tbuckley/cabot-search huggingface dataset:
The Transient Receptor Potential Vanilloid-1 Channel in Thermoregulation: A Thermosensor It Is Not
Authors: Andrej A. Romanovsky, Maria C. Almeida, Andras Garami, Alexandre A. Steiner, Mark H. Norman, Shaun F. Morrison, Kazuhiro Nakamura, Jeffrey J. Burmeister, Tatiane B. Nucci
Journal: Pharmacological Reviews (2009)

The development of antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel as pain therapeutics has revealed that these compounds cause hyperthermia in humans. This undesirable on-target side effect has triggered a surge of interest in the role of TRPV1 in thermoregulation and revived the hypothesis that TRPV1 channels serve as thermosensors. We review literature data on the distribution of TRPV1 channels in the body and on thermoregulatory responses to TRPV1 agonists and antagonists. We propose that two principal populations of TRPV1-expressing cells have connections with efferent thermoeffector pathways: 1) first-order sensory (polymodal), glutamatergic dorsal-root (and possibly nodose) ganglia neurons that innervate the abdominal viscera and 2) higher-order sensory, glutamatergic neurons presumably located in the median preoptic hypothalamic nucleus. We further hypothesize that all thermoregulatory responses to TRPV1 agonists and antagonists and thermoregulatory manifestations of TRPV1 desensitization stem from primary actions on these two neuronal populations. Agonists act primarily centrally on population 2; antagonists act primarily peripherally on population 1. We analyze what roles TRPV1 might play in thermoregulation and conclude that this channel does not serve as a thermosensor, at least not under physiological conditions. In the hypothalamus, TRPV1 channels are inactive at common brain temperatures. In the abdomen, TRPV1 channels are tonically activated, but not by temperature. However, tonic activation of visceral TRPV1 by nonthermal factors suppresses autonomic cold-defense effectors and, consequently, body temperature. Blockade of this activation by TRPV1 antagonists disinhibits thermoeffectors and causes hyperthermia. Strategies for creating hyperthermia-free TRPV1 antagonists are outlined. The potential physiological and pathological significance of TRPV1-mediated thermoregulatory effects is discussed.
Improvement of coping abilities in patients with systemic lupus erythematosus: a prospective study
Authors: M Haupt
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To evaluate a novel specific psychological intervention aimed at improving coping in patients with systemic lupus erythematosus (SLE). <b>Methods:</b> 34 community living SLE patients were recruited for the study. Intervention was undertaken in groups of up to eight patients and in two blocks over six months each. Eight patients were enrolled as a waiting list group. The 18 group sessions focused on information about the disease and specific problems of SLE patients, combining psychoeducative and psychotherapeutic elements. Psychological and medical evaluations were conducted at baseline and after three, six, and 12 months, using validated instruments. <b>Results:</b> The 34 SLE patients (91% female, mean age 42 years) improved significantly over a six month period on most of the psychological measuring instruments applied, such as depression, anxiety, and overall mental burden. The waiting list group showed no significant changes. <b>Conclusions:</b> Conceptualised psychoeducational support may produce a significant and sustained improvement in coping skills of SLE patients and hence in their quality of life.
Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema
Authors: Anne Le, Rachel Zielinski, Chaoxia He, Michael T. Crow, Shyam Biswal, Rubin M. Tuder, Patrice M. Becker
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Cigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease; however, not all smokers develop disease, suggesting that other factors influence disease development.We sought to determine whether neuropilin-1 (Nrp1), an integral component of receptor complexes mediating alveolar septation and vascular development, was involved in maintenance of normal alveolar structure, and/or altered susceptibility to the effects of CS.Transgenic mice were generated to achieve inducible lung-specific deletion of epithelial Nrp1. We determined whether conditional Nrp1 deletion altered airspace size, then compared the effects of chronic CS or filtered air exposure on airspace size, inflammation, and the balance between cell death and proliferation in conditionally Nrp1-deficient adult mice and littermate controls. Finally, we evaluated the effects of Nrp1 silencing on cell death after acute exposure of A549 cells to cigarette smoke extract or short chain ceramides.Genetic deletion of epithelial Nrp1 in either postnatal or adult lungs resulted in a small increase in airspace size. More notably, both airspace enlargement and apoptosis of type I and type II alveolar epithelial cells were significantly enhanced following chronic CS exposure in conditionally Nrp1-deficient adult mice. Silencing of Nrp1 in A549 cells did not alter cell survival after vehicle treatment but significantly augmented apoptosis after exposure to cigarette smoke extract or ceramide.These data support a role for epithelial Nrp1 in the maintenance of normal alveolar structure and suggest that dysregulation of Nrp1 expression may promote epithelial cell death in response to CS exposure, thereby enhancing emphysema development.
Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome
Authors: Cornelis A Albers, Ana Cvejic, Rémi Favier, Evelien E Bouwmans, Marie-Christine Alessi, Paul Bertone, Gregory Jordan, Ross N W Kettleborough, Graham Kiddle, Myrto Kostadima, Randy J Read, Botond Sipos, Suthesh Sivapalaratnam, Peter A Smethurst, Jonathan Stephens, Katrin Voss, Alan Nurden, Augusto Rendon, Paquita Nurden, Willem H Ouwehand
Journal: Nature Genetics (2011)
Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis
Authors: Anne B. Rossebø, Terje R. Pedersen, Kurt Boman, Philippe Brudi, John B. Chambers, Kenneth Egstrup, Eva Gerdts, Christa Gohlke-Bärwolf, Ingar Holme, Y. Antero Kesäniemi, William Malbecq, Christoph A. Nienaber, Simon Ray, Terje Skjærpe, Kristian Wachtell, Ronnie Willenheimer
Journal: New England Journal of Medicine (2008)

Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results.We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events.During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01).Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.)
Tooth Pulp Tissue Pressure and Hydraulic Permeability
Authors: ARTHUR C. BROWN, DAVID YANKOWITZ
Journal: Circulation Research (1964)

The object of these experiments was to evaluate the hydrostatic pressure and hydraulic permeability of the tooth pulp in situ. A small hole was drilled through the enamel and dentin to the dentinal-pulpal junction in canines and third incisors of anesthetized dogs. A threaded cannula filled with mammalian Ringer's solution was screwed into the hole and connected to a microsyringe and a pressure transducer of very low compliance. Pressure was recorded when the cannula was first inserted into the hole; then small amounts of fluid were injected into the system or withdrawn from the system using the micro-syringe. The equilibrium pressure ( P eq ), measured after transients had disappeared, was fairly constant for a given tooth over long periods of time. Referred to tooth level (which was approximately heart level), P eq averaged 57 mm Hg (range 38 to 78 mm Hg) in the ten teeth tested. Superimposed upon the steady value was a random deviation (± 3 mm Hg), a hysteresis effect resulting in a higher pressure if the measurement had been preceded by injection of fluid rather than withdrawal (± 3 mm Hg), and a continuous drift with time ( + 3 mm Hg/hr). The hydrostatic permeability was calculated from the rate of fluid flow when the pressure was above or below its steady state value. When the pressure was high (fluid being forced into the pulp) flow averaged about 0.33 µl/hr-mm Hg over the range P eq to P eq + 20 mm Hg. When the pressure was low (fluid being withdrawn from the tooth), flow averaged about 0.14 µl/hr-mm Hg over the range P eq to P eq - 20 mm Hg. It is concluded that P eq probably represents the true hydrostatic tissue pressure normally existing within the tooth pulp. This implies a high capillary pressure and thus a relatively high resistance in the venous side of the pulp circulation. The interpretation of hydraulic permeability is not certain, but this quantity probably is related to the ease with which fluid passes into or out of the pulp capillaries.
Nonconventional and new methods in the diagnosis of tuberculosis: feasibility and applicability in the field
Authors: J. C. Palomino
Journal: European Respiratory Journal (2005)

Tuberculosis (TB) remains one of the major causes of death from a single infectious agent worldwide. Of great concern for TB control is the emergence of drug resistance. Since there is no cure for some multidrug-resistant strains of Mycobacterium tuberculosis, there is concern that they may spread around the world, stressing the need for additional control measures, such as new diagnostics, better drugs for treatment, and a more effective vaccine. Pulmonary TB can be diagnosed by its symptoms, chest radiography, sputum smear microscopy and by cultivation of M. tuberculosis, which is considered as the gold standard. Recent advances in molecular biology and molecular epidemiology, and a better understanding of the molecular basis of drug resistance in TB, have provided new tools for rapid diagnosis; however, the high cost of most of these techniques, and their requirement for sophisticated equipment and skilled personnel have precluded their implementation on a routine basis, especially in low-income countries. Other nonconventional diagnostic approaches proposed include the search for biochemical markers, detection of immunological response and early detection of M. tuberculosis by methods other than colony counting. In the present article, some of these approaches will be reviewed and the feasibility for their implementation in diagnostic laboratories will be discussed.
Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse
Authors: Takaaki Sugimoto, Yuriko Ishikawa, Tomohiro Yoshimoto, Nobuki Hayashi, Jiro Fujimoto, Kenji Nakanishi
Journal: The Journal of Experimental Medicine (2004)

