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J Madden

Publications and source records attributed to J Madden.

At least 19 recordsLinked to original sources
PubMed1998

Cyclosporin A treatment and airways inflammation in corticosteroid-dependent asthma.

Cyclosporin A is a potent immunosuppressive agent which inhibits activation of T cells and other inflammatory cells. It has been shown to be of clinical benefit in patients with corticosteroid-dependent asthma, but there are no data on its in vivo effects on airways inflammation. In this report, we describe the case of a 47-year-old man with chronic severe corticosteroid-dependent asthma who made a dramatic clinical response to therapy with cyclosporin A. Fibreoptic bronchoscopy with bronchoalveolar lavage and endobronchial biopsy were performed before and after a 12-month period of treatment with cyclosporin A and demonstrated a concomitant reduction in airway inflammatory indices.

Adrenal Cortex Hormones↗
PubMed1998

Effects of 0.2 ppm ozone on biomarkers of inflammation in bronchoalveolar lavage fluid and bronchial mucosa of healthy subjects.

Short-term exposure to ozone at peak ambient levels induces neutrophil influx and impairs lung function in healthy humans. In order to investigate the mechanisms contributing to neutrophil recruitment and to examine the role of T-cells in the acute inflammatory response, we exposed 12 healthy humans to 0.2 parts per million (ppm) of ozone and filtered air on two separate occasions for 2 h with intermittent periods of rest and exercise (minute ventilation = 30 L x min(-1)). Fibreoptic bronchoscopy was performed 6 h after the end of exposures. Total protein, tryptase, histamine, myeloperoxidase, interleukin (IL)-8 and growth-related oncogene-alpha (Gro-alpha) were measured and total and differential cell counts were performed in bronchoalveolar lavage (BAL) fluid. Flow cytometry was performed on BAL cells to study total T-cells, T-cell receptors (alphabeta and gammadelta), T-cell subsets (CD4+ and CD8+ cells) and activated T-cell subsets (CD25+). Using immunohistochemistry, neutrophils, mast cells, total T-cell numbers, T-cell subsets, CD25+ T-cells and leukocyte endothelial adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were quantified in the bronchial biopsies. Paired samples were available from nine subjects. Following ozone exposure there was a threefold increase in the proportion of polymorphonuclear neutrophils (PMNs) (p=0.07) and epithelial cells (p=0.05) in BAL fluid. This was accompanied by increased concentrations of IL-8 (p=0.01), Gro-alpha (p=0.05) and total protein (p=0.058). A significant positive correlation was demonstrated between the two chemokines and proportion of PMNs in BAL fluid. After ozone exposure there was a significant decrease in the CD4/CD8 ratio (p=0.05) and the proportion of activated CD4+ (p=0.01) and CD8+ T-cells (p=0.04). However, no significant changes were demonstrable in any of the inflammatory markers studied in the biopsies. Short-term exposure of healthy humans to 0.2 ppm ozone induced a neutrophil influx in peripheral airways at 6 h post exposure, but no apparent inflammatory response in proximal airways. This response seems to be mediated at least in part by interleukin-8 and growth-related oncogene-alpha.

Adult↗
PubMed1998

Recurrent miscarriage: causes, evaluation, and treatment.

Recurrent miscarriage or fetal loss syndrome (also known as fetal wastage syndrome) is characterized by recurrent spontaneous abortion. There are many syndromes associated with recurrent fetal loss, including anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation protein/platelet defects. Many of these syndromes are treatable, leading to normal term pregnancy, if the clinician is astute and vigorously pursues a thorough evaluation of why the patient has suffered unexplained, spontaneous miscarriages. There is no uniform agreement on how many spontaneous, unexplained miscarriages are needed to diagnose recurrent fetal loss; we generally pursue an evaluation for causation if a women has had 2 or more such events. In this article, we discuss the common reasons for recurrent fetal loss, plus diagnostic procedures to consider in pinpointing the problem, such as cytogenetic studies, blood coagulation protein/platelet tests, hysterosalpingography, sonography, and magnetic resonance imaging. We also describe management strategies that often lead to successful pregnancy outcome when the underlying problem is addressed. For example, in the case of thrombotic defects, a common cause of recurrent fetal loss, we report a 100% success rate in achieving a normal-term delivery among women who took low-dose (81 mg/day) aspirin preconception followed by postconception low-dose (5000 units q 12 h) heparin.

Abortion, Habitual↗
PubMed1997

The effect of treatment with oral corticosteroids on asthma symptoms and airway inflammation.

