tbuckley/cabot-search huggingface dataset:
The costs of adult asthma in Denmark
Authors: Lars Rauff Skadhauge, David Sherson, Baelum Jesper, Soeren Dahl, Carl Lysbeck Hansen, Øyvind Omland, Torben Sigsgaard, Helene V. Thomsen, Gert Thomsen, Jens Olsen
Journal: European Respiratory Journal (2011)

Introduction and background: Asthma is often associated with health deterioration and reduced working capacity resulting in health-related and productivity costs. Population-based studies on the economic burden of asthma on society and individuals are limited.

Aims and objectives: To estimate the extra costs to society due to adult asthma in Denmark.

Methods: In a population-based cross-sectional asthma survey, 6,950 (70%) individuals aged 20-44 completed an extended ECRHS screening questionnaire. Subjects with current asthma were identified by questions on currently taking any asthma medication, having had an attack of asthma or doctor diagnosed asthma plus asthma-like symptoms during the last 12 months. Employment status was defined by current or last held job. The analyses were based on data on individual level extracted from national registers. The direct (health care) costs were estimated by means of multiple regression models. The productivity costs due to absenteeism were estimated using the human capital approach.

Results: The prevalence of current asthma was 7.7% in males and 10.6% in females. The total average annual extra costs per asthmatic subject in comparison with non-asthmatic subjects were € 2,081 and € 1,922 for males and females, respectively. Productivity costs were the major component accounting for 85% in males and 70% in females. Hospital care expenditures accounted for the greatest percentage of the direct costs in both gender. We extrapolated the average annual costs associated with current asthma to € 352 million in the entire Danish population aged 20-44.

Conclusions: The economic burden of asthma in Denmark is substantial and primarily due to productivity costs accounting for three quarters of the total costs.
Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking granzyme B
Authors: Larissa S. Carnevalli, Roberta Scognamiglio, Nina Cabezas-Wallscheid, Susann Rahmig, Elisa Laurenti, Kohei Masuda, Lars Jöckel, Andrea Kuck, Stefanie Sujer, Apostolos Polykratis, Miriam Erlacher, Manolis Pasparakis, Marieke A.G. Essers, Andreas Trumpp
Journal: The Journal of Experimental Medicine (2014)

The serine protease granzyme B (GzmB) is stored in the granules of cytotoxic T and NK cells and facilitates immune-mediated destruction of virus-infected cells. In this study, we use genetic tools to report novel roles for GzmB as an important regulator of hematopoietic stem cell (HSC) function in response to stress. HSCs lacking the GzmB gene show improved bone marrow (BM) reconstitution associated with increased HSC proliferation and mitochondrial activity. In addition, recipients deficient in GzmB support superior engraftment of wild-type HSCs compared with hosts with normal BM niches. Stimulation of mice with lipopolysaccharide strongly induced GzmB protein expression in HSCs, which was mediated by the TLR4–TRIF–p65 NF-κB pathway. This is associated with increased cell death and GzmB secretion into the BM environment, suggesting an extracellular role of GzmB in modulating HSC niches. Moreover, treatment with the chemotherapeutic agent 5-fluorouracil (5-FU) also induces GzmB production in HSCs. In this situation GzmB is not secreted, but instead causes cell-autonomous apoptosis. Accordingly, GzmB-deficient mice are more resistant to serial 5-FU treatments. Collectively, these results identify GzmB as a negative regulator of HSC function that is induced by stress and chemotherapy in both HSCs and their niches. Blockade of GzmB production may help to improve hematopoiesis in various situations of BM stress.
Coexistence of autoimmune bullous diseases (AIBDs) and psoriasis: A series of 145 cases
Authors: Chika Ohata, Norito Ishii, Hiroshi Koga, Shunpei Fukuda, Chiharu Tateishi, Daisuke Tsuruta, Minao Furumura, Takashi Hashimoto
Journal: Journal of the American Academy of Dermatology (2015)
Comparative studies of inhaled corticosteroids in asthma
Authors: R. Beasley, P.J. Sterk, H.A.M. Kerstjens, M. Decramer
Journal: European Respiratory Journal (2001)

With inhaled corticosteroids being the mainstay of anti-inflammatory treatment in asthma, it is necessary to determine the comparative efficacy and safety of different corticosteroids delivered through different inhaler devices. Over recent years this has assumed considerable importance, with the phasing out of metered dose inhalers using chlorofluorocarbon (CFC) propellants, and with the availability of an increasing number of different dry powder devices or aerosol metered dose inhalers in which alternative hydrofluoroalkane (HFA) propellants have been used. This has led to numerous studies in which the efficacy of inhaled corticosteroid preparations, either dry powder or HFA- containing aerosol metered dose inhalers, have been compared with the same or different inhaled corticosteroids via standard CFC-containing preparations in current use.

