bluuebunny/crossref_metadata_2025_split huggingface dataset:
Just around the corner: rhetorics of progress and promise in genetic research
Authors: Evans Robert , Kotchetkova Inna , Langer Susanne 
Published: September 2008

The emerging “diabetes epidemic” threatens to affect 366 million people worldwide by 2030. In the UK, almost 2 million people (about 3.9 percent of the population) are currently diagnosed with diabetes and it is estimated that a further 1 million people have the disease but do not realize it. The prevalence of diabetes, its complications and their effects on the lives of those living with diabetes mean that diabetes research has the potential to bring significant benefits. In this paper, we are concerned with the research involving human embryonic stem (HES) cells that sees diabetes as a potential therapeutic location. Drawing on the idea of the “certainty trough” we examine how the hopes and uncertainties associated with this complex research agenda are understood. We show that those at the research front and those most opposed to the research agenda appear to be the most aware of the uncertainties that need to be resolved. In contrast, funders, typically one-step removed from the research work, see the promise of the research as more real and more likely to be achieved. Significantly, these optimistic funders are supported in their beliefs by the research scientists as constitutive claims are reproduced within the contingent forum. The effect is a collaborative project in which the promise of a technical solution “just around the corner” is sustained whilst concerns about the future difficulties are marginalized. Because the science is so new, we are very hopeful that breakthroughs, particularly using cells in the pancreas for the treatment of diabetes, are on the horizon.
PKC-θ selectively controls the adhesion-stimulating molecule Rap1
Authors: Letschka Thomas , Kollmann Veronika , Pfeifhofer-Obermair Christa , Lutz-Nicoladoni Christina , Obermair Gerald J. , Fresser Friedrich , Leitges Michael , Hermann-Kleiter Natascha , Kaminski Sandra , Baier Gottfried 
Published: September 2008

AbstractThe antigen-specific interaction of a T cell with an antigen-presenting cell (APC) results in the formation of an immunologic synapse (IS) between the membranes of the 2 cells. β2 integrins on the T cell, namely, leukocyte function-associated antigen 1 (LFA-1) and its counter ligand, namely, immunoglobulin-like cell adhesion molecule 1 (ICAM-1) on the APC, critically stabilize this intercellular interaction. The small GTPase Rap1 controls T-cell adhesion through modulating the affinity and/or spatial organization of LFA-1; however, the upstream regulatory components triggered by the T-cell receptor (TCR) have not been resolved. In the present study, we identified a previously unknown function of a protein kinase C-θ (PKC-θ)/RapGEF2 complex in LFA-1 avidity regulation in T lymphocytes. After T-cell activation, the direct phosphorylation of RapGEF2 at Ser960 by PKC-θ regulates Rap1 activation as well as LFA-1 adhesiveness to ICAM-1. In OT-II TCR-transgenic CD4+ T cells, clustering of LFA-1 after antigen activation was impaired in the absence of PKC-θ. These data define that, among other pathways acting on LFA-1 regulation, PKC-θ and its effector RapGEF2 are critical factors in TCR signaling to Rap1. Taken together, PKC-θ sets the threshold for T-cell activation by positively regulating both the cytokine responses and the adhesive capacities of T lymphocytes.
Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis
Authors: Carmona Guillaume , Göttig Stephan , Orlandi Alessia , Scheele Jürgen , Bäuerle Tobias , Jugold Manfred , Kiessling Fabian , Henschler Reinhard , Zeiher Andreas M. , Dimmeler Stefanie , Chavakis Emmanouil 
Published: September 2008

