tbuckley/cabot-search huggingface dataset:
Fine specificity of genetic regulation of guinea pig T lymphocyte responses to angiotensin II and related peptides
Authors: DW Thomas, K-H Hsieh, JL Schauster, GD Wilner
Journal: The Journal of Experimental Medicine (1981)

Guinea pig T lymphocyte responses to the octapeptide antigen angiotensin II (NH(2)-Asp(1)-Arg(2)-Val(3)-Tyr(4)-Ile(5)-His(6)-Pro(7)-Phe(8)-OH; AII) were examined using various synthetic peptide analogues and homologues. Each peptide antigen was assessed for immunogenicity and antigenicity in strain 2 and strain 13 guinea pigs as determined by in vitro T cell proliferative responses. The genetic control of T cell responses to these peptides was found to be highly specific and capable of distinguishing subtle differences in the antigens. For example, strain 2 guinea pigs responded to AII and were low responders to [Val(5)]-AII, whereas strain 13 animals responded to [Val(5)]-AII but not to AII. The genetic control in this case involved the difference of one methyl group between Val(5) and Ile(5). Differences in T cell responsiveness by strain 2 and strain 13 guinea pigs were also observed with analogues involving para substitutions on the phenyl ring of Tyr(4) and of Phe(8). However, the genetic regulation of T cell responses did not seem to be based on a single peptide residue. For example, removal of Asp(1) allowed strain 13 animals to respond to the Ile(5)-containing analogue, but eliminated responsiveness to the Val(5)-containing analogue. Thus, the first and fifth AII residues are both involved in the regulation of strain 13 T cell responses. Substitutions for Tyr(4) and Phe(8) suggested that the same residue may serve to alter the specificity of T cell responses in one strain, and determine responsiveness or unresponsiveness in the other strain. One of the most striking observations is that T cell responsiveness to the various AII analogues and homologues randomly fluctuates between strain 2 and strain 13 guinea pigs, and in general neither strain responds to the same peptide antigens. This suggests that strain 2 and strain 13 T cell responses are rarely directed against the same antigenic determinants, and that the T cell antigen-combining diversity is usually exclusive between these two strains. These results are discussed with respect to the specificity of Ir gene control and the relationship between Ir gene function and antigen recognition by T cells. Note added in proof: More recent experiments using a new lot of [Val(5)]- AII have indicated that [Val(5)]-AII-immune strain 2 T cells show significant stimulation with AII but remain relatively low responders with [Val(5)]-AII, as shown in Table I. The difference in priming for cross-reactivity for AII with the different lots of [Val(5)]-AII is at present unknown.
Risk of Community-Acquired Pneumonia and Use of Gastric Acid–Suppressive Drugs
Authors: Robert J. F. Laheij
Journal: JAMA (2004)

Reduction of gastric acid secretion by acid-suppressive therapy allows pathogen colonization from the upper gastrointestinal tract. The bacteria and viruses in the contaminated stomach have been identified as species from the oral cavity.To examine the association between the use of acid-suppressive drugs and occurrence of community-acquired pneumonia.Incident acid-suppressive drug users with at least 1 year of valid database history were identified from the Integrated Primary Care Information database between January 1, 1995, and December 31, 2002. Incidence rates for pneumonia were calculated for unexposed and exposed individuals. To reduce confounding by indication, a case-control analysis was conducted nested in a cohort of incident users of acid-suppressive drugs. Cases were all individuals with incident pneumonia during or after stopping use of acid-suppressive drugs. Up to 10 controls were matched to each case for practice, year of birth, sex, and index date. Conditional logistic regression was used to compare the risk of community-acquired pneumonia between use of proton pump inhibitors (PPIs) and H2-receptor antagonists.Community-acquired pneumonia defined as certain (proven by radiography or sputum culture) or probable (clinical symptoms consistent with pneumonia).The study population comprised 364,683 individuals who developed 5551 first occurrences of pneumonia during follow-up. The incidence rates of pneumonia in non-acid-suppressive drug users and acid-suppressive drug users were 0.6 and 2.45 per 100 person-years, respectively. The adjusted relative risk for pneumonia among persons currently using PPIs compared with those who stopped using PPIs was 1.89 (95% confidence interval, 1.36-2.62). Current users of H2-receptor antagonists had a 1.63-fold increased risk of pneumonia (95% confidence interval, 1.07-2.48) compared with those who stopped use. For current PPI users, a significant positive dose-response relationship was observed. For H2-receptor antagonist users, the variation in dose was restricted.Current use of gastric acid-suppressive therapy was associated with an increased risk of community-acquired pneumonia.
Gauging heterogeneity in primary versus recurrent glioblastoma
Authors: Simone P. Niclou
Journal: Neuro-Oncology (2015)