Although numerous study designs are available for such comparisons, that most commonly employed has been single high dose comparisons, with the lack of statistical significant differences between the two preparations being proposed to indicate …
Intrarenal Role of Angiotensin II
Authors: RONALD H. FREEMAN, JAMES O. DAVIS, STEPHEN J. VITALE, J. Alan JOHNSON
Journal: Circulation Research (1973)

The analogue, l-sarcosine-8-alanine-angiotensin II, a specific competitive antagonist of the vascular action of angiotensin II in the rat, blocked the decrease in renal blood flow after a single intrarenal injection of angiotensin II but not after an injection of norepinephrine in normal dogs, in a sodium-depleted dog, and in a dog with thoracic vena caval constriction. Infusion of the analogue at 0.2 µg/kg min -1 into the renal artery consistently increased renal blood flow and decreased renal resistance in both sodium-depleted dogs and dogs with vena caval constriction but did not alter these functions in normal dogs. In five sodium-depleted dogs, renal blood flow increased from an average control value of 196 ± 5 ml/min to 222 ± 11 and 246 ± 12 ml/min after 20 and 40 minutes of antagonist infusion (P &lt; 0.01 and P &lt; 0.005, respectively); renal resistance fell from 0.71 ± 0.03 mm Hg/ml min -1 to 0.62 ± 0.06 and 0.54 ± 0.03 mm Hg/ml min -1 (P &lt; 0.005 for the 40-minute value). In five dogs with vena caval constriction, renal blood flow increased from 143 ± 16 ml/min to 178 ± 23 and 190 ± 19 ml/min after 20 and 40 minutes of analogue infusion (P &lt; 0.02 and P &lt; 0.005, respectively); renal resistance fell from 0.90 ± 0.14 mm Hg/ml min -1 to 0.73 ± 0.14 and 0.64 ± 0.10 mm Hg/ml min -1 (P &lt; 0.01 and P &gt; 0.02, respectively). Mean arterial blood pressure was not altered significantly by the analogue when it was infused at 0.2 µg/kg min -1 . Infusion of the analogue at 2.0µ/kg min -1 decreased arterial blood pressure and renal resistance and increased renal blood flow in five sodium-depleted dogs and in three dogs with vena caval constriction. These observations suggest an important intrarenal role for angiotensin II in the homeostatic regulation of renal blood flow in sodium-depleted dogs and in dogs with vena caval constriction.
Farnesoid X receptor is essential for normal glucose homeostasis
Authors: K. Ma
Journal: Journal of Clinical Investigation (2006)

