tbuckley/cabot-search huggingface dataset:
Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection
Authors: Karen Fitzmaurice, Jacob Hurst, Megan Dring, Andri Rauch, Paul J McLaren, Huldrych F Günthard, Clair Gardiner, Paul Klenerman
Journal: Gut (2014)

<h3>Background</h3> Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the <i>IFNL3</i> (<i>IL28B</i>) gene are strongly associated with spontaneous clearance and treatment outcomes. <h3>Objective</h3> This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes <i>IFNL3</i> and <i>KIR2DS3</i>. <h3>Design</h3> We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of <i>IFNL3</i>-linked polymorphisms is profound. <h3>Results</h3> Logistic regression was performed on data from the Irish cohort, and indicates that the <i>HLA</i>-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=&lt;0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC <i>IFNL3</i> rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p&lt;0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), <i>KIR2DS3</i> (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 <i>IFNL3</i> 'T' allele are associated with chronic infection. This study finds no interactive effect between <i>IFNL3</i> and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of <i>HLA</i> Class I, II and <i>IFNL3</i> genes in their prediction of viral outcome. <h3>Conclusions</h3> This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.
Effects of treatment with a fully human anti-tumour necrosis factor alpha monoclonal antibody on the local and systemic homeostasis of interleukin 1 and TNFalpha in patients with rheumatoid arthritis
Authors: P Barrera
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVES</h3> To study the short term effects of a single dose of D2E7, a fully human anti-tumour necrosis factor (TNFα) monoclonal antibody (mAb), on the local and systemic homeostasis of interleukin 1β (IL1β) and TNFα in patients with rheumatoid arthritis (RA). <h3>METHODS</h3> All patients with RA enrolled in a phase I, single dose, placebo controlled study with D2E7 in our centre were studied. Systemic cytokine levels, acute phase reactants, and leucocyte counts were studied at days 0, 1, and 14 after the first administration of anti-TNF mAb (n=39) or placebo (n=11). The cellularity and the expression of IL1 and TNFα in synovial tissue were studied in knee biopsy specimens obtained at baseline and at day 14 in 25 consenting patients. <h3>RESULTS</h3> A single dose of anti-TNF mAb induced a rapid clinical improvement, a decrease in acute phase reaction, and increased lymphocyte counts in patients with active RA. The protein levels of IL1β in the circulation were low and remained unchanged, but the systemic levels of IL1β mRNA (p=0.002) and the concentrations of IL1 receptor antagonist (IL1ra) and IL6 (p=0.0001) had already dropped within 24 hours and this persisted up to day 14. Systemic levels of TNFα mRNA were low and remained unchanged, though total TNFα (free and bound) in the circulation increased after D2E7, probably reflecting the presence of TNF-antiTNF mAb complexes (p&lt;0.005, at days 1 and 14). Both TNF receptors dropped below baseline levels at day 14 (p&lt;0.005). Despite clinical improvement of arthritis, no consistent immunohistological changes were seen two weeks after anti-TNF administration. Endothelial staining for IL1β tended to decrease in treated patients (p=0.06) but not in responders. The staining for IL1β and TNFα in sublining layers and vessels was mutually correlated (<i>r<sub>s</sub></i>=0.47 and 0.58 respectively, p&lt;0.0005) and the microscopic scores for inflammation correlated with sublining TNFα and IL1β scores (<i>r<sub>s</sub></i>=0.65 and 0.54 respectively, p&lt;0.0001), though none of these showed significant changes during the study. <h3>CONCLUSIONS</h3> Blocking TNFα in RA results in down regulation of IL1β mRNA at the systemic level and in reduction of the endogenous antagonists for IL1 and TNF and of other cytokines related to the acute phase response, such as IL6, within days. At the synovial level, anti-TNF treatment does not modulate IL1β and TNFα in the short term. The synovial expression of these cytokines does not reflect clinical response to TNF neutralisation.
Impaired portal circulation resulting from L-arginine deficiency in patients with lysinuric protein intolerance
Authors: T Takeda
Journal: Gut (2006)

Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of the dibasic amino acid transporter, which is caused by mutations in the SLC7A7 gene and results in L-arginine deficiency.1 L-arginine is the only known substrate for nitric oxide (NO) production,2 and thus the availability of L-arginine is crucial for regulation of NO production.3 NO is an endothelium derived vascular relaxation factor that plays an important role in vascular endothelial function.4–6 However, the effects of L-arginine deficiency on portal circulation in humans have not been studied.

