bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of effect of the human GM-CSF analog E21R on the survival of primary human acute myeloid leukemia cells
Authors: Jakupovic Ira , Grandage Victoria L. , Linch David C. , Khwaja Asim
Published: January 2004

The granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R binds to the GM-CSF receptor complex with low affinity and acts as a competitive antagonist. In addition, it has been reported to be a potent direct activator of apoptosis in primary human acute myeloid leukemia (AML) cells. We have confirmed the ability of E21R to neutralize the biologic effects of GM-CSF and investigated its activity on primary AML blasts. We find that it failed to induce cell death in blast cells from 23 separate AML cases treated in vitro at concentrations of E21R up to 30 μg/mL. Significant cell death resulted in all cases after incubation with cytosine arabinoside. The lack of effect of E21R on AML blasts was unlikely to be due to an absence of functional GM-CSF receptors because 13 cases demonstrated an increase in cell number with the addition of exogenous GM-CSF. These results do not support the use of E21R for the treatment of AML. (Blood. 2004;103: 3230-3232)
Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help
Authors: Poeck Hendrik , Wagner Moritz , Battiany Julia , Rothenfusser Simon , Wellisch Daniela , Hornung Veit , Jahrsdorfer Bernd , Giese Thomas , Endres Stefan , Hartmann Gunther
Published: January 2004

It has been reported that interferon α (IFN-α) enhances humoral immunity and that dendritic cells of the myeloid lineage promote B-cell differentiation. Here we studied whether the plasmacytoid dendritic cell (PDC), a subset of dendritic cells specialized for the production of IFN-α, is involved in regulating B-cell differentiation and immunoglobulin production. The recently identified class of CpG oligonucleotides (CpG-C) was used to activate both B cells and PDCs via Toll-like receptor 9 (TLR9). The presence of PDCs synergistically enhanced CD86 expression, cytokine production (interleukin 6 [IL-6], tumor necrosis factor α, and IL-10) and plasma cell differentiation of isolated human peripheral blood B cells stimulated through CpG-C and B-cell antigen receptor (BCR) ligation. This stimulation protocol was sufficient to drive purified naive B cells into IgM-producing plasma cells and to trigger IgG synthesis in memory B cells. PDCs contributed to B-cell activation via IFN-α secretion. Up-regulation of TLR9 on B cells was not involved. These results demonstrate that CpG-stimulated PDCs induce plasma cell differentiation in naive and memory B cells in the absence of T-cell help, providing an explanation for the excellent activity of CpG oligonucleotides as a humoral vaccine adjuvant. (Blood. 2004;103:3058-3064)
L-selectin defines a bone marrow analog to the thymic early T-lineage progenitor
Authors: Perry S. Scott , Wang Hongfang , Pierce L. Jeanne , Yang Anne Marie , Tsai Schickwann , Spangrude Gerald J.
Published: January 2004

The recent description of an early T-lineage progenitor (ETP) population in adult mouse thymus implies the presence of a bone marrow predecessor that has not yet been identified. Here we describe a LinNeg Sca-1Pos c-kitHi Thy-1.1Neg L-selectinPos adult mouse bone marrow population that resembles the thymic ETP in both antigen expression phenotype and posttransplantation lineage potential. These cells produce wavelike kinetics of thymic seeding and reconstitute the irradiated thymus with kinetics comparable to a thymocyte graft after intravenous transplantation. Transient B-lineage reconstitution is also observed, but little myeloid potential can be detected in transplant experiments. A second subset of progenitors is L-selectinNeg and is highly enriched for rapid and persistent T- and B-lineage potential, as well as some myeloid potential. L-selectin (CD62L) is therefore an effective marker for separating lymphoid progenitors from myeloid progenitors and hematopoietic stem cells in mouse bone marrow. (Blood. 2004;103: 2990-2996)
Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice
Authors: Follenzi Antonia , Battaglia Manuela , Lombardo Angelo , Annoni Andrea , Roncarolo Maria Grazia , Naldini Luigi
Published: January 2004

Stable gene replacement by in vivo administration of lentiviral vectors (LVs) has therapeutic potential for metabolic disorders and other systemic diseases. We studied the expression of intracellular and secreted proteins by LVs in immunocompetent mice. Liver, spleen, and bone marrow cells were efficiently transduced. However, transgene expression, driven by a ubiquitous promoter, was limited by transgene-specific cellular and humoral immune responses, leading to the clearance of transduced cells. After green fluorescent protein (GFP) gene transfer, the liver showed infiltration of CD8+ cytotoxic T cells, and GFP-specific CD8+ T cells were isolated from the spleen. After human factor IX (hF.IX) gene transfer, anti-hF.IX antibodies were induced. These immune responses were not detected in mice injected with heat-inactivated or genome-lacking LVs or in GFP-transgenic mice, indicating that they were specifically triggered by transgene expression in vivo. Intriguingly, selective targeting of LV expression to hepatocytes limited the immune responses to the transgenes. By this approach, high levels of hF.IX, potentially in the therapeutic range, were reached and maintained long term in immunocompetent mice, without inducing antibody formation. These results prompt further studies in relevant animal models to explore the potential of in vivo LV administration for the gene therapy of hemophilias and other liver-based diseases.
Gene expression in human embryonic stem cell lines: unique molecular signature
Authors: Bhattacharya Bhaskar , Miura Takumi , Brandenberger Ralph , Mejido Josef , Luo Yongquan , Yang Amy X. , Joshi Bharat H. , Ginis Irene , Thies R. Scott , Amit Michal , Lyons Ian , Condie Brian G. , Itskovitz-Eldor Joseph , Rao Mahendra S. , Puri Raj K.
Published: January 2004

