tbuckley/cabot-search huggingface dataset:
WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis
Authors: Melanie Königshoff, Monika Kramer, Nisha Balsara, Jochen Wilhelm, Oana Veronica Amarie, Andreas Jahn, Frank Rose, Ludger Fink, Werner Seeger, Liliana Schaefer, Andreas Günther, Oliver Eickelberg
Journal: Journal of Clinical Investigation (2009)

Idiopathic pulmonary fibrosis (IPF) is characterized by distorted lung architecture and loss of respiratory function. Enhanced (myo)fibroblast activation, ECM deposition, and alveolar epithelial type II (ATII) cell dysfunction contribute to IPF pathogenesis. However, the molecular pathways linking ATII cell dysfunction with the development of fibrosis are poorly understood. Here, we demonstrate, in a mouse model of pulmonary fibrosis, increased proliferation and altered expression of components of the WNT/β-catenin signaling pathway in ATII cells. Further analysis revealed that expression of WNT1-inducible signaling protein–1 (WISP1), which is encoded by a WNT target gene, was increased in ATII cells in both a mouse model of pulmonary fibrosis and patients with IPF. Treatment of mouse primary ATII cells with recombinant WISP1 led to increased proliferation and epithelial-mesenchymal transition (EMT), while treatment of mouse and human lung fibroblasts with recombinant WISP1 enhanced deposition of ECM components. In the mouse model of pulmonary fibrosis, neutralizing mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT. More importantly, these changes in gene expression were associated with marked attenuation of lung fibrosis, including decreased collagen deposition and improved lung function and survival. Our study thus identifies WISP1 as a key regulator of ATII cell hyperplasia and plasticity as well as a potential therapeutic target for attenuation of pulmonary fibrosis.
Exosomal cell-to-cell transmission of alpha synuclein oligomers
Authors: Karin M Danzer, Lisa R Kranich, Wolfgang P Ruf, Ozge Cagsal-Getkin, Ashley R Winslow, Liya Zhu, Charles R Vanderburg, Pamela J McLean
Journal: Molecular Neurodegeneration (2012)

Aggregation of alpha-synuclein (αsyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson's disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of αsyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted αsyn across membranes. The aim of this study is to characterize the transcellular spread of αsyn oligomers and determine their extracellular location.Using a novel protein fragment complementation assay where αsyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that αsyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated αsyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free αsyn oligomers. Specifically, we determine that αsyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of αsyn oligomers is strongly influenced by autophagic activity.Our data suggest that αsyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of αsyn oligomers is a mechanism whereby cells clear toxic αsyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in αsyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies.
Management of Hypertrophic Cardiomyopathy
Authors: R Hopf, M Kaltenbach
Journal: Annual Review of Medicine (1990)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Asthma in adults and its association with chronic rhinosinusitis: The GA<sup>2</sup>LEN survey in Europe
Authors: D. Jarvis, R. Newson, J. Lotvall, D. Hastan, P. Tomassen, T. Keil, M. Gjomarkaj, B. Forsberg, M. Gunnbjornsdottir, J. Minov, G. Brozek, S. E. Dahlen, E. Toskala, M. L. Kowalski, H. Olze, P. Howarth, U. Krämer, J. Baelum, C. Loureiro, L. Kasper, P. J. Bousquet, J. Bousquet, C. Bachert, W. Fokkens, P. Burney
Journal: Allergy (2011)

