tbuckley/cabot-search huggingface dataset:
The Specific Regulation Of Immune Responses By CD8<sup>+</sup>T Cells Restricted By The MHC Class Ib Molecule, Qa-1
Authors: Hong Jiang, Leonard Chess
Journal: Annual Review of Immunology (2000)

Over the last three decades considerable evidence has accumulated that CD8 + T cells regulate peripheral immune responses, in part, by specifically controlling the outgrowth of antigen-triggered CD4 + T cells. This regulatory function of CD8 + T cells has been shown, in vivo, to control the emergence of autoreactive CD4 + T cells as well as CD4 + T cells reactive to conventional antigens, including alloantigens. In this review, we summarize the evidence that this immune suppression mediated by CD8 + T cells is dependent, in part, on specific cognate interactions between MHC class I–restricted regulatory CD8 + cells and antigen-activated CD4 + T cells. Moreover, we review the evidence that regulatory CD8 + T cells recognize antigen-activated CD4 + T cells in a TCR specific manner restricted by the MHC class Ib molecule, Qa-1. The Qa-1 molecule may be uniquely qualified to serve this MHC restrictive function because, unlike conventional MHC molecules, it is preferentially and transiently expressed on activated and not resting CD4 + T cells. This may assure that only recently antigen-activated CD4 + T cells expressing Qa-1/TCR peptide complexes will induce regulatory CD8 + T cells and subsequently become susceptible to regulation. Because Qa-1 also binds to self Qdm peptides that trigger NK (CD94/ NKG2) receptors on CD8 + T cells, the machinery for homeostatic regulation of regulatory CD8 + T cells can be envisioned. Finally, we propose a model by which these TCR specific, Qa-1-restricted regulatory CD8 + T cells selectively downregulate antigen-activated T cells expressing TCRs of certain affinities. Ultimately these regulatory CD8 + T cells control the peripheral TCR repertoire during the course of immune responses to both self and foreign antigens.
Identification of a biochemical link between energy intake and energy expenditure
Authors: Silvana Obici, Jiali Wang, Rahena Chowdury, Zhaohui Feng, Uma Siddhanta, Kimyata Morgan, Luciano Rossetti
Journal: Journal of Clinical Investigation (2002)

Obesity is the result of an imbalance between energy intake and energy expenditure. Using high-density DNA microarrays and Northern analyses, we demonstrated that the activation of a nutrient-sensing pathway, the hexosamine biosynthesis pathway (HBP), rapidly decreased the expression of a cluster of nuclear-encoded mitochondrial genes involved in skeletal muscle oxidative phosphorylation. Conversely, the expression of uncoupling protein-1 and of the same mitochondrial genes was increased in brown adipose tissue. Most important, these transcriptional changes were accompanied by a marked decrease in whole-body energy expenditure. Short-term overfeeding replicated this transcriptional pattern, suggesting that this adaptation to nutrient abundance occurs under physiological conditions. Thus, the activation of the HBP by nutrients represents a biochemical link between nutrient availability, mitochondrial proteins, and energy expenditure, and it is likely to play an important role in the regulation of energy balance.
Role of Gas6 in erythropoiesis and anemia in mice
Authors: Anne Angelillo-Scherrer, Laurent Burnier, Diether Lambrechts, Richard J. Fish, Marc Tjwa, Stéphane Plaisance, Rocco Sugamele, Maria DeMol, Eduardo Martinez-Soria, Patrick H. Maxwell, Greg Lemke, Stephen P. Goff, Glenn K. Matsushima, H. Shelton Earp, Marc Chanson, Désiré Collen, Shozo Izui, Marc Schapira, Edward M. Conway, Peter Carmeliet
Journal: Journal of Clinical Investigation (2008)

