tbuckley/cabot-search huggingface dataset:
Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports
Authors: Einar S. Björnsson, Jay H. Hoofnagle
Journal: Hepatology (2015)

An important element in assessing causality in drug-induced liver injury is whether the implicated agent is known to cause hepatotoxicity. We classified drugs into categories based on the number of published reports of convincingly documented, clinically apparent, idiosyncratic liver injury. Drugs described in the website LiverTox (http://livertox.nih.gov) were classified into five categories based on the number of published cases (category A, ≥50; category B, 12-49; category C, 4-11; category D, 1-3; category E, none). Case reports in categories C and D were individually reanalyzed using the Roussel Uclaf Causality Assessment Method. Drugs with fatal cases or with rechallenge were noted. Among 671 individual drugs or closely related agents, 353 (53%) were considered convincingly linked to liver injury in published case reports; 48 (13%) were assigned to category A, 76 (22%) were assigned to category B, 96 (27%) were assigned to category C, and 126 (36%) were assigned to category D. Another 7 (2%) were direct hepatotoxins but only in high doses and placed in a separate category (T). The remaining 318 (47%) drugs had no convincing case report of hepatoxicity in the literature (category E). All except one in category A have been available since 1999, 98% had at least one fatal case and 89% a positive rechallenge. In category B, 54% had a fatal case and 41% a rechallenge. Drugs in categories C and D less frequently had instances of fatal (23% and 7%) or rechallenge cases (26% and 11%).Documentation of hepatoxicity in the medical literature is variable, and many published instances do not stand up to critical review. A standardized system for categorizing drugs for hepatotoxicity potential will help develop objective and reliable, computer-based instruments for assessing causality in drug-induced liver injury.
Recovery of Moloney Murine Sarcoma Virus Added to Bovine Milk&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Charles L. Burger, C. Craig Chamberlain, Marilyn C. Barstow, Bernard C. Maher
Journal: JNCI Journal of the National Cancer Institute (1971)

Bovine milk with added murine sarcoma virus (Moloney) was processed by continuous flow centrifugation (CF) followed by either isopycnic banding in sucrose or direct pelleting of density fractions from CF of 1.08–1.17 glcc. Total dilution of virus sample was 2.7 logs. Viral recovery was tested in a tissue culture system by focus assay. Within the limits of the system, all virus was recovered. The experiment demonstrated that the techniques do not inactivate the virus or lower its titer. It also suggested that the failure earlier to detect a biologically active viral leukemic agent in bovine milk could have been due, among other factors, to a low-resolution testing system, to an agent normally inactivated by longer exposure to milk, or to the presence of an agent of a defective type, and that the finding of such leukemia virus at any point in time may be fortuitous. Periodic samplings of animals during the course of disease are suggested for the search of a leukemia virus in cattle. Processing of large volumes of fluids by CF may be used to concentrate by a minimum of 2.7 logs.
B-Cell Maturation Stages of Burkitt's Lymphoma Cell Lines According to Epstein-Barr Virus Status and Type of Chromosome Translocation&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Jacques H. M. Cohen, Jean-Pierre Revillard, Jean-Pierre Magaud, Gilbert Lenoir, Michelle Vuillaume, Anne-Marie Manel, Claude Vincent, Paul-André Bryon
Journal: JNCI Journal of the National Cancer Institute (1987)