Human embryonic stem (huES) cells have the ability to differentiate into a variety of cell lineages and potentially provide a source of differentiated cells for many therapeutic uses. However, little is known about the mechanism of differentiation of huES cells and factors regulating cell development. We have used high-quality microarrays containing 16 659 seventy–base pair oligonucleotides to examine gene expression in 6 of the 11 available huES cell lines. Expression was compared against pooled RNA from multiple tissues (universal RNA) and genes enriched in huES cells were identified. All 6 cell lines expressed multiple markers of the undifferentiated state and shared significant homology in gene expression (overall similarity coefficient > 0.85).A common subset of 92 genes was identified that included Nanog, GTCM-1, connexin 43 (GJA1), oct-4, and TDGF1 (cripto). Gene expression was confirmed by a variety of techniques including comparison with databases, reverse transcriptase–polymerase chain reaction, focused cDNA microarrays, and immunocytochemistry. Comparison with published “stemness” genes revealed a limited overlap, suggesting little similarity with other stem cell populations. Several novel ES cell–specific expressed sequence tags were identified and mapped to the human genome. These results represent the first detailed characterization of undifferentiated huES cells and provide a unique set of markers to profile and better understand the biology of huES cells. (Blood. 2004;103: 2956-2964)
Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support
Authors: del Carmen Rodríguez María , Bernad Antonio , Aracil Miguel
Published: January 2004

Interleukin-6 (IL-6) is a critical factor in the regulation of stromal function and hematopoiesis. In vivo bromodeoxyuridine incorporation analysis indicates that the percentage of Lin-Sca-1+ hematopoietic progenitors undergoing DNA synthesis is diminished in IL-6-deficient (IL-6-/-) bone marrow (BM) compared with wild-type BM. Reduced proliferation of IL-6-/- BM progenitors is also observed in IL-6-/- long-term BM cultures, which show defective hematopoietic support as measured by production of total cells, granulocyte macrophage-colony-forming units (CFU-GMs), and erythroid burst-forming units (BFU-Es). Seeding experiments of wild-type and IL-6-/- BM cells on irradiated wild-type or IL-6-deficient stroma indicate that the hematopoietic defect can be attributed to the stromal and not to the hematopoietic component. In IL-6-/- BM, stromal mesenchymal precursors, fibroblast CFUs (CFU-Fs), and stroma-initiating cells (SICs) are reduced to almost 50% of the wild-type BM value. Moreover, IL-6-/- stromata show increased CD34 and CD49e expression and reduced expression of the membrane antigens vascular cell adhesion molecule-1 (VCAM-1), Sca-1, CD49f, and Thy1. These data strongly suggest that IL-6 is an in vivo growth factor for mesenchymal precursors, which are in part implicated in the reduced longevity of the long-term repopulating stem cell compartment of IL-6-/- mice. (Blood. 2004;103:3349-3354)
Safety and efficacy of the monoclonal anti–interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome
Authors: Klion Amy D. , Law Melissa A. , Noel Pierre , Kim Yae-Jean , Haverty Thomas P. , Nutman Thomas B.
Published: December 2003

Four patients with hypereosinophilic syndrome (HES) refractory to or intolerant of treatment with conventional therapy were treated with a single 1 mg/kg dose of SCH55700. SCH55700 was extremely well tolerated. Two of the 4 patients responded with a fall in eosinophil counts to within the normal range within 48 hours of receiving the drug, accompanied by marked improvement in clinical signs and symptoms. Response was not predicted by serum interleukin-5 (IL-5) levels or presence of the FIP1L1/PDGFRA mutation. Eosinophil counts remained suppressed for up to 12 weeks after treatment; however, exacerbation of symptoms and eosinophilia above baseline levels occurred as drug levels waned. Reinstitution of treatment with monthly SCH55700 led to decreased eosinophilia and symptomatic improvement, albeit to a lesser degree than that seen after the initial dose. These data suggest that anti–IL-5 therapy may be useful in the treatment of HES irrespective of the underlying etiology, although the observed rebound eosinophilia and attenuation of response require further study. (Blood. 2004;103:2939-2941)
T-cell and macrophage subsets in the bronchial wall of clinically healthy subjects
Authors: Power CK , Burke CM , Sreenan S , Hurson B , Poulter LW
Published: January 2004