Genetic heterogeneity of malignant tumors is high on the research agenda. Glioblastoma is a prime example of a heterogeneous tumor, in terms of both heterogeneity among patients and within a given tumor. Heterogeneity has been highlighted in large-scale studies comparing gene expression profiles, copy number alterations, gene mutations, and DNA methylation patterns among large cohorts of patients. – 5 Recently several studies have provided evidence for genetically heterogeneous clones within an individual tumor, at the level of copy number aberration and gene expression, DNA ploidy, gene amplification and expression of receptor tyrosine kinases. Amplification of the epidermal growth factor receptor (EGFR) gene is found in 50%–60% of glioblastomas, and about half of these display concomitant expression of the EGFR deletion mutant lacking exons 2–7, commonly termed EGFR variant (v)III. EGFRvIII displays low-level constitutive pathway activity and represents a promising therapeutic target because of its tumor specificity. However, it has long been known that EGFRvIII is detected in only a fraction of cells in EGFR amplified tumors, challenging the effectiveness of EGFRvIII targeting agents. Of note, expression studies are largely based on primary tumor material, while the distribution of EGFRvIII is hardly known in recurrent glioblastoma.
Physical fitness and indices of lifestyle-related diseases before and after interval walking training in middle-aged and older males and females
Authors: M Morikawa, K Okazaki, S Masuki, Y Kamijo, T Yamazaki, H Gen-no, H Nose
Journal: British Journal of Sports Medicine (2009)

Hypothesis Whether increasing peak aerobic capacity for walking (V̇ 2peak ) by interval walking training (IWT) is closely linked with decreasing the indices of lifestyle-related diseases (LSDs) in middle-aged and older people were examined. Methods For 4 months from April to September 2005 or 2006, 246 males and 580 females (∼65 years) performed IWT consisting of ≥5 sets of fast walking at ≥70% V̇ 2peak for 3 min followed by slow walking at ≤40% V̇ 2peak for 3 min ≥4 days/week. Before and after IWT, we measured V̇ 2peak , body mass index (BMI), %body fat, arterial blood pressure, thigh muscle strength and blood parameters. We analysed 198 males and 468 females who had undergone all the measurements both before and after IWT. To examine the hypothesis, we divided the subjects equally into three groups according to their pretraining V̇ 2peak : low, middle and high groups for each sex. Results Before training, it was found that thigh muscle strength and blood high-density lipoprotein cholesterol concentration were lower, whereas body weight, BMI, %body fat, arterial blood pressure and blood glucose were higher in the low group than the high group (all, p&lt;0.05). After training, although V̇ 2peak and thigh muscle strength increased and body weight, BMI, %body fat, blood pressure and blood glucose concentration decreased in all groups (all, p&lt;0.05), the changes were greatest in the low group for both sexes. Conclusion V̇ 2peak at baseline and changes in response to training were closely linked with indices of LSDs.
Disordered Gambling: Etiology, Trajectory, and Clinical Considerations
Authors: Howard J. Shaffer, Ryan Martin
Journal: Annual Review of Clinical Psychology (2011)