This study addressed the possible relationship between B-cell maturation stage of Burkitt's lymphoma (BL) cell lines and Epstein-Barr virus (EBV) status, ethnic group, or type of chromosome translocation. Fifty-seven cell lines obtained at the International Agency for Research on Cancer from 51 patients were studied. Cytogenetic analyses of 54 cell lines were available. Cell size, surface immunoglobulins (slgs), cytoplasmic immunoglobulins (clgs), mouse red blood cell receptors, and reactivity with various monoclonal antibodies were assessed. Immunoglobulin (lg) class secretions were measured in the supernatant of 2-and 5-day cultures from 33 cell lines, with the use of a sensitive enzyme-linked immunosorbent assay technique. From this study, BL appears to cover a broad range of the B-cell differentiation sequence, since the following Ig phenotypes were observed: null cells (slg−, clg−), large pre-B-cells (intracytoplasmic μ-chains), small B-cells (slg+, clg−), and various types of secreting B-cells (slg+, clg+). Among the latter, various patterns of clg could be defined (perinuclear, paranuclear, and vesicular). B-cell maturation stages were correlated with the amount of secreted Ig. In slg+ cell lines, different classes of Ig were found: 35 IgM, 10 IgM plus IgD, 4 IgG, and 1 IgA. None of the different monoclonal antibodies used was specific to a precise stage of maturation. The stages of maturation were correlated with neither the type of chromosome translocations of BL nor the presence of EBV genome, but the most immature cell lines were all EBV positive and most of them originated from African patients. In contrast with acute lymphoblastic leukemia, the common acute lymphocytic leukemia antigen (CD10) was expressed on nearly all BL cell lines of intermediate maturation stages but only on half of the pre-B ones. In addition, none of the cell lines tested was found to react with CD5 antibodies, which recognize most of the chronic lymphocytic leukemia of the same stage of maturation as that in the B-lymphocyte lineage.
Neuropharmacology of quinolinic and kynurenic acids.
Authors: T W Stone
Journal: Pharmacological Reviews (1993)

In a little more than 10 years, the kynurenine metabolites of tryptophan have emerged from their former position as biochemical curiosities, to occupy a prominent position in research on the causes and treatment of several major CNS disorders. The pathway includes two compounds, quinolinic acid and kynurenic acid, which are remarkably specific in their pharmacological profiles: one is a selective agonist at receptors sensitive to NMDA, whereas the other is a selective antagonist at low concentrations at the strychnine-resistant glycine modulatory site associated with the NMDA receptor. It has been argued that these agents cannot be of physiological or pathological relevance because their normal extracellular concentrations, in the nanomolar range, are at least 3 orders of magnitude lower than those required to act at NMDA receptors. This is a facile argument, however, that ignores at least two possibilities. One is that both quinolinate and kynurenate may be present in very high concentrations locally at some sites in the brain that cannot be reflected in mean extracellular levels. Similar considerations apply to many neuroactive agents in the CNS. The fact that both compounds appear to be synthesised in, and thus emerge from, glial cells that are well recognised as enjoying a close physical and chemical relationship with some neurones in which the intercellular space may be severely restricted may support such a view. Certainly the realisation that NMDA receptors may not be fully saturated functionally with glycine would be consistent with the possibility that even quite low concentrations of kynurenate could maintain a partial antagonism at the glycine receptor. A second possibility is that there may be a subpopulation of NMDA receptors (or, indeed, for a quite different amino acid) that possesses a glycine modulatory site with a much lower sensitivity to glycine or higher sensitivity to kynurenate, making it more susceptible to fluctuations of endogenous kynurenine levels. Whatever the specific nature of their physiological roles, the presence of an endogenous selective agonist and antagonist acting at NMDA receptors must continue to present exciting possibilities for understanding the pathological basis of several CNS disorders as well as developing new therapeutic approaches. An imbalance in the production or removal of either of these substances would be expected to have profound implications for brain function, especially if that imbalance were present chronically.(ABSTRACT TRUNCATED AT 400 WORDS)
Clinical outcome of critically ill, not fully recompensated, patients undergoing <scp>MitraClip</scp> therapy
Authors: Volker Rudolph, Michael Huntgeburth, Ralph Stephan von Bardeleben, Peter Boekstegers, Edith Lubos, Wolfgang Schillinger, Taoufik Ouarrak, Holger Eggebrecht, Christian Butter, Björn Plicht, Andreas May, Olaf Franzen, Joachim Schofer, Jochen Senges, Stephan Baldus
Journal: European Journal of Heart Failure (2014)
Socioeconomical impact of surgical treatment of empyema in adults
Authors: Ioannis Karampinis, Stamatios Kakaris, Anna Dalipi, Dionissios Triantafillou, Christoforos Foroulis, Konstantinos Triantafillou
Journal: European Respiratory Journal (2013)

