bluuebunny/crossref_metadata_2025_split huggingface dataset:
The NO/cGMP pathway inhibits Rap1 activation in human platelets via cGMP-dependent protein kinase I
Authors: Danielewski Oliver , Schultess Jan , Smolenski Albert 
Published: January 2005

SummaryThe NO/cGMP signalling pathway strongly inhibits agonist-induced platelet aggregation. However, the molecular mechanisms involved are not completely defined. We have studied NO/cGMP effects on the activity of Rap1, an abundant guanine-nucleotidebinding protein in platelets. Rap1-GTP levels were reduced by NO-donors and activators of NO-sensitive soluble guanylyl cyclase. Four lines of evidence suggest that NO/cGMP effects are mediated by cGMP-dependent protein kinase (cGKI): (i) Rap1 inhibition correlated with cGKI activity as measured by the phosphorylation state ofVASP, an established substrate of cGKI, (ii) 8-pCPT-cGMP, a membrane permeable cGMP-analog and activator of cGKI, completely blocked Rap1 activation, (iii) Rp- 8pCPT-cGMPS, a cGKI inhibitor, reversed NO effects and (iv) expression of cGKI in cGKI-deficient megakaryocytes inhibited Rap1 activation. NO/cGMP/cGKI effects were independent of the type of stimulus used for Rap1 activation. Thrombin-,ADPand collagen-induced formation of Rap1-GTP in platelets as well as turbulence-induced Rap1 activation in megakaryocytes were inhibited. Furthermore, cGKI inhibited ADP-induced Rap1 activation induced by the G α i -coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling. From these studies we conclude that NO/cGMP inhibit Rap1 activation in human platelets and that this effect is mediated by cGKI. Since Rap1 controls the function of integrin α IIbβ 3 , we propose that Rap1 inhibition might play a central role in the anti-aggregatory actions of NO/cGMP.
A reunification of the US (“NIH”) and International Unit into a single standard for Thrombin
Authors: Whitton Colin , Sands Dawn , Lee Timothy , Chang Andrew , Longstaff Colin 
Published: January 2005

SummaryThe existence of two different units forThrombin in widespread international use has caused confusion for many years. The holders of the WHO International Standard (IS) for Alpha Thrombin and the US Standard (also known as the “NIH Standard”) now report on a collaboration to reunite the International Unit (IU) and the US unit (“NIH unit”).A study was organised involving 25 laboratories in 15 countries to investigate the possibility of preparing a common Standard with a common unit and to investigate aspects of methodology that cause divergence of results using the IS and US Standard. Laboratories were asked to measure the potency of two candidate replacement standards (C, 01/578 and D, 01/580), and potencies were calculated relative to both the existing US Standard (lot J) and the IS (89/588). Data analysis of a total of 128 assays indicated that sample D would make an ideal replacement joint Standard with a potency of 110 IU/ampoule (equivalent to 110 US units per ampoule) based on data from clotting assays. No significant differences in results were observed using fibrinogen of human or bovine origin, or using human plasma. Comparisons of chromogenic and clotting assays indicated that sample D had a similar high proportion of alpha thrombin to the current IS for Alpha Thrombin (89/588). Sample D was adopted as the IS for Thrombin (01/580) and the US Standard (lot K) with a potency of 110 IU/ampoule.
Visual signaling and reproductive biology in a nocturnal treefrog, genus Hyla (Anura: Hylidae)
Authors: Hartmann Paulo , Hartmann Marília , Haddad Célio 
Published: January 2005