Many patients with anemia fail to respond to treatment with erythropoietin (Epo), a commonly used hormone that stimulates erythroid progenitor production and maturation by human BM or by murine spleen. The protein product of growth arrest–specific gene 6 (Gas6) is important for cell survival across several cell types, but its precise physiological role remains largely enigmatic. Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. In the absence of Gas6, erythroid progenitors and erythroblasts were hyporesponsive to the survival activity of Epo and failed to restore hematocrit levels in response to anemia. In addition, Gas6 may influence erythropoiesis via paracrine erythroblast-independent mechanisms involving macrophages. When mice with acute anemia were treated with Gas6, the protein normalized hematocrit levels without causing undesired erythrocytosis. In a transgenic mouse model of chronic anemia caused by insufficient Epo production, Gas6 synergized with Epo in restoring hematocrit levels. These findings may have implications for the treatment of patients with anemia who fail to adequately respond to Epo.
Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma
Authors: L P Malmberg
Journal: Thorax (2003)

Respiratory function and airway inflammation can be evaluated in preschool children with special techniques, but their relative power in identifying young children with asthma has not been studied. This study was undertaken to compare the value of exhaled nitric oxide (FE(NO)), baseline lung function, and bronchodilator responsiveness in identifying children with newly detected probable asthma.Ninety six preschool children (age 3.8-7.5 years) with asthmatic symptoms or history and 62 age matched healthy non-atopic controls were studied. FE(NO) was measured with the standard online single exhalation technique, and baseline lung function and bronchodilator responsiveness were measured using impulse oscillometry (IOS).Children with probable asthma (n=21), characterised by recent recurrent wheeze, had a significantly higher mean (SE) concentration of FE(NO) than controls (22.1 (3.4) ppb v 5.3 (0.4) ppb; mean difference 16.8 ppb, 95% CI 12.0 to 21.5) and also had higher baseline respiratory resistance, lower reactance, and larger bronchodilator responses expressed as the change in resistance after inhalation of salbutamol. Children with chronic cough only (n=46) also had significantly raised mean FE(NO) (9.2 (1.5) ppb; mean difference 3.9 ppb, 95% CI 0.8 to 7.0) but their lung function was not significantly reduced. Children on inhaled steroids due to previously diagnosed asthma (n=29) differed from the controls only in their baseline lung function. The analysis of receiver operating characteristics (ROC) showed that FE(NO) provided the best power for discriminating between children with probable asthma and healthy controls, with a sensitivity of 86% and specificity of 92% at the cut off level of 1.5 SD above predicted.FE(NO) is superior to baseline respiratory function and bronchodilator responsiveness in identifying preschool children with probable asthma. The results emphasise the presence of airway inflammation in the early stages of asthma, even in young children.
Heterozygous α2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction
Authors: R GILSBACH, M BREDE, N BEETZ, E MOURA, V MUTHIG, C GERSTNER, F BARRETO, S NEUBAUER, M VIEIRACOELHO, L HEIN
Journal: Cardiovascular Research (2007)

Feedback regulation of norepinephrine release from sympathetic nerves is essential to control blood pressure, heart rate and contractility. Recent experiments in gene-targeted mice have suggested that alpha(2C)-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human alpha(2C)-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of alpha(2C)-gene copy number for feedback control of epinephrine release in gene-targeted mice.Adrenal catecholamine release, basal hemodynamics and susceptibility to develop heart failure after transverse aortic constriction were tested in mice with two copies (+/+), one copy (+/-) or no functional alpha(2C)-adrenoceptor gene (alpha(2C)-/-).Heterozygous alpha(2C)-receptor deletion (alpha(2C)+/-) resulted in a 43% reduction of adrenal alpha(2C) mRNA copy number and in a similar decrease in alpha(2)-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74+/-15% in alpha(2C)+/- and by 142+/-23% in alpha(2C)-/- mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in alpha(2C)-adrenoceptor-deficient mice. alpha(2C)+/- mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than alpha(2C)+/+ mice.Adrenal alpha(2)-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, alpha(2C), operates without a significant receptor reserve to prevent elevation of circulating epinephrine levels. This genetic model may provide an experimental basis to study the pathophysiology of alpha(2C)-adrenoceptor dysfunction in humans.
Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans
Authors: U Salzer, H M Chapel, A D B Webster, Q Pan-Hammarström, A Schmitt-Graeff, M Schlesier, H H Peter, J K Rockstroh, P Schneider, A A Schäffer, L Hammarström, B Grimbacher
Journal: Nature Genetics (2005)
Extracellular Matrix Remodeling and Organization in Developing and Diseased Aortic Valves
Authors: Robert B. Hinton, Joy Lincoln, Gail H. Deutsch, Hanna Osinska, Peter B. Manning, D. Woodrow Benson, Katherine E. Yutzey
Journal: Circulation Research (2006)

