tbuckley/cabot-search huggingface dataset:
Role of inflammation in the hyperreactivity of the airways in asthma.
Authors: K F Chung
Journal: Thorax (1986)

Role of inflammation in the hyperreactivity of the airways in asthma Although asthma is usually diagnosed because of spontaneous and reversible attacks of broncho- constriction, its most characteristic feature is the increased bronchial reactivity to a large variety of pharmacological and physical agents, such as hist- amine, methacholine, leukotrienes, prostaglandins, cold air, and dust.Thus asthmatic subjects develop a greater degree of bronchoconstriction from exposure to these stimuli than do subjects with normal bron- chial reactivity.That this feature of asthmatic airways appears to have a fundamental role in the pathophysiology of asthma is supported by the observation that the severity of the disease correlates closely with the degree of hyperreactivity.'The precise mechanism underlying the hyperreactivity of asthma is unknown.Whether this abnor- mality is inherent in the intrinsic property of airway smooth muscle or is at the level of its neural control remains unclear.The possibility that airways inflammation could be related to the development and maintenance of the bronchial hyperreactivity of asthma has been the subject of increasing research in recent years.Indeed, inflammation of the airways may create conditions that have themselves been pro- posed as possible mechanisms of hyperreactivity, such as bronchial oedema, mucosal hyperpermeability, exposure of epithelial sensory nerve endings, and release of inflammatory mediators.2This article will review (a) the recent experimental data linking the development of airways inflammation to the induction of airways hyperreactivity and (b) the interactions between inflammatory cells and mediators that may be crucial in the pathophysiology of airways hyperreactivity. Airway inflammation in asthmaThe general features of an inflammatory response include vascular dilatation and increased vascular permeability with the formation of an exudate consis- ting of both plasma proteins and migrating inflammatory cells.Inflammatory reactions that affect mucous membranes such as those of the air- ways are also characterised by mucus hypersecretion
Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis
Authors: Charles Matthews, Isabelle Gorenne, Stephen Scott, Nicola Figg, Peter Kirkpatrick, Andrew Ritchie, Martin Goddard, Martin Bennett
Journal: Circulation Research (2006)

Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. VSMCs in fibrous caps expressed markers of senescence (senescence-associated β-galactosidase [SAβG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels. In matched samples from the same individual, plaques demonstrated markedly shorter telomeres than normal vessels. Fibrous cap VSMCs exhibited markedly shorter telomeres compared with normal medial VSMCs. Telomere shortening was closely associated with increasing severity of atherosclerosis. In vitro, plaque VSMCs demonstrated morphological features of senescence, increased SAβG expression, reduced proliferation, and premature senescence. VSMC senescence was mediated by changes in cyclins D/E, p16, p21, and pRB, and plaque VSMCs could reenter the cell cycle by hyperphosphorylating pRB. Both plaque and normal VSMCs expressed low levels of telomerase. However, telomerase expression alone rescued plaque VSMC senescence despite short telomeres, normalizing the cdki/pRB changes. In vivo, plaque VSMCs exhibited oxidative DNA damage, suggesting that telomere damage may be induced by oxidant stress. Furthermore, oxidants induced premature senescence in vitro, with accelerated telomere shortening and reduced telomerase activity. We conclude that human atherosclerosis is characterized by senescence of VSMCs, accelerated by oxidative stress-induced DNA damage, inhibition of telomerase and marked telomere shortening. Prevention of cellular senescence may be a novel therapeutic target in atherosclerosis.
Visualisation of cell death in vivo in patients with acute myocardial infarction
Authors: Leo Hofstra, Ing Han Liem, Ewald A Dumont, Hendricus H Boersma, Waander L van Heerde, Pieter A Doevendans, Ebo DeMuinck, HJJ Wellens, Gerrit J Kemerink, Chris PM Reutelingsperger, Guido A Heidendal
Journal: The Lancet (2000)
Mealtime Glucose Regulation With Nateglinide in Healthy Volunteers
Authors: Jyoti B. Kalbag, Yulia H. Walter, Jerry R. Nedelman, James F. McLeod
Journal: Diabetes Care (2001)