This study was conducted to obtain quantitative data on the numbers of T-cells and macrophage subsets in the normal bronchial wall of man, and, thus, produce a baseline against which the numbers of these cells present in inflamed bronchi may be judged. Bronchial biopsies were obtained from 27 clinically healthy subjects attending hospital for elective orthopaedic operations. Eight of the subjects were smokers (median 3.5 pack-years), and eight were atopic as defined by skin prick test. Three to eight weeks after biopsy, subjects attended the lung function laboratory for spirometric testing and determination of provocative concentration of histamine producing a 20% fall in forced expiratory volume in one second (PC20FEV1). The bronchial biopsies were frozen and cryostat sections prepared. These sections were investigated with immunohistological techniques to reveal the presence and distribution of T-cell and macrophage subsets. Twenty six out of 27 subjects had spirometric values within the normal range, but a wide spectrum of bronchial reactivity was observed (PC20FEV1 range 2-36 mg histamine). Using monoclonal antibodies in immunohistological techniques, only small numbers of T-cells were seen, the majority being CD8+ cells in the epithelium. In the underlying tissue, CD4+ cells predominated (CD4/CD8 ratio, epithelium 1:9; underlying tissue 4:1). In both cases, approx. 50% of T-cells expressed the CD45Ro isotype. Small numbers of macrophages were observed in all samples. The majority of these cells expressed a "suppressor cell" phenotype (RFD1+RFD7+), whilst only a small proportion (median 11% ) exhibited the phenotype of antigen presenting cells (RFD1+RFD7-).(ABSTRACT TRUNCATED AT 250 WORDS)
Nasal application of the cationic liposome DC-Chol:DOPE does not alter ion transport, lung function or bacterial growth
Authors: Middleton PG , Caplen NJ , Gao X , Huang L , Gaya H , Geddes DM , Alton EW
Published: January 2004

Liposome-mediated gene transfer is commonly used for in vitro transfection of deoxyribonucleic acid (DNA) into mammalian cells. We and others have recently demonstrated that this can be an effective method for in vivo delivery of plasmid DNA containing the human cystic fibrosis transmembrane conductance regulator (CFTR) gene to mouse models of cystic fibrosis (CF). This suggests that cationic liposomes may be useful for transferring CFTR complementary DNA (cDNA) into the airways of CF subjects. In such trials, measurement of nasal potential difference (PD) will be used to monitor the efficacy of correction of the CF bioelectric defect and to provide a sensitive assay of epithelial integrity [corrected]. We therefore assessed whether the cationic liposome DC-Chol: DOPE altered nasal ion transport parameters, in six normal and three CF subjects. Lung function was also measured as a further marker of safety. Finally, as CF airways are chronically infected, we studied whether DC-Chol:DOPE or DC-Chol:DOPE-DNA complexes altered the bacterial growth and sensitivities of CF sputum. No significant effect was seen on any of these parameters, suggesting that DC-Chol:DOPE may be appropriate for use in human trials of liposome-mediated gene therapy for CF.
Effect of sputum induction on arterial oxygen saturation and spirometry in HIV-infected patients
Authors: Leigh TR , Kirby K , Gazzard BG , Collins JV
Published: January 2004

We wanted to study the effect of sputum induction on forced expiratory volume in one second (FEV1) and on oxygen saturation in normal controls, asymptomatic human immunodeficiency virus (HIV)-seropositive individuals, and HIV-seropositive patients under investigation for suspected Pneumocystis carinii pneumonia (PCP). Over a five month period, sputum induction with ultrasonically nebulized 3% saline was performed on 110 HIV-seropositive patients with suspected PCP, 10 asymptomatic HIV-seropositive patients, and 15 normal controls. Oxygen saturation (peak, trough and change in oxygen saturation (delta O2)) was measured throughout the procedure using pulse oximetry, and these results compared with the chest radiograph and the final pulmonary diagnosis. In addition, the effect of sputum induction on FEV1 was measured in the 15 control subjects and 10 asymptomatic HIV-seropositive patients. Compared with bronchoalveolar lavage, sputum induction had a diagnostic sensitivity for PCP of 76%. Chest radiography was 79% sensitive, and had specificity of 83%. Patients with PCP had lower peak and trough oxygen saturation values compared with the non-PCP group (mean peak 95 vs 97%; mean trough 88 vs 91%), and greater falls in O2 saturation during the procedure (mean delta O2 7.6 vs 5.5%). One subject desaturated to 76%, requiring supplemental oxygen. Sputum induction caused significant but temporary falls in FEV1 both in control and HIV-seropositive groups (mean maximum fall in FEV1 10.4 vs 12.5%). We conclude that although sputum induction causes significant falls in oxygen saturation and FEV1, it remains sensitive and safe, and provides a useful alternative to bronchoscopy for the diagnosis of PCP.
Effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responsiveness to leukotriene D4 in normal and asthmatic subjects
Authors: Diamant Z , Timmers MC , van der Veen H , Booms P , Sont JK , Sterk PJ
Published: January 2004