Abstract
Ras-associated protein 1 (Rap1), a small GTPase, attracted attention because of its involvement in several aspects of cell adhesion, including integrin- and cadherin-mediated adhesion. Yet, the role of Rap1 genes and of Rap1 effectors for angiogenesis has not been investigated. Human umbilical vein endothelial cells (HUVECs) express Rap1a and Rap1b mRNA. To determine the contribution of Rap1 activity for angiogenesis, we overexpressed Rap1GAP1, a GTPase-activating protein that inhibits Rap1 activity. Overexpression of Rap1GAP1 significantly blocked angiogenic sprouting and tube-forming activity of HUVECs as well as migration and integrin-dependent adhesion. Silencing of Rap1a, Rap1b, or both significantly blocked HUVECs sprouting under basal and basic fibroblast growth factor-stimulated conditions and reduced HUVEC migration and integrin-dependent adhesion. We found that Rap1a and Rap1b are essential for the conformational activation of β1-integrins in endothelial cells. Furthermore, silencing of Rap1a and Rap1b prevented phosphorylation of tyrosine 397 in focal adhesion kinase (FAK) and vascular endothelial growth factor-induced Akt1-activation. Rap1a−/−-deficient and Rap1a+/− heterozygote mice displayed reduced neovascularization after hind limb ischemia compared with wild-type mice. Silencing of RAPL significantly blocked the Rap1-induced sprouting of HUVECs, suggesting that the angiogenic activity of Rap1 is partly mediated by RAPL. Our data demonstrate a critical role of Rap1 in the regulation of β1-integrin affinity, adhesion, and migration in endothelial cells and in postnatal neovascularization.
UV-C irradiation disrupts platelet surface disulfide bonds and activates the platelet integrin αIIbβ3
Authors: Verhaar Robin , Dekkers David W. C. , De Cuyper Iris M. , Ginsberg Mark H. , de Korte Dirk , Verhoeven Arthur J. 
Published: September 2008

AbstractUV-C irradiation has been shown to be effective for pathogen reduction in platelet concentrates, but preliminary work indicated that UV-C irradiation of platelets can induce platelet aggregation. In this study, the mechanism underlying this phenomenon was investigated. Irradiation of platelets with UV-C light (1500 J/m2) caused platelet aggregation, which was dependent on integrin αIIbβ3 activation (GPIIb/IIIa). This activation occurred despite treatment with several signal transduction inhibitors known to block platelet activation. UV-C also induced activation of recombinant αIIbβ3 in Chinese hamster ovary (CHO) cells, an environment in which physiologic agonists fail to activate. Activation of αIIbβ3 requires talin binding to the β3 tail, yet αIIbβ3-Δ724 (lacking the talin binding site) was activated by UV-C irradiation, excluding a requirement for talin binding. The UV-C effect appears to be general in that β1 and β2 integrins are also activated by UV-C. To explain these findings, we investigated the possibility of UV-C–induced photolysis of disulfide bonds, in analogy with the activating effect of reducing agents on integrins. Indeed, UV-C induced a marked increase in free thiol groups in platelet surface proteins including αIIbβ3. Thus, UV-C appears to activate αIIbβ3 not by affecting intracellular signal transduction, but by reduction of disulfide bonds regulating integrin conformation.
Socioeconomic outcome of subjects experiencing asthma symptoms at work
Authors: Larbanois A. , Jamart J. , Delwiche J‐P. , Vandenplas O. 
Published: September 2008

The aim of this study was to investigate the socioeconomic outcomes of subjects who experienced work­related asthma symptoms in the absence of demonstrable occupational asthma (OA) and to compare these outcomes with those found in subjects with documented OA.Subjects (n=157) who were being investigated for work­related asthma, were surveyed. Of these 86 had OA, ascertained by a positive specific inhalation challenge (SIC), and 71 subjects had a negative SIC response. After a median interval of 43 months (range 12–85 months), the subjects were interviewed to collect information on employment status, income changes, and asthma­related work disability.Rates of work disruption and income loss at follow­up were similar in subjects with negative SIC (46% and 59%, respectively) and in those with OA (38% and 62%). The median loss as a percentage of initial income was 23% in subjects with negative SIC and 22% in subjects with OA. Asthma­related work disability, defined as any job change or work loss due to asthma, was slightly more common in subjects with OA (72%) than in those with negative SIC (54%).This study shows that, even in the absence of demonstrable occupational asthma, work­related asthma symptoms are associated with considerable socioeconomic consequences.
Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis
Authors: Gibson P.G. , Wark P.A.B. , Simpson J.L. , Meldrum C. , Meldrum S. , Saltos N. , Boyle M. 
Published: September 2008

