tbuckley/cabot-search huggingface dataset:
Hepatotoxicity of Pyrazinamide
Authors: Kwok C. Chang, Chi C. Leung, Wing W. Yew, Tat Y. Lau, Cheuk M. Tam
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Relatively little is known about the hepatotoxicity of pyrazinamide.We compared continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampin with those containing isoniazid and rifampin to evaluate the hepatotoxicity of pyrazinamide.Cohort and nested case-control analyses were conducted on a cohort of 3,007 patients with active tuberculosis (TB) managed at government chest clinics under a TB control program with treatment started from January 1 through June 30, 2001. Cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when serum alanine transaminase exceeded three times the upper limit of normal. Each case was matched by sex and age with three control subjects selected randomly from the rest of the cohort. Treatment regimens of cases within 4 weeks preceding hepatotoxicity were compared with those of matched control subjects in comparable periods relative to the date of commencing treatment.Hepatotoxicity occurred in 150 (5.0%) patients at any time including 48 (1.6%) cases. From 12 or more weeks after starting treatment, the estimated risk of hepatotoxicity was 2.6% for regimens incorporating pyrazinamide, isoniazid, and/or rifampin, and 0.8% for standard regimens containing isoniazid and rifampin. Multivariable conditional logistic analysis showed a significant association between hepatotoxicity and, respectively, hepatitis B, previous hepatotoxicity, and treatment regimens. The adjusted odds ratio (95% confidence interval) of hepatotoxicity for regimens incorporating pyrazinamide, isoniazid, and/or rifampin relative to standard regimens was 2.8 (1.4-5.9).Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.
Contrasting Roles of NADPH Oxidase Isoforms in Pressure-Overload Versus Angiotensin II–Induced Cardiac Hypertrophy
Authors: Jonathan A. Byrne,*, David J. Grieve, Jennifer K. Bendall, Jian-Mei Li, Christopher Gove, J. David Lambeth, Alison C. Cave, Ajay M. Shah
Journal: Circulation Research (2003)

Increased production of reactive oxygen species (ROS) is implicated in the development of left ventricular hypertrophy (LVH). Phagocyte-type NADPH oxidases are major cardiovascular sources of ROS, and recent data indicate a pivotal role of a gp91phox-containing NADPH oxidase in angiotensin II (Ang II)-induced LVH. We investigated the role of this oxidase in pressure-overload LVH. gp91phox-/- mice and matched controls underwent chronic Ang II infusion or aortic constriction. Ang II-induced increases in NADPH oxidase activity, atrial natriuretic factor (ANF) expression, and cardiac mass were inhibited in gp91phox-/- mice, whereas aortic constriction-induced increases in cardiac mass and ANF expression were not inhibited. However, aortic constriction increased cardiac NADPH oxidase activity in both gp91phox-/- and wild-type mice. Myocardial expression of an alternative gp91phox isoform, Nox4, was upregulated after aortic constriction in gp91phox-/- mice. The antioxidant, N-acetyl-cysteine, inhibited pressure-overload-induced LVH in both gp91phox-/- and wild-type mice. These data suggest a differential response of the cardiac Nox isoforms, gp91phox and Nox4, to Ang II versus pressure overload.
VARIATION IN THE GROUP-SPECIFIC CARBOHYDRATE OF GROUP A STREPTOCOCCI
Authors: Maclyn McCarty
Journal: The Journal of Experimental Medicine (1956)