Cysteinyl leukotrienes are potent inflammatory mediators that are considered to play a role in the pathophysiology of asthma. It can be postulated that leukotrienes exert their bronchoconstricting effects, in part, through secondary release of endogenous neuropeptides. We examined the effect of inhaled thiorphan, an inhibitor of a neuropeptide degrading enzyme, on the concentration-response curve to leukotriene D4 (LTD4) in a two-period, double-blind, cross-over and placebo-controlled study, in 16 nonasthmatic and 12 asthmatic subjects. Thiorphan or placebo were aerosolized and administered in two 0.5 ml doses of 1.25 mg.ml-1 each, 10 min prior to LTD4 inhalation. The airway response was measured by forced expiratory volume in one second (FEV1) and partial expiratory flow-volume curves (expiratory flow at 40% of forced vital capacity; V40p), and expressed as % fall from baseline. Complete concentration-response curves to inhaled LTD4 were recorded and characterized by their position (provocative concentration producing a 20% fall in FEV1 and a 40% fall in V40p; PC20FEV1 and PC40 V40p) and, in the nonasthmatics, also by the maximal-response plateau (MFEV1, MV40p). Post-pretreatment baseline values of FEV1 and V40p were not different between thiorphan and placebo pretreatment. In both groups of subjects, there was no significant difference in lnPC40V40p or lnPC20FEV1 to LTD4 between the two pretreatments mean difference +/- SD (in doubling concentrations): 0.12 +/- 0.73 and -0.19 +/- 1.23, respectively, in asthmatics; and 0.17 +/- 0.95 and -0.99 +/- 1.95, respectively, in nonasthmatics. The maximal-response plateau could not be obtained in the majority of the asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Patient compliance with inhaled medication: does combining beta-agonists with corticosteroids improve compliance?
Authors: Bosley CM , Parry DT , Cochrane GM
Published: January 2004

Patient compliance with an inhaled corticosteroid may be greater if it is combined with a beta-agonist. This study compared compliance with an inhaled corticosteroid (budesonide), and a short-acting inhaled beta-agonist (terbutaline sulphate), and a Turbuhaler inhaler containing a combination of the two drugs. In an open, multicentre, parallel group study 102 asthmatic patients were randomly divided into two groups, either receiving the two drugs in separate Turbuhalers or combined into one Turbuhaler. A twice daily regimen was prescribed and a preweighed metered-dose inhaler (MDI) of salbutamol was provided for rescue use. Compliance was measured using the Turbuhaler Inhalation Computer (TIC), which recorded the time and date of each inhalation over a 12 week period. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measurements were carried out at week 0, 6 and 12. Results from 72 patients were analysed. The average compliance was 60-70%. Treatment was taken as prescribed on 30-40% of the study days, and over-usage occurred on less than 10% of days. Only 15% of patients took the drugs as prescribed for more than 80% of the days. Compliance was no greater in patients using the combined inhalers. Other ways of improving patient self-management need further investigation.
Non-asphyxiating tracheobronchial foreign bodies in adults
Authors: Lan RS
Published: January 2004

The presentations of 47 adult patients with a non-asphyxiating tracheobronchial foreign body were reviewed. The duration of residence of the foreign body was 1 week or less in nine ("acute group"); 1 month or more in 29 ("chronic group"), uncertain in four ("uncertain group"); and the foreign body was a broncholith in five patients ("broncholith group"). In the chronic and uncertain groups, no precipitating factor was found and bone was the most common foreign body. In the chronic group, a choking history was obtained before bronchoscopy in only 15 patient. Clinical manifestations and roentgenograms were nonspecific in most cases, except in the acute group. In the chronic group, the mean duration of residence of the foreign body was 25.8 months. The diagnosis was delayed due to absence of a choking history and invisibility of the foreign body on chest films in 12, due to patient's ignorance in 14, due to physician's ignorance in 1, and due to previous unsuccessful retrieval attempts in 2 patients. The main indication for bronchoscopy in the acute group was a choking history or a visible foreign body on the chest film. In the chronic group, a choking history or conditions leading to "suspicion of an endobronchial lesion" were the main indications. The foreign body was removed with a fibreoptic bronchoscope in over 90% of patients. It is concluded that the most important diagnostic factor is a high clinical index of suspicion and that flexible fibreoptic bronchoscopy provides a valuable therapeutic option in selected conditions.
Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice
Authors: Piguet PF , Vesin C
Published: January 2004

Intratracheal instillation of bleomycin (0.08 U) or silica (2 mg) to mice leads, after 15 days, to a patchy pulmonary fibrosis associated with a significant increase of the lung hydroxyproline. Since tumour necrosis factor (TNF) seems to be an important mediator in pulmonary fibrosis, we wondered whether this fibrosis might be prevented by a new TNF-alpha antagonist. Infusion of a 55 kD human recombinant soluble TNF receptor rsTNFR-beta, at a rate of 20 micrograms.day-1, prevented the bleomycin/silica induced increase of lung hydroxyproline content, as measured 15 days after instillation. Infusion of rsTNFR-beta was also effective in the treatment of an established fibrosis, i.e. administered 25 or more days after instillation of bleomycin or silica, since it reduced lung collagen content. Recombinant soluble TNFR-beta had no significant influence on the number of cells, mostly macrophages, recovered by bronchoalveolar lavage. The examination of histological sections indicated that the rsTNFR-beta reduced the proportion of areas of damaged lung and, in silicosis, the formation of nodules with a rich collagen content. This study suggests that rsTNFR-beta might be useful in the therapy of pulmonary fibrosis.
Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part I)
Authors: Kroegel C , Virchow JC  , Luttmann W , Walker C , Warner JA
Published: January 2004

