tbuckley/cabot-search huggingface dataset:
Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect
Authors: Stephanie Sisley, Ruth Gutierrez-Aguilar, Michael Scott, David A. D’Alessio, Darleen A. Sandoval, Randy J. Seeley
Journal: Journal of Clinical Investigation (2014)

Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GLP1 analogs, it remains unclear whether the glucose- and body weight-lowering effects of long-acting GLP1R agonists are via direct action on CNS GLP1R or the result of downstream activation of afferent neuronal GLP1R. We generated mice with either neuronal or visceral nerve-specific deletion of Glp1r and then administered liraglutide, a long-acting GLP1R agonist. We found that neither reduction of GLP1R in the CNS nor in the visceral nerves resulted in alterations in body weight or food intake in animals fed normal chow or a high-fat diet. Liraglutide treatment provided beneficial glucose-lowering effects in both chow- and high-fat-fed mice lacking GLP1R in the CNS or visceral nerves; however, liraglutide was ineffective at altering food intake, body weight, or causing a conditioned taste aversion in mice lacking neuronal GLP1R. These data indicate that neuronal GLP1Rs mediate body weight and anorectic effects of liraglutide, but are not required for glucose-lowering effects.
Increased concentrations of interleukin 1 beta, interleukin-2, and soluble interleukin-2 receptors in endoscopical mucosal biopsy specimens with active inflammatory bowel disease.
Authors: J Brynskov, N Tvede, C B Andersen, M Vilien
Journal: Gut (1992)

Concentrations of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), and soluble IL-2 receptors (sIL-2R) were determined by enzyme linked immunosorbent assays (ELISA) in supernatants of sonicated endoscopical mucosal biopsy specimens from 31 patients with inflammatory bowel disease and 19 controls. IL-1 beta was detected in 53% of the patient supernatants (p = 0.0001), IL-2 in 35% (p = 0.0031), compared with none of the controls. Soluble IL-2R was present in 55% and 26% of the specimens, respectively (p = 0.07). The concentrations of IL-1 beta (p = 0.00015), IL-2 (p = 0.0019), and sIL-2R (p = 0.0073) were highest in the most inflamed biopsy specimens, compared with less inflamed specimens and controls. There were no significant differences in IL-1 beta, IL-2, and sIL-2R concentrations between ulcerative colitis (16) and Crohn's disease patients (15). The results suggest that enhanced cellular immunity operates in vivo at the mucosal level in active inflammatory bowel disease.
A striking local esophageal cytokine expression profile in eosinophilic esophagitis
Authors: Carine Blanchard, Emily M. Stucke, Beatriz Rodriguez-Jimenez, Karen Burwinkel, Margaret H. Collins, Annette Ahrens, Eileen S. Alexander, Bridget K. Buckmeier Butz, Sean C. Jameson, Ajay Kaul, James P. Franciosi, Jonathan P. Kushner, Philip E. Putnam, J. Pablo Abonia, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2011)
Progression from Normal Breast Pathology to Breast Cancer Is Associated with Increasing Prevalence of Mouse Mammary Tumor Virus-Like Sequences in Men and Women
Authors: Caroline E. Ford, Margaret Faedo, Roger Crouch, James S. Lawson, William D. Rawlinson
Journal: Cancer Research (2004)

Abstract Mouse mammary tumor virus (MMTV)-like sequences have been found in up to 40% of breast cancer samples but in &amp;lt;2% of normal breast tissue samples from Australian women studied by our group. Screening of a larger and more diverse cohort of female breast cancer samples has now shown a correlation of MMTV-like sequences with the severity (grade) of breast cancer. Thirty-two percent (43 of 136) of female breast cancer samples were positive for MMTV-like sequences when screened using PCR. A significant gradient of MMTV positivity was observed with increasing severity of cancer from 23% of infiltrating ductal carcinoma (IDC) grade I tumors to 34% of IDC grade II tumors (P = 0.00034) and 38% of IDC grade III tumors (P = 0.00002). We also report for the first time the detection of MMTV-like sequences in 62% (8 of 13) of male breast cancer samples and 19% (10 of 52) of male gynecomastia samples screened. MMTV-like sequences were demonstrated in various premalignant breast lesions of females, including fibroadenoma (20%) and fibrocystic disease (28%) samples, at a significantly higher prevalence than that seen in normal breast tissue (1.8%; P = 0.00001). Study of a longitudinal cohort of female breast cancer patients indicated that MMTV was co-incident with tumor but was not present when tumor was absent on histology. These results support the association of MMTV-like sequences with development of breast tumors in men and women and suggest association of MMTV with increasing severity of cancer.
The relationship between indicators of 'high risk' landing mechanics and knee translations in female athletes
Authors: C A Myers, J E Giphart, M R Torry, K B Shelburne, S L Y Woo, J R Steadman
Journal: British Journal of Sports Medicine (2011)

