tbuckley/cabot-search huggingface dataset:
The combination therapy with inhaled tiotropium bromide and indacaterol in COPD improves the peripheral airway function in static and dynamic status
Authors: Yasuhiro Setoguchi
Journal: European Respiratory Journal (2014)

BACKGROUND: Recently, it has been reported that Indacaterol combined with inhaled Tiotropium bromide in COPD has significant benefits in dyspnea and SGRQ score as well as pulmonary function. This report suggests a reduction in pulmonary hyperinflation resulting from the improvement of peripheral airway obstruction by the combination therapy (Mahler DA, et al. Thorax 67:781-8, 2012)  OBJECTIVES: We physiologically examined the effects to peripheral airway obstruction in COPD by the combination therapy with inhaled tiotropium bromide and Indacaterol.  METHODS: Clinically stable COPD patients were enrolled. Following a 2-week run-in period, patients were randomly allocated to three groups by the envelope method; then they received inhaled tiotropium 18ug q.d. monotherapy (Tio), inhaled indacaterol 150ug q.d. monotherapy (Inda) or combination therapy with inhaled tiotropium q.d. and indacaterol 150ug q.d. (COM) for 4 weeks each by the crossover method. Spirometry, and Impulse Oscillometry (IOS) were performed.  RESULTS: 35 patients (11 in Tio , 12 in Inda, 12 in COM) were analyzed. Compared with monotherapy, COM therapy resulted in significantly improvement of FEV1 and FVC. Peripheral airway function in regular ventilation and after 50% increased hyperventilation as evaluated IOS [X5 (reactance of 5Hz) and AX (integration of reactance from 5 to 20 Hz)] exhibited significant improvement in the combination therapy compared to monotherapy.  CONCLUSIONS: These results suggest that the combination therapy may be more effective in improving peripheral airway function in not only static but also dynamic ventilation in COPD than monotherapy.
Time Course and Mechanisms of Circulating Progenitor Cell Reduction in the Natural History of Type 2 Diabetes
Authors: Gian Paolo Fadini, Elisa Boscaro, Saula de Kreutzenberg, Carlo Agostini, Florian Seeger, Stefanie Dimmeler, Andreas Zeiher, Antonio Tiengo, Angelo Avogaro
Journal: Diabetes Care (2010)

OBJECTIVE Reduction of bone marrow–derived circulating progenitor cells has been proposed as a novel mechanism of cardiovascular disease in type 2 diabetes. The present study was designed to describe the extent and potential mechanisms of progenitor cell reduction during the natural history of type 2 diabetes. RESEARCH DESIGN AND METHODS We identified 425 individuals, divided into seven categories according to carbohydrate metabolism status (normal glucose tolerance [NGT], impaired fasting glucose, impaired glucose tolerance [IGT], and newly diagnosed type 2 diabetes) and diabetes duration (0–9, 10–19, and ≥20 years). These categories were examined as ideally describing the natural history of type 2 diabetes development and progression. We measured CD34+ and CD34+KDR+ progenitor cells by flow cytometry. We also evaluated progenitor cells in 20 coupled bone marrow and peripheral blood samples and examined progenitor cell apoptosis in 34 subjects. RESULTS In comparison to NGT, CD34+ cells were significantly reduced in IGT and had a first nadir in newly diagnosed type 2 diabetes and a second nadir after 20 years of diabetes. Statistical adjustment for possible confounders confirmed that CD34+ cell counts are deeply reduced at time of diagnosis, that they partially recover during the subsequent 0–19 years, and that they dip again after ≥20 years. A similar, but less consistent, trend was detected for CD34+KDR+ cells. Peripheral blood CD34+ cells were directly correlated with bone marrow CD34+ cells and inversely correlated with CD34+ cell apoptosis. CONCLUSIONS Circulating progenitor cell reduction marks the clinical onset of type 2 diabetes. Both defective mobilization and increased apoptosis may account for this phenomenon. While a partial recovery occurs during subsequent years, bone marrow reserve seems exhausted in the long term.
Modeling Gene Expression Evolution with an Extended Ornstein–Uhlenbeck Process Accounting for Within-Species Variation
Authors: Rori V. Rohlfs, Patrick Harrigan, Rasmus Nielsen
Journal: Molecular Biology and Evolution (2013)