Increasing evidence has accumulated to suggest that eosinophils play a key role in the pathogenesis of asthma and other pulmonary diseases by damaging infiltrated bronchial tissue and lung parenchyma. The first part of this review on eosinophils describes the cellular characteristics and properties of the cell, which help in understanding its role in disease. The article focuses on origin, maturation and differentiation of the eosinophil, its morphological and phenotypical properties, as well as its preformed and newly generated mediators of inflammation. The cause and putative significance of eosinophil heterogeneity in respect to function and density will also be discussed. In addition, the naturally occurring mediators through which eosinophils are activated and communicate with other inflammatory cells are outlined. The first part closes with new aspects of eosinophil recruitment from the circulation into perivascular tissue, including nonselective and putative selective adhesion mechanisms and chemotaxis.
Mechanisms and pathology of occupational asthma
Authors: Mapp CE , Saetta M , Maestrelli P , Di Stefano A , Chitano P , Boschetto P , Ciaccia A , Fabbri LM
Published: January 2004

Since the pathogenesis and the pathological features of occupational asthma are similar to those of nonoccupational asthma, the former represents a very useful model for the investigation of the pathogenesis of asthma in general. More than one mechanism may be operative in occupational asthma. Among the mechanisms proposed, immunological mechanisms and airway inflammation play an important role. There is evidence to confirm that T-lymphocyte activation and local accumulation in the bronchial wall of activated eosinophils occurs in asthma of diverse aetiology, i.e. immunoglobulin E (IgE)-mediated, occupational and intrinsic. Neurogenic pathways should be further investigated as a potential mechanism of modulation and amplification of airway inflammation in occupational asthma.
Animal models of occupational asthma
Authors: Karol MH
Published: January 2004

Occupational asthma is characterized by variable airflow obstruction occurring in the workplace. The presence of airways inflammation and hyperreactivity provides further evidence for the disease. Since its pathogenic mechanism(s) are unknown, animal models have been developed to investigate the various disease processes, as well as to enable study of environmental and genetic factors which may contribute to disease development. Numerous parameters can be measured in animal systems, including specific and total immunoglobulin E (IgE), pulmonary eosinophilia, diaphragm contractions and airflow muscle hypertrophy. It is recognized that no single factor is sufficient to lead to a conclusion of occupational asthma, but rather that a selected combination of parameters is most fitting. Animal species selected for study have included: mice, rats, guinea-pigs, rabbits, sheep, horses and nonhuman primates. A guinea-pig system has been utilized for more than 90 yrs and has contributed to the basic understanding of physiological and immunological processes involved in allergic respiratory sensitization. The benefits as well as the disadvantages to be derived from each of the animal systems have been enumerated in this review. Certain caveats must be recognized in using animal systems. Attention must always be given to identifying differences which exist between animal and human systems, including morphological, physiological and immunological factors. The extent of bronchus-associated lymphoid tissue (BALT) differs greatly among animal species and probably plays a major role in development of allergic responsiveness in animals. In using animal systems, it must be appreciated that animals are only surrogates. Results from such studies must be compared with information obtained from clinical evaluation in order to avoid faulty extrapolations. Prudent employment of animal models is expected to advance the recognition, treatment and prevention of occupationally-based asthma.
Why are long-acting beta-adrenoceptor agonists long-acting?
Authors: Anderson GP , Linden A , Rabe KF
Published: January 2004

The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.
Theophylline in the management of asthma: time for reappraisal?
Authors: Barnes PJ , Pauwels RA
Published: January 2004

Theophylline has been used for several decades in the treatment of asthma and remains the most widely prescribed anti-asthma drug worldwide, although the development of newer anti-asthma medications, especially inhaled steroids, has resulted in declining use of theophylline in industrialized countries. Theophylline is now considered to be a bronchodilator, but it is increasingly recognized that theophylline has other anti-asthma activities, which may be more important. Theophylline, even at low plasma concentrations, inhibits the late asthmatic reaction following allergen challenge. These clinical pharmacological observations are substantiated by experimental animal and in vitro data showing that theophylline has several anti-inflammatory activities relevant to asthma. These include the inhibition of cytokine synthesis and release, the inhibition of inflammatory cell activation and microvascular leakage, and the prevention of airway hyperresponsiveness induced by airway inflammation. Theophylline appears to have immunomodulatory effects, even at relatively low plasma concentrations. Based on these considerations, theophylline can be regarded as a useful alternative to other anti-inflammatory drugs for the chronic treatment of mild to moderate asthma. Theophylline should be used at lower doses to achieve plasma concentrations of 5-10 mg.l-1, which will avoid the risk of side-effects. Further studies are required to evaluate the role of low-dose theophylline as an adjunct to low-dose inhaled steroids in the management of chronic asthma. It may now be appropriate to re-evaluate the role of theophylline in asthma management.
Contractility of lungs and air-tubes: experiments performed in 1840 by Charles J.B. Williams
Authors: Lotvall J
Published: January 2004

