bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face‐to‐face interviews with 515 users of herbal remedies
Authors: Barnes Joanne , Mills Simon Y. , Abbot Neil C. , Willoughby Martin , Ernst Edzard 
Published: May 2003

Aims To determine whether adverse drug reactions (ADRs) to herbal remedies would be reported differently from similar ADRs to conventional over‐the‐counter (OTC) medicines by herbal‐remedy users. Methods Face‐to‐face interviews (using a structured questionnaire) with 515 users of herbal remedies were conducted in six pharmacy stores and six healthfood stores in the UK. The questionnaire focused on the likely course of action taken by herbal‐remedy users after experiencing an ADR associated with a conventional OTC medicine and a herbal remedy. Results Following a ‘serious’ suspected ADR, 156 respondents (30.3%) would consult their GP irrespective of whether the ADR was associated with the use of a herbal remedy or a conventional OTC medicine, whereas 221 respondents (42.9%) would not consult their GP for a serious ADR associated with either type of preparation. One hundred and thirty‐four respondents (26.0%) would consult their GP for a serious ADR to a conventional OTC medicine, but not for a similar ADR to a herbal remedy, whereas four respondents (0.8%) would consult their GP for a serious ADR to a herbal remedy, but not for a similar ADR to a conventional OTC medicine. Similar differences were found in attitudes towards reporting ‘minor’ suspected ADRs. Conclusions Consumers of herbal remedies would act differently with regard to reporting an ADR (serious or minor) to their GP depending on whether it was associated with a herbal remedy or a conventional OTC medicine. This has implications for herbal pharmacovigilance, particularly given the increasing use of OTC herbal remedies. The finding that a high proportion of respondents would not consult their GP or pharmacist following ADRs to conventional OTC medicines is also of concern.
Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients
Authors: Asai K. , Kanazawa H. , Kamoi H. , Shiraishi S. , Hirata K. , Yoshikawa J. 
Published: May 2003

SummaryBackground Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen.Objective We evaluated the relationship between VEGF levels in induced sputum and eosinophilic inflammatory profiles, and the degree of airway vascular permeability in asthmatic patients and we evaluated the effect of inhaled corticosteroids on VEGF levels in induced sputum.Methods Induced sputum specimens were obtained from 28 glucocorticosteroids free asthmatics and 11 healthy control subjects. We examined VEGF levels and airway vascular permeability index in induced sputum. After the initial sputum induction, 21 asthmatics received 8‐week inhaled beclomethasone dipropionate (BDP, 800 µg/day) therapy, then sputum induction was repeated.Results The VEGF levels in asthmatics were significantly higher than in healthy control subjects (P < 0.0001). The VEGF levels were negatively correlated with forced expiratory volume of 1 s (FEV1, % predicted, r = − 0.68, P < 0.001), the percentage of eosinophils (r = 0.51, P < 0.01) and ECP levels (r = 0.39, P < 0.05). Moreover, the VEGF levels were significantly correlated with airway vascular permeability index (r = 0.61, P < 0.001). After 8‐week inhaled BDP therapy, the VEGF levels were significantly decreased compared to pretreatment levels (P < 0.0001) and the VEGF levels were significantly correlated with airway vascular permeability index even in post‐treatment asthmatics (r = 0.62, P < 0.01).Conclusion The VEGF levels in induced sputum were increased in asthmatics and its levels were associated with degree of airway narrowing and airway vascular permeability. These findings provide strong evidence that VEGF may play an important role in the pathogenesis of bronchial asthma.
Enhancement of gelatinase activity during development of subepithelial fibrosis in a murine model of asthma
Authors: Corbel M. , Caulet‐Maugendre S. , Germain N. , Lagente V. , Boichot E. 
Published: May 2003