Gambling-related research has advanced rapidly during the past 20 years. As a result of expanding interest in pathological gambling (PG), stakeholders (e.g., clinicians, regulators, and policy makers) have a better understanding of excessive gambling, including its etiology (e.g., neurobiological/neurogenetic, psychological, and sociological factors) and trajectory (e.g., initiation, course, and adaptation to gambling exposure). In this article, we examine these advances in PG-related research and then consider some of the clinical implications of these advances. We consider criteria changes for PG recently proposed by the DSM-V Impulse Control Work Group for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). We also review how clinicians can more accurately and efficiently diagnose clients seeking help for gambling-related problems by utilizing brief screens. Finally, we consider the importance of future research that can identify behavioral markers for PG. We suggest that identifying these markers will allow clinicians to make earlier diagnoses, recommend targeted treatments, and advance secondary prevention efforts.
Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling
Authors: Elysia M. Hollams, Marie Deverell, Michael Serralha, Devinda Suriyaarachchi, Faith Parsons, Guicheng Zhang, Nicholas de Klerk, Barbara J. Holt, Claire Ladyman, Agata Sadowska, Julie Rowe, Richard Loh, Peter D. Sly, Patrick G. Holt
Journal: Journal of Allergy and Clinical Immunology (2009)
Involving patients in medical education
Authors: A. Howe
Journal: BMJ (2003)

Patients have always been part of medical education, but we can no longer assume that they will choose to participate. The drive towards informed consent and a more equal partnership in shared decision making in clinical practice implies a need for different approaches to involving patients.1 In addition, recent reforms of medical education now use more structured and extensive patient contact,2 3 and this cannot be achieved solely through opportunistic patient contact in clinics and on wards. Using original data and background literature, we examine what is known about involving patients in medical education and suggest ways to improve learning and patient satisfaction.



Consent must be obtained from all patients before they are involved in teaching

Credit: WILL AND DENI McINTYRE/SPL



This article is based on a search of Medline and references from primary sources, using the keywords consent, patient involvement, patient participation, empowerment, medical, and clinical education and the findings of a workshop at the University of East Anglia examining best practice for involving patients in student learning. The university took its first MBBS students in October 2002. We used purposive sampling to draw participants from groups likely to have a role in involving patients in medical education. Invitations to key organisations resulted in 49 delegates, with about one third clinical staff, one third key education-alists (tutors, faculty members, etc), and one third patients or their advocates. We used focus groups to discuss the following questions:

We compiled data …
Burnout Syndrome in Critical Care Nursing Staff
Authors: Marie Cécile Poncet, Philippe Toullic, Laurent Papazian, Nancy Kentish-Barnes, Jean-Francçois Timsit, Frédéric Pochard, Sylvie Chevret, Benoît Schlemmer, Élie Azoulay
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Burnout syndrome (BOS) associated with stress has been documented in health care professionals in many specialties. The intensive care unit (ICU) is a highly stressful environment. Little is known about BOS in critical care nursing staff.Objectives: To identify determinants of BOS in critical care nurses.Methods: We conducted a questionnaire survey in France. Among 278 ICUs contacted for the study, 165 (59.4%) included 2,525 nursing staff members, of whom 2,392 returned questionnaires with complete Maslach Burnout Inventory data.Measurements and Main Results: Of the 2,392 respondents (82% female), 80% were nurses, 15% nursing assistants, and 5% head nurses. Severe BOS-related symptoms were identified in 790 (33%) respondents. By multivariate analysis, four domains were associated with severe BOS: (1) personal characteristics, such as age (odds ratio [OR], 0.97/yr; confidence interval [CI], 0.96–0.99; p = 0.0008); (2) organizational factors, such as ability to choose days off (OR, 0.69; CI, 0.52–0.91; p = 0.009) or participation in an ICU research group (OR, 0.74; CI, 0.56–0.97; p = 0.03); (3) quality of working relations (1–10 scale), such as conflicts with patients (OR, 1.96; CI, 1.16–1.30; p = 0.01), relationship with head nurse (OR, 0.92/point; CI, 0.86–0.98; p = 0.02) or physicians (OR, 0.81; CI, 0.74–0.87; p = 0.0001); and (4) end-of-life related factors, such as caring for a dying patient (OR, 1.39; CI, 1.04–1.85; p = 0.02), and number of decisions to forego life-sustaining treatments in the last week (OR, 1.14; CI, 1.01–1.29; p = 0.04).Conclusion: One-third of ICU nursing staff had severe BOS. Areas for improvement identified in our study include conflict prevention, participation in ICU research groups, and better management of end-of-life care. Interventional studies are needed to investigate these potentially preventive strategies.
Melanin-concentrating hormone (MCH) modulates C difficile toxin A-mediated enteritis in mice
Authors: E Kokkotou, D O Espinoza, D Torres, I Karagiannides, S Kosteletos, T Savidge, M O'Brien, C Pothoulakis
Journal: Gut (2008)