- INTRODUCTION: Early thoracotomy and decortication is safe and efficient in the treatment of empyema thoracis in adults. However, the socioeconomical impact of this procedure is still vague - OBJECTIVES: To assess ,the socioeconomical impact of surgical treatment for empyema in adults. - METHODS: Prospectively reviewed 53 patients surgically treated for empyema during 2009-2011 in our centre. All patients underwent chest Xrays,pulse oximetry, spirometry and completed the SF-36v2TM Health Survey Score Questionnaire before surgery and at day 7 ,90 and 180 after that. Quality of life, work attendance and health insurance records were followed up during the same intervals and clinical follow up was performed. SPSSv12.0 was used for statistical analysis. - RESULTS: Patients: 12 females and 41 males (mean age 58.9 years, range 18-65 years). Mean duration of procedure was 68 min (range 50-195 min). No procedure associated complications or deaths recorded. Duration of presenting symptoms prior to surgical treatment and clinical severity upon presentation were associated with a deprived quality of social life for 6 months post surgery (p=0.03), signs of depression (p=0.04) and increased rates of sick leave (p=0.04). Clinical status post surgery significantly improved(p=0.02). Mean duration of sick leave: 33 days for white and 50 days for blue collar workers, not significantly affecting their earnings (p> 0.05). - CONCLUSIONS: Complicated empyema thoracis requiring surgical treatment :per se a debilitating clinical entity,with significant impact in quality of life with many professional and social implications.
Abstract P251: Epigenome-Wide Study of Erythrocyte Fatty Acids in the Genetics of Lipid Lowering Drugs and Diet Network
Authors: Stella Aslibekyan, Bertha Hidalgo, Marguerite M Irvin, Jin Sha, Hemant K Tiwari, Degui Zhi, Jose M Ordovas, Devin M Absher, Donna K Arnett
Journal: Circulation (2014)

Introduction: Dietary fatty acids have a role in many physiological mechanisms that influence cardiovascular health. An emerging body of evidence suggests that dietary fats may interact with genetic variants in regulating tissue levels of fatty acids, thus impacting disease risk. Epigenetic changes such as DNA methylation are a promising mechanism underlying such interactions. However, no studies to date have investigated the relationship between DNA methylation and tissue fatty acids at the genome-wide level. Methods: We have performed the first epigenome-wide association study (EWAS) of erythrocyte concentrations of polyunsaturated, monounsaturated, saturated, and trans fatty acids in 958 participants of the Genetics of Diet and Lipid Lowering Drugs Network (GOLDN). We assayed the methylation status of approximately 450,000 CpG sites in CD4+ T-cells. To investigate the associations between methylation of each CpG site and red blood cell fatty acids, we fit linear mixed models adjusted for age, sex, cell purity, and family structure. Results: The strongest association was observed between the methylation status of a CpG site in PDE4D, previously linked to systemic inflammation and stroke, and red blood cell trans fatty acids (P=4x10-7). In the analysis of polyunsaturated fatty acids, we found inverse associations with the methylation status of two CpG sites in BRSK2 (P=9x10-6 and P=1x10-5 respectively), as well as with a CpG site located in a “gene desert” on chromosome 14 proximally to VRK1 (P=5x10-7). BRSK2 encodes a kinase previously shown to control epigenetic programs that determine T-cell function. The top hits for monounsaturated and saturated fatty acids were located in ATL2 (P=1x10-6) and FGD2 (P=1x10-5), respectively. Conclusions: We present preliminary evidence of cross-sectional association between the methylation status of several biologically relevant genomic regions and erythrocyte concentrations of polyunsaturated, trans, monounsaturated, and saturated fatty acids. Upon successful validation, these findings further current understanding of gene-fatty acid interactions in human health and disease.
Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates
Authors: Nolan J. Hoffman, Benjamin L. Parker, Rima Chaudhuri, Kelsey H. Fisher-Wellman, Maximilian Kleinert, Sean J. Humphrey, Pengyi Yang, Mira Holliday, Sophie Trefely, Daniel J. Fazakerley, Jacqueline Stöckli, James G. Burchfield, Thomas E. Jensen, Raja Jothi, Bente Kiens, Jørgen F.P. Wojtaszewski, Erik A. Richter, David E. James
Journal: Cell Metabolism (2015)
Estimation of chest-wall mechanics by laser self mixing interferometer
Authors: Ilaria Milesi, Emanuela Zannin, Peter Kostic, Michele Norgia, Chiara Veneroni, Antonio Pedotti, Peter Frykholm, Raffaele Dellacà
Journal: European Respiratory Journal (2012)

