bluuebunny/crossref_metadata_2025_split huggingface dataset:
The APC-independent anticoagulant activity of protein S in plasma is decreased by elevated prothrombin levels due to the prothrombin G20210A mutation
Authors: Koenen Rory R. , Tans Guido , van Oerle René , Hamulyák Karly , Rosing Jan , Hackeng Tilman M. 
Published: May 2003

AbstractProtein S exhibits anticoagulant activity independent of activated protein C (APC). An automated factor Xa–based one-stage clotting assay was developed that enables quantification of the APC-independent activity of protein S in plasma from the ratio of clotting times (protein S ratio [pSR]) determined in the absence and presence of neutralizing antibodies against protein S. The pSR was 1.62 ± 0.16 (mean ± SD) in a healthy population (n = 60), independent of plasma levels of factors V, VIII, IX, and X; protein C; and antithrombin, and not affected by the presence of factor V Leiden. The pSR strongly correlates with the plasma level of protein S and is modulated by the plasma prothrombin concentration. In a group of 16 heterozygous protein S–deficient patients, the observed mean pSR (1.31 ± 0.09) was significantly lower than the mean pSR of the healthy population, as was the pSR of plasma from carriers of the prothrombin G20210A mutation (1.47 ± 0.21; n = 46). We propose that the decreased APC-independent anticoagulant activity of protein S in plasma with elevated prothrombin levels may contribute to the thrombotic risk associated with the prothrombin G20210A mutation.
Long targeting arms do not increase the efficiency of homologous recombination in the β-globin locus of murine embryonic stem cells
Authors: Lu Zhi Hong , Books Jason T. , Kaufman Richard M. , Ley Timothy J. 
Published: May 2003

AbstractThe correction of mutant β-globin genes has long been a therapeutic goal for patients with β-thalassemia or hemoglobinopathies. The use of homologous recombination (HR) to achieve this goal is an attractive approach because it eliminates the need to include regulatory sequences in the therapeutic construct, and it eliminates mutagenesis induced by random integration. However, HR is a very inefficient process for gene correction, and its efficiency is probably locus dependent. The length of targeting arms is thought to be a determinant of targeting efficiency, so we compared the ability of standard (8-kb) versus very long (16-, 24-, and 110-kb) regions of homology to correct a mutant murine β-globin gene in embryonic stem cells. Increasing the length of the targeting sequences did not increase the efficiency of HR in this locus, suggesting that alternative approaches will be required to improve the efficiency of this approach for globin gene correction.
Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders
Authors: Kralovics Robert , Buser Andreas S. , Teo Soon-Siong , Coers Jörn , Tichelli Andre , van der Maas Anthonie P. C. , Skoda Radek C. 
Published: May 2003

AbstractDecreased expression of c-MPL protein in platelets, increased expression of polycythemia rubra vera 1 (PRV-1) and nuclear factor I-B (NFIB) mRNA in granulocytes, and loss of heterozygosity on chromosome 9p (9pLOH) were described as molecular markers for myeloproliferative disorders (MPDs). To assess whether these markers are clustered in subgroups of MPDs or represent independent phenotypic variations, we simultaneously determined their status in a cohort of MPD patients. Growth of erythropoietin-independent colonies (EECs) was measured for comparison. We observed concordance between EECs and PRV-1 in MPD patients across all diagnostic subclasses, but our results indicate that EECs remain the most reliable auxiliary test for polycythemia vera (PV). In contrast, c-MPL, NFIB, and 9pLOH constitute independent variations. Interestingly, decreased c-MPL and elevated PRV-1 also were observed in patients with hereditary thrombocythemia (HT) who carry a mutation in the thrombopoietin (TPO) gene. Thus, altered c-MPL and PRV-1 expression also can arise through a molecular mechanism different from sporadic MPD.
Decreased factor VIII levels during acetaminophen-induced murine fulminant hepatic failure
Authors: Doering Christopher B. , Parker Ernest T. , Nichols Christopher E. , Lollar Pete 
Published: May 2003