SummaryBackground Chronic asthma is characterized by inflammatory cell infiltration and tissue remodelling leading to subepithelial fibrosis. Metalloproteinases (MMPs) are involved in degradation of extracellular matrix in most chronic inflammatory diseases.Objective The aim of this study was to investigate the expression of MMPs in the development of inflammatory processes associated or not with the concomitant development of subepithelial fibrosis in an experimental model of asthma.Methods Sensitized BP2 mice were challenged with ovalbumin (OA) every 2 weeks during 8 months. Several mice were removed once a month and bronchoalveolar lavages (BAL) or lung biopsies were performed.Results Lung sections stained with picrosirius and hydroxyproline measurements showed a significant collagen deposition after 16 weeks of OA challenge, demonstrating the development of subepithelial fibrosis. Pulmonary inflammation was present from the first OA challenge and was consistent throughout the 8 months of the study. Moreover, an up‐regulation and activation of MMP‐9 and, to a less extent, MMP‐2 were observed in BAL fluid from challenged mice. The level of tissue inhibitor of metalloproteinases (TIMP)‐1 increased after 12 weeks of OA challenge vs. control mice.Conclusion This study reveals that a decrease in the activation of the MMP‐9 due to the increase in TIMP‐1, could contribute to excessive collagen deposition following repeated antigen challenge in sensitized mice.
The production, storage and release of the neurotrophins nerve growth factor, brain‐derived neurotrophic factor and neurotrophin‐3 by human peripheral eosinophils in allergics and non‐allergics
Authors: Noga O. , Englmann C. , Hanf G. , Grützkau A. , Seybold J. , Kunkel G. 
Published: May 2003

SummaryBackground Recent studies have shown that neurotrophins are produced by and can act on several immune‐inflammatory cells. The origin of circulating as well as local neurotrophins is unknown.Objectives The aim of this study was to assess whether eosinophils of allergic and non‐allergic donors produce, store and release the neurotrophic factors NGF, BDNF and NT‐3.Methods Eosinophils were purified by negative immunoselection (purity > 96%) from allergic asthmatics and non‐allergic donors (25 to 53 years). The presence of mRNA for neurotrophic factors was evaluated by reverse transcription PCR. Specificity was demonstrated by cloning products and sequencing. Stored NGF, BDNF and NT‐3 was demonstrated by Western‐blotting and flow cytometry. Eosinophils were incubated and supernatants were collected for measurement of neurotrophic factors after cell stimulation with PAF. Neurotrophin content in eosinophil lysates was determined by ELISA.Results Eosinophils demonstrate mRNA for neurotrophins. Proteins were detectable by Western blot and FACS analysis. Neurotrophins were found in the eosinophil lysates at different amounts comparing allergic and non‐allergic donors. Cell stimulation with PAF (10‐8–10‐5 M) after priming with GM‐CSF leads to a dose‐dependant release of NGF and BDNF.Conclusions Eosinophils store, produce and release NGF, BDNF and NT‐3. They are a possible source of elevated neurotrophin levels found in allergy and asthma.
Mast cells play a partial role in allergen‐induced subepithelial fibrosis in a murine model of allergic asthma
Authors: Masuda T. , Tanaka H. , Komai M. , Nagao K. , Ishizaki M. , Kajiwara D. , Nagai H. 
Published: May 2003

SummaryBackground Role of mast cells in the development of allergen‐induced airway remodelling has not been fully investigated in vivo.Objective To clarify the possible role of mast cells in the development of allergen‐induced airway remodelling, we compared their responses of genetically mast cell‐deficient mice, WBB6F1‐W/Wv (c‐kit mutant) and Sl/Sld (c‐kit ligand mutant) mice with those of congenic normal mice in a murine model of allergic asthma.Methods Mice were sensitized to ovalbumin (OA) with alum, and exposed daily for 3 weeks to aerosolized OA. Twenty‐four hours after the last inhalation, bronchial responsiveness to acetylcholine (Ach) was measured, and bronchoalveolar lavage (BAL), and biochemical and histological examinations were performed.Results In both sensitized mast cell‐deficient mice, the degree of bronchial hyper‐responsiveness to Ach, the number of inflammatory cells and the level of transforming growth factor‐β1 in BAL fluid, IgE response and goblet cell hyperplasia in the epithelium after repeated allergen provocation were not significantly different from those of congenic mice. In contrast, subepithelial fibrosis, evaluated in the fibrotic area around the airways, observed in congenic mice after repeated allergen challenge was partially attenuated in both mast cell‐deficient mice. In addition, the amount of hydroxyproline in the lung of mast cell‐deficient mice was significantly lower than that of congenic mice. Furthermore, the decreased fibrotic area and amount of hydroxyproline in W/Wv mice was completely recovered by reconstitution of tissue mast cells with bone marrow‐derived mast cells of congenic mice.Conclusion These findings suggest that mast cells play a partial role in the development of allergen‐induced subepithelial fibrosis, although airway inflammation, epithelial remodelling and BHR caused by repeated allergen challenge are independent of mast cells, at least in this model.
Calcineurin antagonists differentially affect mediator secretion, p38 mitogen‐activated protein kinase and extracellular signal‐regulated kinases from immunologically activated human basophils
Authors: Plath K. E. S. , Grabbe J. , Gibbs B. F. 
Published: May 2003