To cite this article: Jarvis D, Newson R, Lotvall J, Hastan D, Tomassen P, Keil T, Gjomarkaj M, Forsberg B, Gunnbjornsdottir M, Minov J, Brozek G, Dahlen SE, Toskala E, Kowalski ML, Olze H, Howarth P, Krämer U, Baelum J, Loureiro C, Kasper L, Bousquet PJ, Bousquet J, Bachert C, Fokkens W, Burney P. Asthma in adults and its association with chronic rhinosinusitis: The GA 2 LEN survey in Europe. Allergy 2012; 67 : 91–98. Abstract Background: The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population‐based epidemiological surveys. Methods: The Global Allergy and Asthma Network of Excellence (GA 2 LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self‐reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta‐analysis. Results: Over 52 000 adults aged 18–75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65–74 years compared with 15–24 years: 0.72; 95% CI: 0.63–0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20–3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57–13.17). CRS in the absence of nasal allergies was positively associated with late‐onset asthma. Conclusion: Geographical variation in the prevalence of self‐reported asthma was observed across Europe, but overall, self‐reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.
Permeation Properties of Neurotransmitter Transporters
Authors: H A Lester, S Mager, M W Quick, J L Corey
Journal: The Annual Review of Pharmacology and Toxicology (1994)

Since the spread of tobacco from the Americas hundreds of years ago, tobacco cigarettes and, more recently, alternative tobacco products have become global products of nicotine addiction. Within the evolving alternative tobacco product space, electronic ...Read More
Analysis of all New Cases Seen in a Busy Regional Centre Ophthalmic Casualty Department during 24-Week Period
Authors: Stephen A Vernon
Journal: Journal of the Royal Society of Medicine (1983)

A prospective study to record numerical data pertaining to diagnosis, aetiology, modes of referral and disposal of all new cases presenting to a busy city-centre ophthalmic casualty department was carried out between February and July 1981. No restrictions of access were imposed on individuals seeking medical advice. Of the 10 575 patient visits, 7113 were classified as new cases, of which 45% were traumatic in origin, 35% the result of inflammatory processes and 6% of an iatrogenic nature; many of this last group had contact lens-induced disease. An average of 63 patients was seen daily during the study period, although the variation was from 33 to 141. It is suggested that such a service can be highly efficient in terms of man hours per patient in the management of acute ophthalmic problems.
A Clinical Tool for the Prediction of Venous Thromboembolism in Pediatric Trauma Patients
Authors: Christopher R. Connelly, Amy Laird, Jeffrey S. Barton, Peter E. Fischer, Sanjay Krishnaswami, Martin A. Schreiber, David H. Zonies, Jennifer M. Watters
Journal: JAMA Surgery (2015)

Although rare, the incidence of venous thromboembolism (VTE) in pediatric trauma patients is increasing, and the consequences of VTE in children are significant. Studies have demonstrated increasing VTE risk in older pediatric trauma patients and improved VTE rates with institutional interventions. While national evidence-based guidelines for VTE screening and prevention are in place for adults, none exist for pediatric patients, to our knowledge.To develop a risk prediction calculator for VTE in children admitted to the hospital after traumatic injury to assist efforts in developing screening and prophylaxis guidelines for this population.Retrospective review of 536,423 pediatric patients 0 to 17 years old using the National Trauma Data Bank from January 1, 2007, to December 31, 2012. Five mixed-effects logistic regression models of varying complexity were fit on a training data set. Model validity was determined by comparison of the area under the receiver operating characteristic curve (AUROC) for the training and validation data sets from the original model fit. A clinical tool to predict the risk of VTE based on individual patient clinical characteristics was developed from the optimal model.Diagnosis of VTE during hospital admission.Venous thromboembolism was diagnosed in 1141 of 536,423 children (overall rate, 0.2%). The AUROCs in the training data set were high (range, 0.873-0.946) for each model, with minimal AUROC attenuation in the validation data set. A prediction tool was developed from a model that achieved a balance of high performance (AUROCs, 0.945 and 0.932 in the training and validation data sets, respectively; P = .048) and parsimony. Points are assigned to each variable considered (Glasgow Coma Scale score, age, sex, intensive care unit admission, intubation, transfusion of blood products, central venous catheter placement, presence of pelvic or lower extremity fractures, and major surgery), and the points total is converted to a VTE risk score. The predicted risk of VTE ranged from 0.0% to 14.4%.We developed a simple clinical tool to predict the risk of developing VTE in pediatric trauma patients. It is based on a model created using a large national database and was internally validated. The clinical tool requires external validation but provides an initial step toward the development of the specific VTE protocols for pediatric trauma patients.
A Novel Use of Structural Equation Models to Examine Factors Associated With Prediabetes Among Adults Aged 50 Years and Older
Authors: Barbara H. Bardenheier, Kai McKeever Bullard, Carl J. Caspersen, Yiling J. Cheng, Edward W. Gregg, Linda S. Geiss
Journal: Diabetes Care (2013)

