tbuckley/cabot-search huggingface dataset:
Longitudinal Development of Left Ventricular Diastolic Function in Patients With Type 2 Diabetes
Authors: Laura Venskutonyte, Christina Jarnert, Lars Rydén, Barbro Kjellström
Journal: Diabetes Care (2014)

OBJECTIVE Left ventricular diastolic dysfunction (LVDD) is considered to be common in patients with type 2 diabetes mellitus (T2DM), but information on its progression over time is lacking. We studied the longitudinal development of left ventricular diastolic function (LVDF) and myocardial blood flow reserve in patients with T2DM who were free from clinically detectable cardiovascular disease. RESEARCH DESIGN AND METHODS The LVDF was assessed in 73 patients with T2DM (mean age 67 ± 7 years; males 51%) on two occasions separated by 6.4 ± 0.8 years. RESULTS At baseline, LVDD was observed in 23 of the patients (32%). During follow-up, the LVDF normalized in 10 of these patients (43%) and remained unchanged in 13 of them (57%). Of the 50 patients (68%) with normal LVDF at baseline, LVDD developed in 9 (18%). Paired evaluation of myocardial blood volume index was available from 22 patients with LVDD and remained unchanged over time. CONCLUSIONS The condition of the majority of the investigated patients with LVDD improved or remained stable over a period of 6 years.
Inspiratory neural drive response to hypoxia adequately estimates peripheral chemosensitivity in OSAHS patients
Authors: F. García-Río, J.M. Pino, T. Ramirez, D. Alvaro, A. Alonso, C. Villasante, J. Villamor
Journal: European Respiratory Journal (2002)

The aim of the present study was to examine the relationships between the responses to progressive isocapnic hypoxia and hypoxic withdrawal test in patients with obstructive sleep apnoea-hypopnoea syndrome (OSAHS) and to analyse the determinants of carotid body sensitivity in OSAHS. Nineteen consecutive OSAHS patients and 13 healthy subjects were selected. Ventilatory (Δ V ′ I / S a,O 2 /BSA) and inspiratory neural drive (Δ P 0.1 / S a,O 2 ) responses to progressive isocapnic hypoxia were determined. Peripheral chemosensitivity was evaluated by the hypoxic withdrawal test, which measures the decrease in ventilation caused by two breaths of 100% oxygen (%Δ V ′ I ). Withdrawal response and ventilatory and inspiratory neural drive responses to hypoxia were lower in OSAHS patients than in control subjects. In patients with OSAHS, %Δ V ′ I correlated significantly with Δ V ′ I / S a,O 2 /BSA and with Δ P 0.1 / S a,O 2 . On stepwise multiple linear regression analysis, a strong correlation between %Δ V ′ I and Δ P 0.1 / S a,O 2 was found. Moreover, %Δ V ′ I , Δ V ′ I / S a,O 2 /BSA and Δ P 0.1 / S a,O 2 were significantly correlated with minimum arterial oxygen saturation and with arousal index. Obstructive sleep apnoea-hypopnoea syndrome patients have a strong relationship between peripheral chemosensitivity and respiratory response to hypoxia, suggesting that hypoxic stimulation of central chemoreceptors is minimally relevant in obstructive sleep apnoea-hypopnoea syndrome. Moreover, sensitivity of the carotid body in patients with obstructive sleep apnoea-hypopnoea syndrome is related to sleep disruption and to nocturnal hypoxia.
Role of the Human ST6GalNAc-I and ST6GalNAc-II in the Synthesis of the Cancer-Associated Sialyl-Tn Antigen
Authors: Nuno T. Marcos, Sandra Pinho, Catarina Grandela, Andrea Cruz, Bénédicte Samyn-Petit, Anne Harduin-Lepers, Raquel Almeida, Filipe Silva, Vanessa Morais, Julia Costa, Jan Kihlberg, Henrik Clausen, Celso A. Reis
Journal: Cancer Research (2004)