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-γ production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-γ–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-γ–expressing Th1 cells, both of which express IL-18 receptor α chain strongly, produce IFN-γ, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor α, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1α upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.
Clinical and Genetic Determinants of Progression of Type 2 Diabetes: A DIRECT Study
Authors: Kaixin Zhou, Louise A. Donnelly, Andrew D. Morris, Paul W. Franks, Chris Jennison, Colin N.A. Palmer, Ewan R. Pearson
Journal: Diabetes Care (2013)

To identify the clinical and genetic factors that explain why the rate of diabetes progression is highly variable between individuals following diagnosis of type 2 diabetes.
Breaking Bad News in Oncology: A Metasynthesis
Authors: Guilhem Bousquet, Massimiliano Orri, Sabine Winterman, Charlotte Brugière, Laurence Verneuil, Anne Revah-Levy
Journal: Journal of Clinical Oncology (2015)

The delivery of bad news by oncologists to their patients is a key moment in the physician-patient relationship. We performed a systematic review of qualitative studies (a metasynthesis) that focused on the experiences and points of view of oncologists about breaking bad news to patients.We searched international publications to identify relevant qualitative research exploring oncologists' perspectives about this topic. Thematic analysis, which compensates for the potential lack of generalizability of the primary studies by their conjoint interpretation, was used to identify key themes and synthesize them. NVivo qualitative analysis software was used.We identified 40 articles (> 600 oncologists) from 12 countries and assessed their quality as good according to the Critical Appraisal Skills Programme (CASP). Two main themes emerged: the patient-oncologist encounter during the breaking of bad news, comprising essential aspects of the communication, including the process of dealing with emotions; and external factors shaping the patient-oncologist encounter, composed of factors that influence the announcement beyond the physician-patient relationship: the family, systemic and institutional factors, and cultural factors.Breaking bad news is a balancing act that requires oncologists to adapt continually to different factors: their individual relationships with the patient, the patient's family, the institutional and systemic environment, and the cultural milieu. Extending the development of the ability to personalize and adapt therapeutic treatment to this realm of communications would be a major step forward from the stereotyped way that oncologists are currently trained in communication skills.
Changes in sequential coronary arteriograms and subsequent coronary events. Surgical Control of the Hyperlipidemias (POSCH) Group
Authors: H Buchwald, J P Matts, L L Fitch, C T Campos, M E Sanmarco, K Amplatz, W R Castaneda-Zuniga, D W Hunter, M B Pearce, J K Bissett
Journal: JAMA (1992)

Assessment of the relationship between changes in sequential coronary arteriograms and subsequent clinical coronary events.The Program on the Surgical Control of the Hyperlipidemias, a randomized secondary atherosclerosis intervention trial, obtained coronary arteriograms at baseline, 3, 5, and 7 or 10 years of follow-up. Assessments of changes between pairs of coronary arteriograms were made by two-member panels blinded to the patients' assigned treatment and to the temporal sequence of the films. The relationship of changes between the baseline and the 3-year follow-up arteriograms and subsequent clinical coronary events was examined.Three university hospitals and one private primary care facility.A total of 838 patients, with 417 patients randomized to the control group and 421 to the intervention group. Of all patients, 695 had baseline and 3-year arteriograms.The control group received American Heart Association Phase II diet instruction and the intervention group received identical dietary instruction plus a partial ileal bypass operation.The use of arteriographic changes as a predictor of subsequent clinical coronary events.Changes between the baseline and the 3-year coronary arteriographic overall disease assessment were significantly associated with subsequent overall and atherosclerotic coronary heart disease mortality (P less than .01). For the combined end point of atherosclerotic coronary heart disease mortality or confirmed nonfatal myocardial infarction, a significant relationship between the overall disease assessment and subsequent clinical events was found in the control group (P less than .0001) and in the surgery group (P = .04). For this combined end point, however, the control and the surgery groups were different with respect to clinical coronary events after 3 years, stratified by the baseline to 3-year overall disease assessment (P less than .001, unadjusted; P = .06, adjusted for 3-year clinical covariates).Coronary arteriographic changes can be used in atherosclerosis intervention trials as a limited surrogate end point for certain clinical coronary events. This relationship is statistically compelling for overall mortality and atherosclerotic coronary heart disease mortality. For an individual patient, changes in the severity of coronary atherosclerosis seen on sequential coronary arteriograms can serve as prognostic indicators for subsequent overall or atherosclerotic coronary heart disease mortality.
Repeatability of cough‐related variables during fog challenges at threshold and suprathreshold stimulus intensity in humans
Authors: G.A. Fontana, T Pantaleo, F. Lavorini, N.M. Maluccio, D Mutolo, M. Pistolesi
Journal: European Respiratory Journal (1999)