In the 18th century, some medical practitioners considered the main pathological feature of asthma to be the production of mucus. Later, during the 19th century, airway smooth muscle contraction was recognized to be a possible cause of airflow obstruction. However, not until 1840 was the contractility of airway smooth muscle clearly established by Charles J.B. Williams, a famous London physician. In a number of innovative experiments in dogs, rabbits, livestock and even donkeys, he showed: 1) that airways contract in response to electrical stimulation; 2) that the observed contractions are almost totally abolished by belladonna and stramonium (anticholinergics); 3) that the responses faded over time; and 4) that morphine inhibited the observed responses. Application of irritant fluids into the tracheal lumen produced similar responses. These interesting observations made by Williams will be reviewed, and related to current theories concerning modulation of airway smooth muscle responsiveness.
Respiratory and systemic reaction following exposure to heated electrostatic polyester paint
Authors: Cartier A , Vandenplas O , Grammer LC , Shaughnessy MA , Malo JL
Published: January 2004

A 39 year old nonatopic man developed episodes of cough, dyspnoea, sweating and shivers within 2-3 weeks of starting a new job in a factory where metallic boards were treated with an electrostatic powder paint, made of an epoxy resin and a carboxylated polyester containing polyethylene terephthalate and polybutylene terephthalate. The subject sprayed the metallic boards which were then heated in 200 degrees C ovens. The subject was first seen in an emergency room after being at work for 4 h. The physical examination revealed bilateral wheezing with fever (39 degrees C), hypoxaemia (arterial oxygen tension (PaO2) 58 torr (7.7 kPa), leucocytosis (white blood count cells.mm-3 17,000 (17 x 10(9) cells.l-1) and severe airway obstruction (forced expiratory volume in one second (FEV1)/forced vital capacity, (FVC) 1.3/2.4 l, improving to 2.2/3.8 l after bronchodilator; predicted values = 3.4/4.1 l). The subjects condition improved after being treated with oral steroids. His spirometry was normal two weeks later, although he showed mild bronchial hyperresponsiveness to methacholine with the (provocative concentration producing a 20% fall in FEV1 (PC20) being 1.7 mg.ml-1). The subject underwent specific inhalation challenges at the workplace 4 months later. After being exposed at work for 4 h, he developed a significant fall in FEV1 (-40%), fever, leucocytosis, and a fall in diffusing capacity. Lung function tests were back to normal two weeks later. Exposing the subject to heated granulated polyester for one hour in a hospital laboratory produced a fall in FEV1 of 41%, fever, leucocytosis and a fall in diffusing capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
Rapidly growing Epstein-Barr virus-associated pulmonary lymphoma after heart transplantation
Authors: Schwend M , Tiemann M , Kreipe HH , Parwaresch MR , Kraatz EG , Herrmann G , Spielmann RP , Barth J
Published: January 2004

There is strong evidence to show an association of Epstein-Barr virus (EBV) infection with the development of post-transplant lymphoproliferative disease. We report the rapid development of a malignant lymphoma in a heart transplant recipient, which occurred within less than eight weeks. The diagnosis of this malignant high grade B-cell lymphoma was established by open lung biopsy, and classified as centroblastic lymphoma of polymorphic subtype. Immunohistochemically, the lymphoma showed reactivity with the B-cell markers L-26 (CD20) and Ki-B5 and with the activation marker Ber-H2 (CD30). Furthermore, an expression of the bcl-2 oncoprotein was detected. Monoclonal JH gene rearrangement was demonstrated by polymerase chain reaction (PCR), indicating monoclonal proliferation of B-blasts. Although serum EBV immunoglobulin M (IgM) antibodies were negative, the association to an EBV infection could be demonstrated by EBV immunostaining pattern which revealed an expression of the latent membrane protein (LMP) of EBV in the atypical blasts. The results give clear evidence of an EBV association of this rapidly growing lymphoma developed after heart transplantation.
Down-regulation of Hox A7 is required for cell adhesion and migration on fibronectin during early HL-60 monocytic differentiation
Authors: Leroy Pascale , Berto Fréderick , Bourget Isabelle , Rossi Bernard
Published: January 2004

Hox genes, which are key regulators of cell fate and pattern formation during embryogenesis, are also important regulators of hematopoiesis, and different combinations of Hox gene products are involved in lineage commitment or maturation. However, their molecular and cellular modes of action are not yet completely understood. Recent studies have indicated that Hox genes are involved in the regulation of cell–extracellular matrix (ECM) interactions and cell migration. Here, we report that Hox A7, a gene frequently overexpressed in acute myeloid leukemia, is down-regulated during HL-60 monocytic differentiation. Using a model in which HL-60 cells are induced to differentiate toward the monocytic lineage with bone marrow stromal-like cells, we demonstrate that Hox A7-sustained expression disturbs the regulation of cell adhesive and migratory capacities on fibronectin during early differentiation. We show that this is accompanied by a partial blockage of the transcriptional induction of proline-rich tyrosine kinase 2, a gene coding for a focal adhesion kinase active in monocytes, and of tissue transglutaminase, a gene coding for a fibronectin coreceptor in monocytes. This is the first report that demonstrates the involvement of a Hox gene in the regulation of adhesion and migration of hematopoietic cells and that links it to the deregulation of genes involved in cell–ECM interactions and downstream signaling pathways.
Expression and synthesis of fibroblast growth factor-9 in human γδ T-lymphocytes. Response to isopentenyl pyrophosphate and TGF-β1/IL-15
Authors: Workalemahu Grefachew , Foerster Martin , Kroegel Claus
Published: January 2004