To improve understanding of the mechanisms of action of oral corticosteroids in asthma, we have conducted a double-blind, placebo-controlled study with prednisolone (20 mg for 2 wk followed by 10 mg for 4 wk) or placebo in 14 and 13 atopic corticosteroid-naive asthmatic subjects, respectively. Before and after treatment subjects underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy. Treatment with prednisolone, but not placebo, significantly reduced asthma symptoms (from mean +/- SEM total weekly score of 34 +/- 6.2 to 15.7 +/- 3.2, p = 0.02) and albuterol usage (from mean +/- SEM number of puffs/wk of 29.7 +/- 6.2 to 18.2 +/- 3.7, p = 0.01) and significantly increased FEV1 (from 89.8 +/- 4.4% to 99.3 +/- 4.1% of predicted, p = 0.03). There were no significant changes in inflammatory or epithelial cell counts, levels of T-cell activation or albumin concentration in BAL. However, immunohistochemistry of bronchial biopsies showed that in the submucosa prednisolone significantly decreased numbers of mast cells by 62% (from median 45 to 17/mm2, p = 0.01), eosinophils by 81% (from median 30.1 to 5.7/mm2, p = 0.004), and CD4+ T-cells by 68% (from median 64.6 to 18.5/mm2, p = 0.02). In the epithelium only the reduction in the numbers of eosinophils was significant (from median 1.1 to 0/mm of epithelium, p = 0.02). There were no significant changes in any cell counts in the subjects receiving placebo, and comparison of the changes between the treatment groups identified a significant prednisolone-related reduction in submucosal eosinophil and mast cell counts (p = 0.003 and 0.03, respectively). The temporal association between the clinical and physiologic improvement, and the correlation between the magnitude of change in CD4+ T-cell counts in the submucosa and increase in PC20 methacholine (rs = 0.60, p = 0.049) suggests that the reduction in airways inflammatory cell numbers underlies the clinical efficacy of oral corticosteroids.

Administration, Oral↗
PubMed1997

Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid.

Airway wall remodeling is an established pathological feature in asthma. Its causes are not well understood, but one mediator of potential relevance is transforming growth factor-beta 1 (TGF-beta 1). We have measured levels of immunoreactive TGF-beta 1 in bronchoalveolar lavage (BAL) fluid from clinically stable atopic asthmatics and healthy control subjects. We have also examined the influence of allergen exposure on TGF-beta 1 release in the airways using a segmental bronchoprovocation model, with BAL performed at two time points following endobronchial allergen and sham saline challenges. Basal concentrations of TGF-beta 1 were significantly higher in asthmatics than control subjects (median 8.0 versus 5.5 pg/ml, p = 0.027). Following segmental bronchoprovocation, concentrations of TGF-beta 1 at the allergen- and saline-challenged sites were not significantly different after 10 min, (31.3 versus 25.0 pg/ml, p = 0.78), but after 24 h there were significantly higher TGF-beta 1 concentrations at the allergen-challenged sites (46.0 versus 21.5 pg/ml, p = 0.017). We conclude that basal TGF-beta 1 levels in the airways are elevated in atopic asthma and that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-beta 1 is implicated in airway wall remodeling in asthma.

Adult↗
PubMed1997

Airway endothelin levels in asthma: influence of endobronchial allergen challenge and maintenance corticosteroid therapy.

Endothelins (ETs) are 21 amino acid peptides which, in addition to their other properties, are potent bronchoconstrictors. Whilst there is evidence of the involvement of ET in the pathophysiology of chronic asthma, its contribution to the acute allergic response is undefined. To examine this, we have undertaken segmental bronchoprovocation with allergen and saline at separate sites in six atopic asthmatics receiving treatment with bronchodilators only and six atopic asthmatics additionally receiving treatment with inhaled corticosteroids. Each challenged segment was lavaged 10 min after bronchoprovocation and concentrations of immunoreactive ET were measured in bronchoalveolar lavage fluid. In the non-steroid-treated subjects, there were significantly lower ET levels at the allergen-challenged sites compared to the saline-challenged sites (p<0.05). In the steroid-treated subjects, on the other hand, there was no significant difference between the two sites. Levels of ET at the saline-challenged sites were significantly lower in the steroid-treated subjects compared to the non-steroid-treated subjects (p<0.04). These findings do not support the hypothesis that allergen exposure in asthma results in immediate release of endothelin. However, release at later time-points and a role for endothelin in late-phase bronchoconstriction are not excluded.

Adrenal Cortex Hormones↗
PubMed1997

Infections in patients with cystic fibrosis following lung transplantation.