Portal circulation was evaluated in seven Japanese LPI patients (six males). Seven healthy subjects (six males) without liver disease served as controls. The study was approved by the ethics committee of our university. Mean age of the LPI patients was 18.9 (10.7) years (range 5–32) and that of the controls …
The clinical course of health status and association with outcomes in patients hospitalized for heart failure: insights from ASCEND‐HF
Authors: Andrew P. Ambrosy, Adrian F. Hernandez, Paul W. Armstrong, Javed Butler, Allison Dunning, Justin A. Ezekowitz, G. Michael Felker, Stephen J. Greene, Padma Kaul, John J. McMurray, Marco Metra, Christopher M. O'Connor, Shelby D. Reed, Phillip J. Schulte, Randall C. Starling, W.H. Wilson Tang, Adriaan A. Voors, Robert J. Mentz
Journal: European Journal of Heart Failure (2015)
AUTOGENOUS IMMUNITY TO ENDOGENOUS RNA TUMOR VIRUS
Authors: J. N. Ihle, M. Yurconic, M. G. Hanna
Journal: The Journal of Experimental Medicine (1973)

The radioimmune precipitation assay using (3)H-labeled AKR leukemia virus was applied to the detection and quantitation of natural serum antibodies directed against endogenous murine leukemia virus (MuLV) envelope antigens B6C3F(1) and BALB/c mice, which have low natural incidences of leukemia and lymphoma, and AKR mice, which have a high incidence, were used in this study. Sera from mice of various age groups were assayed. A marked difference in age-associated levels of the autogenous immune response to endogenous murine leukemia virus was detected, and the quantitative differences among these strains were inversely related to the incidence of lymphoma. The radioimmune precipitation test as applied was 500 times more sensitive than virus neutralization. That the reactions we have observed are specific is suggested by several lines of evidence, including the nonreactivity of normal hamster and absorbed rat serum, the positive reaction of absorbed rat anti-AKR serum, the inhibition of precipitation of labeled virus by purified unlabeled virus, and isopycnic gradient analysis of the reactive products.
PTU-047 The clinical utility and cost-effectiveness of non-invasive tests for detecting fibrosis in patients with suspected alcohol-related liver disease
Authors: M Y Morgan, M D Stevenson, M Lloyd Jones
Journal: Gut (2012)