Heart valve disease is an important cause of morbidity and mortality worldwide. Little is known about valve disease pathogenesis, but increasing evidence implicates a genetic basis for valve disease, suggesting a developmental origin. Although the cellular and molecular processes involved in early valvulogenesis have been well described, less is known about the regulation of valve extracellular matrix (ECM) organization and valvular interstitial cell (VIC) distribution that characterize the mature valve structure. Histochemistry, immunohistochemistry, and electron microscopy were used to examine ECM organization, VIC distribution, and cell proliferation during late valvulogenesis in chicken and mouse. In mature valves, ECM organization is conserved across species, and developmental studies demonstrate that ECM stratification begins during late embryonic cusp remodeling and continues into postnatal life. Cell proliferation decreases concomitant with ECM stratification and VIC compartmentalization. Explanted, stenotic bicuspid aortic valves (BAVs) from pediatric patients were also examined. The diseased valves exhibited disruption of the highly organized ECM and VIC distribution seen in normal valves. Cusps from diseased valves were thickened with increased and disorganized collagens and proteoglycans, decreased and fragmented elastic fibers, and cellular disarray without calcification or cell proliferation. Taken together, these studies show that normal valve development is characterized by spatiotemporal coordination of ECM organization and VIC compartmentalization and that these developmental processes are disrupted in pediatric patients with diseased BAVs.
Glucocorticosteroid therapy in acute severe asthma--a critical review
Authors: T Engel, JH Heinig
Journal: European Respiratory Journal (1991)

Glucocorticosteroid (GCS) therapy is one of the corner-stones in the treatment of asthma. Its value in acute severe asthma is still open for debate. Many of the papers published on the topic are subject to methodological problems. In 8 of 13 placebo-controlled studies, GCS therapy proved to be superior to placebo, evaluated either as result of pulmonary function, blood gas tension, or hospital admission rate. The most important point for GCS therapy in acute severe asthma seems to be frequent dosage, typically 4 times daily. Oral and intravenous administration seem to have equal efficacy. Only 2 of 10 studies were able to prove a dose-response relationship. Both studies included very low doses of GCS. Doses of 100-200 mg of methylprednisolone for 24 h seem as effective as high doses. A protective effect against relapses within a certain time after the GCS therapy has been demonstrated only for periods not exceeding 4 weeks, and only in children. So far, no study has been able to depict the categories of patients who may or may not benefit by the addition of GCS therapy to the symptomatic treatment of acute severe asthma.
Disordered Cellular Migration and Angiogenesis in <i>cd39-</i> Null Mice
Authors: Christian Goepfert, Christian Sundberg, Jean Sévigny, Keiichi Enjyoji, Tomokazu Hoshi, Eva Csizmadia, Simon Robson
Journal: Circulation (2001)

Background — Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 is the major ectonucleotidase of endothelial cells and monocytes and catalyzes phosphohydrolysis of extracellular nucleoside diphosphates (NDP) and triphosphates (NTP, eg, ATP and UTP). Deletion of cd39 causes perturbations in the hydrolysis of NTP and NDP in the vasculature. Activation of P2 receptors appears to influence endothelial cell chemotactic and mitogenic responses in vitro. Therefore, aberrant regulation of nucleotide P2 receptors may influence angiogenesis in cd39 -null mice. Methods and Results — In control mice, implanted Matrigel plugs containing growth factors were rapidly populated by monocyte/macrophages, endothelial cells, and pericytes, with the development of new vessels over days. In cd39 -null mice, migrating cells were completely confined to the tissue-Matrigel interface in a clearly stratified manner. Absolute failure of new vessel ingrowth was consistently observed in the mutant mice. Linked to these findings, chemotaxis of cd39 -null monocyte/macrophages to nucleotides was impaired in vitro. This abnormality was associated with desensitization of nucleotide receptor P2Y-mediated signaling pathways. Conclusions — Our findings demonstrate a role for NTPDase1 and phosphohydrolysis of extracellular nucleotides in the regulation of the cellular infiltration and new vessel growth in a model of angiogenesis.
When to Start Antiretroviral Therapy in Resource-Limited Settings
Authors: Rochelle P. Walensky
Journal: Annals of Internal Medicine (2009)