Soil organisms have been isolated which elaborate induced enzymes capable of attacking group A and variant (V) streptococcal carbohydrates. The V enzyme hydrolyzes V carbohydrate extensively to dialyzable split products with resultant total loss of precipitating activity with homologous antisera. The split products inhibit the reaction between intact V carbohydrate and its antiserum: evidence is presented which indicates that rhamnose oligosaccharides are responsible for the inhibitory effect. The serological specificity of the V carbohydrate thus appears to be primarily dependent on a rhamnose-rhamnose linkage. The effect of the A enzyme on A carbohydrate is characterized by the removal of 50 to 70 per cent of the total glucosamine in the form of free N-acetyl-glucosamine. As a result of this treatment, the residual carbohydrate loses its reactivity with specific group A antisera and at the same time develops markedly increased cross-reactivity with V antisera. This cross-reactivity is in turn eliminated by treatment with V enzyme. The evidence suggests that the specificity of group A carbohydrate is determined to a large extent by side chains of N-acetyl-glucosamine which also serve to mask underlying rhamnose-rhamnose linkages with V specificity.
Duration of peginterferon therapy in acute hepatitis C: A randomized trial
Authors: Sanaa M. Kamal, Khairy N. Moustafa, Jason Chen, Jutta Fehr, Azza Abdel Moneim, Khalifa E. Khalifa, Leila A. El Gohary, Amr H. Ramy, Mohamed A. Madwar, Jens Rasenack, Nezam H. Afdhal
Journal: Hepatology (2006)

Spontaneous resolution of acute hepatitis C virus infection cannot be predicted, and chronic evolution of the disease occurs in a majority of cases. To assess the efficacy and safety of peginterferon alpha-2b administered for 8, 12, or 24 weeks in patients with acute hepatitis C virus infection a total of 161 patients were identified with acute hepatitis C virus infection. Of these, 30 patients refused treatment but were retained in the study as a nonrandomized comparison group. Of the 131 patients who consented to treatment, 29 patients spontaneously resolved, leaving 102 patients randomly assigned to peginterferon alpha-2b (1.5 microg/kg) for 8 weeks (group A; n=34), 12 weeks (group B; n=34), and 24 weeks (group C; n=34). The primary end point was sustained virologic response. An intent-to-treat analysis was used for efficacy and safety end points. Sustained virologic response was achieved in 23/34 (67.6%), 28/34 (82.4%), and 31/34 (91.2%) of patients in groups A, B, and C, respectively; all had undetectable hepatitis C virus RNA 48 weeks after the end of therapy. Treatment for 8 or 12 weeks was effective in genotypes 2, 3, and 4, whereas genotype 1 required 24 weeks of therapy. The 8- and 12-week regimens were associated with fewer adverse events compared with the 24-week regimen. In conclusion, peginterferon alpha-2b effectively induces high sustained virologic response rates in patients with acute hepatitis C virus infection, thus preventing development of chronic hepatitis C. Duration of treatment should be further optimized based on genotype and rapid virologic response at week 4.
Reply to F. Campodonico et al
Authors: Laurence Klotz, Andrew Loblaw
Journal: Journal of Clinical Oncology (2010)

The view that sextant biopsies were insufficient to evaluate prostate cancer emerged in the mid-1990s, around the time that our prospective trial was initiated. This became widely accepted by 2000 to 2003. Our group thought from the beginning that as thorough an assessment as possible of the extent of pathologic disease should be performed, and adopted an extended biopsy strategy in the surveillance patients early on. In many patients whose initial biopsy was performed elsewhere, sextant biopsies were performed. These patients had extended biopsies on the 12-month biopsy in most cases. We adopted the formal Vienna nomogram when it became available, and used this term to describe our technique. Campodonico et al are correct that, strictly speaking, the extended biopsies performed between 1995 and 2003 were not performed according to the Vienna nomogram. We agree that taking more cores depending on age and prostate volume enhances the accuracy of prostate biopsy. Even with the Vienna nomogram approach, however, some patients with large anterior cancers are missed. Currently, we specifically target this area on repeat biopsy. Nonetheless, despite the inaccuracies of biopsy and prostate-specific antigen kinetics, the prostate cancer mortality in this population remains reassuringly low. Laurence Klotz and Andrew Loblaw Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes
Authors: Sigurdur Y. Kristinsson, Magnus Björkholm, Malin Hultcrantz, Åsa R. Derolf, Ola Landgren, Lynn R. Goldin
Journal: Journal of Clinical Oncology (2011)