AbstractWe investigated reproductive activity, courtship behavior, call structure, body size, clutch size, oviposition site, and reproductive mode of Hyla sp. (aff. ehrhardti). Males called in all months, but showed a peak of activity during the rainy season. Three pair formations were observed and courtship involved stereotyped behavioral sequences, including visual signaling. Males emitted three different vocalization types: advertisement calls, courtship calls, and a vocalization of unknown function. Females attained larger body sizes than males and deposited an average of 74.5 unpigmented eggs per clutch. Early larval stages are aquatic but restricted to water in constructed subterranean nests; subsequent to flooding of nests, exotrophic tadpoles live in ponds or streams. Courtship behavior in Hyla sp. (aff. ehrhardti) is complex and the diverse repertoire of limb movements, exhibited by males, probably provide visual stimuli to females in this nocturnal treefrog. Hyla sp. (aff. ehrhardti) belongs to the H. albomarginata group. Considering the reproductive modes in this group, the complexes of H. albosignata and of H. albofrenata can be considered more close related to each other than to the H. albomarginata complex.
Physiological relevance of antigen presentasome (APS), an acquired MHC/costimulatory complex, in the sustained activation of CD4+ T cells in the absence of APCs
Authors: Zhou Jun , Tagaya Yutaka , Tolouei-Semnani Roshanak , Schlom Jeffrey , Sabzevari Helen 
Published: January 2005

AbstractT-cell interaction with antigen-presenting cells (APCs) results in activation and clonal expansion of naive T cells. CD80 expression/acquisition in T cells has been implicated in disease processes in patients with rheumatoid arthritis and multiple myeloma and patients infected with HIV. Our previous data indicate that antigen-specific activation of naive T cells results in T-cell acquisition of CD80 molecules from APCs. However, the functional relevance of the acquired CD80 by T cells in signal pathways has remained unresolved. This study aims to define for the first time the role of acquired CD80 in T-cell clonal expansion. We demonstrate the following: (1) T cells, upon CD80 acquisition, sustain their proliferative response in the absence of APCs; (2) T cells that acquire CD80 sustain the activity of transcriptional factors such as nuclear factor-κB (NFκB) and activator protein-1 (AP1) for 24 hours after separation from APCs and up-regulate signal transducer and activator of transcription-5 (Stat5) in the absence of APCs or exogenous signal 1; and (3) maintenance of these signals results in unique cytokine production. Collectively, our data support the unique concept that naive T cells sustain their activation by removing “antigen presentasome” (APS; eg, antigen-presenting complex) from APCs, thereby releasing the constraint of APC requirement for further activation. (Blood. 2005;105: 3238-3246)
Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia
Authors: Sanders Jean E. , Im Ho Joon , Hoffmeister Paul A. , Gooley Ted A. , Woolfrey Ann E. , Carpenter Paul A. , Andrews Robert G. , Bryant Eileen M. , Appelbaum Frederick R. 
Published: January 2005

AbstractThe role of transplantation in infants with acute lymphoblastic leukemia (ALL) is not defined. We analyzed results of 40 infants diagnosed before age 12 months who received a hematopoietic cell transplant (HCT) between July 1982 and February 2003 in first complete remission (CR1; n = 17), CR2/3 (n = 7), or relapse (n = 16). Patients were conditioned with cyclophosphamide with total body irradiation (n = 39) or busulfan (n = 1). Donors were matched related (n = 8), mismatched related (n = 16), or unrelated (n = 16). Graft-versus-host disease (GVHD) prophylaxis was methotrexate or cyclosporine (n = 7) or methotrexate plus cyclosporine (n = 33). Thirty-nine patients engrafted, 20 developed acute GVHD, and 7 developed chronic GVHD. Sixteen patients relapsed and 7 died of other causes. Patients in CR1 had disease-free survival (DFS) of 76% compared with 45% for CR2/CR3 and 8% for relapse (P &lt; .001). Of 33 patients with cytogenetic data, 26 (79%) had MLL gene rearrangement. Fourteen of these 26 were in CR1 and 11 survive in remission. Outcome was associated with phase of disease, but having the MLL gene was not a factor predictive of outcome. Late effects included growth and other hormone deficiencies. These data demonstrate that infants with ALL and MLL gene have excellent DFS when they received transplants in CR1, and consideration for transplantation in CR1 is warranted.
Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study
Authors: Asnafi Vahid , Buzyn Agnes , Thomas Xavier , Huguet Francoise , Vey Norbert , Boiron Jean-Michel , Reman Oumedaly , Cayuela Jean-Michel , Lheritier Veronique , Vernant Jean-Paul , Fiere Denis , Macintyre Elizabeth , Dombret Hervé 
Published: January 2005