Abstract The Sialyl-Tn antigen (Neu5Acα2–6GalNAc-O-Ser/Thr) is highly expressed in several human carcinomas and is associated with carcinoma aggressiveness and poor prognosis. We characterized two human sialyltransferases, CMP-Neu5Ac:GalNAc-R α2,6-sialyltransferase (ST6GalNAc)-I and ST6GalNAc-II, that are candidate enzymes for Sialyl-Tn synthases. We expressed soluble recombinant hST6GalNAc-I and hST6GalNAc-II and characterized the substrate specificity of both enzymes toward a panel of glycopeptides, glycoproteins, and other synthetic glycoconjugates. The recombinant ST6GalNAc-I and ST6GalNAc-II showed similar substrate specificity toward glycoproteins and GalNAcα-O-Ser/Thr glycopeptides, such as glycopeptides derived from the MUC2 mucin and the HIVgp120. We also observed that the amino acid sequence of the acceptor glycopeptide contributes to the in vitro substrate specificity of both enzymes. We additionally established a gastric cell line, MKN45, stably transfected with the full length of either ST6GalNAc-I or ST6GalNAc-II and evaluated the carbohydrate antigens expression profile induced by each enzyme. MKN45 transfected with ST6GalNAc-I showed high expression of Sialyl-Tn, whereas MKN45 transfected with ST6GalNAc-II showed the biosynthesis of the Sialyl-6T structure [Galβ1–3 (Neu5Acα2–6)GalNAc-O-Ser/Thr]. In conclusion, although both enzymes show similar in vitro activities when Tn antigen alone is available, whenever both Tn and T antigens are present, ST6GalNAc-I acts preferentially on Tn antigen, whereas the ST6GalNAc-II acts preferentially on T antigen. Our results show that ST6GalNAc-I is the major Sialyl-Tn synthase and strongly support the hypothesis that the expression of the Sialyl-Tn antigen in cancer cells is due to ST6GalNAc-I activity.
Mycobacterial culture results of smear-positive patients with suspected pulmonary tuberculosis in Liverpool
Authors: JA Corless, PA Stockton, PD Davies
Journal: European Respiratory Journal (2000)

The aim of this study was to assess the final mycobacterial culture results of patients with smear-positive sputum or bronchial washings and to investigate the efficiency of local tuberculosis (TB) contact-tracing. Retrospective analysis of mycobacterial cultures and contact-tracing was performed in every patient with smear-positive sputum or bronchoalveolar lavage (BAL) in two Liverpool teaching hospitals (1996-1998). Of these patients 116 with smear-positive sputum or BAL were identified. Mycobacterium tuberculosis (M. tuberculosis) was cultured in 57 (49%), environmental mycobacteria in 37 (32%) and cultures were negative in 22 (19%) of the patients. Contact-tracing information was available in 107 of the 116 (92%) patients. A total number of 1,357 contacts were screened for possible tuberculosis. Of these, 420 (31%) were contacts of patients who cultured environmental organisms or had negative cultures. In this study, 51% of smear-positive patients in Liverpool did not have tuberculosis. Inefficiencies in current contact-tracing procedures have been identified which result from screening contacts of index cases that are subsequently found not to have cultured Mycobacterium tuberculosis. The authors believe that there are clear grounds for using rapid tests to identify and type mycobacteria more quickly than current solid or liquid media methods. It is also suggested that regional variations in the frequency of infection with environmental mycobacteria should be considered when formulating tuberculosis contact-tracing procedures.
Autoreactive cytotoxic T lymphocytes in human immunodeficiency virus type 1-infected subjects.
Authors: F di Marzo Veronese, D Arnott, V Barnaba, D J Loftus, K Sakaguchi, C B Thompson, S Salemi, C Mastroianni, A Sette, J Shabanowitz, D F Hunt, E Appella
Journal: The Journal of Experimental Medicine (1996)