Abstract
During human fulminant hepatic failure (FHF) circulating levels of most hemostatic proteins fall dramatically. Concurrently, factor VIII (fVIII) procoagulant activity rises despite destruction of the hepatocytes considered responsible for fVIII synthesis. This observation suggests a role for cells other than hepatocytes in fVIII biosynthesis during FHF. We have attempted to identify nonhepatocytic sites of fVIII biosynthesis by inducing FHF in mice using acetaminophen overdose, a common cause of human FHF. Acetaminophen-treated mice consistently displayed signs characteristic of FHF, including elevated plasma aminotransferase activity. However, acetaminophen-treated mice demonstrated markedly reduced fVIII activity, contrary to the observation in human FHF. von Willebrand factor antigen levels were only mildly reduced, suggesting that the decrease in fVIII is not secondary to loss of von Willebrand factor. These results imply that there are fundamental differences in the regulation of plasma fVIII levels between humans and mice.
Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis
Authors: Borgmann Anja , von Stackelberg Arend , Hartmann Reinhard , Ebell Wolfram , Klingebiel Thomas , Peters Christina , Henze Günter 
Published: May 2003

Abstract
Allogeneic stem cell transplantation (SCT) is frequently considered as treatment for relapsed childhood acute lymphoblastic leukemia (ALL). For patients without a matched sibling donor, SCT from unrelated donors (UD-SCT) has been increasingly performed during the past years. However, UD-SCT–related mortality and morbidity is still considerable, and the question remains as to which patients are at such high risk of recurrence that UD-SCT is indicated and, conversely, which patients do not require transplantation for long-term disease control. A matched-pair analysis was performed among patients treated according to Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group protocols after first relapse with chemotherapy or UD-SCT. Altogether 81 pairs were identified that could be matched exactly for site of relapse and immunophenotype, and as closely as possible for duration of first remission, age, diagnosis date, and peripheral blast cell count at relapse. No significant difference in the probability of event-free survival (pEFS) between UD-SCT and chemotherapy existed regarding 28 pairs with an intermediate prognosis (0.39 ± 0.10 vs 0.49 ± 0.11,P = .105), whereas the pEFS was significantly different in the 53 pairs with a poor prognosis (0.44 ± 0.07 vs 0.00 ± 0.00, P < .001). The major reasons of treatment failure among patients who underwent UD-SCT were therapy-related death (TRD; 24/81) and relapses (20/81). In contrast, TRD rarely occurred in patients treated with chemotherapy alone (3/81), but relapse was much more common (62/81). In conclusion, UD-SCT provides better event-free survival for children with high-risk relapsed ALL. However, there is no clear advantage of UD-SCT in patients with intermediate prognosis.
Megakaryocytes require thrombospondin-2 for normal platelet formation and function
Authors: Kyriakides Themis R. , Rojnuckarin Ponlapat , Reidy Michael A. , Hankenson Kurt D. , Papayannopoulou Thalia , Kaushansky Kenneth , Bornstein Paul 
Published: May 2003

AbstractMice that lack the matricellular angiogenesis inhibitor, thrombospondin-2 (TSP2), display a bleeding diathesis, despite normal blood coagulation and the lack of thrombocytopenia. Although platelets do not contain detectable levels of TSP2, TSP2-null platelets are compromised in their ability to aggregate in vivo in response to denudation of the carotid artery endothelium, and in vitro following exposure to adenosine diphosphate (ADP). Megakaryocytes (MKs) show high levels of TSP2 by immunohistochemical analysis of bone marrow. However, when cultured in vitro, MKs contain little TSP2 protein or mRNA. These findings suggest that most TSP2 is acquired from the bone marrow microenvironment. Consistent with this hypothesis, MKs take up recombinant TSP2 in an integrin-dependent manner when it is supplied in the culture medium. Furthermore, uptake of TSP2 in vitro affects MK differentiation and proplatelet formation. The functional significance of this process is supported by the presence of ultrastructural abnormalities in TSP2-null bone marrow, including extensive fragmentation of the peripheral zone in MKs and failure of this zone to form close associations with vascular sinuses. We conclude that the uptake of TSP2 by MKs from the marrow milieu is required for proper MK function and the release of functionally competent platelets.
Diagnosing occupational asthma: how, how much, how far?: Table 1
Authors: Moscato G. , Malo J-L. , Bernstein D. 
Published: May 2003