Much of the phenotypic variation observed between even closely related species may be driven by differences in gene expression levels. The current availability of reliable techniques like RNA-Seq, which can quantify expression levels across species, has enabled comparative studies. Ornstein–Uhlenbeck (OU) processes have been proposed to model gene expression evolution as they model both random drift and stabilizing selection and can be extended to model changes in selection regimes. The OU models provide a statistical framework that allows comparisons of specific hypotheses of selective regimes, including random drift, constrained drift, and expression level shifts. In this way, inferences may be made about the mode of selection acting on the expression level of a gene. We augment this model to include within-species expression variance, allowing for modeling of nonevolutionary expression variance that could be caused by individual genetic, environmental, or technical variation. Through simulations, we explore the reliability of parameter estimates and the extent to which different selective regimes can be distinguished using phylogenies of varying size using both the typical OU model and our extended model. We find that if individual variation is not accounted for, nonevolutionary expression variation is often mistaken for strong stabilizing selection. The methods presented in this article are increasingly relevant as comparative expression data becomes more available and researchers turn to expression as a primary evolving phenotype.
Comparison of nose and face mask CPAP therapy for sleep apnoea
Authors: I L Mortimore, A T Whittle, N J Douglas
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Many patients with sleep apnoea/hypopnoea syndrome (SAHS) find nasal continuous positive airway pressure (CPAP) treatment unsatisfactory due to side effects related to mouth air leakage. A study was performed to compare side effects with face mask and nose mask CPAP therapy in patients with SAHS, with and without uvulopalatopharyngoplasty (U3P). <h3>METHODS</h3> Twenty newly diagnosed patients with SAHS took part in a randomised double limb trial of face or nose mask CPAP therapy (four weeks per limb) in which CPAP compliance in terms of machine run time was measured and patients answered a symptom questionnaire on side effects resulting from the mask. Ten patients with SAHS with U3P (SAHS/U3P) who were already regular users of nasal CPAP were also given a four week trial of face mask CPAP to compare compliance and symptoms. Ten patients with SAHS were matched with the 10 SAHS/U3P patients for body mass index, age, apnoea/hypopnoea index, and CPAP pressure. Long term compliance was estimated one year after the mask comparison studies. <h3>RESULTS</h3> For patients with SAHS nightly compliance was higher with a nose mask (mean (SE) 5.3 (0.4) hours/night CPAP) than with a face mask (4.3 (0.5) hours/night CPAP), p = 0.01 (mean difference 1.0 hour/night, 95% CI 1.8 to 0.3). Nose masks were rated more comfortable by 19 of 20 patients (p&lt;0.001) despite more mouth leak related symptoms. For SAHS/U3P patients compliance was marginally higher with nose masks (5.1 (0.7) hours/night CPAP) than with face masks (4.0 (0.8) hours/night CPAP), p = 0.07 (mean difference 1.1 hour/night, 95% CI 2.1 to 0.1). Nose masks were rated more comfortable by seven of 10 patients. There were no significant differences in side effect scores with face and nose masks. At one year nine of 10 SAHS patients and nine of 10 SAHS/U3P patients were still using CPAP. Compliance was 5.4 (0.6) hours/night for the SAHS patients and 3.5 (0.4) hours/night for the SAHS/U3P patients, p = 0.02 (mean difference 1.9 hour/night, 95% CI 3.6 to 0.3). <h3>CONCLUSIONS</h3> Compliance is greater with nose mask CPAP than with face mask CPAP because the overall comfort is better and compensates for increased symptoms associated with mouth leakage. Improved face mask design is needed.
Microbes, immunoregulation, and the gut
Authors: G A W Rook
Journal: Gut (2005)

Two distinct, but rapidly converging, areas of research (the hygiene hypothesis and the study of probiotic/prebiotic effects) have emphasised the need to understand, and ultimately to manipulate, our physiological interactions with commensal flora, and with other transient but harmless organisms from the environment that affect immunoregulatory circuits. The story began with allergic disorders but now inflammatory bowel disease is increasingly involved.
MHC class II–dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies
Authors: Nicolas Molnarfi, Ulf Schulze-Topphoff, Martin S. Weber, Juan C. Patarroyo, Thomas Prod’homme, Michel Varrin-Doyer, Aparna Shetty, Christopher Linington, Anthony J. Slavin, Juan Hidalgo, Dieter E. Jenne, Hartmut Wekerle, Raymond A. Sobel, Claude C.A. Bernard, Mark J. Shlomchik, Scott S. Zamvil
Journal: The Journal of Experimental Medicine (2013)

Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B–MHC II−/−), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)–specific B cell receptor (BCR; IgHMOG-mem) but cannot secrete antibodies. B–MHC II−/− mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell– and B cell–dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B–MHC II−/− mice. In the absence of antibodies, IgHMOG-mem mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle–like structures were observed in IgHMOG-mem mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell–targeted therapies.
Cationic solid lipid nanoparticles loaded by cystein proteinase genes as a novel anti-leishmaniasis DNA vaccine delivery system: Characterization and in vitro evaluations
Authors: Delaram Doroud, Alireza Vatanara, Farnaz Zahedifard, Elham Gholami, Rouhollah Vahabpour, Abdolhossein Rouholamini Najafabadi, Sima Rafati
Journal: Journal of Controlled Release (2010)
Prevention of Arthritis by Interleukin 10–producing B Cells
Authors: Claudia Mauri, David Gray, Naseem Mushtaq, Marco Londei
Journal: The Journal of Experimental Medicine (2003)

In this study we have shown that activation of arthritogenic splenocytes with antigen and agonistic anti-CD40 gives raise to a B cell population that produce high levels of interleukin (IL)-10 and low levels of interferon (IFN)-γ. Transfer of these B cells into DBA/1-TcR-β-Tg mice, immunized with bovine collagen (CII) emulsified in complete Freund's adjuvant inhibited T helper type 1 differentiation, prevented arthritis development, and was also effective in ameliorating established disease. IL-10 is essential for the regulatory function of this subset of B cells, as the B cells population isolated from IL-10 knockout mice failed to mediate this protective function. Furthermore, B cells isolated from arthritogenic splenocytes treated in vitro with anti–IL-10/anti–IL-10R were unable to protect recipient mice from developing arthritis. Our results suggest a new role of a subset of B cells in controlling T cell differentiation and autoimmune disorders.
Pertussis toxin inhibits migration of B and T lymphocytes into splenic white pulp cords.
Authors: J G Cyster, C C Goodnow
Journal: The Journal of Experimental Medicine (1995)

The normal migration route of B cells into follicular areas of spleen and lymph nodes is altered in the case of autoreactive cells that have bound self-antigen. To begin characterizing the molecular requirements for B cell migration into follicles, cells were treated with pertussis toxin (PTX), an inhibitor of signaling by many G protein-coupled chemokine receptors. Lymphocyte accumulation in the spleen is not inhibited by PTX and, therefore, the distribution of transferred cells was examined in this tissue. In contrast to untreated cells that localized predominantly in follicular areas within white pulp cords, PTX-treated B cells failed to enter white pulp areas altogether and accumulated in the splenic red pulp. T cells were also excluded from white pulp cords and in the case of both cell types, the adenosine diphosphate-ribosylating subunit of the toxin was required to block white pulp entry. These findings implicate a G protein-coupled receptor in lymphocyte migration into splenic white pulp cords. Exclusion of PTX-treated cells from all organized areas of secondary lymphoid tissues raises the possibility that the association observed between PTX treatment and predisposition to autoimmune disease results from inhibition of tolerance mechanisms that normally operate within secondary lymphoid tissues.
Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial
Authors: Marie Overgaard, Maj-Britt Jensen, Jens Overgaard, Per S Hansen, Carsten Rose, Michael Andersson, Claus Kamby, Mogens Kjaer, Carl C Gadeberg, Birgitte Bruun Rasmussen, Mogens Blichert-Toft, Henning T Mouridsen
Journal: The Lancet (1999)
THE POINTS OF INCIDENCE COMPARED IN CANCER, LEUCODERMA, AND SCLERODERMA
Authors: G. L. Cheatle
Journal: BMJ (1905)

a malignant nature P I was not present at the operation, and as x-ray treatment was not thought of at the time no portion of the growth was removed for examination.As Mr. I?ay says in his notes, which I have already quoted, there was no doubt in his mind or in the minds of those assisting him at the operation that the disease was of a malignant nature, and the clinical history of the case during the eight or ten weeks immediately following the laparotomy seems to justify that conclusion.
Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis
Authors: Dontscho Kerjaschki
Journal: Journal of Clinical Investigation (2001)