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungusAspergillus fumigatus, causing severe asthma that may progress to bronchiectasis. Sputum neutrophilia can occur in association with sputum eosinophilia and correlates with the degree of bronchiectasis. The mechanisms of sputum neutrophilia in ABPA are not known. The aim of this study was to investigate the role of the chemokine interleukin (IL)-8 in sputum neutrophilia in ABPA.Induced sputum was obtained from subjects with ABPA (n=29), and compared to nonsensitised asthma (n=9) and healthy controls (n=21). Semiquantitative polymerase chain reaction was used to assess IL-8 gene expression in induced sputum and IL-8 protein was measured by enzyme-linked immunosorbent assay.Sputum IL-8 protein was significantly higher in ABPA compared to asthma and controls. IL-8 messenger ribonucleic acid/glyceraldehyde-3-phosphate dehydrogenase ratio was elevated in ABPA compared to asthma and controls. Sputum IL-8 correlated with sputum neutrophils, matrix metalloproteinase-9 levels and forced expiratory volume in one second.Interleukin-8 gene expression and protein release were increased in allergic bronchopulmonary aspergillosis and correlated with airway neutrophilia and airway obstruction. The interleukin-8-mediated neutrophil influx in allergic bronchopulmonary aspergillosis may induce lung damageviarelease of matrix metalloproteinase-9, potentially leading to bronchiectasis.
Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis
Authors: Ziegenhagen M.W. , Rothe M.E. , Schlaak M. , Müller-Quernheim J. 
Published: September 2008

The aim of the present study was to determine which bronchoalveolar lavage fluid (BALF) and serological parameters reflect the severity of newly diagnosed pulmonary sarcoidosis.Seventy-four previously untreated sarcoid patients were categorised into three groups: 10 patients with Löfgren's syndrome, 51 patients with stable disease and 13 patients with progressing disease requiring systemic steroid treatment.Total BALF cell count, percentage of alveolar lymphocytes and lymphocyte CD4/CD8 ratio were not associated with severity of disease. Interestingly, a significant increase in percentages of BALF neutrophils (5.2±1.1%) and eosinophils (1.7±0.6%) was observed in sarcoid patients with progressing disease. Elevated percentages of these two cell types were the only BALF parameters associated with a more frequent necessity for systemic steroid therapy. This association between an elevated percentage of BALF neutrophils and the necessity for steroid treatment was observed in advanced as well as early sarcoidosis (radiological types I and II). Serum levels of soluble interleukin‐2 receptor and neopterin were significantly elevated in progressing disease compared to stable disease or Löfgren's syndrome.The present results demonstrate that increased percentages of neutrophils (>3.0%) and eosinophils (>1%) in bronchoalveolar lavage fluid from newly diagnosed pulmonary sarcoidosis is associated with a significantly higher risk of necessity for steroid therapy and may be helpful markers of progressive disease. Furthermore, of the serological parameters investigated, only serum levels of soluble interleukin‐2 receptor and neopterin were associated with disease severity.
Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction
Authors: Hubloue I. , Biarent D. , Kafi S. Abdel , Bejjani G. , Kerbaul F. , Naeije R. , Leeman M. 
Published: September 2008

The effects of endothelin receptor blockade on the pulmonary circulation have been reported variably, possibly in relation to a more or less important associated release of endogenous nitric oxide (NO). The aim of this study was to test whether endothelin antagonism would inhibit hypoxic pulmonary vasoconstriction, and if it would not, then would it do so after NO synthase inhibition.Hypoxic pulmonary vasoconstriction (HPV) was evaluated in anesthetised dogs by the increase in the mean pulmonary artery pressure (Ppa) minus occludedPpa(Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at constant pulmonary blood flow.Bosentan, an endothelin A and B receptor antagonist, did not affect baselinePpa,Ppaoor systemic arterial pressure (Psa) and did not alter HPV (n=8). The NO synthase inhibitor NG­nitro‐l‐arginine (l‐NA) did not affect baselinePpaandPpao, but increasedPsaand enhanced HPV (n=12). The addition of bosentan in these dogs did not affect baselinePpaorPpao, but decreasedPsaand inhibited HPV. Exhaled NO was decreased byl‐NA and by bosentan and abolished byl‐NA+bosentan (n=9).The authors conclude that endogenous nitric oxide is released by, and opposes the vasoconstricting effects of, endothelinsin vivo, reducing systemic blood pressure and limiting hypoxic pulmonary vasoconstriction.
Organising pneumonia caused by transtuzumab (Herceptin) therapy for breast cancer
Authors: Radzikowska E. , Szczepulska E. , Chabowski M. , Bestry I. 
Published: September 2008