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases.By using population-based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases.Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS.Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions.
Genetics and specific immune response in allergy to birch pollen and food: Evidence of a strong, positive association between atopy and the HLA class II allele HLA-DR7☆☆☆★
Authors: Hélène Sénéchal, Sylvie Geny, François-Xavier Desvaux, Marc Busson, Christiane Mayer, Yolande Aron, Jean-Philippe Oster, Jean-Claude Bessot, Gabriel Peltre, Gabrielle Pauli
Journal: Journal of Allergy and Clinical Immunology (1999)
Tracheo-bronchial involvement in Sweet syndrome
Authors: K. Tanimura, H. Kita, Y. Kanemitsu, Y. Fuseya, Y. Katayama
Journal: Thorax (2010)

A 70-year-old man with myelofibrosis and Sweet syndrome (acute febrile neutrophilic dermatosis) presented with a 2 month history of cough with bloody sputum (figure 1). No infiltration was visible on a chest radiograph.



Figure 1 
A well-defined erythematous plaque on the dorsal surface of the hand.



On bronchoscopic examination, a centrally depressed macular lesion with an eroded surface was revealed in the anterior tracheal wall, …
Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation
Authors: L A Borthwick, S M Parker, K A Brougham, G E Johnson, M R Gorowiec, C Ward, J L Lordan, P A Corris, J A Kirby, A J Fisher
Journal: Thorax (2009)

<h3>Background:</h3> Aberrant epithelial repair is a key event in the airway remodelling which characterises obliterative bronchiolitis (OB) in the transplanted lung. The potential for airway epithelium from lung transplant recipients to undergo epithelial to mesenchymal cell transition (EMT) was assessed in culture and in vivo in lung allograft tissue. <h3>Methods:</h3> Change in epithelial and mesenchymal marker expression was assessed after stimulation with transforming growth factor β<sub>1</sub> (TGF-β<sub>1</sub>) alone or in combination with tumour necrosis factor α (TNFα) and compared with untreated controls. The ability of cells to deposit extracellular matrix, secrete matrix metalloproteinases (MMPs) and invade collagen was investigated. Immunolocalisation of epithelial and mesenchymal markers was compared in airway tissue from stable recipients and those with OB. <h3>Results:</h3> Untreated cells maintained epithelial morphology and phenotype. TGF-β<sub>1</sub> reduced expression of epithelial markers, increased expression of vimentin and fibronectin, promoted collagen I and fibronectin deposition and increased MMP-9 production. Co-treatment with TNFα dramatically accentuated phenotypic and some functional features of EMT. Airway epithelial biopsies from recipients with OB demonstrated significantly increased staining for mesenchymal markers and significantly reduced E-cadherin staining compared with stable recipients. <h3>Conclusions:</h3> These observations demonstrate the ability of human airway epithelium to undergo EMT and suggest this phenomenon may be a potential link between inflammatory injury and TGF-β<sub>1</sub>-driven airway remodelling in the development of OB.
Depressed T cell reactivity to recall antigens in Crohn's disease before and after surgical resection.
Authors: G D'Haens, M Hiele, P Rutgeerts, K Geboes, J L Ceuppens
Journal: Gut (1994)

