tbuckley/cabot-search huggingface dataset:
Gm allotypes and HLA in rheumatoid arthritis patients with circulating antibodies to native type II collagen.
Authors: P.A Sanders, D.M Grennan, P.S Klimiuk, R.B Clague, G.G deLange, I Collins, P.A Dyer
Journal: Annals of the Rheumatic Diseases (1987)

HLA antigens and immunoglobulin heavy chain allotypes (Gm) were determined in 166 unrelated patients with rheumatoid arthritis (RA), 44 of whom had circulating antibodies to native type II collagen. Collagen antibody positive patients showed an association with HLA-DR3 and DR7 (68% compared with 39% of collagen antibody negative RA, p less than 0.005), and with the Gm phenotype, Gm(zafngb). This contrasted with the collagen antibody negative RA patients where there was an association with HLA-DR4 and, in DR4 positive disease only, with the Gm allotype, G1m(x). The Gm(zafngb) phenotype was found in 26% of DR3 or DR7 positive patients overall and only 9% of RA patients negative for these DR antigens (p less than 0.005), suggesting an interaction between HLA-DR3/7 and Gm(zafngb). The differing Gm associations for collagen antibody positive and negative RA provide further evidence for genetic heterogeneity in susceptibility to RA.
Clinical relevance of non-tuberculous mycobacteria isolated in the Nijmegen-Arnhem region, The Netherlands
Authors: J van Ingen, S A Bendien, W C M de Lange, W Hoefsloot, P N R Dekhuijzen, M J Boeree, D van Soolingen
Journal: Thorax (2009)

<h3>Background:</h3> The frequency of clinical isolation of non-tuberculous mycobacteria (NTM) in the Netherlands is increasing, but its clinical relevance is often uncertain. <h3>Objective:</h3> To assess the frequency and clinical relevance of isolation of NTM in four associated hospitals in a single region in the Netherlands. <h3>Methods:</h3> Medical files of all patients from whom NTM were isolated between January 1999 and January 2005 were reviewed retrospectively. Diagnostic criteria for non-tuberculous mycobacterial disease published by the American Thoracic Society (ATS) were used to determine clinical relevance. <h3>Results:</h3> 232 patients were found, from whom NTM were isolated from the respiratory tract in 91% of cases. Patients were mostly white men, with an average age of 60 years and pre-existing pulmonary disease. Fifty-three of 212 patients (25%) with pulmonary isolates met the ATS diagnostic criteria for pulmonary NTM disease; this percentage differed by species. Most patients were treated with rifampicin, ethambutol and clarithromycin. Treatment outcome for pulmonary NTM disease was suboptimal but differed by species: overall, improvement was seen in 67% of treated patients, but in only 50% of those with pulmonary <i>M avium</i> disease. Lymphadenitis was the most common extrapulmonary disease type. <h3>Conclusions:</h3> Twenty-five per cent of all patients with pulmonary NTM isolates met the ATS criteria. Clinical relevance differs by species. NTM isolation increases over time. Species distribution differs from that of neighbouring countries and the <i>M avium</i> complex isolates have traits different from those reported in the USA. Adherence to diagnostic and treatment guidelines can be improved.
AUTOIMMUNITY AND NEUROLOGICAL DISEASE: Antibody Modulation of Synaptic Transmission
Authors: K. D. Whitney, J. O. McNamara
Journal: Annual Review of Neuroscience (1999)

▪ Abstract Over the past three decades, compelling evidence has emerged that the immune system can attack the nervous system with devastating consequences for human health. Either cell-mediated or humoral (antibody-mediated) autoimmune mechanisms may predominate in effecting a given disease, and either glia or neurons may fall under immune attack. A subset of these diseases has been particularly useful for understanding fundamental neuroscience as well as mechanisms of human disease. This subset involves humoral autoimmune attack on cell surface molecules subserving transmembrane signaling of excitable cells; special emphasis is placed here on proteins involved in synaptic transmission. We begin by reviewing the prototypic humoral autoimmune disease of synaptic transmission, myasthenia gravis. This provides a context for insights obtained from the study of diseases targeting molecules that regulate synaptic transmission at the neuromuscular junction and in the central nervous system. We also explore a disease where autoimmunity produces agonist antibodies acting at two distinct G-protein-coupled receptors. We conclude with an exploration of the vital issue of access of antibodies to targets within the central nervous system and the implications that such access may have in the pathogenesis of poorly understood idiopathic central nervous system diseases.
A Randomized, Double-Blind, Placebo-Controlled Trial of Metformin Treatment of Weight Gain Associated With Initiation of Atypical Antipsychotic Therapy in Children and Adolescents
Authors: David J Klein, Elizabeth M Cottingham, Michael Sorter, Bruce A Barton, John A Morrison
Journal: American Journal of Psychiatry (2006)