OBJECTIVE— This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide,and placebo on mealtime insulin secretion and glycemic control in healthy subjects. RESEARCH DESIGN AND METHODS— Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose. RESULTS— Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 μU ·ml-1 · min-1, respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P &amp;lt; 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose. CONCLUSIONS— In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.
A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta
Authors: Christopher Whidbey, Maria Isabel Harrell, Kellie Burnside, Lisa Ngo, Alexis K. Becraft, Lakshminarayan M. Iyer, L. Aravind, Jane Hitti, Kristina M. Adams Waldorf, Lakshmi Rajagopal
Journal: The Journal of Experimental Medicine (2013)

Microbial infection of the amniotic fluid is a significant cause of fetal injury, preterm birth, and newborn infections. Group B Streptococcus (GBS) is an important human bacterial pathogen associated with preterm birth, fetal injury, and neonatal mortality. Although GBS has been isolated from amniotic fluid of women in preterm labor, mechanisms of in utero infection remain unknown. Previous studies indicated that GBS are unable to invade human amniotic epithelial cells (hAECs), which represent the last barrier to the amniotic cavity and fetus. We show that GBS invades hAECs and strains lacking the hemolysin repressor CovR/S accelerate amniotic barrier failure and penetrate chorioamniotic membranes in a hemolysin-dependent manner. Clinical GBS isolates obtained from women in preterm labor are hyperhemolytic and some are associated with covR/S mutations. We demonstrate for the first time that hemolytic and cytolytic activity of GBS is due to the ornithine rhamnolipid pigment and not due to a pore-forming protein toxin. Our studies emphasize the importance of the hemolytic GBS pigment in ascending infection and fetal injury.
ERBB2-Mediated Transcriptional Up-regulation of the α5β1 Integrin Fibronectin Receptor Promotes Tumor Cell Survival Under Adverse Conditions
Authors: Christian Spangenberg, Ekkehart U. Lausch, Tatjana M. Trost, Dirk Prawitt, Andreas May, Romy Keppler, Stephan A. Fees, Dirk Reutzel, Carolin Bell, Steffen Schmitt, Ilka B. Schiffer, Achim Weber, Walburgis Brenner, Matthias Hermes, Ugur Sahin, Özlem Türeci, Heinz Koelbl, Jan G. Hengstler, Bernhard U. Zabel
Journal: Cancer Research (2006)

Oncogenic activation of the receptor tyrosine kinase ERBB2 is a key event in the development of a number of epithelial malignancies. In these tumors, high levels of ERBB2 are strongly associated with metastatic disease and poor prognosis. Paradoxically, an inherent cellular response to hypermitogenic signaling by ERBB2 and other oncogenes seems to be growth arrest, rather than proliferation. Molecular characterization of this yet undefined antiproliferative state in independent cell lines overexpressing either wild-type ERBB2 or the mutationally activated receptor unveiled a dramatic induction of the alpha5beta1 integrin fibronectin receptor. alpha5 Integrin up-regulation is mainly a transcriptional response mediated by the hypoxia-inducible transcription factors (HIF), leading to a massive increase in membrane-resident receptor molecules and enhanced fibronectin adhesiveness of the respective cells. Functionally, ERBB2-dependent ligation of fibronectin results in improved survival of mammary adenocarcinoma cells under adverse conditions, like serum withdrawal, hypoxia, and chemotherapy. HIF-1alpha is an independent predictor of poor overall survival in patients with breast cancer. In particular, HIF-1alpha overexpression correlates significantly with early local relapse and distant metastasis, a phenotype also highly characteristic of ERBB2-positive tumors. As HIF-1alpha is known to be stabilized by ERBB2 signaling under normoxic conditions, we propose that alpha5 integrin is a major effector in this regulatory circuit and may represent the molecular basis for the HIF-1alpha-dependent aggressiveness observed in ERBB2-overexpressing breast carcinomas. Hypermitogenic ERBB2 signaling and tumor hypoxia may act synergistically to favor the establishment of chemoresistant dormant micrometastatic cells frequently observed in patients with breast cancer. This new insight could be the basis for additional approaches complementing current cancer therapy.
Spread of Electrical Activity Through the Wall of the Ventricle
Authors: ALLEN M. SCHER, ALLAN C. YOUNG, ARTHUR L. MALMGHEN, RICHARD R. PATON
Journal: Circulation Research (1953)