BACKGROUND: Several studies demonstrated that the chest wall (CW) may be split into at least two compartments (rib cage and abdomen) characterized by spatial distribution inhomogeneities in CW mechanics. Up to now, it has been assessed by means of complex technique such as Optoelectronic Plethysmography (OEP). We have developed a CW scanning system (CWSS) based on self-mixing laser interferometers that allows measuring relative displacement contactless with high spatial resolution (<1 μm) in an economical and easy to use way.

METHODS: five healthy subjects, in supine position, were analyzed while submitted to a sinusoidal pressure forcing at the mouth with components at 5, 11 and 19 Hz. Displacement of several points on their CW has been measured with the CWSS and phase shift among these points and the pressure stimulus was estimated by spectral analysis.

RESULTS: The impedance averaged maps in the figure below show high spatial inhomogeneities, in particular one may appreciate that at 5 Hz it is possible to identify the region of the rib cage, where the pressure stimulus moves fast, and the abdomen where the pressure wave is slowed down by the high inertive component. This trend tends to be less marked as the frequency increased, indeed at 19 Hz, we can still see heterogeneity, but the phase shift tends to get similar to a line. In the figure the phase shift color map is reported.

![Figure][1]  [1]: pending:yes
Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway
Authors: Diane M. Duffy
Journal: Human Reproduction Update (2015)

Prostaglandin E2 (PGE2) is an essential intrafollicular regulator of ovulation. In contrast with the one-gene, one-protein concept for synthesis of peptide signaling molecules, production and metabolism of bioactive PGE2 requires controlled expression of many proteins, correct subcellular localization of enzymes, coordinated PGE2 synthesis and metabolism, and prostaglandin transport in and out of cells to facilitate PGE2 action and degradation. Elevated intrafollicular PGE2 is required for successful ovulation, so disruption of PGE2 synthesis, metabolism or transport may yield effective contraceptive strategies. This review summarizes case reports and studies on ovulation inhibition in women and macaques treated with cyclooxygenase inhibitors published from 1987 to 2014. These findings are discussed in the context of studies describing levels of mRNA, protein, and activity of prostaglandin synthesis and metabolic enzymes as well as prostaglandin transporters in ovarian cells. The ovulatory surge of LH regulates the expression of each component of the PGE2 synthesis-metabolism-transport pathway within the ovulatory follicle. Data from primary ovarian cells and cancer cell lines suggest that enzymes and transporters can cooperate to optimize bioactive PGE2 levels. Elevated intrafollicular PGE2 mediates key ovulatory events including cumulus expansion, follicle rupture and oocyte release. Inhibitors of the prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme (also known as cyclooxygenase-2 or COX2) reduce ovulation rates in women. Studies in macaques show that PTGS2 inhibitors can reduce the rates of cumulus expansion, oocyte release, follicle rupture, oocyte nuclear maturation and fertilization. A PTGS2 inhibitor reduced pregnancy rates in breeding macaques when administered to simulate emergency contraception. However, PTGS2 inhibition did not prevent pregnancy in monkeys when administered to simulate monthly contraceptive use. PTGS2 inhibitors alone may be suitable for use as emergency contraceptives. However, drugs of this class are unlikely to be effective as monthly contraceptives. Inhibitors of additional PGE2 synthesis enzymes or modulation of PGE2 metabolism or transport also hold potential for reducing follicular PGE2 and preventing ovulation. Approaches which target multiple components of the PGE2 synthesis-metabolism-transport pathway may be required to effectively block ovulation and lead to the development of novel contraceptive options for women. Therapies which target PGE2 may also impact disorders of the uterus and could also have benefits for women's health in addition to contraception.
Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma
Authors: R. Motley, P. Kersey, C. Lawrence
Journal: British Journal of Dermatology (2002)