Background When assessing non-contact anterior cruciate ligament (ACL) injury risk, prospective measures of high valgus knee angle (&gt;8°) and high knee abduction moment (&gt;25 Nm) measured during landings have been shown to predict ACL injury in female athletes. Objective The purpose of this study was to determine the relationships between these ‘high risk’ landing variables and anterior tibial translation (ATT) and lateral tibial translations (LTT). We hypothesised individuals exhibiting high knee valgus angles and/or knee abductor moments will also experience larger ATT and/or LTT during a landing. Design Descriptive laboratory study. Setting Controlled laboratory setting; highly active recreational, high school and college athletes. Participants 15 healthy female athletes (26.1 ± 6.3 years; 167.9 cm ± 6.3, 58.2 ± 5.2 Kg). Assessment of risk factors The subjects performed a drop-landing motion by stepping off a 40 cm platform onto a force plate and then immediately performed a maximum effort vertical jump. Main outcome measurements Knee abductor moment and valgus angle were measured using motion capture and inverse dynamic analyses. ATT and LTT were measured concurrently using high-speed biplane fluoroscopy with sub-millimeter accuracy. Results No significant relationship was noted between peak knee valgus angle (range: −2.9° to 20.8°) and peak ATT or LTT (r=−0.17, r=-0.42, respectively); nor, between peak knee abductor moment (range: 2.5–37.2 N*m) and peak ATT or LTT (r=-0.23, r=-0.09, respectively)(p&gt;0.05). Conclusion The results did not support the hypothesis that high knee valgus angles or abductor moment values will lead to larger ATT or LTT during landing. Although compelling evidence has identified high knee valgus angle and high knee abductor moment as predictive of ACL injury, these parameters did not result in greater knee translations during landing.
Users' Guides to the Medical Literature
Authors: M K Giacomini, D J Cook
Journal: JAMA (2000)

Quantitative research is designed to test well-specified hypotheses, determine whether an intervention did more harm than good, and find out how much a risk factor predisposes persons to disease. Equally important, qualitative research offers insight into emotional and experiential phenomena in health care to determine what, how, and why. There are 4 essential aspects of qualitative analysis. First, the participant selection must be well reasoned and their inclusion must be relevant to the research question. Second, the data collection methods must be appropriate for the research objectives and setting. Third, the data collection process, which includes field observation, interviews, and document analysis, must be comprehensive enough to support rich and robust descriptions of the observed events. Fourth, the data must be appropriately analyzed and the findings adequately corroborated by using multiple sources of information, more than 1 investigator to collect and analyze the raw data, member checking to establish whether the participants' viewpoints were adequately interpreted, or by comparison with existing social science theories. Qualitative studies offer an alternative when insight into the research is not well established or when conventional theories seem inadequate. JAMA. 2000;284:357-362
Alexander Iain Munro Glen
Authors: A. G. D. Glen
Journal: BMJ (2013)

Alexander Iain Munro was born in Govan and followed his father to study medicine at Glasgow University, where he met Evelyne Fisher, his future wife. Iain spent his national service with the frigate flotilla based in Hong Kong. Sea time was mainly on HMS Crane , a veteran of the second world war’s Atlantic convoys, where he was occasionally spotted high in the crow’s nest, reading a correspondence course for the diploma of psychological medicine. Evelyne based herself in Hong Kong, where she was involved in setting up the local blood transfusion service and where the two of them started their great adventure of married life.