Multipolar recording technics have been employed to record the spread of excitation through the wall of the ventricle. The construction of isochronous planes in a block of tissue aids in visualizing the direction of spread. The results give direct support to the idea of fast endocardial spread followed by syncytial spread through the wall at a slower rate. No evidence is found that the impulse spreads through the individual cardiac muscle bundles.
PITUITRIN IN LABOUR: A RECORD OF SIXTY CASES, WITH NOTES ON ITS ADMINISTRATION
Authors: P. A. Hendley
Journal: BMJ (1914)

EAPRIL 25, 1914 4. Arrangements -by which every, poor woman-can have mnedical supervision during -pignaucy.Pregnant women who are themselves insured under* the National Insurance Act are entitled to a " Pregnancy sickness benefit " if cer- tified to be incapable of work,.and also to a " Maternity benefit" after parturition.Such women, therefore, should be encouraged to voluntarily notify their pregnancy to their panel doctor or midwife.If to the latter, the midwife should notify the medical officer of health, and these voluntary notifications would enable the potential mother to be medically supervised by the panel doctor or by the medical officer of health's representative.Medical super- vision of pregnant women would be made easy.if the administration of maternitv benefit and pregnancy sick- ness benefit were transferred from the approved societies to the local health authorities.5. As advocated by Dr. Ballantyne in 1891, prematernity wards in large towns, and reserved beds in cottage lhos- pitals in rural districts, should be provided where pregnant women can receive medical treatment.
EGFRvIII Deletion Mutations in Pediatric High-Grade Glioma and Response to Targeted Therapy in Pediatric Glioma Cell Lines
Authors: Dorine A. Bax, Nathalie Gaspar, Suzanne E. Little, Lynley Marshall, Lara Perryman, Marie Regairaz, Marta Viana-Pereira, Raisa Vuononvirta, Swee Y. Sharp, Jorge S. Reis-Filho, João N. Stávale, Safa Al-Sarraj, Rui M. Reis, Gilles Vassal, Andrew D.J. Pearson, Darren Hargrave, David W. Ellison, Paul Workman, Chris Jones
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The epidermal growth factor receptor (EGFR) is amplified and overexpressed in adult glioblastoma, with response to targeted inhibition dependent on the underlying biology of the disease. EGFR has thus far been considered to play a less important role in pediatric glioma, although extensive data are lacking. We have sought to clarify the role of EGFR in pediatric high-grade glioma (HGG). Experimental Design: We retrospectively studied a total of 90 archival pediatric HGG specimens for EGFR protein overexpression, gene amplification, and mutation and assessed the in vitro sensitivity of pediatric glioma cell line models to the small-molecule EGFR inhibitor erlotinib. Results: Amplification was detected in 11% of cases, with corresponding overexpression of the receptor. No kinase or extracellular domain mutations were observed; however, 6 of 35 (17%) cases harbored the EGFRvIII deletion, including two anaplastic oligodendrogliomas and a gliosarcoma overexpressing EGFRvIII in the absence of gene amplification and coexpressing platelet-derived growth factor receptor α. Pediatric glioblastoma cells transduced with wild-type or deletion mutant EGFRvIII were not rendered more sensitive to erlotinib despite expressing wild-type PTEN. Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor α/β in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model. Conclusions: These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric HGG than previously recognized and show the likely necessity of targeting multiple genetic alterations in the tumors of these children. (Clin Cancer Res 2009;15(18):5753–61)
Distinguishing Inflammation from Tumor and Peritumoral Edema by Myeloperoxidase Magnetic Resonance Imaging
Authors: Anne Kleijn, John W. Chen, Jason S. Buhrman, Gregory R. Wojtkiewicz, Yoshiko Iwamoto, Martine L. Lamfers, Anat O. Stemmer-Rachamimov, Samuel D. Rabkin, Ralph Weissleder, Robert L. Martuza, Giulia Fulci
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Inflammation occurs routinely when managing gliomas and is not easily distinguishable from tumor regrowth by current MRI methods. The lack of noninvasive technologies that monitor inflammation prevents us to understand whether it is beneficial or detrimental for the patient, and current therapies do not take this host response in consideration. We aim to establish whether a gadolinium (Gd)-based agent targeting the inflammatory enzyme myeloperoxidase (MPO) can selectively detect intra- and peritumoral inflammation as well as glioma response to treatment by MRI. Methods: We carried out serial Gd-bis-5-HT-DTPA (MPO-Gd) MRI before and after treating rodent gliomas with different doses of oncolytic virus (OV) and analyzed animal survival. The imaging results were compared with histopathologic and molecular analyses of the tumors for macrophage/microglia infiltration, virus persistence, and MPO levels. Results: Elevated MPO activity was observed by MRI inside the tumor and in the peritumoral cerebrum at day 1 post–OV injection, which corresponded with activation/infiltration of myeloid cells inhibiting OV intratumoral persistence. MPO activity decreased, whereas tumor size increased, as the virus and the immune cells were cleared (days 1–7 post–OV injection). A 10-fold increase in viral dose temporally decreased tumor size, but augmented MPO activity, thus preventing extension of viral intratumoral persistence. Conclusions: MPO-Gd MRI can distinguish enhancement patterns that reflect treatment-induced spatiotemporal changes of intratumoral and intracerebral inflammation from those indicating tumor and peritumoral edema. This technology improves the posttreatment diagnosis of gliomas and will increase our understanding of the role of inflammation in cancer therapy. Clin Cancer Res; 17(13); 4484–93. ©2011 AACR.
Effect of oral isotretinoin therapy on saliva volume and composition
Authors: N.J. Reynolds, M. Gough, J.R. Clamp, J.L. Burtn
Journal: British Journal of Dermatology (1991)