Objective: Second-generation, or atypical, antipsychotics effectively treat psychiatric illness in children and adolescents. However, weight gain and abnormalities in insulin sensitivity, including diabetes, complicate this therapy. Method: A 16-week double-blind, placebo-controlled trial was conducted to evaluate the effectiveness of metformin in managing weight gain in 39 subjects, ages 10–17, whose weight had increased by more than 10% during less than 1 year of olanzapine, risperidone, or quetiapine therapy. Body weight, body mass index (kilograms per square meter of height), and waist circumference were measured regularly, as were fasting insulin and glucose levels. Results: Weight was stabilized in subjects receiving metformin, while those receiving placebo continued to gain weight (0.31 kg/week). Because the study was conducted with growing children, metformin treatment resulted in reduction in z scores for both weight and body mass index. The homeostasis model assessment, a surrogate indicator of insulin sensitivity, decreased in treated subjects. Overt diabetes was diagnosed in two subjects before treatment (elevated baseline fasting glucose and insulin values) and in two placebo-treated subjects (one at week 12 and the other after study completion). One subject taking placebo developed impaired fasting glucose. Placebo treatment was associated with the need to perform oral glucose tolerance testing upon study completion, by which three additional subjects were identified with impaired glucose tolerance. No serious adverse events resulted from metformin treatment. Conclusions: Metformin therapy is safe and effective in abrogating weight gain, decreased insulin sensitivity, and abnormal glucose metabolism resulting from treatment of children and adolescents with atypicals.
Effect of curing Helicobacter pylori infection on intragastric acidity during treatment with ranitidine in patients with duodenal ulcer.
Authors: J Labenz, B Tillenburg, U Peitz, E Verdu, M Stolte, G Borsch, A L Blum
Journal: Gut (1997)

In patients with duodenal ulcer cure of Helicobacter pylori infection resulted in a pronounced decrease in intragastric pH during treatment with omeprazole.To test the hypothesis that treatment of H pylori adversely affects the pH response to ranitidine.Eighteen patients with duodenal ulcer who were infected with H pylori were studied.Twenty four hour pH recordings were performed during treatment with ranitidine (300 mg) at night before and four to six weeks after cure of H pylori infection. Presence of H pylori was assessed by a rapid urease test, culture, histology, and a 13C urea breath test. Also, the fasting gastrin concentrations were measured before and after treatment for H pylori infection.Cure of H pylori infection resulted in a considerable improvement in both antral and corpus gastritis and a decrease in fasting gastrin concentrations. As a result of the cure the night time intragastric pH during treatment with ranitidine decreased (median pH 6.8 v 5.4; p = 0.007), whereas the acidity during the daytime was not affected.In patients with duodenal ulcer the intragastric pH during treatment with ranitidine depends on H pylori. However, the loss of effectiveness in altering pH seems to be less pronounced than previously found with omeprazole.
Na <sup>+</sup> -Ca <sup>2+</sup> Exchange in Intact Endothelium of Rabbit Cardiac Valve
Authors: Li Li, Cornelis van Breemen
Journal: Circulation Research (1995)