Diagnosing occupational asthma is still a challenge because it is based on a stepwise approach in which the depth of investigative means may vary depending on resources. The authors herewith review the existing investigative means from the approach of outlining controversies and queries.There is no validated clinical questionnaire for diagnosing occupational asthma. Immunological investigation is limited by the lack of standardised extracts for skin-prick testing and specific immunoglobulin E assessments. Criteria for interpretation of changes in peak expiratory flow rates and bronchial responsiveness to pharmacological agents are still open to discussion.It is worth improving the methodology of specific inhalation challenges, either in the laboratory or in the workplace, to facilitate more extensive use of these tests. Validation of new means that assess airway inflammation, such as exhaled nitric oxide and induced sputum, needs to be performed. There is a need to increase the use of these diagnostic tests because the diagnosis is still too often based on “clinical impression”.
Monoclonal anti-interleukin‐5 treatment suppresses eosinophil but not T‐cell functions
Authors: Büttner C. , Lun A. , Splettstoesser T. , Kunkel G. , Renz H. 
Published: May 2003

Influx of eosinophils in airway mucosa and airway lumen is a hallmark of bronchial asthma.In-vitrodata and animal studies indicate that the T‐helper (Th) type‐2 cell cytokine, interleukin (IL)‐5, plays an important role in eosinophil maturation, differentiation, recruitment, and survival. The objective of this study was to determine whether intravenous treatment with monoclonal anti-IL‐5 would affect the number of peripheral blood eosinophils, their activation status, T‐cell activation or the pattern of Th1 and Th2 cytokine production.Over a period of 6 months, 19 asthmatics were investigated in a double-blind, placebo-controlled, multicentre study with mepolizumab (SB 240563) anti-IL‐5 antibody administered three times. Before each infusion and 12 weeks after the last infusion, peripheral blood leukocytes were examined, qualitative and quantitative distribution of eosinophils and lymphocyte subpopulations, frequencies of IL‐2, ‐3, ‐4, ‐5, -10, -13, interferon‐γ‐producing CD4 T‐cells and serum eosinophil cationic protein (ECP) levels were determined.Treatment with mepolizumab resulted in a marked, rapid and sustained decrease of eosinophil numbers (median values from 300 to 45 per µL) paralleled by decreased levels of serum ECP (median values from 15 to 5 µg·L−1). Distribution of T‐cell subsets and T‐cell cytokine production were not altered during antibody treatment.In conclusion, administration of mepolizumab to asthmatic patients markedly reduces peripheral blood eosinophils without altering the distribution and activation status of lymphocytes.
Effects of tobacco smoking on findings in chest computed tomography among asbestos-exposed workers
Authors: Vehmas T. , Kivisaari L. , Huuskonen M.S. , Jaakkola M.S. 
Published: May 2003

This study examined the effects of smoking on the findings in chest computed tomography (CT) in 587 asbestos-exposed construction workers (11 females, 576 males, mean age 62 yrs; 18 never-smokers, 406 exsmokers and 163 current smokers). The workers were imaged with spiral CT and high-resolution CT. A total of 13 radiological signs were scored by three radiologists independently. The workers' medical data, smoking habits and occupational exposures were collected at an interview. The effects of smoking status and smoked pack-yrs (0–87.5) on the CT signs were studied using multivariate analysis adjusted for confounding factors.Smoking increased all emphysema signs and contributed to bronchial wall thickening. Smoking was negatively associated with curvilinear and septal lines as well as with parenchymal bands. In persons who had smoked <10 pack-yrs, smoking was positively related to paraseptal emphysema and to bronchial wall thickening and negatively related to septal lines, subpleural nodules and honeycombing.Smoking was related to several abnormal computed tomography signs even among those with relatively small exposure. Computed tomography can detect changes due to smoking at an early stage.
Transient early wheeze is not associated with impaired lung function in 7‐yr-old children
Authors: Lau S. , Illi S. , Sommerfeld C. , Niggemann B. , Völkel K. , Madloch C. , Grüber C. , Nickel R. , Forster J. , Wahn U. ,   the Multicentre Allergy Study Group
Published: May 2003