A subtractive analysis of peptides eluted from major histocompatibility complex (MHC) class I human histocompatibility leukocyte antigen (HLA)-A2.1 molecules purified from either human immunodeficiency virus type-1 (HIV-1)-infected or uninfected cells was performed using micro high-performance liquid chromatography and mass spectrometry. Three peptides unique to infected cells were identified and found to derive from a single protein, human vinculin, a structural protein not known to be involved in viral pathogenesis. Molecular and cytofluorometric analyses revealed vinculin mRNA and vinculin protein overexpression in B and T lymphocytes from HIV-1-infected individuals. Vinculin peptide-specific CTL activity was readily elicited from peripheral blood lymphocytes of the majority of HLA-A2.1+, HIV+ patients tested. Our observations suggest that atypical vinculin expression and MHC class I-mediated presentation of vinculin-derived peptides accompany HIV infection of lymphoid cells in vivo, with a resultant induction of antivinculin CTL in a significant portion of HIV+ (HLA-A2.1+) individuals.
LYMPHOID CELLS IN DELAYED HYPERSENSITIVITY
Authors: S. B. Salvin, J. Nishio
Journal: The Journal of Experimental Medicine (1972)

X-irradiation up to 480 R does not inhibit either adoptive transfer of delayed hypersensitivity or production in vitro of soluble mediators, such as migration-inhibitory factor (MIF). Above that dosage and as high as 3000 R, adoptive transfer is inhibited, but production of MIF is not. An increase in skin response occurred when 24-48 hr were allowed to elapse after intravenous transfer and before skin testing. Treatment of recipients with colchicine at the time of adoptive transfer inhibited the development of a skin reaction to specific antigen.
Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial
Authors: Oliver A Cornely, Derrick W Crook, Roberto Esposito, André Poirier, Michael S Somero, Karl Weiss, Pamela Sears, Sherwood Gorbach
Journal: The Lancet Infectious Diseases (2012)
CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia
Authors: Joris M. van Montfrans, Andy I.M. Hoepelman, Sigrid Otto, Marielle van Gijn, Lisette van de Corput, Roel A. de Weger, Linda Monaco-Shawver, Pinaki P. Banerjee, Elisabeth A.M. Sanders, Cornelia M. Jol–van der Zijde, Michael R. Betts, Jordan S. Orange, Andries C. Bloem, Kiki Tesselaar
Journal: Journal of Allergy and Clinical Immunology (2011)
A role for prostaglandins and thromboxanes in the exposure of platelet fibrinogen receptors.
Authors: J S Bennett, G Vilaire, J W Burch
Journal: Journal of Clinical Investigation (1981)

Exposure of fibrinogen receptors by a variety of agonists is a prerequisite for platelet aggregation. Because the synthesis of prostaglandins and thromboxane A2 also occurs during platelet aggregation we wondered whether these agents participate in the exposure of platelet fibrinogen receptors. Therefore, we measured the binding of human 125I-fibrinogen to gel-filtered normal human platelets after prostaglandin and thromboxane synthesis had been inhibited by aspirin or indomethacin. The fibrinogen binding assay was performed at 37 degrees C but without stirring to prevent the formation of platelet aggregates. Platelet secretion, measured with [14C]serotonin, did not occur during the procedure. Aspirin or indomethacin inhibited fibrinogen binding stimulated by 10 microM epinephrine by 53%, and inhibited fibrinogen binding stimulated by 1-2 microM ADP by 37.1%. However, ADP at concentrations greater than 2 microM returned fibrinogen binding toward control values. Scatchard analysis demonstrated that aspirin decreased the number but not the affinity of the exposed fibrinogen receptors. To determine whether prostaglandins are capable of directly exposing fibrinogen receptors, prostaglandin H2 was used to stimulate platelets in the fibrinogen binding assay. Prostaglandin H2 exposed approximately 54,000 fibrinogen receptors/platelet and corrected the deficit in receptor exposure induced by aspirin. These studies demonstrate that platelet prostaglandins or thromboxane A2 can play a direct role in the exposure of platelet fibrinogen receptors. In addition, they suggest that the synthesis of prostaglandins and thromboxane A2 by stimulated platelets may be all that is required for optimal secondary platelet aggregation.
Cooperative Inhibition of T-Cell Antigen Receptor Signaling by a Complex between a Kinase and a Phosphatase
Authors: Jean-François Cloutier, André Veillette
Journal: The Journal of Experimental Medicine (1999)