The renal glomerulus, the site of plasma ultrafiltration and the production of primary urine (1), is the locus of a number of progressive disorders that lead to chronic renal insufficiency.Before the advent of renal replacement therapies, these diseases invariably led to death by uremia.Still, while these treatments save, or at least extend, patient's lives, they do so at an enormous price, both in human and financial terms.
Electrophysiological Modeling of Cardiac Ventricular Function: From Cell to Organ
Authors: R. L. Winslow, D. F. Scollan, A. Holmes, C. K. Yung, J. Zhang, M. S. Jafri
Journal: Annual Review of Biomedical Engineering (2000)

Three topics of importance to modeling the integrative function of the heart are reviewed. The first is modeling of the ventricular myocyte. Emphasis is placed on excitation-contraction coupling and intracellular Ca2+ handling, and the interpretation of experimental data regarding interval-force relationships. Second, data on use of diffusion tensor magnetic resonance (DTMR) imaging for measuring the anatomical structure of the cardiac ventricles are presented. A method for the semi-automated reconstruction of the ventricles using a combination of gradient recalled acquisition in the steady state (GRASS) and DTMR images is described. Third, we describe how these anatomically and biophysically based models of the cardiac ventricles can be implemented on parallel computers.
Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer
Authors: S.K. Sandhu, A. Omlin, L. Hylands, S. Miranda, L.J. Barber, R. Riisnaes, A.H. Reid, G. Attard, L. Chen, I. Kozarewa, H. Gevensleben, J. Campbell, K. Fenwick, I. Assiotis, D. Olmos, T.A. Yap, P. Fong, N. Tunariu, D. Koh, L.R. Molife, S. Kaye, C.J. Lord, A. Ashworth, J. de Bono
Journal: Annals of Oncology (2013)
Screening for Prostate Cancer: The Roles of Science, Policy, and Opinion in Determining What is Best for Patients
Authors: Steven H. Woolf, MD, MPH, Stephen F. Rothemich, MD
Journal: Annual Review of Medicine (1999)

Controversy over screening for prostate cancer involves both scientific and policy considerations. The principal scientific questions are whether tumors detected by screening are clinically significant, whether screening generates too many false-positive results, and whether early detection lowers morbidity or mortality. Both screening and treatment of prostate cancer can be harmful, making the tradeoff between benefits and risks especially relevant. Studies suggest that this judgment is highly personal, depending on the relative importance that individuals assign to potential outcomes. Opinions and policy considerations also influence views about the appropriateness of screening. Chief among these are personal beliefs about benefits and harms, medicolegal concerns, patient expectations, resource constraints, and opportunity costs. Appropriate policy must discriminate between what is best for populations and for individual patients. The lack of evidence of benefit and the potential harms argue against a societal policy of routine screening. Individual patients who could benefit from screening should be informed about the potential benefits and harms and invited to make a personal choice based on their priorities and concerns.
Genetic control of specific immune suppression. IV. Responsiveness to the random copolymer L-glutamic acid(50)-L-tyrosine(50) induced in BALB/c mice by cyclophosphamide
Authors: P Debre, C Waltenbaugh, ME Dorf, B Benacerraf
Journal: The Journal of Experimental Medicine (1976)