Abstract A new method of measuring cytoplasmic free Ca 2+ ([Ca 2+ ] i ) of individual intact cardiovascular endothelial cells by using imaging fluorescence microscopy was designed. Application of agonist to the aortic or pulmonary valve of the rabbit triggered an increase in [Ca 2+ ] i , which depended on the existence of endothelium on the surface of the valve. Under resting conditions, sudden reversal of the Na + gradient by substituting external Na + with N -methyl d -glucamine (NMDG) resulted in a [Ca 2+ ] i spike, which then returned toward the resting level. Increasing intracellular Na + concentration ([Na + ] i ) by application of ouabain or monensin induced a sustained [Ca 2+ ] i increase. Na + substitution by NMDG during the agonist- or monensin-induced [Ca 2+ ] i increase gave rise to a further [Ca 2+ ] i spike, which subsequently declined to a level higher than that before removal of external Na + . A selective inhibitor of Na + -Ca 2+ exchange, 3′,4′-dichlorobenzamyl (DCB), abolished the transient [Ca 2+ ] i increase induced by Na + substitution, and Mg 2+ , an inorganic inhibitor of Na + -Ca 2+ exchanger, markedly reduced this transient [Ca 2+ ] i increase. On the other hand, the selective Na + -H + exchanger blocker 5-( N,N -hexamethylene)amiloride (HMA) did not abolish the transient [Ca 2+ ] i increase caused by Na + substitution. In summary, decreasing the Na + gradient of the endothelial cells through either receptor stimulation (agonist), Na + -K + pump inhibition (ouabain), pretreatment with Na + ionophore (monensin), or reversing the Na + gradient through Na + substitution (NMDG) all increased [Ca 2+ ] i . This raised [Ca 2+ ] i was antagonized by agents such as DCB or Mg 2+ , which are thought to inhibit Na + -Ca 2+ exchange, but not by HMA, an inhibitor of Na + -H + exchange. Taken together, these results strongly imply the presence of Na + -Ca 2+ exchange as a viable mechanism for Ca 2+ transport in intact cardiovascular endothelium and that the Ca 2+ entry component is enhanced when [Na + ] i is elevated.
Adoptively Transferred Tumor-Specific T Cells Stimulated<i>Ex vivo</i>Using Herpes Simplex Virus Amplicons Encoding 4-1BBL Persist in the Host and Show Antitumor Activity<i>In vivo</i>
Authors: Kyung H. Yi, Hovav Nechushtan, William J. Bowers, Gail R. Walker, Yu Zhang, Dien G. Pham, Eckhard R. Podack, Howard J. Federoff, Khaled A. Tolba, Joseph D. Rosenblatt
Journal: Cancer Research (2007)

Abstract 4-1BB is a T-cell costimulatory receptor which binds its ligand 4-1BBL, resulting in prolonged T cell survival. We studied the antitumor effects of adoptively transferred tumor-specific T cells expanded ex vivo using tumors transduced with herpes simplex virus (HSV) amplicons expressing 4-1BBL as a direct source of antigen and costimulation. We constructed HSV amplicons encoding either the 4-1BBL (HSV.4-1BBL) or B7.1 (HSV.B7.1) costimulatory ligands. Lewis lung carcinoma cells expressing ovalbumin (LLC/OVA) were transduced with HSV.4-1BBL, HSV.B7.1, or control HSV amplicons and used to stimulate GFP+ OVA-specific CD8+ T cells (OT-1/GFP) ex vivo. Naive or ex vivo stimulated OT-1/GFP cells were adoptively transferred into LLC/OVA tumor-bearing mice. Higher percentages of OT-1/GFP cells were seen in the peripheral blood, spleen, and tumor bed of the HSV.4-1BBL–stimulated OT-1/GFP group compared with all other experimental groups. OT-1 cells identified within the tumor bed and draining lymph nodes of the HSV.4-1BBL–stimulated OT-1 group showed enhanced bromodeoxyuridine (BrdUrd) incorporation, suggesting ongoing expansion in vivo. Mice receiving HSV.4-1BBL–stimulated OT-1/GFP had significantly decreased tumor volumes compared with untreated mice (P &amp;lt; 0.001) or to mice receiving naive OT-1/GFP (P &amp;lt; 0.001). Transfer of HSV.B7.1-stimulated OT-1/GFP did not protect mice from tumor. Mice that received HSV.4-1BBL–stimulated OT-1/GFP exhibited increased cytolytic activity against LLC/OVA and higher percentages of Ly-6C+ OT-1/GFP in the spleen and tumor bed compared with controls. Tumor-specific T cells stimulated ex vivo using tumor transduced with HSV.4-1BBL expand in vivo following adoptive transfer, resulting in tumor eradication and the generation of tumor-specific CD44+Ly-6C+CD62L− effector memory T cells. [Cancer Res 2007;67(20):10027–37]
Amplification/Overexpression of a Mitotic Kinase Gene in Human Bladder Cancer
Authors: S. Sen
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: The mitotic kinase-encoding gene STK15/BTAK/ AuroraA is associated with aneuploidy and transformation when overexpressed in mammalian cells. STK15 overexpression activates an unknown oncogenic pathway that involves centrosome amplification and results in missegregation of chromosomes. Because clinical prognosis and tumor aneuploidy are tightly linked in human bladder cancer, we examined whether increased STK15 copy number and protein levels are linked to aneuploidy in bladder cancers. Methods: STK15 protein was visualized by immunohistochemistry in 205 formalin-fixed, paraffin-embedded human bladder tumors. STK15 gene copy number was evaluated in 61 tumors by Southern blot hybridization and in 21 of these 61 tumors by fluorescence in situ hybridization (FISH). Copy numbers of chromosomes 3, 17, 20, and 21 were evaluated by FISH with chromosome-specific probes. STK15 expression levels were related to histologic grade, stage, and DNA ploidy of the tumors and to the patients' follow-up data. The chi-square test for association was used to analyze the relationship between STK15 expression and pathologic features. All statistical tests were two-sided. Results: Tumors with low levels of STK15 amplification (3–4 copies) showed minimal deviation in their chromosome copy number and diploid or near-diploid total nuclear DNA content. Tumors with higher levels of STK15 amplification (>4 copies) had a major increase of chromosome copy number and of their total nuclear DNA content, i.e., exhibited pronounced aneuploidy. Elevated expression of STK15 was strongly associated with parameters of clinical aggressiveness including high histologic grade (P<.001), invasion (P<.001), increased rate of metastasis (P<.001), and decreased metastasis-free (P<.001) and overall (P<.001) survival of patients with bladder cancer. Conclusion: STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer.
Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia
Authors: G R Bergfeld, T Forrester
Journal: Cardiovascular Research (1992)