Antigen receptor–triggered T-cell activation is mediated by the sequential action of the Src and Syk/Zap-70 families of protein tyrosine kinases (PTKs). Previously, we reported that another PTK termed p50csk was a potent negative regulator of T-cell receptor (TCR) signaling because of its ability to inactivate Src-related kinases. This inhibitory effect required the catalytic activity of Csk, as well as its Src homology (SH)3 and SH2 domains. Subsequent studies uncovered that, via its SH3 domain, p50csk was associated with PEP, a proline-enriched protein tyrosine phosphatase (PTP) of unknown function expressed in hemopoietic cells. Herein, we have attempted to identify the role of the Csk-PEP complex in T lymphocytes. The results of our experiments showed that, like Csk, PEP was a strong repressor of TCR signaling. This property was dependent on the phosphatase activity of PEP, as well as on the sequence mediating its binding to p50csk. Through reconstitution experiments in Cos-1 cells, evidence was obtained that Csk and PEP act synergistically to inhibit protein tyrosine phosphorylation by Src-related kinases, and that this effect requires their association. Finally, experiments with a substrate-trapping mutant of PEP suggested that PEP functions by dephosphorylating and inactivating the PTKs responsible for T-cell activation. In addition to giving novel insights into the mechanisms involved in the negative regulation of T-cell activation, these findings indicate that the association of an inhibitory PTK with a PTP constitutes a more efficient means of inhibiting signal transduction by Src family kinases in vivo.
Flexible positive airway pressure improves treatment adherence compared with auto-adjusting PAP
Authors: Yuichi Chihara, Tomomasa Tsuboi, Takefumi Hitomi, Masanori Azuma, Kimihiko Murase, Yoshiro Toyama, Yuka Harada, Kensaku Aihara, Kiminobu Tanizawa, Tomohiro Handa, Chikara Yoshimura, Toru Oga, Kazuhiko Yamamoto, Michiaki Mishima, Kazuo Chin
Journal: European Respiratory Journal (2012)

Background: There are no clinical data comparing adherence and quality of life between auto-adjusting positive airway pressure (APAP) and two different flex PAP devices (A-Flex, C-Flex) in patients with obstructive sleep apnea (OSA).

Methods: Ninety-three patients with OSA who were newly diagnosed were randomly assigned to receive 3 months of APAP (n=31), APAP with C-Flex (n=31), or APAP with A-Flex (n=31). Objective adherence was determined after 3 months of CPAP treatment, and the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Calgary Sleep Apnea Quality of Life Index (SAQLI) were examined at baseline and after 3 months. After 3 months, patients in the APAP with A-Flex group and those in the APAP with C-Flex group were crossed over and those in the APAP group were switched to A-Flex for 3 additional months.

Results: The groups were similar demographically. Treatment adherence during the first 3 months was significantly greater in the APAP with C-Flex group (APAP with C-Flex: 5.19±1.84 h/night vs. APAP: 3.96±1.66 h/night vs. APAP with A-Flex: 4.27±2.12 h/night, p = 0.04). There was a significant improvement in 2 of 4 of the SAQLI domain scores and in the ESS and PSQI in the APAP with C-Flex group. Adherence significantly improved among the poor compliers (< 4 h/night of use) in the APAP group after change to APAP with A-Flex (p=0.01).

Conclusions: APAP with C-Flex was a suitable CPAP modality in three type CPAP modalities. Clinical Trial Registration— URL:http://www.clinicaltrials.gov. Unique identifier: [NCT00873977][1].