Journal Article Effect of oral isotretinoin therapy on saliva volume and composition Get access N.J. Reynolds, N.J. Reynolds Departmeiit of Medicine, Bristol Royal Infirmarif, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar M. Gough, M. Gough Departmeiit of Medicine, Bristol Royal Infirmarif, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.R. Clamp, J.R. Clamp Departmeiit of Medicine, Bristol Royal Infirmarif, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.L. Burtn J.L. Burtn Departmeiit of Medicine, Bristol Royal Infirmarif, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 125, Issue 2, 1 August 1991, Pages 189–190, https://doi.org/10.1111/j.1365-2133.1991.tb06071.x Published: 01 August 1991
A review of human carcinogens—Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish
Authors: Béatrice Secretan, Kurt Straif, Robert Baan, Yann Grosse, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Crystal Freeman, Laurent Galichet, Vincent Cogliano
Journal: The Lancet Oncology (2009)
Chronic Orthostatic Intolerance
Authors: Raffaello Furlan, Giris Jacob, Marie Snell, David Robertson, Alberto Porta, Paul Harris, Rogelio Mosqueda-Garcia
Journal: Circulation (1998)

Chronic orthostatic intolerance (COI) is a debilitating autonomic condition in young adults. Its neurohumoral and hemodynamic profiles suggest possible alterations of postural sympathetic function and of baroreflex control of heart rate (HR).In 16 COI patients and 16 healthy volunteers, intra-arterial blood pressure (BP), ECG, central venous pressure (CVP), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during 75 degrees tilt. Spectral analysis of RR interval and systolic arterial pressure (SAP) variabilities provided indices of sympathovagal modulation of the sinoatrial node (ratio of low-frequency to high-frequency components, LF/HF) and of sympathetic vasomotor control (LFSAP). Baroreflex mechanisms were assessed (1) by the slope of the regression line obtained from changes of RR interval and MSNA evoked by pharmacologically induced alterations in BP and (2) by the index alpha, obtained from cross-spectral analysis of RR and SAP variabilities. At rest, HR, MSNA, LF/HF, and LFSAP were higher in COI patients, whereas BP and CVP were similar in the two groups. During tilt, BP did not change and CVP fell by the same extent in the 2 groups; the increase of HR and LF/HF was more pronounced in COI patients. Conversely, the increase of MSNA was lower in COI than in control subjects. Baroreflex sensitivity was similar in COI and control subjects at rest; tilt reduced alpha similarly in both groups.COI is characterized by an overall enhancement of noradrenergic tone at rest and by a blunted postganglionic sympathetic response to standing, with a compensatory cardiac sympathetic overactivity. Baroreflex mechanisms maintain their functional responsiveness. These data suggest that in COI, the functional distribution of central sympathetic tone to the heart and vasculature is abnormal.
Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors
Authors: Daniel Sifrim, Frank Zerbib
Journal: Gut (2012)