Previous reports from our laboratory have demonstrated the stimulation of specific suppressor T cells in genetic nonresponder mice after immunization with the terpolymer of L- glutamic acid, L-alanine, and L-tyrosine (GAT) (1,2) and with the copolymer of L-glutamic acid and L-tyrosine (GT) (3-5). These findings raise two important questions: (a) do the specific suppressor T cells inhibit an antibody response which would otherwise develop in nonresponder mice; and, (b) can specific helper T cells inhibit an antibody response which would otherwise develop in nonresponder mice; and, (b) can specific helper T-cell activity be detected in these animals. Responsiveness appears to be completely dominant over suppression in (responder x suppressor)F(1) hybrids, therefore, we have been unable to detect suppressor cells in these hybrids after conventional immunization with GAT (2). However , using special conditions of antigen administration, GAT helper activity could be demonstrated in nonresponder DBA/1 (suppressor) mice. Thus, GAT-specific helper activity was not detected in these nonresponder animals after immunization with GAT irrespective of the adjuvant used, but could be stimulated by macrophage-bound GAT or by GAT complexed with methylated bovine serum albumin GAT-MBSA (6). In the current report we have taken advantage of the fact that suppressor T-cell activity is more sensitive to cyclophosphamide treatment than T-cell helper activity (7) to demonstrate the presence of GT-specific helper activity in nonresponder BALB/c mice. We describe: (a) the dose of cyclophosphamide and conditions of treatment which inhibits the well-documented stimulation of specific suppressor T cells in BALB/c mice injected with GT previous to immunization with GT-MBSA, and (b) the ability of cyclophosphamide to permit the development of primary PFC responses to GT in these nonresponder mice. These cyclophosphamide-induced responses are not characterized by the high levels of antibody detected in genetic responder animals.
Rate of Progression of Albuminuria in Type II Diabetes: Five-year prospective study from South India
Authors: Lily John, P S S Sunder, AS Kanagasabapathy
Journal: Diabetes Care (1994)

OBJECTIVE To evaluate the potential risk factors for the progression of albuminuria in type II diabetes. RESEARCH DESIGN AND METHODS A cohort of 481 type II diabetic patients were followed prospectively for 5 years. Blood glucose (BG) and blood pressure (BP) were checkedat 2 monthly intervals, and urinary albumin excretion (UAE) was checked at yearly intervals. Progression of albuminuria was recognized by the development of microalbuminuria and macroalbuminuria and a significant increase in albuminuria within the microalbuminuric range. RESULTS UAE was normal in 349 patients, 93 patients were microalbuminuric, and the rest (39) were macroalbuminuric. Sixty-two patients with normal UAE developed microalbuminuria. Ten patients with normoalbuminuria and 23 with microalbuminuria developed macroalbuminuria during the 5-year observation period with overall incidence of 46.9/1,000 person-years for normoalbuminuria and 58.7/1,000 person-years for microalbuminuria. Baseline UAE was significantly higher in those patients who progressed compared with those patients who did not (normoalbuminuria: 8.5 ± 6 vs. 5.3 ± 4 μg/min, P &amp;lt; 0.001; microalbuminuria: 68.5 ± 57 vs. 47.4 ± 34 μg/min, P &amp;lt; 0.01). Multiple regression analysis revealed initial UAE and diabetes durationto be predictors of albuminuria progression. CONCLUSIONS Initial UAE is a strong predictor of albuminuria progression intype II diabetic patients.
Comorbid Bipolar Disorder and Panic Disorder in Families With a High Prevalence of Bipolar Disorder
Authors: Dean F MacKinnon, Peter P Zandi, Jennifer Cooper, James B Potash, Sylvia G Simpson, Elliot Gershon, John Nurnberger, Theodore Reich, J Raymond DePaulo
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Panic attacks are a common complication of affective disorder, although the etiologic relationship of panic and affective symptoms has not been determined. Evidence from a family study suggests that panic attacks and panic disorder may be related genetically to bipolar disorder. This study used diagnostic data from the NIMH Bipolar Disorder Genetics Initiative to assess in a separate, larger family set the familiality of panic combined with bipolar disorder. METHOD: First-degree relatives (N=966) of probands with bipolar I disorder (N=192) and schizoaffective disorder, bipolar type, (N=11) were included in the study. All subjects were interviewed directly and were assigned best-estimate diagnoses for major affective and other psychiatric disorders. The risk of a family member being diagnosed with panic disorder if the proband with bipolar disorder had panic attacks or panic disorder was calculated with logistic regression analysis with generalized estimating equations that controlled for sex and affective disorder subdiagnosis. RESULTS: More than 90% of the probands and first-degree relatives with panic disorder also had an affective disorder diagnosis. Panic disorder was present in 17% of the relatives with recurrent major affective disorder and in 3% of the relatives without recurrent major affective disorder. Risk of panic disorder in relatives with bipolar disorder was increased significantly if the proband had panic attacks or panic disorder. CONCLUSIONS: Risk for panic disorder with familial bipolar disorder appears to be inherited. Inherited risk for panic disorder with bipolar disorder may indicate a shared genetic etiology for both disorders in some families. The patterns of bipolar disorder and panic disorder comorbidity observed in families imply a complex genetic etiology, which may be elucidated by using endophenotypes.