<h3>Introduction</h3> The use of non-invasive liver tests (NILTs) for assessing hepatic fibrosis carries fewer risks than liver biopsy. However, their clinical utility and cost-effectiveness, in patients with suspected alcohol-related liver disease, are unknown. This study explored whether the Enhanced Liver Fibrosis (ELF) test, FibroTest, and FibroScan are likely to be cost-effective in a UK setting. <h3>Methods</h3> Systematic reviews of the clinical effectiveness of the three NILTs under study and of the morbidity/mortality associated with liver biopsy were undertaken and used, where possible, to populate a mathematical model constructed to simulate the experience of patients suspected of having alcohol-related liver injury. The model used the following strategies: (1) biopsy all; (2) use a NILT for triage and biopsy more selectively; and (3) use a NILT alone to determine diagnosis and subsequent management. Thirty-six separate scenarios were evaluated varying the type and sensitivity of the liver biopsy, the accuracy of the non-invasive tests, and the disutility associated with the biopsy procedure. <h3>Results</h3> No clear conclusions could be drawn, following the systematic reviews, about the accuracy of these three NILTs in the diagnosis of alcohol-related liver disease because there was significant heterogeneity in the published studies, particularly in relation to drinking behaviour and diagnostic cut-offs. The assessment was also confounded by the paucity/absence of data on: (1) the sensitivity of the liver biopsy; and (2) the difference in costs and health between abstinent patients and those who continued to drink. There was wide variation in the threshold level for a decrease in abstinence rates using NILTs in both triage and replacement strategies. The maximum threshold value was 6.1 percentage points with the minimum value being zero percentage points. There was also wide variation in the threshold levels for the incidental gains associated with biopsy using NILTs in both triage and replacement strategies. The maximum value was 0.188 QALYs with the minimum value being zero QALYs. <h3>Conclusion</h3> The clinical utility and cost-effectiveness of these three NILTs cannot be assessed, at the present time, primarily because information on the key variables needed to populate the model are lacking. Thus, caution should be exercised in their use, in patients with suspected alcohol-related liver disease, at the present time. <h3>Competing interests</h3> None declared.
Heritage-Specific Mechanisms for Cancer Adverse Reactions: One Gene Does Not Explain the World
Authors: Todd C. Knepper, Howard L. McLeod
Journal: Journal of Clinical Oncology (2015)

One of the challenges in the treatment of cancer is ensuring the safety and efficacy of drugs across all global racial and ethnic populations.Thisdiversityofraceandethnicityisacriticalfactorguidingthe regulatoryapprovalofnewdrugs, 1 butitisalsoimportantthatsimilar rigorous, science-driven standards continue to be upheld for older drugsaswell.Thearticlethataccompaniesthiseditorial,byYangetal, 2 demonstrates the power of genome-wide association across diverse geographic heritages in the quest for better drug safety. Includedamongtheolderdrugsstillinusearemedicinesthatare more than 50 years old. Mercaptopurine (6-MP) remains a critical partofthesuccessfultreatmentofchildhoodleukemia,providinga 2- to 3-year therapeutic backbone that enables the sequential delivery of additional chemotherapy. 3 6-MP is a thiopurine-derivative antimetabolite with antineoplastic and immunosuppressive activity that is an integral component of therapy for acute lymphoblastic leukemia (ALL). The occurrence of severe myelosuppression is a major treatment-interrupting toxicity, with negative impact on survival. Analysis of patients who experienced extreme toxicity while receiving thiopurine therapy led to the discovery that genetic variation in drug metabolism by thiopurine methyltransferase (TPMT) identified significant patient risk. 4 The metabolism of 6-MP involves a diverging pathway that leads to the inactivation through thiol methylation by TPMT into 6-methyl mercaptopurine or conversion to the active 6-thioguanine by hypoxanthine phosphoribosyltransferase. Patients with TPMT deficiency cannot tolerate conventional doses of 6-MP because of excessive accumulation of thioguanine nucleotides and subsequentseveretofatalmyelosuppression. 5 Prospectivegenotyping
Brief Communication: Duration of Platelet Dysfunction after a 7-Day Course of Ibuprofen
Authors: Neil A. Goldenberg, Linda Jacobson, Marilyn J. Manco-Johnson
Journal: Annals of Internal Medicine (2005)

Background: Despite a paucity of evidence, clinicians routinely advise that patients discontinue using nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, at least 1 week before most surgical procedures. Objective: To define the duration of ibuprofen-induced platelet dysfunction. Design: Prospective cohort study. Setting: Denver/Aurora, Colorado. Participants: 11 healthy adult volunteers. Measurements: Individuals were tested at baseline and serially after completion of a 7-day course of ibuprofen (600 mg orally every 8 hours). The platelet function analyzer (PFA-100, Dade Behring, Newark, Delaware), a test that has replaced the bleeding time in many clinical settings, was used. Results: All participants exhibited normal platelet function before starting ibuprofen. Platelet dysfunction was apparent after completion of the ibuprofen course in 7 of the 11 participants and normalized by 24 hours after the last ibuprofen dose. Limitations: The sample size in this study was small, and no participants had a major illness. Correlation between PFA-100 results and clinical bleeding has not been established. Conclusions: Platelet function seems to normalize within 24 hours after cessation of regular ibuprofen use in healthy individuals. Further studies are warranted to provide a rational basis for timing of NSAID withdrawal in a range of patients undergoing surgery.
Associations Between Serum Lipids and Hepatitis C Antiviral Treatment Efficacy†,‡
Authors: Darmendra Ramcharran, Abdus S. Wahed, Hari S. Conjeevaram, Rhobert W. Evans, Tianyi Wang, Steven H. Belle, Leland J. Yee
Journal: Hepatology (2010)