Approximately a third of patients with suspected gastro-oesophageal reflux disease are resistant or partial responders to proton pump inhibitors (PPIs). Many of these patients do not have gastro-oesophageal reflux disease, but suffer from functional heartburn or dyspepsia. The potential mechanisms underlying failure of PPI treatment in patients with reflux-related symptoms include persistence of isolated or mixed acid, weakly acidic, bile or gas reflux, impaired oesophageal mucosal integrity, chemical or mechanical hypersensitivity to refluxates and psychological comorbidity. After thorough clinical evaluation and failure of empirical changes in PPI dose regime, diagnostic investigations include endoscopy and reflux monitoring with pH or pH-impedance monitoring. If symptoms are clearly related to persistent reflux, baclofen, antireflux surgery or pain modulators can be considered. If not, pain modulators are the only currently available therapy.
Impact of heavy metals on hormonal and immunological factors in women with repeated miscarriages
Authors: I Gerhard, S Waibel, V Daniel, B Runnebaum
Journal: Human Reproduction Update (1998)

In 111 women with repeated miscarriages, the urinary excretion of heavy metals was determined in a challenge test with the chelating agent 2,3-dimercaptopropane-l-sulphonic acid in addition to hormonal, chromosomal, immunological and uterine investigations. The heavy metal excretion was correlated to different immunological (natural killer cells, T cell subpopulations) and hormonal (progesterone, oestradiol, prolactin, thyroid stimulating hormone) parameters. We conclude that heavy metals seem to have a negative impact on ovarian as well as on pituitary function. The heavy metal-induced immunological changes may interfere with the physiological adaptation of the immune system to the state of pregnancy with the result of a miscarriage. The observed heavy metal-induced hormonal and immunological changes may be important factors in the pathogenesis of repeated miscarriages.
Selective Rac-1 Inhibition Protects From Diabetes-Induced Vascular Injury
Authors: Carmine Vecchione, Alessandra Aretini, Gennaro Marino, Umberto Bettarini, Roberta Poulet, Angelo Maffei, Mauro Sbroggiò, Lucio Pastore, Maria Teresa Gentile, Antonella Notte, Luca Iorio, Emilio Hirsch, Guido Tarone, Giuseppe Lembo
Journal: Circulation Research (2005)

Diabetes mellitus is a main risk factor for vascular diseases. Vascular injury induced by diabetes mellitus is characterized by endothelial dysfunction attributable to an increased oxidative stress. So far, the molecular mechanisms involved in the vasculotoxic effects of diabetes are only partially known. We examined the effect of diabetes mellitus on oxidative stress and Rac-1 activation, a small G-protein involved in the activation of NADPH oxidase. Our results show that oxidative stress in vessels of different murine models of diabetes mellitus and in endothelial cells treated with high glucose is associated with an increased Rac-1/PAK binding and Rac-1 translocation from cytosol to plasma membrane, thus demonstrating an enhanced Rac-1 activity. More important, selective Rac-1 inhibition by an adenoviral vector carrying a dominant negative mutant of Rac-1 protected from oxidative stress and vascular dysfunction induced by diabetes mellitus. Our study demonstrates that Rac-1 plays a crucial role in diabetes-induced vascular injury, and it could be a target of novel therapeutic approaches to reduce vascular risk in diabetes mellitus.