The bile acid receptor farnesoid X receptor (FXR; NR1H4) is a central regulator of bile acid and lipid metabolism. We show here that FXR plays a key regulatory role in glucose homeostasis. FXR-null mice developed severe fatty liver and elevated circulating FFAs, which was associated with elevated serum glucose and impaired glucose and insulin tolerance. Their insulin resistance was confirmed by the hyperinsulinemic euglycemic clamp, which showed attenuated inhibition of hepatic glucose production by insulin and reduced peripheral glucose disposal. In FXR–/– skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted. In skeletal muscle, which does not express FXR, triglyceride and FFA levels were increased, and we propose that their inhibitory effects account for insulin resistance in that tissue. In contrast to the results in FXR–/– mice, bile acid activation of FXR in WT mice repressed expression of gluconeogenic genes and decreased serum glucose. The absence of this repression in both FXR–/– and small heterodimer partner–null (SHP–/–) mice demonstrated that the previously described FXR-SHP nuclear receptor cascade also targets glucose metabolism. Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade.
The Site and Nature of Airway Obstruction after Lung Transplantation
Authors: Stijn E. Verleden, Dragoş M. Vasilescu, Stijn Willems, David Ruttens, Robin Vos, Elly Vandermeulen, Jeroen Hostens, John E. McDonough, Erik K. Verbeken, Johny Verschakelen, Dirk E. Van Raemdonck, Benoît Rondelet, Christiane Knoop, Marc Decramer, Joel Cooper, James C. Hogg, Geert M. Verleden, Bart M. Vanaudenaerde
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: The chronic rejection of lung allografts is attributable to progressive small airway obstruction.Objectives: To determine precisely the site and nature of this type of airway obstruction.Methods: Lungs from patients with rejected lung allografts treated by a second transplant (n = 7) were compared with unused donor (control) lungs (n = 7) using multidetector computed tomography (MDCT) to determine the percentage of visible airways obstructed in each airway generation, micro–computed tomography (microCT) to visualize the site of obstruction, and histology to determine the nature of this obstruction.Measurements and Main Results: The number of airways visible with MDCT was not different between rejected and control lungs. However, 10 ± 7% of observed airways greater than 2 mm in diameter, 50 ± 22% of airways between 1 and 2 mm in diameter, and 73 ± 10% of airways less than 1 mm in diameter were obstructed in the rejected lungs. MicroCT confirmed that the mean lumen diameter of obstructed airways was 647 ± 317 μm but showed no difference in either total number and cross-sectional area of the terminal bronchioles or in alveolar dimensions (mean linear intercept) between groups (P > 0.05). In addition, microCT demonstrated that only segments of the airways are obstructed. Histology confirmed a constrictive form of bronchiolitis caused by expansion of microvascular-rich granulation tissue in some locations and collagen-rich scar tissue in others.Conclusions: Chronic lung allograft rejection is associated with a progressive form of constrictive bronchiolitis that targets conducting airways while sparing larger airways as well as terminal bronchioles and the alveolar surface.
Enhanced binding of peptide antigen to purified class II major histocompatibility glycoproteins at acidic pH.
Authors: P E Jensen
Journal: The Journal of Experimental Medicine (1991)

Helper T lymphocytes recognize peptide antigens stably associated with class II major histocompatibility complex (MHC) glycoproteins on the surface of antigen-presenting cells and serve to regulate a wide variety of immune responses. A previous study from our laboratory had demonstrated that the functional association of various peptide antigens with the antigen-presenting cell membrane was increased at pH 5 as compared to pH 7, consistent with the potential role of acidic endosomal compartments in antigen processing. The mechanism for this effect was not determined. In the present study, assays using purified class II glycoprotein were used to further define this mechanism. The potential requirement for pH-dependent interactions involving non-MHC membrane components was excluded in functional assays with purified class II reconstituted in artificial membranes containing only neutral phospholipids and cholesterol. The association of HEL(104-120) with I-Ed, and OVA(323-339) with I-Ad, was increased at pH 5, as measured by activation of specific T cell hybridomas. An enzyme immunoassay was developed to measure the binding of biotin-labeled peptides to purified class II in detergent micelles. The pH dependence of binding paralleled our previous functional results. Optimum binding of biotin-HEL(104-120) to I-Ed was observed at pH approximately 4.5, whereas maximum binding of biotin-Myo(106-118) to I-Ad occurred at pH approximately 5.5. The latter peptide also bound weakly to I-Ed, but with a pH dependence similar to that observed using HEL(104-120). Further experiments with biotin-HEL(104-120)/I-Ed indicated that both the apparent affinity and the apparent concentration of peptide-binding sites are increased as hydrogen ion concentration is increased from pH 7 to pH 5. The effect of pH in this range was largely reversible and was not associated with a change in peptide dissociation that could be measured with our assay system. Binding was not inhibited in the presence of 1.5 M NaCl, suggesting that electrostatic interactions between HEL(104-120) and I-Ed are not essential for binding. It is proposed that protonation of a critical group(s) in the class II molecule regulates its capacity to form stable complexes with peptide. However, this effect alone does not fully account for the rapid kinetics of peptide binding observed in experiments with intact antigen-presenting cells.
Dual Targeting of EWS-FLI1 Activity and the Associated DNA Damage Response with Trabectedin and SN38 Synergistically Inhibits Ewing Sarcoma Cell Growth
Authors: Patrick J. Grohar, Laure E. Segars, Choh Yeung, Yves Pommier, Maurizio D'Incalci, Arnulfo Mendoza, Lee J. Helman
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The goal of this study is to optimize the activity of trabectedin for Ewing sarcoma by developing a molecularly targeted combination therapy. Experimental Design: We have recently shown that trabectedin interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. In this report, we build on this work to develop a trabectedin-based combination therapy with improved EWS-FLI1 suppression that also targets the drug-associated DNA damage to Ewing sarcoma cells. Results: We demonstrate by siRNA experiments that EWS-FLI1 drives the expression of the Werner syndrome protein (WRN) in Ewing sarcoma cells. Because WRN-deficient cells are known to be hypersensitive to camptothecins, we utilize trabectedin to block EWS-FLI1 activity, suppress WRN expression, and selectively sensitize Ewing sarcoma cells to the DNA-damaging effects of SN38. We show that trabectedin and SN38 are synergistic, demonstrate an increase in DNA double-strand breaks, an accumulation of cells in S-phase and a low picomolar IC50. In addition, SN38 cooperates with trabectedin to augment the suppression of EWS-FLI1 downstream targets, leading to an improved therapeutic index in vivo. These effects translate into the marked regression of two Ewing sarcoma xenografts at a fraction of the dose of camptothecin used in other xenograft studies. Conclusions: These results provide the basis and rationale for translating this drug combination to the clinic. In addition, the study highlights an approach that utilizes a targeted agent to interfere with an oncogenic transcription factor and then exploits the resulting changes in gene expression to develop a molecularly targeted combination therapy. Clin Cancer Res; 20(5); 1190–203. ©2013 AACR.
Reduced Incidence of Invasive Breast Cancer With Raloxifene Among Women at Increased Coronary Risk
Authors: D. Grady, J. A. Cauley, M. J. Geiger, M. Kornitzer, L. Mosca, P. Collins, N. K. Wenger, J. Song, J. Mershon, E. Barrett-Connor
Journal: JNCI Journal of the National Cancer Institute (2008)