The case of a 49-yr-old female, who developed fever, effort dyspnoea and cough, with patchy migratory bilateral pulmonary infiltrates 6 weeks after starting transtuzumab therapy, following breast-conserving surgery with adjuvant chemoradiotherapy and hormone therapy for breast carcinoma, is reported here.Chest radiograph and thin section computed tomography demonstrated alveolar opacities with air bronchogram in both lungs. A lung biopsy was performed in a nonirradiated area of the contralateral lung and revealed a typical histological pattern of organising pneumonia (previously known as bronchiolitis obliterans organising pneumonia). Transtuzumab therapy was discontinued and subsequent gradual clinical and radiological improvement was observed. After 3 months, complete resolution of symptoms and radiographical abnormalities were noted.This is the first case report that suggests that transtuzumab therapy might induce the development of lung infiltrates with the histological appearance of organising pneumonia.
Bronchoalveolar lavage fluid findings in children with hypersensitivity pneumonitis
Authors: Ratjen F. , Costabel U. , Griese M. , Paul K. 
Published: September 2008

Bronchoalveolar lavage (BAL) has been shown to be useful in the diagnosis of hypersensitivity pneumonitis (HP) in adults, the typical constellation being lymphocytosis with a decrease in the CD4/CD8 ratio. Only limited data exist for the diagnostic value of BAL cytology in paediatric patients with this disorder.Children aged 6–15 yrs (n=9) with acute HP were studied. BAL was performed before initiation of anti­inflammatory treatmentviaa flexible bronchoscope in the middle lobe with 3 mL·kg body weight−1normal saline warmed to body temperature; BAL cytology and lymphocyte surface markers were compared with age­matched controls.The percentage of lymphocytes was significantly increased in all patients with HP. No significant differences were observed in the CD4/CD8 ratio between children without lung disease and those with HP. Increased expression of human leukocyte antigen­DR was found in seven of eight children with HP, whereas natural killer cells were elevated in five of eight children. Every patient had at least one of these two alterations in BAL fluid in addition to lymphocytosis.It was concluded that while lymphocytosis is generally present in children with hypersensitivity pneumonitis, the CD4/CD8 ratio is not increased in these patients. Assessing natural killer cells and human leukocyte antigen­DR expression appears to be a helpful adjunct in the diagnosis of paediatric patients with this disorder.
Longitudinal changes in the nature, severity and frequency of COPD exacerbations
Authors: Donaldson G.C. , Seemungal T.A.R. , Patel I.S. , Lloyd-Owen S.J. , Wilkinson T.M.A. , Wedzicha J.A. 
Published: September 2008

Exacerbations are an important feature and outcome measure in chronic obstructive pulmonary disease (COPD), but little is known about changes in their severity, recovery, symptom composition or frequency over time.In this study 132 patients (91 male; median age 68.4 yrs and median forced expiratory volume in one second (FEV1) 38.4% predicted) recorded daily symptoms and morning peak expiratory flow.Patients were monitored for a median of 918 days and 1,111 exacerbations were identified. Patients with severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) category III, n=38) had an annual exacerbation frequency of 3.43·yr−1, 0.75·yr−1higher than those with moderate COPD (GOLD II, n=94). Exacerbation frequency did not change significantly during the study. At exacerbation onset, symptom count increased to 2.23, relative to a baseline of 0.36 set 8–14 days previously, and this increase rose by 0.05·yr−1. Recovery to baseline levels in symptoms and FEV1took longer (0.32 and 0.55 days·yr−1). Sputum purulence at exacerbation became more prevalent over time by 4.1%·yr−1from an initial value of 17%.The results of this study suggest that over time, individual patients have more symptoms during exacerbations, with an increased chance of sputum purulence and longer recovery times.
The cost-effectiveness of nCPAP treatment in patients with moderate-to-severe obstructive sleep apnoea
Authors: Mar J. , Rueda J.R. , Durán-Cantolla J. , Schechter C. , Chilcott J. 
Published: September 2008