To use structural modeling to test a hypothesized model of causal pathways related with prediabetes among older adults in the U.S.Cross-sectional study of 2,230 older adults (≥ 50 years) without diabetes included in the morning fasting sample of the 2001-2006 National Health and Nutrition Examination Surveys. Demographic data included age, income, marital status, race/ethnicity, and education. Behavioral data included physical activity (metabolic equivalent hours per week for vigorous or moderate muscle strengthening, walking/biking, and house/yard work), and poor diet (refined grains, red meat, added sugars, solid fats, and high-fat dairy). Structural-equation modeling was performed to examine the interrelationships among these variables with family history of diabetes, high blood pressure, BMI, large waist (waist circumference: women, ≥ 35 inches; men, ≥ 40 inches), triglycerides ≥ 200 mg/dL, and total and HDL (≥ 60 mg/dL) cholesterol.After dropping BMI and total cholesterol, our best-fit model included three single factors: socioeconomic position (SEP), physical activity, and poor diet. Large waist had the strongest direct effect on prediabetes (0.279), followed by male sex (0.270), SEP (-0.157), high blood pressure (0.122), family history of diabetes (0.070), and age (0.033). Physical activity had direct effects on HDL (0.137), triglycerides (-0.136), high blood pressure (-0.132), and large waist (-0.067); poor diet had direct effects on large waist (0.146) and triglycerides (0.148).Our results confirmed that, while including factors known to be associated with high risk of developing prediabetes, large waist circumference had the strongest direct effect. The direct effect of SEP on prediabetes suggests mediation by some unmeasured factor(s).
Deterioration of exercise capacity after neonatal extracorporeal membrane oxygenation
Authors: M.H.M. van der Cammen-van Zijp, S.J. Gischler, W.C.J. Hop, J.C. de Jongste, D. Tibboel, H. IJsselstijn
Journal: European Respiratory Journal (2011)

Extracorporeal membrane oxygenation (ECMO) provides life support in acute reversible cardiorespiratory failure. Assessment of long-term morbidity is essential to confirm survival advantage. This study aimed to assess exercise capacity in the first 12 yrs of life after neonatal ECMO, and to evaluate the effect of primary diagnosis, lung function or perinatal characteristics on exercise capacity. 120 children who, as neonates, underwent ECMO performed 191 reliable exercise tests according to the Bruce treadmill protocol at ages 5, 8 and/or 12 yrs between 2001 and 2010. Primary diagnoses were meconium aspiration syndrome (n=66), congenital diaphragmatic hernia (n=18) and other diagnoses (n=36). At ages 5, 8 and 12 yrs, ANOVA resulted in mean± se standard deviation score endurance time on the treadmill of -0.5±0.1, -1.1±0.1, and -1.5±0.2, respectively, all significantly less than zero (p&lt;0.001). Exercise capacity declined significantly over time irrespective of the primary diagnosis. Neonates treated with ECMO are at risk of decreased exercise capacity at school age. We therefore propose prolonged follow-up. Proactive advice on sports participation or referral to a physical therapist is recommended, especially when either the parents or the children themselves report impaired exercise capacity.
Effect of pelvic floor muscle training compared with watchful waiting in older women with symptomatic mild pelvic organ prolapse: randomised controlled trial in primary care
Authors: M. Wiegersma, C. M. C. R. Panman, B. J. Kollen, M. Y. Berger, Y. Lisman-Van Leeuwen, J. H. Dekker
Journal: BMJ (2014)