Abstract Approximately one half of patients who undergo antiviral therapy for chronic hepatitis C virus (HCV) genotype 1 infection do not respond to treatment. African Americans (AAs) are less responsive to treatment than Caucasian Americans (CAs), but the reasons for this disparity are largely unknown. Recent studies suggest that serum lipids may be associated with treatment response. The aims of this study were to evaluate baseline and changes in serum lipids during therapy, determine whether serum lipids are associated with virological response, and assess whether these measures explain the racial difference in efficacy. The study participants were from Virahep-C, a prospective study of treatment-naïve patients with genotype 1 HCV infection who received peginterferon (PEG-IN) alfa-2a plus ribavirin therapy for up to 48 weeks. Fasting serum lipids were analyzed at baseline and during and after therapy in 160 AAs and 170 CAs. A relative risk (RR) model was employed to evaluate characteristics associated with sustained virological response (SVR). Antiviral therapy was associated with changes in serum lipids during and after antiviral therapy, with the changes differing by race and the amount of PEG-IFN taken. Baseline lipid measures independently associated with higher rates of SVR were lower triglyceride and higher low-density lipoprotein cholesterol, with an interaction between high-density lipoprotein cholesterol (HDLc) and gender. Lipid measures did not contribute significantly to an explanation of the racial difference in SVR. Conclusion: Serum lipids are associated with SVR, although these paramaters did not explain the racial difference in treatment response. The results of this study are compatible with proposed biological mechanisms of HCV entry, replication, and secretion, and may underscore new potential therapeutic targets for HCV eradication.
CONCUEEENT HERPES ZOSTEE AND VAEICELLA.
Authors: A.C. ROXBURGH, P.H. MARTIN
Journal: British Journal of Dermatology (1926)

Journal Article CONCUEEENT HERPES ZOSTEE AND VAEICELLA. Get access A.C. ROXBURGH, M.D., M.R.C.P., A.C. ROXBURGH, M.D., M.R.C.P. Acting Assistant Physician for Diseases of the Skin, St. Bartholomew's Hospital; Search for other works by this author on: Oxford Academic Google Scholar P.H. MARTIN, B.M., B. Ch P.H. MARTIN, B.M., B. Ch Late House Physician, St. Bartholomew's Hospital Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 38, Issue 7, 1 July 1926, Pages 286–289, https://doi.org/10.1111/j.1365-2133.1926.tb09997.x Published: 01 July 1926
Filterability of mixtures of sickle and normal erythrocytes
Authors: Setsuo Hasegawa, Hiroyuki Hiruma, Nobuhiro Uyesaka, Constance T. Noguchi, Alan N. Schechter, Griffin P. Rodgers
Journal: American Journal of Hematology (1995)