SummaryBackground Basophils participate in allergic diseases by invading affected tissues and secreting histamine, leukotriene (LT)C4, IL‐4 and IL‐13 following FcεRI cross‐linking. A reduction of basophil mediator production is therefore of considerable therapeutical interest. Macrolactam derivatives, which inhibit calcineurin activation, may be candidates for antiallergic therapy as they reduce both symptoms of inflammatory skin disease in animal models and mast cell degranulation.Objective To investigate the effects of the calcineurin antagonists ascomycin and cyclosporin A on IgE‐dependent mediator release from human basophils.Methods Basophils were purified by Ficoll density centrifugation, elutriation and negative selection. Histamine release was measured spectrofluorometrically; LTC4, IL‐4 and IL‐13 secretions were assayed by enzyme‐linked immunosorbent assay (ELISA). Lysed cells were subjected to Western blotting using specific antibodies to phospho‐p38 mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (ERK)‐1 and ‐2.Results Ascomycin (0.01 nm to 1 µm) and cyclosporin A (0.1 nm to 10 µm) strikingly inhibited (maximally 100%) anti‐IgE‐induced histamine and cytokine release from basophils, and these actions were unaffected by IL‐3 priming. Ascomycin, however, was less potent at blocking LTC4 secretion, whereas cyclosporin A was unable to block production of this mediator. In immunoblotting studies, ascomycin and cyclosporin A reduced IgE‐dependent p38 MAPK activation but were less potent at reducing ERK phosphorylation in basophils.Conclusion Calcineurin antagonists like ascomycin and cyclosporin A block IgE‐dependent basophil degranulation and cytokine synthesis. Calcineurin may target p38 MAPK activation, but seems to have less activity on ERK phosphorylation. This is paralleled by a reduced or even absent effect of calcineurin antagonists on eicosanoid production.
Characterization of immunoglobulin E responses in Balb/c mice against the major allergens of timothy grass (Phleum pratense) pollen
Authors: Seitzer U. , Bussler H. , Kullmann B. , Petersen A. , Becker W.‐M. , Ahmed J. 
Published: May 2003

SummaryBackground Grass pollen, such as that from timothy grass (Phleum pratense), represents a major cause of type I allergy.Objective To characterize the IgE immune response and to identify the major allergens eliciting an IgE response in a mouse model using pollen extract of P. pratense for sensitization, in order to assess analogies to human hyperreactivity and to gain information on the allergenic potential as determined by the IgE‐reactivity kinetics of defined allergens.Methods Balb/c mice were sensitized with pollen extract or with purified natural allergens. Serum IgE levels, the induction of specific IgE antibodies and immediate hypersensitivity were monitored by ELISA, Western blot and a skin test, respectively.Results The sensitized mice mounted a strong IgE response and showed IgE‐reactivity first against Phl p 5a and 5b, then Phl p 4 and 13 and lastly against Phl p 6. No IgE response was mounted against Phl p 1. However, all purified fractions examined (Phl p 5a, 5b, 6 and 1) induced specific IgE and showed similar kinetics of IgE induction as pollen extract (first Phl p 5a and 5b, then Phl p 6). Skin test experiments demonstrated positive reactivity only in sensitized mice.Conclusion The IgE reactivity induced by the major allergens in Balb/c mice was very similar to that found in allergic patients, with the exception of Phl p 1. The kinetics of the specific IgE response was comparable using either pollen extract or the purified major allergens, indicating that the intrinsic properties of the allergens are of importance rather than their proportionate amounts in pollen extract. This model should prove to be suitable for investigations regarding the mechanisms of induction and manifestation of timothy grass pollen allergy and for the evaluation of therapeutic strategies.
In vitro effects of eicosanoids derived from different 20‐carbon fatty acids on T helper type 1 and T helper type 2 cytokine production in human whole‐blood cultures
Authors: Miles E. A. , Aston L. , Calder P. C. 
Published: May 2003