The aims were, first, to detect and quantify the release of ATP from human erythrocytes in response to a brief exposure to a hypoxic/hypercapnic environment, similar to that found in vigorously exercising skeletal or cardiac muscle; and second, to explore the mechanism of ATP release in response to hypoxia.Washed human erythrocytes suspended in Krebs-Henseleit solution were exposed for 50 s to an atmosphere of approximately 8.0 kPa PCO2 and 2.7 kPa PO2; ATP released into the suspension was assayed using the firefly luminescence technique. Samples of human blood were obtained by venepuncture of the median cubital vein from male and female volunteers ranging in age from 21 to 74 years. Anticoagulation was with EDTA.A background of 0.49 x 10(6) (SEM 0.037 x 10(6)) ATP molecules.cell-1 was attributed to spontaneous haemolysis of 1% of the cell population, as estimated by levels of haemoglobin measured in the suspension fluid. When the erythrocytes were exposed to the hypoxic/hypercapnic gas mixture at 37 degrees C the ATP concentration in the suspension fluid rose to 2.67 x 10(6) (0.27 x 10(6)) molecules.cell-1. An efflux rate of 276(37) molecules.mu-2.s-1 was calculated. The hypoxia induced ATP release was blocked in three different ways: first, by application of 50 microM of the specific band 3 anion channel blocking agents niflumic acid (a translocation inhibitor), DIDS (a transport site inhibitor), or dipyridamole (a channel blocker); secondly, by replacement of extracellular chloride and bicarbonate with the impermeant anion methanesulphonate; and thirdly, by application of 5 nM of the nucleoside transport blocker nitrobenzylthioinosine. None of these blocking techniques affected the background levels of ATP attributed to haemolysis.A situation of hypoxia/hypercapnia, such as would be found in exercising muscle, induces release of ATP from the erythrocyte via the plasma membrane protein moiety known as band 4.5 (a nucleoside transporter) and electrical balance across the erythrocyte membrane is maintained by the simultaneous influx of extracellular chloride and/or bicarbonate via the plasma membrane protein known as band 3 (anion channel). The circulation of erythrocytes into a region of hypoxia in vivo could promote an increase in local blood flow through release of endothelium dependent relaxing factor in response to released ATP.
A Multicenter, Randomized Trial of Coronary Angioplasty Versus Directional Atherectomy for Patients With Saphenous Vein Bypass Graft Lesions
Authors: David R. Holmes, Eric J. Topol, Robert M. Califf, Lisa G. Berdan, Ferdinand Leya, Peter B. Berger, Patrick L. Whitlow, Robert D. Safian, Allan G. Adelman, Mirle A. Kellett, J. David Talley, Jacob Shani, Ronald S. Gottlieb, Cass A. Pinkerton, Kerry L. Lee, Gordon P. Keeler, Stephen G. Ellis
Journal: Circulation (1995)