 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00873977&atom=%2Ferj%2F40%2FSuppl_56%2FP3832.atom
Acute Regulation of the Epithelial Na+ Channel by Phosphatidylinositide 3-OH Kinase Signaling in Native Collecting Duct Principal Cells
Authors: Alexander Staruschenko, Oleh Pochynyuk, Alain Vandewalle, Vladislav Bugaj, James D. Stockand
Journal: Journal of the American Society of Nephrology (2007)

Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ reabsorption in the aldosterone-sensitive distal nephron. Hormones, including aldosterone and insulin, increase ENaC activity, in part by stimulating phosphatidylinositide 3-OH kinase (PI3-K) signaling. Recent studies in heterologous expression systems reveal a close spatiotemporal coupling between PI3-K signaling and ENaC activity with the phospholipid product of this kinase, PI(3,4,5)P3, in some cases, directly binding the channel and increasing open probability (Po). This study tested whether this tight coupling plays a physiologic role in modulating ENaC activity in native tissue and polarized epithelial cells. IGF-I was found to increase Na+ reabsorption across mpkCCDc14 principal cell monolayers in a PI3-K–sensitive manner. Inhibition of PI3-K signaling, moreover, rapidly decreased Na+ reabsorption and ENaC activity in mpkCCDc14 cells that were treated with corticosteroids and IGF-I. These decreases paralleled changes in apical membrane PI(3,4,5)P3 levels, demonstrating tight spatiotemporal coupling between ENaC activity and PI3-K/PI(3,4,5)P3 signaling within this membrane. For further probing of the mechanism underpinning this coupling, cortical collecting ducts (CCD) were isolated from rat and split open to expose the apical membrane for patch-clamp analysis. Inhibition of PI3-K signaling with wortmannin and LY294002 but not its inactive analogue rapidly and markedly decreased the Po of ENaC. Moreover, IGF-I acutely increased Po of ENaC in CCD principal cells in a PI3-K–sensitive manner. Together, these observations stress the importance of tight spatiotemporal coupling between PI3-K signaling and ENaC within the apical membrane of principal cells to the physiologic control of this ion channel.
Mitochondrial DNA Mutation at the D310 (Displacement Loop) Mononucleotide Sequence in the Pathogenesis of Gallbladder Carcinoma
Authors: Moying Tang, Sergio Baez, Martha Pruyas, Alfonso Diaz, Alfonso Calvo, Erick Riquelme, Ignacio I. Wistuba
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Mutations in the mitochondrial DNA (mtDNA) have been observed frequently in human neoplasia, in both coding and noncoding regions. A mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310) within the regulatory displacement loop has been identified recently as a frequent hot spot of deletion/insertion mutations in tumors. We investigated the frequency and pattern of D310 abnormalities in the pathogenesis of gallbladder carcinoma (GBC). Experimental Design: DNA extracted from neoplastic and nonneoplastic archival gallbladder tissue including 123 tumors, 53 dysplastic areas, and 90 histologically normal epithelia adjacent to GBC, chronic cholecystitis, and 15 normal gallbladders were examined by PCR-based assay for D310 mutations, followed by sequencing in a subset of cases. Results: D310 mutation was a relatively frequent (47 of 123; 38%) abnormality in GBC. A very high frequency of mutations were detected in dysplastic (8 of 14; 57%) and normal-appearing gallbladder epithelia (10 of 22; 46%) accompanying GBC, showing a clonal relationship compared with the corresponding tumors. D310 mutations were also detected in dysplastic (8 of 39; 21%) and normal (17 of 68; 25%) epithelia obtained from chronic cholecystitis. A single case of 15 normal gallbladders showed a D310 abnormality. Overall, deletions (67 of 91; 74%) at D310 were more frequent than insertions. Conclusions: D310 mutation at the mtDNA displacement loop is a relatively frequent and early event in the sequential pathogenesis of GBC, being detected in normal-appearing epithelium from chronic cholecystitis. Our findings suggest that mtDNA mutations should be additionally investigated in GBC pathogenesis, and D310 mononucleotide abnormalities could be included in a panel of molecular biomarkers for GBC early detection strategy.
Use of nitric oxide inhalation in COPD
Authors: T. W HIGENBOTTAM
Journal: Thorax (2000)