We investigated the deformability of sickle (SS) cells from 25 patients and mixtures of these SS cells with blood type-compatible normal (AA) cells, using a nickel mesh filtration system, with the aim of determining optimal goals for exchange therapy. We found that for air-equilibrated SS/AA cell mixtures the fraction of dense cells (MCHC > 37 g/dl) is the determinant factor in filterability and that the dense cells contribute in a linear fashion to the loss of filtration up to 15% dense cells (y = -4.41x + 98.23, r = 0.945, P < 0.0001). The slope of this effect is approximately 25 times steeper than that of the relationship between filtration and percent nondense (MCHC < 37/g/dl) SS cells (y = -0.17x + 106.53, r = 0.772, P < 0.0001). A comparison of the proportion of high fluorescence reticulocytes to total reticulocytes (HFR ratio), indicating an elevation of immature reticulocytes, between six nontransfused patients and six exchange-transfused patients showed significant higher values in the nontransfused individuals (0.154 +/- 0.051 versus 0.070 +/- 0.054, P < 0.003). These results may have implications regarding targets for exchange transfusion therapy. Further studies of the effect on transfusion, both simple and exchange, on the numbers of dense cells and the proportions and populations of reticulocytes and the rheological characteristics of the erythrocyte subpopulations seems warranted.
HEMORRHAGIC AND ISCHEMIC OUTCOMES FOLLOWING BIVALIRUDIN VS UNFRACTIONATED HEPARIN DURING CAROTID ARTERY STENTING: ANALYSIS FROM THE NCDR(&amp;reg;)
Authors: Siddharth A. Wayangankar, Mazen Abu-Fadel, Herbert Aronow, Kevin Kennedy, Raghav Gupta, William Gray, Kenneth Rosenfield, Thomas Hennebry
Journal: Journal of the American College of Cardiology (2012)
Increased activity of group II phospholipase A<sub>2</sub> in plasma in rat sodium deoxycholate induced acute pancreatitis
Authors: S Furue, Y Hori, K Kuwabara, J Ikeuchi, H Onoyama, M Yamamoto, K Tanaka
Journal: Gut (1997)

Two different types of secretory phospholipase A2 (PLA2), pancreatic group I (PLA2-I) and non-pancreatic group II (PLA2-II), have been identified and postulated to be associated with the pathogenesis of various diseases, such as acute pancreatitis, septic shock, and multiple organ failure.To investigate the type of secretory PLA2 responsible for its catalytic activity found in plasma and ascites of experimental acute pancreatitis.Acute pancreatitis of differing severity was induced by the injection of different concentrations (1% or 10%) of sodium deoxycholate (DCA) into the common biliopancreatic duct in rats, and catalytic PLA2 activity in plasma and ascites were differentiated by anti-PLA2-I antibody and specific inhibitor of PLA2-II. Survival rate and plasma amylase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were also measured.In 1% and 10% DCA induced acute pancreatitis, plasma amylase values as well as PLA2 activity in ascites were greatly increased. PLA2 activity in plasma was also notably increased in 10% DCA induced acute pancreatitis, but not in 1% DCA induced acute pancreatitis. PLA2-I specific polyclonal antibody significantly inhibited PLA2 activity in ascites but not that in plasma. In contrast, plasma PLA2 activity was completely suppressed by PLA2-II specific inhibitor. In addition, a high mortality (93% at five hours) and a significant increase in plasma AST and ALT were noted in 10% DCA induced pancreatitis.Ascites PLA2 activity is mainly derived from PLA2-I, whereas plasma PLA2 activity is mostly derived from PLA2-II in severe acute pancreatitis, suggesting that increased plasma PLA2-II activity might be implicated in hepatic failure arising after severe acute pancreatitis.
COW SERUM AS A SUBSTITUTE FOR COLOSTRUM IN NEW-BORN CALVES
Authors: Theobald Smith, Ralph B. Little
Journal: The Journal of Experimental Medicine (1922)

The serum of a normal lactating cow when injected into calves a few hours after birth saved only two out of five calves so treated. Serum added to the milk of the first two meals saved three out of five. When the two methods were combined and the serum was both injected and fed all five calves so treated survived as normal calves. These figures to be significant should be compared with the controls of both series. Since the beginning of this investigation twelve out of thirteen colostrum-fed calves have survived and only four out of fifteen from which colostrum has been withheld. In those that died the serum whether fed or injected protected the internal organs against the invasion and multiplication of Bacillus coli and other intestinal types and in this respect its protective action is equivalent to that of colostrum in those calves which die of spontaneous scours.