<h3>Objective:</h3> Melanin-concentrating hormone (MCH) is a hypothalamic orexigenic neuropeptide that regulates energy balance. However, the distribution of MCH and its receptor MCHR1 in tissues other than brain suggested additional, as yet unappreciated, roles for this neuropeptide. Based on previous paradigms and the presence of MCH in the intestine as well as in immune cells, its potential role in gut innate immune responses was examined. <h3>Methods:</h3> In human intestinal xenografts grown in mice, changes in the expression of MCH and its receptors following treatment with <i>Clostridium difficile</i> toxin A, the causative agent of antibiotic-associated diarrhoea in hospitalised patients, were examined. In colonocytes, the effect of <i>C difficile</i> toxin A treatment on MCHR1 expression, and of MCH on interleukin 8 (IL8) expression was examined. MCH-deficient mice and immunoneutralisation approaches were used to examine the role of MCH in the pathogenesis of <i>C difficile</i> toxin A-mediated acute enteritis. <h3>Results:</h3> Upregulation of MCH and MCHR1 expression was found in the human intestinal xenograft model, and of MCHR1 in colonocytes following exposure to toxin A. Treatment of colonocytes with MCH resulted in IL8 transcriptional upregulation, implying a link between MCH and inflammatory pathways. In further support of this view, MCH-deficient mice developed attenuated toxin A-mediated intestinal inflammation and secretion, as did wild-type mice treated with an antibody against MCH or MCHR1. <h3>Conclusion:</h3> These findings signify MCH as a mediator of <i>C difficile</i>-associated enteritis and possibly of additional gut pathogens. MCH may mediate its proinflammatory effects at least in part by acting on epithelial cells in the intestine.
A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy
Authors: Sören Bruhn, Yu Fang, Fredrik Barrenäs, Mika Gustafsson, Huan Zhang, Aelita Konstantinell, Andrea Krönke, Birte Sönnichsen, Anne Bresnick, Natalya Dulyaninova, Hui Wang, Yelin Zhao, Jörg Klingelhöfer, Noona Ambartsumian, Mette K. Beck, Colm Nestor, Elsa Bona, Zou Xiang, Mikael Benson
Journal: Science Translational Medicine (2014)

A module-based strategy identified and validated an important diagnostic and therapeutic candidate gene in allergy.
Imatinib Mesylate Enhances Therapeutic Effects of Gemcitabine in Human Malignant Mesothelioma Xenografts
Authors: Pietro Bertino, Federica Piccardi, Camillo Porta, Roberto Favoni, Michele Cilli, Luciano Mutti, Giovanni Gaudino
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Platelet-derived growth factor receptor β (PDGFRβ), frequently activated in malignant mesothelioma, is a promising cancer therapeutic target. Imatinib mesylate (STI571; Glivec) is a selective inhibitor of tyrosine kinases as bcr-abl, c-kit, c-fms, and PDGFRβ and enhances tumor drug uptake by reducing the interstitial fluid pressure. We previously showed that imatinib mesylate synergizes with gemcitabine and pemetrexed in PDGFRβ-positive mesothelioma cells. Here, we aimed at investigating these combined treatments in a novel mesothelioma model. Experimental Design: REN mesothelioma cells, infected with a lentiviral vector carrying the luciferase gene, were injected in the peritoneum of severe combined immunodeficient mice. This model allowed imaging of live animals treated with pemetrexed or gemcitabine chemotherapeutics, or with imatinib mesylate alone, as well as with a combination of gemcitabine and imatinib mesylate. Results: We show here that, consistent with our previous in vitro studies, gemcitabine inhibited tumor growth, whereas pemetrexed was ineffective, even at the highest dosage tested. Compared with monotreatment, the combination of gemcitabine with imatinib mesylate led to a further tumor growth inhibition and improved mice survival, by a decrease rate of tumor cell proliferation and an increase in number of apoptotic tumor cells. Conclusions: Imatinib mesylate enhances the therapeutic response to gemcitabine, in accordance with our previous in vitro data. These in vivo results validate imatinib mesylate and gemcitabine as a combination treatment of malignant mesothelioma, also in view of its known positive effects on tumor drug uptake. These evidences provide the rationale for the currently ongoing clinical trials.
Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 <scp>G</scp>aucher disease
Authors: Ari Zimran, Nan Wang, Carol Ogg, Eric Crombez, Gabriel M. Cohn, Deborah Elstein
Journal: American Journal of Hematology (2015)