Earlier studies regarding possible primary immune disturbances participating in the pathogenesis of Crohn's disease yielded conflicting results. Peripheral blood lymphocyte subsets and lymphocyte proliferative responses to five soluble recall antigens and to the polyclonal stimulator phythaemagglutinin were therefore measured in 17 patients with active Crohn's disease, before and six months after surgical resection of the inflamed intestine and in 16 healthy controls. Lymphocyte proliferation in response to all five recall antigens was significantly lower in patients than in controls. No significant differences with controls were detected after surgery. Addition of indomethacin to phythaemagglutinin stimulated lymphocyte cultures had a stronger proliferation enhancing effect in patients than in controls, resulting in comparable proliferative responses in both groups. When both indomethacin and prostaglandin E2 were added, inhibition of reactivity by prostaglandin E2 was stronger in patients' cultures. This suggests a higher sensitivity to inflammatory prostaglandins in Crohn's disease. The degree of lymphocyte stimulation by antigens correlated positively with the percentage of circulating memory T cells (CD 45 RA-). The percentage of activated (HLA-DR+) CD8 cells was higher in patients than in controls. The CD4/CD8 ratio, which was not significantly different between patients and controls, correlated significantly with disease activity and characteristics, even in the postoperative phase. These findings suggest that immune abnormalities in Crohn's disease fluctuate with and are probably secondary to inflammatory activity.
Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease
Authors: Malte Lenders, Jörg Stypmann, Thomas Duning, Boris Schmitz, Stefan-Martin Brand, Eva Brand
Journal: Journal of the American Society of Nephrology (2015)

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m(2); P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.
Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction
Authors: Robert P. Giugliano, Matthew T. Roe, Lynn H. Woodlief, Robert A. Harrington, Karen L. Hannan, Robert M. Califf, C.Michael Gibson, Uwe Zeymer, Frans Van de Werf, Kenneth W. Baran, Hans-Peter Hobbach, Sally Greenberg, Joanne Miller, Michael M. Kitt, John Strony, Carolyn H. McCabe, Eugene Braunwald
Journal: Journal of the American College of Cardiology (2003)
Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis
Authors: Hayan Dayoub, Vinod Achan, Shanthi Adimoolam, Johannes Jacobi, Marcus C. Stuehlinger, Bing-yin Wang, Philip S. Tsao, M. Kimoto, Patrick Vallance, Andrew J. Patterson, John P. Cooke
Journal: Circulation (2003)

NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis.We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed approximately 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production.DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.
AN ELECTROPHORETIC EXAMINATION OF A URINARY MUCOPROTEIN WHICH REACTS WITH VARIOUS VIRUSES
Authors: Gertrude E. Perlmann, Igor Tamm, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1952)

A mucoprotein isolated from human urine and possessing the capacity to react with a number of viruses is electrophoretically homogeneous at pH 6.8 and 8.6. After treatment with influenza virus and elimination of its biological activity, the substance remains homogeneous and its electrophoretic mobility is decreased by approximately 20 per cent.
Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma
Authors: Raphaël Maréchal, John R. Mackey, Raymond Lai, Pieter Demetter, Marc Peeters, Marc Polus, Carol E. Cass, James Young, Isabelle Salmon, Jacques Devière, Jean-Luc Van Laethem
Journal: Clinical Cancer Research (2009)

Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1 (hENT1) and human concentrative nucleoside transporter (hCNT) 1 and 3 are the major transporters responsible for 2',2'-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen.We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1 and hCNT3 expression using immunohistochemistry.When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1(high)/hCNT3(high) expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor.Pancreatic adenocarcinoma patients with a high expression of hENT1 and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabine-based adjuvant therapy.
Regression of Renal Disease by Angiotensin II Antagonism Is Caused by Regeneration of Kidney Vasculature
Authors: Andrea Remuzzi, Fabio Sangalli, Daniela Macconi, Susanna Tomasoni, Irene Cattaneo, Paola Rizzo, Barbara Bonandrini, Elena Bresciani, Lorena Longaretti, Elena Gagliardini, Sara Conti, Ariela Benigni, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2015)

Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Frömter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-β and endothelin-1 gene expression with age. Notably, 10-week inhibition of the renin-angiotensin system regenerated kidney vasculature and normalized Tgf-β and endothelin-1 gene expression in aged MWF rats. These changes were associated with reduced apoptosis, increased endothelial cell proliferation, and restoration of Nrf2 expression, suggesting mechanisms by which angiotensin II antagonism mediates regeneration of capillary segments. These results have important implications in the clinical setting of chronic renal insufficiency.