On returning to Scotland, Iain started training in psychiatry at Woodilee mental hospital in Glasgow. His father disapproved, saying, “I think it is too early for psychiatry.” Iain, not impressed by the treatments that were available for mental illness, thought the time for psychiatry had come, and his future work was committed to trying to make it so. He realised that there was much he needed to know about medicine and research. Work at Glasgow’s Western Infirmary equipped him for a post in the Medical Research Council’s clinical psychiatry research unit.

The family, now including four children, moved to Chichester in Sussex, and Iain worked with Hugh Davson, the director of …
Associative learning requires associations, not propositions
Authors: Frank Baeyens, Debora Vansteenwegen, Dirk Hermans
Journal: Behavioral and Brain Sciences (2009)

Abstract We discuss findings on evaluative conditioning (EC) that are problematic for the “conscious reasoning/propositional knowledge” account of learning, namely, dissociations between conscious beliefs and acquired (dis)liking. We next argue that, both for EC and for Pavlovian learning in general, conditioned responding cannot rationally be inferred from propositional knowledge type “CS refers to/signals US,” and that, therefore, performance cannot be explained.
Neuroendocrine Prostate Cancer (NEPC) Progressing From Conventional Prostatic Adenocarcinoma: Factors Associated With Time to Development of NEPC and Survival From NEPC Diagnosis—A Systematic Review and Pooled Analysis
Authors: Hai Tao Wang, Yan Hong Yao, Bao Guo Li, Yong Tang, Ji Wu Chang, Jiao Zhang
Journal: Journal of Clinical Oncology (2014)

Purpose An often under-recognized late manifestation of prostate adenocarcinoma (PCa) is the development of treatment-related neuroendocrine prostate cancer (NEPC). The aim of this study is to identify the risk factors related to survival after NEPC diagnosis (NEPCS) and time from initial diagnosis of PCa to development of NEPC (TTNEPC). Patients and Methods A literature search on NEPC was performed using databases such as MEDLINE and EMBASE. Studies were eligible if outcomes data (NEPCS and/or TTNEPC) were reported in patients with a prior history of PCa and histopathologically confirmed NEPC. NEPCS and TTNEPC were evaluated using the Cox regression model with the robust sandwich estimates of the covariance matrix. Results There were 54 eligible publications, contributing 123 patients. The median TTNEPC was 20 months. In multivariable analyses, the Gleason score was significantly associated with shorter TTNEPC (hazard ratio [HR], 1.66; P = .032). The median NEPCS was 7 months. In multivariable analyses, the number of organs with metastatic disease at NEPC was significantly associated with shorter NEPCS (HR, 3.31; P = .001). Type of treatment after NEPC was significantly associated with longer NEPCS, with HRs of 0.66 (radiotherapy v palliative therapy; P = .034), 0.38 (chemotherapy v palliative therapy; P = .018), and 0.29 (chemoradiotherapy v palliative therapy; P = .012), respectively. Conclusion Treatment-related NEPC is an often under-recognized late manifestation of PCa with poor prognosis. Our study found that Gleason score was the only independent factor contributing to TTNEPC. Once NEPC is diagnosed, type of treatment and the number of organs with metastatic disease were the most important factors related to survival.
Front-Line Treatment of Advanced Non–Small-Cell Lung Cancer With Docetaxel and Gemcitabine: A Multicenter Phase II Trial
Authors: Vassilis Georgoulias, Charalambos Kouroussis, Nikos Androulakis, Stelios Kakolyris, Meletios-Athanasios Dimopoulos, Emmanuel Papadakis, Dimosthenis Bouros, Fotini Apostolopoulou, Christos Papadimitriou, Athina Agelidou, Kostas Hatzakis, Kostas Kalbakis, Athanasios Kotsakis, Nikos Vardakis, John Vlachonicolis
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To evaluate the tolerance and efficacy of the combination of docetaxel and gemcitabine in patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-one chemotherapy-naive patients with NSCLC were treated with gemcitabine 900 mg/m 2 intravenously on days 1 and 8 and docetaxel 100 mg/m 2 intravenously on day 8 with granulocyte colony-stimulating factor (150 μg/m 2 , subcutaneously) support from day 9 to day 15. Treatment was repeated every 3 weeks. RESULTS: The patients' median age was 64 years. The World Health Organization performance status was 0 to 1 in 39 patients and 2 in 12 patients. Fifteen patients (29%) had stage IIIB disease, and 36 (71%) had stage IV; histology was mainly squamous cell carcinoma (59%). A partial response was achieved in 19 patients (37.5%; 95% confidence interval, 24% to 50%); stable disease and progressive disease were each observed in 16 patients (31.4%). The median duration of response and the time to tumor progression were 5 and 6 months, respectively. The median survival was 13 months, and the actuarial 1-year survival was 50.7%. Grade 4 anemia and thrombocytopenia were rare (2%). Four patients (8%) developed grade 3 or 4 neutropenia, and all were complicated with fever; there was no treatment-related death. Grade 3 or 4 diarrhea occurred in three patients (6%), grade 2 or 3 neurotoxicity in four patients (8%), grade 2 or 3 asthenia in 10 patients (20%), and grade 2 or 3 edema in 10 patients (20%). CONCLUSION: The combination of docetaxel/gemcitabine is well tolerated, can be used for outpatients, and is active for the treatment of advanced NSCLC. This treatment merits further comparison with other cisplatin- or carboplatin-based combinations.
Concept and Evaluation of Hibernating Myocardium
Authors: Shahbudin H. Rahimtoola, MB, FRCP, MACP
Journal: Annual Review of Medicine (1999)

Hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flows. It can be defined as an exquisitely regulated tissue successfully adapting its activity to prevailing circumstances. It has been documented in patients with angina (chronic stable and/or unstable), acute myocardial infarction, heart failure and/or severe left ventricular dysfunction, and anomalous left coronary artery from the pulmonary artery. The diagnosis of hibernating myocardium involves (a) documenting left ventricular dysfunction at rest and (b) documenting that there is viable myocardium in the area of dysfunction. Tests commonly used for the latter are dobutamine echocardiography, 201Tl isotope studies, and positron image tomography. Revascularization, either by surgery or by interventional catheter techniques, has been shown to improve or normalize the abnormal left ventricular function at rest.
Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination
Authors: Roland Diel, Robert Loddenkemper, Jean-Pierre Zellweger, Giovanni Sotgiu, Lia D'Ambrosio, Rosella Centis, Marieke J. van der Werf, Masoud Dara, Anne Detjen, Peter Gondrie, Lee Reichman, Francesco Blasi, Giovanni Battista Migliori
Journal: European Respiratory Journal (2013)

The introduction of new rapid diagnostic tools for tuberculosis (TB) and the promising TB drugs pipeline together with the development of a new World Health Organization Strategy post 2015 allows new discussions on how to direct TB control. The European Respiratory Society’s European Forum for TB Innovation was created to stimulate discussion on how to best take advantage of old and new opportunities, and advances, to improve TB control and eventually progress towards the elimination of TB. While TB control is aimed at reducing the incidence of TB by early diagnosis and treatment of infectious cases of TB, TB elimination requires focus on sterilising the pool of latently infected individuals, from which future TB cases would be generated. This manuscript describes the three core components that are necessary to implement the elimination strategy fully. 1) Improve diagnosis of latent TB infected individuals. 2) Improve regimens to treat latent TB infection. 3) ensure public health commitment to make both 1) and 2) possible. Old and new evidence is critically described, focusing on the European commitment to reach elimination and on the innovative experiences and best practices available.
Inhaled corticosteroids: a controversial add-on treatment in COPD
Authors: M.A. Puhan
Journal: European Respiratory Journal (2010)