Ashutosh et al 1report that inhaled nitric oxide (iNO) lowers pulmonary vascular resistance (PVR) in stable patients with chronic obstructive pulmonary disease (COPD) receiving long term oxygen therapy (24 hours' treatment, randomised, double blind, crossover study). Oxygen was delivered via face mask at a rate of 2 l/min into which NO was diluted down from 200 ppm (cylinder) to achieve a final concentration of 25 ppm inspired. The authors conclude that vasodilation and relaxation of the pulmonary arterial bed is responsible for the fall in PVR.

Pulmonary arterial pressures were measured by cardiac catheterisation. Expired air was collected for five minutes and carbon dioxide output (V˙co 2) and deadspace/tidal volume ratio (Vd/Vt) were measured. Cardiac output (CO) was determined by the Fick equation using V˙co 2 and calculations of arterial and mixed venous carbon dioxide contents from directly measured mixed venous and arterial oxygen and carbon dioxide (Po …
Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy
Authors: Jing Wang, Robert A. Anders, Qiang Wu, Dacheng Peng, Judy H. Cho, Yonglian Sun, Reda Karaliukas, Hyung-Sik Kang, Jerrold R. Turner, Yang-Xin Fu
Journal: Journal of Clinical Investigation (2004)

Whether and how T cells contribute to the pathogenesis of immunoglobulin A nephropathy (IgAN) has not been well defined. Here, we explore a murine model that spontaneously develops T cell–mediated intestinal inflammation accompanied by pathological features similar to those of human IgAN. Intestinal inflammation mediated by LIGHT, a ligand for lymphotoxin β receptor (LTβR), not only stimulates IgA overproduction in the gut but also results in defective IgA transportation into the gut lumen, causing a dramatic increase in serum polymeric IgA. Engagement of LTβR by LIGHT is essential for both intestinal inflammation and hyperserum IgA syndrome in our LIGHT transgenic model. Impressively, the majority of patients with inflammatory bowel disease showed increased IgA-producing cells in the gut, elevated serum IgA levels, and severe hematuria, a hallmark of IgAN. These observations indicate the critical contributions of dysregulated LIGHT expression and intestinal inflammation to the pathogenesis of IgAN.
Multistep Nature of Microvascular Recruitment of Ex Vivo–expanded Embryonic Endothelial Progenitor Cells during Tumor Angiogenesis
Authors: Peter Vajkoczy, Sabine Blum, Mathias Lamparter, Reinhard Mailhammer, Ralph Erber, Britta Engelhardt, Dietmar Vestweber, Antonis K. Hatzopoulos
Journal: The Journal of Experimental Medicine (2003)

Tissue neovascularization involves recruitment of circulating endothelial progenitor cells that originate in the bone marrow. Here, we show that a class of embryonic endothelial progenitor cells (Tie-2+, c-Kit+, Sca-1+, and Flk-1-/low), which were isolated at E7.5 of mouse development at the onset of vasculogenesis, retain their ability to contribute to tumor angiogenesis in the adult. Using intravital fluorescence videomicroscopy, we further defined the multistep process of embryonic endothelial progenitor cell (eEPC) homing and incorporation. Circulating eEPCs are specifically arrested in "hot spots" within the tumor microvasculature, extravasate into the interstitium, form multicellular clusters, and incorporate into functional vascular networks. Expression analysis and in vivo blocking experiments provide evidence that the initial cell arrest of eEPC homing is mediated by E- and P-selectin and P-selectin glycoprotein ligand 1. This paper provides the first in vivo insights into the mechanisms of endothelial progenitor cell recruitment and, thus, indicates novel ways to interfere with pathological neovascularization.