BACKGROUND: There is controversy over whether colonization with drug-resistant organisms is a contraindication to lung transplantation. METHODS: We undertook a retrospective review of the results of lung transplantation for patients with cystic fibrosis (CF) at Duke University Medical Center. RESULTS: As of May 1996, 21 patients with CF underwent bilateral lung transplantation. The first patient died within 24 h of transplantation from sepsis due to Stenotrophomonas maltophilia. Of the remaining 20 patients, 17 (85%) are alive and in stable condition. The three deaths were related primarily to bronchiolitis obliterans at 4 and 18 months in two patients and to cytomegalovirus pneumonitis at 5 months in the other patient. The 17 surviving patients have been followed up for a mean of 13 months (range, 0.5 to 34 months). Most of them were colonized and infected with multidrug-resistant organisms before transplantation. Following transplantation, 11 patients had complications from infections. One patient had bacteremia due to a panresistant Burkholderia cepacia and was treated successfully. Two patients had bacteremia and wound infection due to Burkholderia gladioli, previously thought to be pathogenic only in plants. Both patients were treated successfully. Of the six patients with Aspergillus fumigatus isolated from cultures before transplantation, only one had invasive disease following transplantation and responded to treatment. CONCLUSION: The organisms present before transplantation were not the primary cause of mortality in our patient population. Our findings suggest that lung transplantation should be considered in CF patients infected with multidrug-resistant organisms.

Adolescent↗
PubMed1997

Epidemiology and control of egg-associated Salmonella enteritidis in the United States of America.

The isolation rate for Salmonella enterica serotype Enteritidis (SE) in humans in the United States of America (USA) increased from 1,207 sporadic isolates identified in 1976 (0.6 isolates/100,000 population) to 10,201 identified in 1995 (4.0/100,000 population). The proportion of reported Salmonella isolates which were SE increased from 5% to 25% during the same time period. In 1990, 1994, and 1995, SE was the most commonly reported reported Salmonella serotype in the USA. Much of this increase has been associated with the consumption of contaminated shell eggs. An examination of the results of a United States Department of Agriculture (USDA) survey of spent hens at slaughter and unpasteurised liquid egg at breaker plants (liquid egg processors) in 1991 and 1995 reveals an increase in the prevalence of SE isolates overall and in most regions of the USA. SE phage type 4 (pt 4), the predominant SE phage type in other parts of the world, has emerged in the egg industry in the western USA concurrent with a sharp increase in the number of sporadic human SE pt 4 isolates in California and Utah. Research on the molecular structure and virulence of SE pt 4 isolates from the USA as compared with isolates from other parts of the world (human and poultry) should be a priority. A comparison of DNA from pt 4 isolates from the USA and Europe may provide information about the potential threat to public health and poultry in the USA from this phage type. Some regional success in the reduction of human illness as a result of SE control efforts is apparent. The Pennsylvania Egg Quality Assurance Program has shown progress in reducing SE infection in participating flocks. At a national level, however, neither the incidence of human illness due to SE nor the prevalence of SE in flocks and unpasteurised liquid eggs have decreased significantly, despite the implementation of the USDA 'trace back' regulation from 1990 to 1995, and intensified efforts to educate food handlers and to enforce safe food handling practices. More effort is needed to control SE at every stage of the egg continuum, from production through to consumption. A risk-reduction approach, with barriers to the introduction and multiplication of the pathogen throughout the farm-to-table continuum, is the most practical method for reducing human illness from SE in shell eggs at present. An effective long-term solution will require interdisciplinary efforts involving government, industry, consumers, and academics. Interventions should be developed and evaluated in compliance with the potential for reducing the risk to human health and cost-effectiveness.

Animal Husbandry↗
PubMed1996

Cellular and mediator responses twenty-four hours after local endobronchial allergen challenge of asthmatic airways.

The effects of acute allergen exposure on bronchoalveolar lavage cells and mediators and mucosal inflammatory cells were evaluated in 10 subjects with atopic asthma who underwent lavage and biopsy 24 hours after segmental endobronchial allergen challenge. Increased numbers of bronchoalveolar lavage eosinophils were retrieved from the allergen-challenged sites compared with the saline-challenged sites (mean 21.4 vs 1.5 x 10(3) cells/ml; p < 0.02). Numbers of neutrophils and proportions of CD4+, CD8+, CD25+, and HLA-DR+ T cells were similar at the saline- and allergen-challenged sites. In contrast to the bronchoalveolar lavage findings, eosinophil numbers were not increased in the bronchial submucosa or epithelium. There was also no significant difference in neutrophils, mast cells, CD3+, CD4+, or CD8+ T cells in the submucosa after allergen challenge, but the number of activated (CD25+) T lymphocytes in the mucosa did increase after allergen challenge. Allergen challenge did not induce any significant change in endothelial expression of P-selectin, E-selectin, intercellular adhesion molecule-1, or vascular cell adhesion molecule-1. CD11a+ and very late antigen-4+ cell numbers were similar in the saline- and allergen-challenged sites. This study suggests that in patients with very mild asthma, local allergen challenge induces persistent bronchoalveolar lavage eosinophilia, but the recruitment process seems to have diminished or ceased by 24 hours.