The aim of the present study was to analyse determinants of lung function in 7‐yr-old children with different wheezing patterns (early, persistent and late onset) in a prospective cohort study.The German Multicentre Allergy Study (MAS) followed 1,314 children from birth onwards. Annual assessments included clinical check-ups, a structured interview and repeated measurement of specific immunoglobulins Ig(E) directed against food and inhalant allergens. At the age of 7 yrs, lung function was measured by body plethysmography in 800 children.Episodes of wheezing in the past 12 months (“current wheeze”) were strongly associated with reduced lung function at age 7 yrs. Children with wheezing episodes only during the first 3 yrs of life showed a slight impairment in maximal expiratory flow when 50% of the forced vital capacity remains to be exhaled (98.9±24.2versus103.2±22.8% of the predicted value in children who never wheeze). Separate analysis of determinants of pulmonary function within these subgroups resulted in distinctly different patterns. Determinants of impaired lung function in the group of current wheezers were: time in years since first wheeze, a parental history of atopy, current sensitisation to indoor allergens, elevated cord blood IgE levels and a low ponderal index at birth. In the group of transient early wheezers, frequent lower respiratory tract infections early in life and maternal smoking during pregnancy were significant but weak determinants of impaired lung function.The present results indicate that determinants of pulmonary function in 7‐yr-old children differ with respect to different wheezing phenotypes, demanding different therapeutic strategies. Although transient early wheezers were found to have normal-to-subnormal lung function, children with asthmatic symptoms (persistent and late-onset disease) at age 7 yrs already show significant impairment of expiratory flow volumes.
Increased tumour necrosis factor‐α plasma levels during moderate-intensity exercise in COPD patients
Authors: Rabinovich R.A. , Figueras M. , Ardite E. , Carbó N. , Troosters T. , Filella X. , Barberà J.A. , Fernandez-Checa J.C. , Argilés J.M. , Roca J. 
Published: May 2003

Post-training downregulation of muscle tumour necrosis factor (TNF)‐α messenger ribonucleic acid (mRNA) expression and decrease in cellular TNF‐α levels have been reported in the elderly. It is hypothesised that chronic obstructive pulmonary disease (COPD) patients may not show these adaptations due to their reduced ability to increase muscle antioxidant capacity with training.Eleven COPD patients (forced expiratory volume in one second 40±4.4% of the predicted value) and six age-matched controls were studied. Pre- and post-training levels of TNF‐α, soluble TNF receptors (sTNFRs: sTNFR55 and sTNFR75) and interleukin (IL)‐6 in plasma at rest and during exercise and vastus lateralis TNF‐α mRNA were examined.Moderate-intensity constant-work-rate exercise (11 min at 40% of pretraining peak work-rate) increased pretraining plasma TNF‐α levels in COPD patients (from 17±3.2 to 23±2.7 pg·mL−1; p<0.005) but not in controls (from 19±4.6 to 19±3.2 pg·mL−1). No changes were observed in sTNFRs or IL‐6 levels. After 8 weeks' endurance training, moderate-intensity exercise increased plasma TNF‐α levels similarly to pretraining (from 16±3 to 21±4 pg·mL−1; p<0.01). Pretraining muscle TNF‐α mRNA expression was significantly higher in COPD patients than in controls (29.3±13.9versus5.0±1.5 TNF‐α/18S ribonucleic acid, respectively), but no changes were observed after exercise or training.It is concluded that moderate-intensity exercise abnormally increases plasma tumour necrosis factor‐α levels in chronic obstructive pulmonary disease patients without exercise-induced upregulation of the tumour necrosis factor‐α gene in skeletal muscle.
To clip or not to clip? Noseclips for spirometry
Authors: Chavasse R. , Johnson P. , Francis J. , Balfour-Lynn I. , Rosenthal M. , Bush A. 
Published: May 2003

The use of noseclips for open-circuit spirometry is sporadic, despite guidelines encouraging their use. The authors aimed to evaluate whether noseclips significantly affected measurements of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) in children attending a tertiary, paediatric respiratory centre.Children attending the asthma and cystic fibrosis (CF) clinics were asked to perform two sets of spirometry, one with and one without noseclips in random order, 20-min apart.Paired data was obtained on 62 patients (32 asthma, 30 CF) with a median age of 11.4 yrs (range 7.2–17.2 yrs). There were no systematic differences in FEV1or FVC measured with and without noseclips, although seven children (11%) had clinically significant differences in FEV1of >190 mL.There is no clear advantage to wearing noseclips when performing open-circuit spirometry. Individuals should be assessed to ascertain their optimal technique, which should then be used consistently in clinical practice. Noseclips should probably be retained for research protocols.
Spirometry in young children: should computer-animation programs be used during testing?
Authors: Gracchi V. , Boel M. , van der Laag J. , van der Ent C.K. 
Published: May 2003