The demand for diagnostic and therapeutic services for obstructive sleep apnoea syndrome (OSAS) showed marked growth during the 1990s. This paper analyses the long-term cost-effectiveness of nasal continuous positive airway pressure (nCPAP) treatment in comparison to conventional null treatment.A Markov model was used to represent the natural history of OSAS based upon published evidence. Utility values came from a survey of OSAS patients. Data on health costs were collected from hospitals in the Basque Country, Spain.The incremental cost-effectiveness ratio of nCPAP treatment is <6,000 Euros per quality-adjusted life year. On disaggregated analysis, nCPAP treatment accounts for 86% of incremental costs; 84% of incremental effectiveness is attributable to improved quality of life.Treatment of obstructive sleep apnoea syndrome with nasal continuous positive airway pressure has a cost-effectiveness that is in line with that of other commonly funded treatments such as antihypertensive drugs. The key clinical benefit of nasal continuous positive airway pressure treatment is improvement in the quality of life of patients with obstructive sleep apnoea syndrome. This benefit is also precisely the one for which the evidence base is strongest. The remaining uncertainties concerning the impact of nasal continuous positive airway pressure on long-term mortality have only a relatively small impact on the economics of treatment.
Urban traffic and pollutant exposure related to respiratory outcomes and atopy in a large sample of children
Authors: Nicolai T. , Carr D. , Weiland S.K. , Duhme H. , von Ehrenstein O. , Wagner C. , von Mutius E. 
Published: September 2008

Conflicting results have been reported for the relationship between traffic exposure and inception of atopy. The effect of traffic on the prevalence of asthma and atopy at school age was investigated in a representative population.Random samples of schoolchildren (n=7,509, response rate 83.7%) were studied using the International Study of Asthma and Allergies in Childhood phase­II protocol with skin­prick tests, measurements of specific immunoglobulin E and lung function. Traffic exposure was assessedviatraffic counts and by an emission model which predicted soot, benzene and nitrogen dioxide (NO2).Traffic counts were associated with current asthma, wheeze and cough. In children with tobacco­smoke exposure, traffic volume was additionally associated with a positive skin­prick test. Cough was associated with soot, benzene and NO2, current asthma with soot and benzene, and current wheeze with benzene and NO2. No pollutant was associated with allergic sensitisation.High vehicle traffic was associated with asthma, cough and wheeze, and in children additionally exposed to environmental tobacco smoke, with allergic sensitisation. However, effects of socioeconomic factors associated with living close to busy roads cannot be ruled out.
Long­term noninvasive ventilation in children and adolescents with neuromuscular disorders
Authors: Mellies U. , Ragette R. , Dohna Schwake C. , Boehm H. , Voit T. , Teschler H. 
Published: September 2008

The aim of the current study was to investigate the long­term impact of nocturnal noninvasive (positive­pressure) ventilation (NIV) on sleep, sleep­disordered breathing (SDB) and respiratory function in children and adolescents with progressive neuromuscular disorders (NMD).Thirty patients (12.3±4.1 yrs) with various inherited NMD were treated with NIV for ventilatory insufficiency (n=14) or symptomatic SDB (n=16). Patients were prospectively followed with sleep studies, spirometry and peak inspiratory muscle pressure. Ten patients were studied before and after 3 nights withdrawal from NIV.NIV normalised nocturnal gas exchange in all patients and diurnal gas exchange in patients with ventilatory insufficiency. The effects persisted over 25.3±12.7 months. Nocturnal transcutaneous partial pressure of carbon dioxide improved from (baselineversuslatest control) 7.1±1.3 to 5.5±0.6 kPa (53.7±9.9 to 41.6±4.8 mmHg), diurnalcarbon dioxide arterial tension from 6.3±1.6 to 5.4±0.5 kPa (47.5±11.9 to 40.6±3.6 mmHg).NIV improved respiratory disturbance index, arousals from sleep, nocturnal heart rate and sleep architecture. Vital capacity decreased in five adolescents with Duchenne muscular dystrophy −183±111 mL·yr−1but remained stable in 25 children with other conditions (8±78 mL·yr−1). Three nights withdrawal of NIV in 10 previously stable patients resulted in prompt deterioration of SDB and gas exchange back to baseline but could be instantly normalised by resumption of NIV.Noninvasive (positive­pressure) ventilation has favourable long­term impact on nocturnal and diurnal gas exchange and sleep and in patients with non­Duchenne neuromuscular disorders on vital capacity as well. It is indicated in children and adolescents with symptomatic sleep­disordered breathing or ventilatory insufficiency due to neuromuscular disorders.