AbstractPatients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucémies Aiguës Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)–expressing T-ALL patients (TCRαβ+ or TCRγδ+), pre-αβ T-ALL patients (cTCRβ+, TCR–), and immature (IM) cTCRβ–, TCR– T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P &lt; .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-αβ, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.
Transglutaminase-mediated oligomerization of the fibrin(ogen) αC domains promotes integrin-dependent cell adhesion and signaling
Authors: Belkin Alexey M. , Tsurupa Galina , Zemskov Evgeny , Veklich Yuri , Weisel John W. , Medved Leonid 
Published: January 2005

AbstractInteractions of endothelial cells with fibrin(ogen) are implicated in inflammation, angiogenesis, and wound healing. Cross-linking of the fibrinogen αC domains with factor XIIIa generates ordered αC oligomers mimicking polymeric arrangement of the αC domains in fibrin. These oligomers and those prepared with tissue transglutaminase were used to establish a mechanism of the αC domain–mediated interaction of fibrin with endothelial cells. Cell adhesion and chemical cross-linking experiments revealed that oligomerization of the αC domains by both transglutaminases significantly increases their RGD (arginyl–glycyl–aspartate)–dependent interaction with endothelial αVβ3 and to a lesser extent with αVβ5 and α5β1 integrins. The oligomerization promotes integrin clustering, thereby increasing cell adhesion, spreading, formation of prominent peripheral focal contacts, and integrin-mediated activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) signaling pathways. The enhanced integrin clustering is likely caused by ordered juxtaposition of RGD-containing integrin-binding sites upon oligomerization of the αC domains and increased affinity of these domains for integrins. Our findings provide new insights into the mechanism of the αC domain–mediated interaction of endothelial cells with fibrin and imply its potential involvement in cell migration. They also suggest a new role for transglutaminases in regulation of integrin-mediated adhesion and signaling via covalent modification of integrin ligands.
Airway responsiveness to hypertonic saline: dose-response slope or PD15?
Authors: de Meer G. , Marks G. B. , de Jongste J. C. , Brunekreef B. 
Published: January 2005

The result of airway challenge test with hypertonic saline (HS) is expressed as the dose causing a 15% fall in forced expiratory volume in one second (FEV1; PD15). A noncensored measure, such as the dose-response slope (DRS), allows the evaluation of the risk of asthma for subjects with a fall in FEV1 <15%. The aim of this study was to assess the relationship between airway responsiveness to HS by PD15 or DRS, asthma symptoms and markers of eosinophilic inflammation.Data on current wheeze and airway responsiveness were obtained for 1,107 children (aged 8–13 yrs). Blood eosinophils and serum eosinophil cationic protein (ECP) were assessed in subsets (n = 683 and 485). PD15 was assessed if FEV1 fell ≥15%, and the DRS was calculated for all tests. Graphs were constructed to visualise relationships with current wheeze, blood eosinophils and serum ECP. Odds ratios and Spearman's correlation coefficients were calculated to quantify these relationships.Children with features of asthma had lower PD15 and higher DRS, and separation was most pronounced for DRS. Prevalence of current wheeze increased continuously over the entire range of DRS values. Blood eosinophils were significantly higher only for the highest values of DRS.In conclusion, the continuous relationship between airway responsiveness and asthma symptoms is in favour of a noncensored measure of airway responsiveness, such as the dose-response slope.
Metalloproteinases and tissue inhibitors of metalloproteinases in exudative pleural effusions
Authors: Iglesias D. , Alegre J. , Alemán C. , Ruíz E. , Soriano T. , Armadans L. I. , Segura R. M. , Anglés A. , Monasterio J. , Fernández de Sevilla T. 
Published: January 2005