<b>Objective</b> To compare the effects of pelvic floor muscle training and watchful waiting on pelvic floor symptoms in a primary care population of women aged 55 years and over with symptomatic mild pelvic organ prolapse. <b>Design</b> Randomised controlled trial. <b>Setting</b> Dutch primary care. <b>Participants</b> Women aged 55 years or over with symptomatic mild prolapse (leading edge above the hymen) were identified by screening. Exclusion criteria were current prolapse treatment or treatment in the previous year, malignancy of pelvic organs, current treatment for another gynaecological disorder, severe/terminal illness, impaired mobility, cognitive impairment, and insufficient command of the Dutch language. <b>Interventions</b> Pelvic floor muscle training versus watchful waiting. <b>Main outcome measures</b> The primary outcome was change in bladder, bowel, and pelvic floor symptoms measured with the Pelvic Floor Distress Inventory-20 (PFDI-20), three months after the start of treatment. Secondary outcomes were changes in condition specific and general quality of life, sexual function, degree of prolapse, pelvic floor muscle function, and patients' perceived change in symptoms. <b>Results</b> Of the 287 women who were randomised to pelvic floor muscle training (n=145) or watchful waiting (n=142), 250 (87%) completed follow-up. Participants in the intervention group improved by (on average) 9.1 (95% confidence interval 2.8 to 15.4) points more on the PFDI-20 than did participants in the watchful waiting group (P=0.005). Of women in the pelvic floor muscle training group, 57% (82/145) reported an improvement in overall symptoms from the start of the study compared with 13% (18/142) in the watchful waiting group (P&lt;0.001). Other secondary outcomes showed no significant difference between the groups. <b>Conclusions</b> Although pelvic floor muscle training led to a significantly greater improvement in PFDI-20 score, the difference between the groups was below the presumed level of clinical relevance (15 points). Nevertheless, 57% of the participants in the intervention group reported an improvement of overall symptoms. More studies are needed to identify factors related to success of pelvic floor muscle training and to investigate long term effects. <b>Trial registration</b> Dutch Trial Register (www.trialregister.nl) identifier: NTR2047.
Human natural resistance-associated macrophage protein: cDNA cloning, chromosomal mapping, genomic organization, and tissue-specific expression.
Authors: M Cellier, G Govoni, S Vidal, T Kwan, N Groulx, J Liu, F Sanchez, E Skamene, E Schurr, P Gros
Journal: The Journal of Experimental Medicine (1994)

Natural resistance to infection with unrelated intracellular parasites such as Mycobacteria, Salmonella, and Leishmania is controlled in the mouse by a single gene on chromosome 1, designated Bcg, Ity, or Lsh. A candidate gene for Bcg, designated natural resistance-associated macrophage protein (Nramp), has been isolated and shown to encode a novel macrophage-specific membrane protein, which is altered in susceptible animals. We have cloned and characterized cDNA clones corresponding to the human NRAMP gene. Nucleotide and predicted amino acid sequence analyses indicate that the human NRAMP polypeptide encodes a 550-amino acid residue membrane protein with 10-12 putative transmembrane domains, two N-linked glycosylation sites, and an evolutionary conserved consensus transport motif. Identification of genomic clones corresponding to human NRAMP indicates that the gene maps to chromosome 2q35 within a group of syntenic loci conserved with proximal mouse 1. The gene is composed of at least 15 exons, with several exons encoding discrete predicted structural domains of the protein. These studies have also identified an alternatively spliced exon encoded by an Alu element present within intron 4. Although this novel exon was found expressed in vivo, it would introduce a termination codon in the downstream exon V, resulting in a severely truncated protein. Northern blot analyses indicate that NRAMP mRNA expression is tightly controlled in a tissue-specific fashion, with the highest sites of expression being peripheral blood leukocytes, lungs, and spleen. Additional RNA expression studies in cultured cells identified the macrophage as a site of expression of human NRAMP and indicated that increased expression was correlated with an advanced state of differentiation of this lineage.
Biochemical Alterations in Sex Hormone-Induced Hyperplasia and Dysplasia of the Dorsolateral Prostates of Noble Rats
Authors: I. Leav, S.-M. Ho, P. Ofner, F. B. Merk, P. W-L Kwan, D. Damassa
Journal: JNCI Journal of the National Cancer Institute (1988)