Background: The results of international clinical trials that are assessing when to initiate antiretroviral therapy (ART) will not be available for several years. Objective: To inform HIV treatment decisions about the optimal CD4 threshold at which to initiate ART in South Africa while awaiting the results of these trials. Design: Cost-effectiveness analysis by using a computer simulation model of HIV disease. Data Sources: Published data from randomized trials and observational cohorts in South Africa. Target Population: HIV-infected patients in South Africa. Time Horizon: 5-year and lifetime. Perspective: Modified societal. Intervention: No treatment, ART initiated at a CD4 count less than 0.250 × 109 cells/L, and ART initiated at a CD4 count less than 0.350 × 109 cells/L. Outcome Measures: Morbidity, mortality, life expectancy, medical costs, and cost-effectiveness. Results of Base-Case Analysis: If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 × 109 cells/L would reduce severe opportunistic diseases by 22 000 to 221 000 and deaths by 25 000 to 253 000 during the next 5 years compared with ART initiation at 0.250 × 109 cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 × 109 cells/L. Compared with an initiation threshold of 0.250 × 109 cells/L, a threshold of 0.350 × 109 cells/L has an incremental cost-effectiveness ratio of $1200 per year of life saved. Results of Sensitivity Analysis: Initiating ART at a CD4 count less than 0.350 × 109 cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%. Limitation: This model does not consider the possible benefits of initiating ART at a CD4 count greater than 0.350 × 109 cells/L or of reduced HIV transmission. Conclusion: Earlier initiation of ART in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 × 109 cells/L, earlier than is currently recommended. Primary Funding Source: National Institute of Allergy and Infectious Diseases and the Doris Duke Charitable Foundation.
Tough at the top: must end-expiratory lung volume make way for end-inspiratory lung volume?
Authors: Yuan Ming Luo, Nicholas S. Hopkinson, Michael I. Polkey
Journal: European Respiratory Journal (2012)

A reduced exercise capacity, which limits the performance of activities of daily living and social participation, is a cardinal feature of chronic obstructive pulmonary disease (COPD). Breathlessness is the main limiting symptom, although, depending on the task undertaken [1], leg discomfort is prominent in a substantial minority of patients. Dyspnoea arises through the interplay of pulmonary manifestations of COPD (airflow obstruction, emphysema and destruction of the pulmonary vascular bed) [2], systemic effects of the disease [3] and neural mechanisms [4, 5]. These complex relationships remain incompletely understood. Traditionally, both the severity of COPD and the efficacy of treatment interventions have been assessed using resting lung function measures, particularly forced expiratory volume in 1 s (FEV1). However, health status is more closely associated with lung volume measurements [6] than FEV1, and bronchodilator-based therapies can improve lung volumes at rest [7] and during exercise [8] without change in FEV1, prompting interest in the study of dynamic lung volumes and dyspnoea arising during exercise.

The metabolic demands of exercise at a given intensity require a corresponding minute ventilation in order to sustain them. Indeed, the levels of ventilation achievable during exercise in relation to oxygen consumption or carbon dioxide production are used as measures of cardiopulmonary fitness ( e.g. before surgery). An increase in ventilation can occur through an increase in tidal volume or respiratory rate. Healthy individuals can increase their tidal volume during exercise by breathing out further to a lower end-expiratory lung volume (EELV) by contracting their abdominal …
Ophthalmological effects of 13-cis-retinoic acid therapy for acne vulgaris
Authors: Jane Milson, D.H. Jones, Kathrine King, W.J. Cunliffe
Journal: British Journal of Dermatology (1982)