The aim of this study was to assess the expression of several metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in exudative pleural effusions, and their relationship with inflammatory and fibrinolytic mediators in parapneumonic effusions.The study included 51 parapneumonic effusions (30 empyema or complicated parapneumonic, 21 noncomplicated parapneumonic), 28 tuberculous, 30 malignant and 30 transudates. Inflammatory markers (tumour necrosis factor-α, interleukin-8, polymorphonuclear elastase), fibrinolytic system variables (tissue plasminogen activator (PA), urokinase PA (u-PA), plasminogen activation inhibitor (PAI)-1, PAI-2), and several MMPs (MMP-1, MMP-2, MMP-8, MMP-9) and TIMPs (TIMP-1, TIMP-2) were determined by ELISA in plasma and pleural fluid.Elevated MMP-2 and TIMP-1 concentrations were observed in all the pleural fluid samples studied. The group of empyema or complicated parapneumonic effusions showed higher MMP-1, MMP-8 and MMP-9 concentrations than the remaining exudates. There was no correlation between MMP and TIMP levels in plasma and pleural fluid in this group of effusions. In parapneumonic effusions, MMP-1, MMP-8 and MMP-9 showed a positive correlation with the inflammatory markers and with u-PA and PAI-1. Moreover, there was a relationship between MMP-8 concentration in pleural fluid and pleural thickening at the end of treatment.In conclusion, elevated metalloproteinase-1, -8 and -9 expression was found in parapneumonic pleural effusions. These metalloproteinases could be implicated in the local inflammatory response existing in this group of effusions.
Most obstructive sleep apnoea patients exhibit vigilance and attention deficits on an extended battery of tests
Authors: Mazza S. , Pépin J-L. , Naëgelé B. , Plante J. , Deschaux C. , Lévy P. 
Published: January 2005

Excessive daytime sleepiness, fatigue and altered attention are often experienced by obstructive sleep apnoea (OSA) patients. Although attentional problems are presumably responsible for part of the daytime functioning impairment in OSA, thorough investigation is unusual. Clinicians usually attribute these symptoms to somnolence. In clinical practice, only one isolated test is generally used to assess vigilance and attentional defects. It was hypothesised that most OSA patients exhibit a broad range of attentional deficits, beyond impaired maintenance of wakefulness, and a specific battery of tests is needed to correctly assess them.Three attentional tests were performed at 9:00, 11:00 and 13:30 h, measuring maintenance of wakefulness, sustained attention and divided attention. Twenty OSA patients (aged 51±12 yrs, apnoea/hypopnoea index 45±22 h) and 40 control subjects (aged 48.4±9.9 yrs) were tested.OSA patients performed significantly less well on the three tests than the controls at the three sessions. This battery of tests demonstrated that 95% of patients had vigilance and/or attentional impairment. Impairment patterns varied between patients.Vigilance is impaired in obstructive sleep apnoea patients over a wide range of attentional processes. Not only is their ability to remain awake in monotonous situations impaired but their ability to maintain attention in more stimulating conditions is also affected. A single test of vigilance is not sufficient and could underestimate impaired vigilance and attention in some patients.
Efficacy of fluticasone on cough: a randomised controlled trial
Authors: Ponsioen B. P. , Hop W. C. J. , Vermue N. A. , Dekhuijzen P. N. R. , Bohnen A. M. 
Published: January 2005

Cough may be the consequence of bronchial hyperresponsiveness (BHR) and inflammation. This study was designed to investigate the short-term effects of an inhaled steroid (fluticasone propionate (FP)) on cough, and to determine the effects of smoking, BHR, allergy and forced expiratory volume in one second (FEV1) on the efficacy of FP.In a community-based primary healthcare centre, 135 previously healthy adults suffering from cough for ≥2 weeks were enrolled in a randomised, double-blind, placebo-controlled trial of inhaled FP 500 µgb.i.d.for 2 weeks. Participants completed daily diary cards of lower respiratory tract symptoms. The primary outcome measure was the decrease in mean total daily cough score (0–6) during the second week of treatment.In the FP group, the cough score decreased from 3.8 at baseline to mean±sem1.4±0.2 during the second week. In the placebo group, this decrease was from 3.8 to 1.9±0.1 and was statistically significantly less. A favourable effect of FP was only detectable in nonsmokers, in whom the score was 0.9 points lower compared with placebo. The clinical relevance of this finding has to be established further. Allergy, FEV1 and BHR at baseline did not affect the efficacy of FP.In conclusion, anti-inflammatory treatment with the inhaled steroid fluticasone propionate reduces cough in otherwise healthy adults who do not smoke.
Oral L-arginine supplementation in cystic fibrosis patients: a placebo-controlled study
Authors: Grasemann H. , Grasemann C. , Kurtz F. , Tietze-Schillings G. , Vester U. , Ratjen F. 
Published: January 2005