In the Raloxifene Use for The Heart trial, 10 101 postmenopausal women with coronary heart disease (CHD) or multiple CHD risk factors were randomly assigned to 60 mg/d raloxifene or to placebo and followed for a median of 5.6 years. Raloxifene, a selective estrogen receptor modulator, was found to reduce the risk of invasive breast cancer and vertebral fractures but not the risk of cardiovascular events. Here, we provide further details about breast cancer incidence by tumor characteristics, duration of treatment, and subgroup. Reported breast cancer was adjudicated by an independent committee based on medical records and pathology reports. The primary analyses used Cox proportional hazards models with time to first breast cancer as the outcome. Subgroup effects were analyzed using similar models with terms for treatment by subgroup. All statistical tests were two-sided. As previously reported, raloxifene reduced the incidence of invasive breast cancer by 44% (hazard ratio [HR] = 0.56; 95% confidence interval [CI] = 0.38 to 0.83; absolute risk reduction = 1.2 invasive breast cancers per 1000 women treated for 1 year). The lower incidence of invasive breast cancer reflected a 55% lower incidence of invasive estrogen receptor (ER)–positive tumors (HR = 0.45; 95% CI = 0.28 to 0.72). However, raloxifene treatment did not reduce the incidence of noninvasive breast cancer or of invasive ER-negative breast cancer. The reduced incidence of invasive breast cancer was similar across subgroups, including those defined by age, body mass index, family history of breast cancer, prior use of postmenopausal hormones, and 5-year estimated risk of invasive breast cancer. Raloxifene reduces risk of invasive ER-positive breast cancer regardless of a woman's baseline breast cancer risk but does not reduce risk of noninvasive or ER-negative breast cancers. These results confirm those of the Multiple Outcomes of Raloxifene Evaluation, a previous randomized trial among women with osteoporosis.
Wilson's disease in Scotland.
Authors: R H Park, P McCabe, G S Fell, R I Russell
Journal: Gut (1991)