Journal Article Ophthalmological effects of 13‐cis‐retinoic acid therapy for acne vulgaris Get access Jane Milson, Jane Milson Department of Ophthalmology, The General Infirmary, Leeds Search for other works by this author on: Oxford Academic Google Scholar D.H. Jones, D.H. Jones Department of Dermatology, The General Infirmary, Leeds Search for other works by this author on: Oxford Academic Google Scholar Kathrine King, Kathrine King Department of Dermatology, The General Infirmary, Leeds Search for other works by this author on: Oxford Academic Google Scholar W.J. Cunliffe W.J. Cunliffe Department of Dermatology, The General Infirmary, Leeds Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 107, Issue 4, 1 October 1982, Page 491, https://doi.org/10.1111/j.1365-2133.1982.tb00395.x Published: 01 October 1982
Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer
Authors: P. van der Groep, A. Bouter, R. van der Zanden, F. H. Menko, H. Buerger, R. H.M. Verheijen, E. van der Wall, P. J. van Diest
Journal: JNCI Journal of the National Cancer Institute (2004)

A basal epithelial phenotype is found in not more than 15% of all invasive breast cancers. Microarray studies have shown that this phenotype is associated with breast cancers that express neither estrogen receptor (ER) nor erbB-2 (HER2/neu) (i.e., ER/erbB-2-negative tumors). The ER/erbB-2- negative phenotype is also found in breast cancers occurring in BRCA1 mutation carriers (i.e., BRCA1-related breast cancers). We tested the hypothesis that BRCA1-related breast cancers are more likely than non-BRCA1/ 2-related breast cancer to express a basal epithelial phenotype. Among 292 breast cancer specimens previously analyzed for ER, erbB-2, p53, and germline mutations in BRCA1 and BRCA2, we identified 76 that did not overexpress ER or erbB-2. Of the 72 specimens with sufficient material for testing, 40 expressed stratified epithelial cytokeratin 5 and/or 6 (5/6). In univariate analysis, the expression of cytokeratin 5/6 was statistically significantly associated with BRCA1-related breast cancers (odds ratio = 9.0, 95% confidence interval = 1.9 to 43; P =.002, two-sided Fisher's exact test). Thus, germline BRCA1 mutations appear to be associated with a distinctive breast cancer phenotype.
European pulmonary alveolar proteinosis network (EuPAPNet): Results from biomarkersÂ´ investigation
Authors: Francesco Bonella, Ilaria Campo, Coline H.M. van Moorsel, Matthias Griese, Jan C. Grutters, Ulrich Costabel, Maurizio Luisetti
Journal: European Respiratory Journal (2014)

Background Pulmonary Alveolar Proteinosis (PAP) is an orphan disease with a prevalence of six cases per million. EuPAPNet project was aimed at creating a network among four European PAP reference centers in three countries (Italy, Germany and the Netherlands), in order to establish a database of PAP patients, to investigate biomarkers for predicting disease outcome, and to identify candidate genes for PAP susceptibility.

Patients and Methods 165 patients have been included in EuPAPNet between 2010 and 2013 (81 from Italy, 75 from Germany and 9 from the Netherlands). KL-6, CCL-18, GM-CSF, LDH, YKL-40, SP-A have been measured in serum and bronchoalveolar lavage (BAL) samples by ELISA. Single nucleotide polymorphisms (SNPs) for MUC 1 and CHI3L1 genes were genotyped using polymerase chain reaction. The correlation between biomarkers, disease outcome and SNPs was evaluated.

Main Results Differences in KL-6 serum levels but not YKL-40, CCL18 or SP-A were found among the three cohorts, with the highest levels in the Italian patients (p<0.01). Serum KL-6 has been found to predict the disease outcome and the necessity of treatment with whole lung lavage. MUC1 rs4072037 genotype A/A seems to be associated with higher serum KL-6 levels (p<0.05 vs A/A patients and healthy controls) while genotype A/G may predict clinical remission (HR 5.4, p=0.03). Serum YKL-40 and CHI3L1 SNPs showed a similar predicting profile as KL-6 for disease outcome.

Conclusions Through a proof-of-concept approach it has been found that serum KL-6 and YKL-40 can predict outcome in PAP. Differences in serum levels of the biomarkers can be explained by different SNPs genotypes and their distribution in the studied cohorts.