SummaryBackground Different series prostaglandins (PGs) and leukotrienes (LTs) are synthesized from different 20 carbon fatty acid precursors. The effects of the different series of PGs and LTs on production of T helper type 1 (Th1) and Th2 cytokines by human cells are not well established.Objective To characterize the influence of PGs and LTs produced from different fatty acid precursors on the Th1 and Th2 cytokine profile in mitogen‐stimulated human whole‐blood cultures.Methods Blood from healthy adult males was diluted and cultured with concanavalin A in the presence or absence of a range of concentrations of various PGs or LTs. Cytokine concentrations in culture supernatants were analysed by enzyme‐linked immunosorbent assay (ELISA).Results PGE1, PGE2 and PGE3 significantly and dose‐dependently decreased the concentrations of the Th1 cytokines IL‐2 and IFN‐γ by up to 50% and 70%, respectively. The three PGs exhibited similar potency towards IFN‐γ production. At the highest concentration used (10−6 m) PGE1, but not PGE2 or PGE3, increased the concentration of the Th2 cytokine IL‐4 by about 70%. IL‐10 production was not affected by PGs. The ratio of the concentrations of IFN‐γ to IL‐4 was significantly decreased at PGE concentrations of 10−7 and 10−6 M with all three PGEs having similar effects. LTB4, LTC4 and LTC5 did not significantly affect production of the cytokines studied.Conclusion PGE produced from different fatty acids significantly decrease Th1 cytokine production resulting in a shift in the Th1, Th2 balance in favour of a Th2 response. PGE produced from different fatty acid precursors are equipotent in their effects on human T lymphocytes. Thus, although changes in the pattern of dietary fatty intakes may contribute to the increased prevalence of atopic disease, this would probably not be mediated through substitution of one PGE with another from a different series. It may, however, be mediated through a change in the total amount of PGE produced at the site of antigen presentation.
Granule protein changes and membrane receptor phenotype in maturing human eosinophils cultured from CD34+ progenitors
Authors: Al‐Rabia M. W. , Blaylock M. G. , Sexton D. W. , Thomson L. , Walsh G. M. 
Published: May 2003

SummaryBackground Eosinophils are now recognized as major effector cells in allergic and asthmatic disease with a potent armoury of mediators whose release makes a major contribution to the inflammation underlying these conditions.Objectives The purpose of this study was to compare cultured eosinophils (CE) with normal‐density peripheral blood eosinophils (PBE) in terms of their membrane receptor expression and to analyse the expression and storage of the eosinophil granule proteins major basic protein (MBP) and eosinophil cationic protein (ECP) during eosinophil maturation in vitro.Methods Purified human peripheral blood CD34+ cells were cultured in the presence of recombinant human IL‐3, IL‐5, rhGM‐CSF, SCF, and FLT‐3 ligand. PBE were isolated by density gradient centrifugation and negative immunomagnetic selection. Expression of CD11b, CD18, CD45, CD45RA, CD45RB, CD45RO, CD69, CD95, IL‐5Rα, IL‐9Rα, CCR1, CCR3, and CXCR4 by CE as they matured in culture were assessed by immunostaining and flow cytometry and expression of these receptors compared with freshly isolated PBE. Immunohistochemical staining and labophot‐2TM light microscopy determined expression of MBP, ECP, and CD69 during eosinophil maturation.Results Positive immunostaining for MBP and ECP was detectable in a proportion (15–20%) of CE as early as 3 days of culture even though these cells were mononuclear in appearance. The numbers of CE positive for both granule proteins increased in rhIL‐3 and rhIL‐5 treated cells to a maximum of ∼ 80% by day 28. Maturing eosinophils exhibited positive immunostaining for CD69 after 14, 21 and 28 days of culture. Compared with PBE, CE had lower expression of pan‐CD45 and CD45 isoforms, CD95 and CD11b. In contrast, the specific mean fluorescence for CD69, CD18, IL‐5Rα, and IL‐9Rα was significantly elevated for CE compared with PBE. CCR3 expression by CE and PBE was similar with no expression of CXCR4 detected by either CE or PBE. No significant difference in expression of CCR1 was found between CE and PBE.Conclusion These data suggest that CE and PBE share many phenotypic properties and both MBP and ECP appear early in eosinophil development in vitro. However, there are quantitative differences that may be a consequence of their immaturity and/or the influence of the cytokines used in their culture.
Inhaled endotoxin and organic dust particulates have synergistic proinflammatory effects in equine heaves (organic dust‐induced asthma)
Authors: Pirie R. S. , Collie D. D. S. , Dixon P. M. , McGorum B. C. 
Published: May 2003