We would like to thank J.E. Hansen for his detailed response to our recently published analysis regarding prevalence of bronchoreversibility in subjects enrolled in the National Emphysema Treatment Trial [1].J.E. Hansen raises a concern that the American Thoracic Society (ATS)/European Respiratory Society (ERS) definition of bronchoreversibility is too restrictive in that it requires both an absolute forced expiratory volume in 1 s (FEV1) o200 mL and a 12% increase in FEV1 to qualify as a positive test, which may underestimate bronchoreversibility in a patient population with very low lung function.J.E. Hansen has asked us for a reanalysis of the data with this in mind.If we use the ATS criteria for bronchoreversibility, 121 (22.2%) subjects met these criteria at least once during the period of evaluation.If we choose a 12% absolute increase in FEV1 alone as our definition for bronchoreversibility, 452 (83%) subjects met this criterion at least once during the period of evaluation.As J.E. Hansen suspected, the number of subjects meeting this less restrictive criterion is significantly higher, although possibly too high, making the clinical utility less clear.As J.E. Hansen pointed out, identifying the ''perfect'' measure for bronchoreversibility is not an easy task and perhaps should depend on the subject population being studied.The data we present in our paper helps us to better understand the prevalence of bronchoreversibility in the severe emphysema patient population, but the choice of definition for bronchoreversibility should ultimately be determined by the definition that best discriminates patients as they relate to clinically meaningful outcomes.
Targeted Ablation of the Phospholamban Gene Is Associated With a Marked Decrease in Sensitivity in Aortic Smooth Muscle
Authors: Jane Lalli, Judy M. Harrer, Wusheng Luo, Evangelia G. Kranias, Richard J. Paul
Journal: Circulation Research (1997)

Abstract Phospholamban (PLB) is a protein associated with the Ca 2+ -ATPase of the sarcoplasmic reticulum (SR) in cardiac, slow-twitch skeletal, and smooth muscle. PLB inhibits the SR Ca 2+ -ATPase in cardiac muscle; this inhibition is relieved on phosphorylation. The role of PLB in smooth muscle contractility is less clear. To elucidate the role of PLB in vascular smooth muscle contractility in vivo, we used a model in which the PLB gene was targeted in murine embryonic stem cells, generating mice deficient in PLB (PLB − ). The PLB − mice exhibited no gross developmental abnormalities, but marked changes in aortic contractility were observed. The time course of force development with phenylephrine stimulation was faster in the PLB − aorta, suggesting changes in SR Ca 2+ release. No differences were observed for KCl contractures between tissue types for either maximum forces observed or time course of force production; relaxation was faster in 7 of 11 arteries, but this trend did not attain statistical significance. The cumulative concentration–isometric force relations for the PLB − aorta were to the right of the wild-type for both KCl and phenylephrine stimulation, indicating a less sensitive tissue. To investigate whether the observed changes were related to SR function, we inhibited the SR Ca 2+ -ATPase with cyclopiazonic acid (CPA). CPA treatment resulted in a leftward shift of the concentration–isometric force relations for both aorta types, as expected after removal of a major Ca 2+ uptake system. Most interestingly, the differences between PLB and wild-type aorta were abolished by SR inhibition. Our results suggest that PLB is a regulator of the SR Ca 2+ pump in mouse aorta and plays a regulatory role in both KCl-induced and receptor-mediated contractility in vascular smooth muscle.
Subcellular Creatine Kinase Alterations
Authors: E. De Sousa, V. Veksler, A. Minajeva, A. Kaasik, P. Mateo, E. Mayoux, J. Hoerter, X. Bigard, B. Serrurier, R. Ventura-Clapier
Journal: Circulation Research (1999)

Abstract —We have tested the hypothesis that decreased functioning of creatine kinase (CK) at sites of energy production and utilization may contribute to alterations in energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart failure was induced by aortic banding in 3-week-old rats. Myofilaments, sarcoplasmic reticulum (SR), mitochondrial functions, and CK compartmentation were studied in situ using selective membrane permeabilization of left ventricular fibers with detergents (saponin for mitochondria and SR and Triton X-100 for myofibrils). Seven months after surgery, animals were in CHF. A decrease in total CK activity could be accounted for by a 4-fold decrease in activity and content (Western blots) of mitochondrial CK and a 30% decrease in M isoform of CK (MM-CK) activity. In myofibrils, maximal force, crossbridge kinetics, and α-myosin heavy-chain expression decreased, whereas calcium sensitivity of tension development remained unaltered. Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR were estimated from the surface of caffeine-induced tension transient (S Ca ) after loading with different substrates. In CHF, S Ca decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing calcium uptake. Oxidative capacities of the failing myocardium measured as oxygen consumption per gram of fiber dry weight decreased by 28%. Moreover, the control of respiration by creatine, ADP, and AMP was severely impaired. Our observations provide evidence that alterations in CK compartmentation may contribute to alterations of energy fluxes and calcium homeostasis in CHF.