γδ T-lymphocytes are believed to play a role in maintaining the normal configuration of epithelial tissue. As little is known about the factors mediating this function, we addressed the question of whether γδ T-lymphocytes produce fibroblast growth factor (FGF)-9 as well as two other growth factors associated with epithelial tissue reconstitution. Blood γδ T cells isolated from healthy donors were grown in the presence of isopentenyl pyrophosphate (IPP) or transforming growth factor-β1 (TGF-β1)/interleukin-15 (IL-15) for 24 h and were assessed for the expression and synthesis of FGF-9, keratinocyte growth factor (KGF), and epidermal growth factor (EGF). Resting human γδ T cells constitutively expressed KGF and FGF-9 mRNA but no EGF mRNA. In the presence of IPP, FGF-9 mRNA expression significantly increased in a dose-dependent manner, expression of KGF remained unaltered, and EGF mRNA could not be detected. In contrast to IPP, stimulation of the cells with TGF-β1/IL-15 did not alter FGF-9 expression. Moreover, stimulation with anti-CD3 does not induce FGF-9 expression but triggers a high signal of interferon-γ mRNA. Western blot analysis of γδ T cell lysates, prepared 4 days following stimulation with IPP, showed an increase of FGF-9 protein as compared with control cells. In conclusion, the results demonstrate for the first time that human blood and bronchoalveolar lavage γδ T-lymphocytes are capable of expressing FGF-9. The data also provide novel evidence that immunoregulatory cells can synthesize FGF-9.
Limitations with in vitro production of dendritic cells using cytokines
Authors: O’Neill Helen C , Wilson Heather L
Published: January 2004

Dendritic cells (DC) are the most effective antigen-presenting cells. Many studies now show that DC can be generated in vitro from a number of starting cell populations containing hematopoietic precursors. The protocols used involve different combinations of cytokines including granulocyte macrophage-colony stimulating factor (GM-CSF), which supports myeloid precursors, or interleukin-7, which supports lymphoid precursors. DC are commonly generated by in vitro culture of bone marrow or monocytes with GM-CSF and other cytokines. However, these cultures do not sustain DC production for long periods of time and do not allow the identification or study of intermediate stages in cell development. In vitro cytokine-dependent cultures of DC precursors do provide a reliable source of DC for stimulating immune responses. However, use of cells produced in cytokine-dependent cultures for the study of DC differentiation is limited, as DC development in vivo differs in cytokine dependency.
Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent
Authors: Lavelle Ed C , Jarnicki Andrew , McNeela Edel , Armstrong Michelle E , Higgins Sarah C , Leavy Olive , Mills Kingston H G
Published: January 2004

Cholera toxin (CT) is a potent vaccine adjuvant when administered via parenteral, mucosal, or transcutaneous routes. It also inhibits innate inflammatory responses induced by pathogen-derived molecules, such as lipopolysaccharide (LPS). We demonstrated previously that CT promotes the induction of regulatory type 1 T cells (Tr1) as well as T helper type 2 cells (Th2). T cells from mice immunized with antigen in the presence of CT produced high levels of interleukin (IL)-10 and IL-5 and low levels of IL-4 and interferon-γ (IFN-γ). Here, we demonstrate that immunization with antigen in the presence of CT induced a population of antigen-specific CD4+ T cells that produced IL-10 in the absence of IL-4, in addition to cells that coexpressed IL-4 and IL-10 or produced IL-4 only. CT-generated Tr1 cells inhibited antigen-specific proliferation as well as IFN-γ production by Th1 cells, and this suppression was cell contact-independent. It is interesting that coincubation with Th1 cells significantly enhanced IL-10 production by the Tr1 cells. As IL-10 can promote the differentiation of Tr1 cells, we investigated cytokine production by dendritic cells (DC) following exposure to CT. Previous data showed that CT can modulate the expression of costimulatory molecules and inhibit the production of chemokines and cytokines, including IL-12 and tumor necrosis factor α and enhance IL-10 production. Here, we show that CT synergizes with LPS to induce IL-6 and IL-1β in addition to IL-10 production by immature DC. Therefore, CT may promote the induction of Th2 and Tr1 cells in part via selective modulation of DC cytokine production and costimulatory molecule expression.
Actuation, monitoring and closed-loop control of sewing machine presser foot
Authors: Silva Luís F. , Lima Mário , Carvalho Helder , Rocha Ana M. , Ferreira Fernando N. , Monteiro João L. , Couto Carlos
Published: January 2004

Sewing is one of the most important processes in the apparel industry for the production of high-quality garments. Although some research and improvements have been carried out in this area, the sewing process has remained almost unchanged throughout the years, staying largely dependent on the operator skills to set up sewing parameters and to handle the fabrics being sewn. Slight changes in sewing machine settings can influence the quality of seams, as well as sewing operation time. To avoid these empirical settings, reduce set-up times and improve machine performance, flexibility and sewing quality, an electromagnetic actuated presser foot, based on the use of a proportional force solenoid, was developed and implemented on an industrial overlock sewing machine. The compression force and displacement waveforms from the presser foot bar will be studied in this paper, as well as the admissible displacement limits used to monitor (on- and offline) fabrics’ feeding efficiency. Following this analysis, a new research programme was established to enable a PC-based open- and closed-loop control of the presser foot system. This paper also highlights these recent developments, presenting and discussing, in detail, a PID closed-loop control strategy. The obtained results show that the presser foot closed-loop control has improved performance for a wide speed variation range.
Genetic algorithms applied in online autotuning PID parameters of a liquid-level control system
Authors: Teng T. K. , Shieh J. S. , Chen C. S.
Published: January 2004