Directional coronary atherectomy and percutaneous transluminal coronary angioplasty have both been used in symptomatic patients with coronary saphenous vein bypass graft stenoses. The relative merits of plaque excision and removal versus balloon dilatation remain uncertain. We compared outcomes after directional coronary atherectomy or angioplasty in patients with de novo bypass graft stenoses.Fifty-four North American and European sites randomized 305 patients with de novo vein graft lesions to atherectomy (n = 149) or angioplasty (n = 156). Quantitative coronary angiography at a core laboratory assessed initial and 6-month results. Initial angiographic success was greater with atherectomy (89.2% versus 79.0%), as was initial luminal gain (1.45 versus 1.12 mm, P < .001). Distal embolization was increased with atherectomy (P = .012), and a trend was shown toward more non-Q-wave myocardial infarction (P = .09). Although the 6-month net minimum luminal diameter gain was 0.68 mm for atherectomy and 0.50 mm for angioplasty, the restenosis rates were similar, 45.6% for atherectomy and 50.5% for angioplasty (P = .491). At 6 months, there was a trend toward decreased repeated target-vessel interventions for atherectomy (P = .092); in addition, 13.2% of patients treated with atherectomy versus 22.4% of the angioplasty patients (P = .041) required repeated percutaneous intervention of the initial target lesion.Atherectomy of de novo vein graft lesions was associated with improved initial angiographic success and luminal diameter but also with increased distal embolization. There was no difference in 6-month restenosis rates, although primary atherectomy patients tended to require fewer target-vessel revascularization procedures.
Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial
Authors: S.T. Holgate, M. Noonan, P. Chanez, W. Busse, L. Dupont, I. Pavord, A. Hakulinen, L. Paolozzi, J. Wajdula, C. Zang, H. Nelson, D. Raible
Journal: European Respiratory Journal (2010)

Increased tumour necrosis factor-α levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma. In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n = 132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) % predicted. Secondary end-points included morning peak expiratory flow, FEV 1 % pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV 1 , and the Asthma Quality of Life Questionnaire. No significant differences were observed between ETN and placebo for any of the efficacy end-points. ETN treatment was well tolerated, with no unexpected safety findings observed during the study. Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.
Effect of p53 Status and STAT1 on Chemotherapy-Induced, Fas-Mediated Apoptosis in Colorectal Cancer
Authors: Ultan McDermott, Daniel B. Longley, Leeona Galligan, Wendy Allen, Timothy Wilson, Patrick G. Johnston
Journal: Cancer Research (2005)

Abstract We investigated the role of p53 and the signal transducer and activator of transcription 1 (STAT1) in regulating Fas-mediated apoptosis in response to chemotherapies used to treat colorectal cancer. We found that 5-fluorouracil (5-FU) and oxaliplatin only sensitized p53 wild-type (WT) colorectal cancer cell lines to Fas-mediated apoptosis. In contrast, irinotecan (CPT-11) and tomudex sensitized p53 WT, mutant, and null cells to Fas-mediated cell death. Furthermore, CPT-11 and tomudex, but not 5-FU or oxaliplatin, up-regulated Fas cell surface expression in a p53-independent manner. In addition, increased Fas cell surface expression in p53 mutant and null cell lines in response to CPT-11 and tomudex was accompanied by only a slight increase in total Fas mRNA and protein expression, suggesting that these agents trigger p53-independent trafficking of Fas to the plasma membrane. Treatment with CPT-11 or tomudex induced STAT1 phosphorylation (Ser727) in the p53-null HCT116 cell line but not the p53 WT cell line. Furthermore, STAT1-targeted small interfering RNA (siRNA) inhibited up-regulation of Fas cell surface expression in response to CPT-11 and tomudex in these cells. However, we found no evidence of altered Fas gene expression following siRNA-mediated down-regulation of STAT1 in drug-treated cells. This suggests that STAT1 regulates expression of gene(s) involved in cell surface trafficking of Fas in response to CPT-11 or tomudex. We conclude that CPT-11 and tomudex may be more effective than 5-FU and oxaliplatin in the treatment of p53 mutant colorectal cancer tumors by sensitizing them to Fas-mediated apoptosis in a STAT1-dependent manner.