu-like syndrome (2.2%), and anorexia (2.2%). Sorafenib-treated patients reported fewer symptoms, better quality of life (QOL), and greater treatment satisfaction. In period 2, 41.9% of patients who received sorafenib 600 mg twice daily (n = 43) experienced tumor reduction (median PFS, 3.6 months). After the switch to sorafenib 400 mg twice daily, tumors were reduced in 76.2% of 50 patients (median PFS, 5.3 months). AEs were mostly grade 1 to 2; no increase in AEs of grades > or = 3 occurred after sorafenib dose escalation.In this study, sorafenib resulted in similar PFS as IFN-alpha-2a in patients with untreated RCC. However, sorafenib-treated patients experienced greater rates of tumor size reduction, better QOL, and improved tolerability. Both dose escalation of sorafenib after progression and a switch to sorafenib after progression on IFN-alpha-2a resulted in clinical benefit.
Exercise-induced upward shift of diastolic left ventricular pressure-volume relation in patients with dilated cardiomyopathy. Effects of beta-adrenoceptor blockade.
Authors: H Sato, M Hori, H Ozaki, H Yokoyama, K Imai, M Morikawa, H Takeda, M Inoue, T Kamada
Journal: Circulation (1993)

BACKGROUND The effectiveness of beta-blocker therapy for dilated cardiomyopathy (DCM) may be attributed to the inhibition of detrimental effects on the failing heart of sympathetic stimulation during exertion. However, the harmful effects of activity as well as the protective effects of beta-blockers have not been demonstrated. Diastolic ventricular function is known to be sensitive to transient myocardial metabolic insult. In this study, we investigated the effect of modest exercise with or without beta-blockade on the diastolic left ventricular pressure-volume (P-V) relation in patients with DCM. METHODS AND RESULTS The diastolic left ventricular P-V relation was obtained by high-fidelity pressure measurements and digital subtraction left ventriculography at rest and immediately after modest supine bicycle exercise in 12 patients with DCM. The effects of intravenous administration of 0.1 mg/kg propranolol on resting and exercise P-V relations were studied. The end-diastolic and lowest left ventricular pressures were significantly elevated by exercise (20 +/- 9 to 32 +/- 13 mm Hg, P &lt; .01, and 12 +/- 6 to 21 +/- 11 mm Hg, P &lt; .01, respectively) despite insignificant changes in left ventricular volumes. The administration of propranolol did not alter the resting diastolic P-V relation. However, propranolol significantly attenuated the exercise-induced upward shift of the diastolic P-V relation despite a significant increase in end-diastolic volume. The significant upward shift and attenuation by propranolol were also observed even when the left ventricular pressure was corrected by the subtraction of right atrial pressure. CONCLUSIONS These results indicate that even modest exercise exerts detrimental effects on diastolic left ventricular function of the failing heart through beta-adrenergic stimulation. The clinical effectiveness of beta-blocker therapy in patients with DCM can be attributed in part to the inhibition of detrimental myocardial effects of sympathetic stimulation during daily activity.
Phase I Clinical and Pharmacokinetic Study of Kahalalide F in Patients with Advanced Androgen Refractory Prostate Cancer
Authors: Jeany M. Rademaker-Lakhai, Simon Horenblas, Willem Meinhardt, Ellen Stokvis, Theo M. de Reijke, José M. Jimeno, Luis Lopez-Lazaro, José A. Lopez Martin, Jos H. Beijnen, Jan H.M. Schellens
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid–containing peptide isolated from the marine herbivorous mollusk, Elysia rufescens. Experimental Design: Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 μg per m2 per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer. Results: Thirty-two patients were treated at nine dose levels (20-930 μg per m2 per day). The maximum tolerated dose on this schedule was 930 μg per m2 per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 μg per m2 per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t1/2) of 0.47 hour (0.11 hour). One patient at dose level 80 μg per m2 per day had a partial response with a prostate-specific antigen decline by at least 50% for ≥4 weeks. Five patients showed stable disease. Conclusions: KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 μg per m2 per day once every 3 weeks.