Summary These guidelines for management of primary cutaneous squamous cell carcinoma present evidence‐based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
Increased risk of obstructive sleep apnoea in patients with non-alcoholic fatty liver disease
Authors: Sarah Wiscombe, Julia Newton, Chris Day, John Gibson, Sophie West
Journal: European Respiratory Journal (2012)

Background:  Increasing prevalence of Obstructive Sleep Apnoea (OSA) and Non-alcoholic Fatty Liver Disease (NAFLD) are linked through the epidemic of obesity and metabolic syndrome. Patients with NAFLD often present with fatigue and daytime sleepiness and it has been postulated that intermittent hypoxia in OSA may accelerate liver cirrhosis in this group.  Aims:  We hypothesised that OSA would be prevalent in patients with NAFLD. We aimed to determine whether those with OSA had different clinical or biochemical characteristics to the rest of the cohort.  Methods:  We conducted a retrospective database and case note review of patients with known NAFLD. The database was reviewed for detailed liver investigations and notes examined for any clinical referral for sleep investigations and outcome.  Results:  Liver database and case notes of 385 patients with biopsy proven NAFLD were examined. Forty-seven patients were referred to sleep services on clinical grounds (12%); 38 were found to have OSA, 10% of the whole cohort but 86% of those referred. Analysis of variance showed no difference between groups (those with OSA, those without OSA and those with no previous sleep investigations) in: baseline liver function, diabetes, body mass index, liver biopsy scores or any other marker of metabolic syndrome. Patients referred for sleep studies had higher ESS than those not referred (mean 13 vs.7, p=0.004) but there was no difference in ESS between those with or without OSA.  Conclusions:  In a well-defined population of biopsy-proven NAFLD patients, OSA is common and mostly undiagnosed. There are no differences in the clinical characteristics of those referred for sleep studies and those not, other than ESS.
Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study.
Authors: S Rodenhuis, L Boerrigter, B Top, R J Slebos, W J Mooi, L van't Veer, N van Zandwijk
Journal: Journal of Clinical Oncology (1997)

To determine whether the clinical course and the response to chemotherapy of patients with advanced adenocarcinoma of the lung depends on the presence or absence of a ras mutation in the tumor. Mutational activation of K-ras is a strong adverse prognostic factor in stage I or II lung cancer and laboratory studies have suggested that ras mutations lead to resistance against ionizing radiation and chemotherapy.Patients with advanced adenocarcinoma of the lung with measurable or assessable disease received chemotherapy with mesna, ifosfamide, carboplatin, and etoposide (MICE). Archival biopsies, fresh biopsies, or fine-needle aspirations were tested for the presence of ras gene mutations. Associations of ras mutations with clinical characteristics, response to chemotherapy, and survival were studied.The presence or absence of ras gene mutations could be established in 69 of 83 patients (83%). A total of 261 courses of MICE were administered to 62 informative patients, 16 of whom were shown to have a K-ras mutation-positive tumor. The frequency of mutations (26%) and the type of mutations closely matched the pattern we have previously reported in operable disease. Patients with a ras mutation in their tumor were more likely to have a close relative with lung cancer, but other clinical characteristics, such as pattern of metastases, response, and survival, were similar between the ras mutation-positive and ras mutation-negative groups.Patients with advanced lung adenocarcinoma who harbor a ras mutation may have major responses to chemotherapy and have similar progression-free and overall survival as patients with ras mutation-negative tumors. K-ras mutations may represent one of several ways in which early tumors are enabled to metastasize to distant sites.