SummaryBackground Equine heaves is a naturally occurring organic dust‐induced asthma characterized by airway neutrophilia, mucus hypersecretion and obstructive lung dysfunction. However, the relative role of different dust components in disease severity remains unclear.Objective This study investigated the relative contribution of inhaled endotoxin and organic dust particulates (mainly mould spores) in inducing heaves in heaves‐susceptible horses.Methods Control and heaves‐susceptible horses received inhalation challenges with hay dust suspension (HDS) before and after lipopolysaccharide (LPS) depletion. Heaves‐susceptible horses also received inhalation challenge with HDS particulates with and without the addition of LPS and were housed in two separate dusty environments during which mould and endotoxin exposure was measured. The airway inflammatory and functional response to each challenge was measured.Results Depletion of endotoxin from HDS attenuated the airway neutrophilia and abrogated the airway dysfunction induced in heaves horses by inhaled HDS. The airway response was re‐established by adding back LPS to the depleted HDS, confirming that the attenuation in airway response was due specifically to endotoxin depletion. Interestingly, the magnitude of alteration in airway response following endotoxin depletion and add‐back was greater than that which could be attributed solely to endotoxin per se, indicating that the LPS activity was enhanced by the other dust components. Consistent with this possibility, washed particulates harvested from HDS enhanced the airway response to inhaled LPS in heaves horses. Heaves horses given two different hay/straw challenges had a significantly different severity of airway inflammation and dysfunction, despite airborne dust and endotoxin concentrations in the horses' breathing zones being similar.Conclusion Although inhaled endotoxin appears not to be the only determinant of disease severity in heaves, it does contribute significantly to the induction of airway inflammation and dysfunction. This contribution is largely via the synergistic action of inhaled endotoxin and organic dust particulates, although other soluble dust components also contribute to a lesser degree.
Cytokine production by cord blood mononuclear cells stimulated with cows milk proteins in vitro: interleukin‐4 and transforming growth factor β‐secreting cells detected in the CD45RO T cell population in children of atopic mothers
Authors: Hauer A. C. , Riederer M. , Griessl A. , Rosegger H. , MacDonald T. T. 
Published: May 2003

SummaryBackground Food antigens from the maternal circulation may sensitize fetal T cells in utero and be an important determinant in the development of food allergy.Methods Here we have examined the spontaneous and recall response to cow's milk proteins of cord blood mononuclear cells (CBMC) of newborn children, using single cell ELISPOT assays.Results In term newborns, confirming previous studies, the spontaneous cytokine response of CBMC is dominated by IL‐4, IL‐5, IL‐10, and as shown here for the first time, TGF‐β. For TGF‐β only, the response of samples from infants of atopic mothers was significantly lower than samples from infants of non‐atopic mothers. In vitro stimulation of CBMC with bovine serum albumin, casein and β‐lactoglobulin resulted in a significant increase of all cytokine‐secreting cells, again dominated by T helper type 2 (Th2) cytokines. There was a clear tendency for samples from infants of atopic mothers to have lower Th2 responses than samples from infants of non‐atopic mothers, which was particularly significant for both IL‐4 and TGF‐β. Spontaneous cytokine secreting cells were virtually absent in cord blood from infants < 34 weeks gestation, as were cows milk protein‐induced responses, although they were readily detectable in samples from infants aged > 34 weeks. To explore whether the cytokine secreting cells were in the naive CD4+ CD45RA population or memory CD4+ CD45RO T cells, these subsets were purified by positive and negative selection and tested for spontaneous and cows milk protein‐induced cytokine responses. Strikingly, although the responses were small, the CD45RO+ cells from children of atopic mothers showed significant spontaneous and antigen‐specific IL‐4 and TGF‐β responses, whereas the same population from infants of non‐atopic mothers showed virtually no response. In addition CD45RA+ cells from infants of mothers with maternal atopy showed decreased IL‐4 and TGF‐β responses, especially the latter.Conclusions The cows milk antigen‐specific IL‐4 and TGF‐β responses preferentially seen in the memory cell subset of infants with a maternal history of atopy strongly suggests Th2 skewing to dietary antigens in utero.