The prevalence and clinical features of Wilson9s disease in Scotland were investigated. Thirty three cases were identified but adequate information was available on only 28. In 1989, the prevalence rate was 4 per million. Ten patients with a mean (SEM) age of 18 (1.9) years presented with neurological symptoms, 12 patients aged 14 (1.7) years presented with hepatic symptoms, and six patients aged 12 (0.9) years were asymptomatic siblings of patients with Wilson9s disease. Nine (56%) of the 16 patients who underwent liver biopsy on presentation were found to have cirrhosis. Penicillamine treatment was stopped in nine patients because of: abnormal peripheral blood count (6), rash (2), and patient9s own choice (1). Nineteen patients were alive in 1989 -12 were well, one had chronic liver failure, four chronic neurological disabilities, and two had both chronic liver failure and neurological disabilities. Twelve patients died from: complications of chronic liver failure (2), acute liver failure (4), pneumonia associated with immobility (4), and other causes (2). Several patients who died had received incomplete medical supervision.
Association of Online Patient Access to Clinicians and Medical Records With Use of Clinical Services
Authors: Ted E. Palen, Colleen Ross, J. David Powers, Stanley Xu
Journal: JAMA (2012)

<h3>Context</h3>Prior studies suggest that providing patients with online access to health records and e-mail communication with physicians may substitute for traditional health care services.<h3>Objective</h3>To assess health care utilization by both users and nonusers of online access to health records before and after initiation of MyHealthManager (MHM), a patient online access system.<h3>Design, Setting, and Participants</h3>Retrospective cohort study of the use of health care services by members (≥18 years old) who were continuously enrolled for at least 24 months during the study period March 2005 through June 2010 in Kaiser Permanente Colorado, a group model, integrated health care delivery system. Propensity scores (using age, sex, utilization frequencies, and chronic illnesses) were used for cohort matching. Unadjusted utilization rates were calculated for both MHM users and nonusers and were the basis for difference-of-differences analyses. We also used generalized estimating equations to compare the adjusted rates of utilization of health care services before and after online access.<h3>Main Outcome Measures</h3>Rates of office visits, telephone encounters, after-hours clinic visits, emergency department encounters, and hospitalizations between members with and without online access.<h3>Results</h3>Comparing the unadjusted rates for use of clinical services before and after the index date between the matched cohorts, there was a significant increase in the per-member rates of office visits (0.7 per member per year; 95% CI, 0.6-0.7; P &lt; .001) and telephone encounters (0.3 per member per year; 95% CI, 0.2-0.3; P &lt; .001). There was also a significant increase in per-1000-member rates of after-hours clinic visits (18.7 per 1000 members per year; 95% CI, 12.8-24.3; P &lt; .001), emergency department encounters (11.2 per 1000 members per year; 95% CI, 2.6-19.7; P = .01), and hospitalizations (19.9 per 1000 members per year; 95% CI, 14.6-25.3; P &lt; .001) for MHM users vs nonusers.<h3>Conclusion</h3>Having online access to medical records and clinicians was associated with increased use of clinical services compared with group members who did not have online access.
Ageing and Parkinson's disease: Why is advancing age the biggest risk factor?
Authors: Amy Reeve, Eve Simcox, Doug Turnbull
Journal: Ageing Research Reviews (2014)

As the second most common age related neurodegenerative disease after Alzheimer's disease, the health, social and economic impact resulting from Parkinson's disease will continue to increase alongside the longevity of the population. Ageing remains the biggest risk factor for developing idiopathic Parkinson's disease. Although research into the mechanisms leading to cell death in Parkinson's disease has shed light on many aspects of the pathogenesis of this disorder, we still cannot answer the fundamental question, what specific age related factors predispose some individuals to develop this common neurodegenerative disease. In this review we focus specifically on the neuronal population associated with the motor symptoms of Parkinson's disease, the dopaminergic neurons of the substantia nigra, and try to understand how ageing puts these neurons at risk to the extent that a slight change in protein metabolism or mitochondrial function can push the cells over the edge leading to catastrophic cell death and many of the symptoms seen in Parkinson's disease. We review the evidence that ageing is important for the development of Parkinson's disease and how age related decline leads to the loss of neurons within this disease, before describing exactly how advancing age may lead to substantia nigra neuronal loss and Parkinson's disease in some individuals.
Perioperative Betamethasone Treatment Reduces Signs of Bladder Dysfunction in a Rat Model for Neurapraxia in Female Urogenital Surgery
Authors: Fabio Castiglione, Alice Bergamini, Arianna Bettiga, Trinity J. Bivalacqua, Fabio Benigni, Frank Strittmatter, Giorgio Gandaglia, Patrizio Rigatti, Francesco Montorsi, Petter Hedlund
Journal: European Urology (2012)