Cough-related variables such as cough frequency, time to onset (i.e. the time until the first cough occurs) and the cough index (i.e. the ratio between the cough frequency and the time to onset) may be important when interpreting results of cough challenges for therapeutic interventions or for comparative research purposes. Nevertheless, repeatability (or reproducibility) for these widely used variables has been poorly studied. In thirty normal subjects, coughing was induced by inhalation of threshold (T) and suprathreshold (1.6 x T) concentrations of ultrasonically nebulized distilled water (fog). Cough threshold was taken as the lowest fog concentration that evoked at least one cough effort during two challenges separated by a 30-min interval. During challenges performed at both threshold and suprathreshold stimulus intensity, cough frequency, time to onset, and the cough index were assessed; within-subject repeatability for these variables was subsequently evaluated. Median +/- interquartile range cough threshold value was 0.9+/-0.5 mL x min(-1). During the two challenges performed to assess cough threshold, the mean +/-SD values of cough frequency, time to onset, and cough index were similar (5.0+/-2.7 and 5.3+/-3.1 coughs x min(-1), 32.4+/-13.3 and 32.9+/-13.6 s, and 0.2+/-0.2 and 0.2+/-0.2, respectively). However, none of these cough-related variables proved to be sufficiently repeatable. During the two challenges performed at suprathreshold stimulus intensity, mean values of cough frequency, time to onset, and cough index were also similar (20.0+/-9.0 and 18.2+/-10.2 coughs x min(-1), 13.5+/-5.8 and 12.0+/-4.62 s, and 1.7+/-1.0 and 1.8+/-1.2); furthermore, all considered variable of suprathreshold challenge turned out to be reproducible. In conclusion, during fog challenges at threshold stimulus intensity, cough frequency, time to onset and cough index cannot reliably be used for evaluating cough responses. However, these cough-related variables may represent useful and reliable research tools in the evaluation of suprathreshold cough responses.
A Simple Risk Stratification for Time to Development of Sight-Threatening Diabetic Retinopathy
Authors: Irene M. Stratton, Stephen J. Aldington, David J. Taylor, Amanda I. Adler, Peter H. Scanlon
Journal: Diabetes Care (2012)

The American Diabetes Association and the English NHS Diabetic Eye Screening Program recommend annual screening for diabetic retinopathy (DR) with referral to ophthalmology clinics of patients with sight-threatening DR (STDR). Using only longitudinal data from retinal photographs in the population-based NHS Diabetic Eye Screening Program in Gloucestershire, we developed a simple means to estimate risk of STDR.From 2005, 14,554 patients with no DR or mild nonproliferative DR only at two consecutive annual digital photographic screenings were categorized by the presence of DR in neither, one, or both eyes at each screening and were followed for a further median 2.8 years.Of 7,246 with no DR at either screening, 120 progressed to STDR, equivalent to an annual rate of 0.7%. Of 1,778 with no DR in either eye at first screening and in one eye at second screening, 80 progressed to STDR, equivalent to an annual rate of 1.9% and to a hazard ratio (HR) of 2.9 (95% CI 2.2-3.8) compared with those with no DR. Of 1,159 with background DR in both eyes at both screenings, 299 progressed to STDR equivalent to an annual rate of 11% and an HR of 18.2 (14.7-22.5) compared with individuals with no DR.Combining the results from 2 consecutive years of photographic screening enables estimation of the risk of future development of STDR. In countries with systematic screening programs, these results could inform decisions about screening frequency.