Exhaled nitric oxide (eNO) is decreased in cystic fibrosis (CF). The effect of oralL-arginine, the precursor of enzymatic nitric oxide (NO) formation, on airway NO in patients with CF was studied.In a pilot study, oralL-arginine was given in a single dose of 200 mg·kg−1body weight to eight healthy controls and eight CF patients. Subsequently, the sameL-arginine dose was given to 10 patients with CF (five females)t.i.d.for 6 weeks in a randomised double-blind placebo-controlled crossover study.A single dose of oralL-arginine resulted in a 5.5-fold increase ofL-arginine in plasma and a 1.3-fold increase ofL-arginine in sputum after 2 h. Maximum eNO, within 3 h ofL-arginine intake, increased significantly in both CF patients (5.4±2.1 ppbversus8.3±3.5 ppb) and controls (18.0±8.1 ppbversus26.4±12.3 ppb). Supplementation ofL-arginine for 6 weeks resulted in a sustained increase in eNO compared to placebo (9.7±5.7 ppbversus6.3±3.1 ppb). An effect ofL-arginine supplementation on forced expiratory volume in one second was not observed.These data indicate that airway nitric oxide formation in cystic fibrosis patients can be augmented with oralL-arginine supplementation.
Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology
Authors: Calverley P. M. A. , Koulouris N. G. 
Published: January 2005

Fashions in ideas, like clothes, come and go. From approximately 1950–1980, physiological research was seen as the key discipline in understanding lung disease and was at the cutting edge of pulmonary science. Subsequently, its importance has been down played amid a widely accepted but unfounded assumption that we now have a perfect working understanding of the physiological behaviour of the respiratory system in health and disease. Although it seems improbable that completely new disciplines within respiratory physiology will emerge with fundamentally different ways of describing the mechanical or gas exchanging function of the lung, advances in computing and new observations in disease have highlighted previously unsuspected physiological abnormalities that have changed the way we view lung disease and the interface between disordered lung mechanics, symptomatology and disability.This is especially true for the two related physiological concepts of expiratory flow limitation and dynamic hyperinflation, which are now being taken from the physiological laboratory to the bedside with dramatic effect. Each arises from well-established theoretical and practical observations first made 40 yrs ago and now adapted to a range of settings, particularly in the field of obstructive lung disease. This review focuses on how these conditions are defined and assessed and what evidence there is that they might be important in lung disease.
Asthma: prevalence and cost of illness
Authors: Stock S. , Redaelli M. , Luengen M. , Wendland G. , Civello D. , Lauterbach K. W. 
Published: January 2005

The purpose of this study was to estimate the prevalence and cost of illness of asthma in Germany by retrospectively analysing routine health insurance data.This analysis investigated claims data from all insured persons of six large sickness funds. Insurants with asthma were identifiedviathe International Classification of Diseases (ninth revision) diagnosis and the Anatomical Therapeutic Chemical Classification System Code for regular medication prescriptions. Costs for hospital care, medication and sick benefit were taken from claims data. Costs for rehabilitation, premature death and early retirement were estimated using the human capital approach and data from national statistics.Prevalence of asthma in the German statutory health insurance was 6.34%. Total costs for asthma, including direct and indirect costs, were calculated at \#8364;2.74 billion during 1999.The prevalence of asthma in the German statutory health insurance has previously been estimated to be 4–6%. The results of this large study show the prevalence of asthma in the German social insurance system to be ∼6%. The study also indicates that there is room for substantial savings in the German social insurance system, with indirect costs amounting to 74.8% of total costs and payment of sick benefits through the sickness funds amounting to 58.3% of indirect costs. These costs may be reduced with better asthma control in patients.