Simultaneous implantation of intact Noble (Nb) rats with testosterone and 17β-estradiol (E2)-filled silastic capsules for 16 weeks caused atypical hyperplasia (dysplasia) and striking enlargement exclusively in the dorsolateral prostates (DLPs) of all animals. The dysplastic lesion may be preneoplastic since long-term administration of these steroids to Nb rats is known to induce a high incidence of adenocarcinoma in the DLP. Treatment of rats with nonaromatizable 5α-dihydrotestosterone (DHT) for 16 weeks caused enlargement but not dysplasia, implicating estrogen as a key factor in the genesis of the proliferative lesion. Compared with controls, the testosterone plue E2 treatment caused a 2.5-fold increase in nuclear type II estrogen binding sites which were confined to the DLP. Neither treatment significantly altered androgen content or levels of androgen receptor in the ventral prostate or DLP. Organ cultures of enlarged DLP containing foci of dysplasia metabolized more [3H]DHT than control tissue, which resulted in increased formation of the 5α-androstane-3β-androstanediol has previously been shown to displace [3H]E2 from cytosolic type I estrogen binding sites, the dysplasia may be caused by hyperstimulation of the DLP by the hormones and their normal metabolites produced in abnormal amounts. [J Natl Cancer Inst 1988;80:1045–1053]
Nuclear Signaling in Smooth Muscle Cells
Authors: Karin E. Bornfeldt
Journal: Circulation Research (2006)

he second messenger cyclic GMP (cGMP) mediates signaling in the nervous system, genitourinary system, and the gastrointestinal tract.In the cardiovascular system, cGMP regulates vasorelaxation, vascular remodeling, platelet activation, and cardiac contractility.The ability of cGMP to regulate such a large number of temporally and spatially disparate processes is attributable to the many different isozymes that exist for synthesis and degradation of cGMP.These enzymes exhibit different subcellular localization and mechanisms of activation.Thus, cGMP is synthesized from GTP by both soluble and particulate forms of guanylyl cyclase.Soluble guanylyl cyclases are heterodimeric cytosolic enzymes that consist of ␣ and ␤ subunits.2][3] Soluble guanylyl cyclase is activated by nitric oxide (NO) and NO-releasing drugs.Particulate forms of guanylyl cyclase, on the other hand, are transmembrane proteins that are activated by the natriuretic peptides ANP, BNP, and CNP. 4 Similarly, cGMP is degraded by a large number of cyclic nucleotide phosphodiesterases (PDEs).To date, 21 different PDE genes divided among 11 gene families have been identified in mammals.Most PDE families contain more than one gene, and most genes code for more than one mRNA.Although some PDE gene families hydrolyze cAMP exclusively (PDE4, PDE7, PDE8), many of these enzymes hydrolyze cGMP, or both cAMP and cGMP. 5PDE5 is the major cGMP-specific PDE gene family in some cell types.Other cGMP-hydrolyzing PDE gene families include PDE1, PDE2, PDE6, PDE9, PDE10, PDE11, and possibly PDE3. 6ny particular cell type typically expresses several different guanylyl cyclases and cGMP-hydrolyzing PDEs, which provide the cell with tools to precisely regulate cGMP synthesis and hydrolysis in different subcellular compartments and following exposure to different stimuli.Many of the effects of cGMP are mediated by cGMPdependent protein kinases. 7The cGMP-dependent kinases (cGK or PKG) are serine/threonine kinase dimers encoded by two genes in mammals, cGKI and cGKII.Binding of cGMP to cGK induces a conformational change and exposure of the catalytic center of the molecule, which is then able to phosphorylate a number of substrates in vivo.8] In addition, cGMP exerts effects that are cGK-independent.For example, cGMP can regulate cAMP-dependent protein kinases (PKA) through direct or indirect mechanisms, as well as ion channels and guanine nucleotide exchange factors.