Velaglucerase alfa is a human β-glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7-year experience of the now-completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9-month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ≥1 adverse event, no patient withdrew due to a drug-related adverse event or required premedication. No patient developed anti-drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and -42% (-53%, -31%) and -78% (-94%, -62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near-normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters.
Long Noncoding RNA in Neuroblastoma: New Light on the (Old) N-Myc Story
Authors: Martin Pichler, George Adrian Calin
Journal: JNCI Journal of the National Cancer Institute (2014)

Neuroblastoma is the most common cancer diagnosed during the first year of life (1). Neural crest cells, which normally differenti-ate and migrate to locations of the emerging sympathetic nervous system and adrenal medulla, are the presumptive source of this neoplasm (2). In a comprehensive whole-genome and trancriptome analysis of high-risk neuroblastoma patients, a low median exonic mutation frequency of 0.60 per mega base and notably few recur-rently mutated genes were identified (3). This molecular diversity is reflected by the widely varying disease course, which comprises a range from spontaneous tumor regression to chemotherapy-refrac-tory, highly aggressive disease. Besides the rare familial neuroblas-toma cases (<2%) and their yet-to be identified germline mutations in genes, including the paired-like homeobox 2b (
Neurotoxins that Act on Voltage-Sensitive Sodium Channels in Excitable Membranes
Authors: W A Catterall
Journal: The Annual Review of Pharmacology and Toxicology (1980)

A large number of biological toxins exert their toxic effects by modifying the properties of voltage-sensitive sodium channels involved in action po­ tential generation in nerve, heart, and skeletal muscle. These include the water-soluble heterocyclic guanidines, tetrodotoxin and saxitoxin, the lipid­ soluble polycyclic compounds, veratridine, aconitine, batrachotoxin, and grayanotoxin, and the low-molecular weight, basic polypeptide toxins iso­ lated from scorpion venoms and sea anemone nematocysts. The isolation, chemical characterization, and structure determination of many of these toxins as well as their systematic and comparative pharmacology have been the subject of previous excellent reviews. These aspects are, therefore, not treated in detail here. This review focuses on experiments that have given insight into the cellular and molecular mechanisms of action of these toxins and have revealed common features of their interaction with voltage-sensi­ tive sodium channels.
Sinus Node Reentry
Authors: KARLEN L. PAULAY, P. JACOB VARGHESE, ANTHONY N. DAMATO
Journal: Circulation Research (1973)

The phenomenon of sinus node reentry was investigated in 20 dogs by programed atrial stimulation during sinus rhythm and atrial pacing. Recordings were made simultaneously at multiple atrial sites. In 18 dogs, a closely coupled premature atrial beat (A 2 ) introduced into the region of the coronary sinus, the right or the left atrial appendage, or the Bachmann bundle was followed 100-300 msec later by an accelerated beat (A 3 ) consistent with sinus node reentry. The atrial activation sequence and the P-wave morphology of A 3 and of the spontaneous sinus beats were similar. The occurrence of A 3 during sinus rhythm and atrial pacing was dependent on the coupling interval of A 2 and the arrival time of excitation in the region of the sinus node but was independent of the atrial site at which A 2 was introduced; A 3 could be clearly distinguished from local or atrioventricular node reentry and sinus node entrance block. Moreover, crushing of the sinus node (10 dogs) or vagal stimulation (7 dogs) prevented the appearance of A 3 in all dogs, presumably by blocking the sinus node reentry pathway. During graded vagal stimulation a progressive increase in the A 2 -A 3 interval occurred. Sinus node reentry was sustained for three cycles in 1 dog. Sinus node reentry may be one mechanism for interpolated atrial premature depolarization and some atrial tachyarrhythmias seen clinically.