In this paper, a simple genetic algorithm (GA) method has been applied in a real-time experiment on a liquid-level control system for online autotuning proportional-integral-derivative (PID) parameters. Our proposed method can automatically choose the best PID parameters for each generation. Then, using the reproduction, crossover and mutation to create the new population for other PID parameters, it can continuously control the liquid-level system until the preset iteration number is reached. Finally, the best PID parameters can be obtained. Furthermore, two selection methods, roulette wheel and tournament, have been compared in real-time experiments. Real-time experimental results are given to demonstrate the effectiveness and usefulness for online tuning PID parameters via this evolution process.
Diagnostic information on gearbox condition for mechatronic systems
Authors: Bartelmus Walter
Published: January 2004

To maintain mechatronic systems, operational current diagnostic information on gearing condition is needed. Diagnostic information on gearbox condition can be gained from vibration signals. To extract suitable information from the signal we need to know the relation between factors influencing the diagnostic signal and the gearbox condition. There are several factors that have influence on diagnostic signals and these may be divided into four groups: design (DF), production technology (PTF) operational (OF) and change of condition (CCF). To gain information from the vibration signal, many experiments have to be carried out. Because many factors influence the vibration signal, the experiments on real objects are very expensive. To reduce the cost, mathematical modelling and computer simulation may be used. Papers devoted to mathematical modelling and computer simulation are concentrated on one-stage gearboxes. In this research work, a system that consists of a driving motor, coupling, double-stage gearbox and driven machine is considered. Using the model, it is possible to investigate the above-mentioned factors that influence the vibration signal. Faults occur during a gearbox operation. Gearing faults may be divided into single faults (a crack in a tooth or its breakage) and distributed faults caused by gearing wear (pitting, scuffing, abrasion and erosion). The methods of fault detection using signal analysis is given in this paper. The paper shows how mathematical modelling and computer simulations help signal interpretation, taken from real measurements. Frequency, time and time-frequency analysis are used for signal interpretation. As a result, we obtain spectra, cepstra and time-frequency spectrograms. The paper refers to the condition monitoring method, which used simple wide-band signal estimators. The method may be easily adopted for use in monitoring the online gearbox condition in mechatronics systems, whereas an advanced signal interpretation may be used for offline condition monitoring.
Multi-way optimal control of a benchmark fed-batch fermentation process
Authors: Zhang Hongwei , Lennox Barry
Published: January 2004

A novel optimal control algorithm is presented for application to batch processes. The algorithm utilizes a linear model of the process that is identified using multi-way partial least squares. This linear model is used within an optimal control law to regulate the productivity of the batch by manipulating the substrates that are fed into the fermentation vessel. The proposed control algorithm is successfully applied to a benchmark fed-batch fermentation process and its performance compared with alternative control algorithms that have been applied to this application in the past. The proposed controller is found to compare favourably with these alternative algorithms.
Is hand splinting effective for adults following stroke? A systematic review and methodological critique of published research
Authors: Lannin N A , Herbert R D
Published: January 2004

Background: Upper limb hemiplegia after stroke is common and disabling. Hand splints are widely used to prevent contracture and reduce spasticity.

Objective: To assess the effectiveness of hand splinting on the hemiplegic upper extremity following stroke.

Search strategy: A search was conducted of the Cochrane Central Register of Controlled Trials; the electronic databases MEDLINE, EMBASE, CINAHL, PEDro, SCI, SSCI; websites of professional associations; reference lists in trial reports and other relevant articles.

Selection criteria: Studies of the effect of upper extremity splinting on motor control, functional abilities, contracture, spasticity, or pain in the hand or wrist.

Data collection and analysis: Validity of studies was assessed systematically and a content analysis was conducted of the methodologies used. Methodological quality of randomized trials was rated by two independent assessors using the PEDro scale.

Results: Nineteen studies were appraised for content. Of these, most (63%) were reports of case series. Four studies (21%) were randomized controlled trials. Methodological scores of trials ranged from 2 to 8 (maximum possible score 10). One trial of nominally ‘medium’ quality reported that in‘atable arm splinting makes no difference to hand function (mean difference on Fugl-Meyer Assessment –0.12, 95% confidence interval (CI) –9.8 to 9.6). The remaining trials investigated effects of thermoplastic splints; one trial of ‘high quality’ reported no difference in contracture formation in the wrist and finger ‘exor muscles after wearing a hand splint which positioned the wrist in the traditional functional position for 12 hours each night for four weeks (mean difference in range of movement after four weeks was 1°, 95% CI –3.7° to 6.1°; power >80%). All remaining trials were of poor methodological quality. Limited research and lack of a no-splint control group in all trials to date limit the usefulness of these results.

Reviewer's conclusion: There is insufficient evidence to either support or refute the effectiveness of hand splinting for adults following stroke.