Currently, computer-animation programs are frequently used to instruct and stimulate young children in performing maximal expiratory flow/volume (MEFV) curves. The reproducibility and maximal performance of MEFV manoeuvres with and without the use of two computer-animation programs (the “candles” and the “balloon” programs) were evaluated.Eighty-eight children, aged 4–8 yrs, were randomly assigned to one of the two animation programs. All children performed two series of at least three technically acceptable curves, one series with the incentive and one without, in random order.With the use of computer-animation programs, a lower proportion of children were able to fulfil international criteria for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) reproducibility. The use of incentives improved reproducibility and performance of peak expiratory flow (PEF). Performance of FVC decreased significantly in 6–8‐yr-old children using the animation programs.Training with a program for a short period of time before the formal lung-function test may be valuable. According to the results, however, the use of these programs during tests under the guidance of an experienced lung-function technician cannot be routinely recommended because of possible deteriorating effects on reproducibility and performance of forced expiratory manoeuvres.
N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease
Authors: Gerrits C.M.J.M. , Herings R.M.C. , Leufkens H.G.M. , Lammers J-W.J. 
Published: May 2003

The aim of this study was to evaluate the effect of oralN‐acetylcysteine in the prevention of re-hospitalisation for chronic obstructive pulmonary disease (COPD) exacerbations.Using the PHARmacoMOrbidity linkage (PHARMO) system the authors included all patients aged ≥55 yrs who had been dispensed medication, labelled for respiratory indications (anatomical therapeutic chemical (ATC) classification system: R03), between 1986–1998 and who had also been hospitalised for COPD (International Classification of Diseases (ICD)‐9: 491, 492, 496) in this time frame. These subjects were subsequently divided into two groups, those who had receivedN‐acetylcysteine following discharge from their first admission between 1986–1998 and those who had not. All the patients were studied starting from their initial discharge, until their first readmission, death or end of data collection period. The maximum follow-up period was 1 yr.A total of 1,219 patients, who were hospitalised for COPD between 1986–1998, were included in this study. After adjustment for disease severity, it was observed that the use ofN‐acetylcysteine was significantly associated with a reduced risk of readmission. The readmission risk was significantly lower in patients with high average daily doses ofN‐acetylcysteine.In conclusion it was observed thatN‐acetylcysteine reduces the risk of re-hospitalisation for chronic obstructive pulmonary disease by ∼30% and that this risk reduction is dose-dependent.
Uptake of18fluorodeoxyglucose in the cystic fibrosis lung: a measure of lung inflammation?
Authors: Labiris N.R. , Nahmias C. , Freitag A.P. , Thompson M.L. , Dolovich M.B. 
Published: May 2003

Positron emission tomography is a three-dimensional imaging technique that measures physiological effects, including metabolism.18Fluorodeoxyglucose has been extensively used as a tracer of cellular energy metabolism in the brain and in tumour detection. As neutrophils utilise glucose as an energy source during their respiratory burst, it was hypothesised that18fluorodeoxyglucose uptake, by these cells, could be interpreted as a measure of neutrophil activation in cystic fibrosis (CF).Ten adult CF patients were given a bolus intravenous injection of18fluorodeoxyglucose, followed by a 90-min dynamic mid-lung acquisition scan. Right-lung18fluorodeoxyglucose uptake was assessed using a Patlak plot and values were converted to glucose utilisation. Three clinically inactive pulmonary sarcoidosis patients served as controls.From the 10 CF patients with baseline sputum neutrophils of 14×106cells·mL−1who were investigated, seven were found to have sputum at a normal or slightly depressed glucose utilisation rate (mean 1.33 µmol·g−1·h−1) compared with a mean of 2.82 µmol·g−1·h−1for the sarcoidosis patients. In eight patients, receiving inhaled tobramycin therapy, no change in lung glucose utilisation or sputum neutrophil counts were found.Despite high-sputum neutrophil levels, lung glucose utilisation was not elevated in patients with cystic fibrosis.