Adult↗
PubMed1996

Spinal endothelin content is elevated after moderate local trauma in the rat to levels associated with locomotor dysfunction after intrathecal injection.

The role of endothelin (ET) in the pathophysiology of secondary neural damage after experimental spinal cord injury (SCI) was examined in a rat model of weight-drop contusion injury. Initial studies demonstrated a significant increase in spinal ET concentrations in a 7.5-mm segment of tissue (centered at the impact site) at 30 min, 4 h, and 24 h after a moderate (50 g-cm) contusion injury. Subsequent experiments were aimed at reproducing these elevations by the intrathecal (i.t.) administration of ET and observing the effect on locomotor function. These studies showed that i.t. dosage of 9.6 ng produced spinal cord elevations of ET similar to those seen 30 min after moderate SCI as well as mild locomotor deficits. A 48 ng dose of ET resulted in moderate to severe locomotor deficits that were associated with spinal ET elevations much greater than those seen after injury. The mild deficits attributable to the lower dose of ET could contribute to the pathophysiological actions of other purported secondary injury mediators. The more pronounced locomotor deficits associated with the higher dose could be of relevance for severe SCI.

Animals↗
PubMed1996

Fungal infections in lung and heart-lung transplant recipients. Report of 9 cases and review of the literature.

We reviewed the pattern and incidence of fungal infections in patients undergoing lung and heart-lung transplantation at Duke University Medical Center from September 1992 until August 1995, and present here 9 illustrative cases. Of the 73 lung and heart-lung transplant recipients studied, 59 (81%) had positive fungal cultures at some point after transplantation. The cases presented here illustrate that lung transplant recipients are predisposed to a wide variety of fungal infections. The clinical pattern of these infections ranges from asymptomatic to rapidly progressive fatal disease. In addition to the reactivation of previous fungal infections and recent exposure to new environmental sources, the donor lung itself can be the source of fungal infection, as we showed by using molecular epidemiology techniques. Because of the associated morbidity and mortality, efforts should be directed at investigating prophylactic antifungal regimens in lung transplant recipients. Preliminary reports on the use of itraconazole and aerosolized amphotericin B have been encouraging. Prospective randomized studies are needed to assess the safety and cost effectiveness of different regimens. Fungal infections in patients after lung transplantation can significantly impede recovery and lead to substantial mortality.

Adult↗
PubMed1996

T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma.

Atopic asthma is characterized by bronchial mucosal inflammation, involving eosinophils, mast cells, and lymphocytes. It has been suggested that the development and maintenance of this allergic inflammation is due to T-lymphocyte activation with predominant production of the cytokines interleukin 4 (IL-4) and IL-5. To address the ability of peripheral blood and bronchoalveolar lavage T-cells to generate IL-2, IL-4, or interferon gamma (IFN-gamma), we have employed a flow cytometric method which permits analysis of cytokine production at the single cell level within 5 h of obtaining cell samples. When stimulated with PMA and ionomycin, there was a greatly increased percentage of IFN-gamma-producing cells among bronchoalveolar lavage (BAL) T-cells from the subjects with asthma (median 74%), compared with atopic and nonatopic controls (35 and 43%, respectively; P>0.01). The proportion of BAL T-cells producing IL-4 was small (median 1.7%, range 0 to 7.8% in the asthmatic group). In all three groups, the proportion of BAL T-cells producing IL-2 or IFN-gamma was increased compared with T-cells from peripheral blood. There was no significant difference between the three groups in the percentage of BAL T-cells producing IL-2, or in the percentage of peripheral blood T-cells producing IFN-gamma, IL-2 or IL-4. These findings indicate that IL-4 production is confined to a relatively small proportion of airway and blood T-cells and that there is selective enhancement of IFN-gamma production by airway T-cells in asthma.

Adult↗
PubMed1996

Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study.

The anti-inflammatory effects of oral theophylline on cells in bronchial biopsies of symptomatic atopic asthmatic subjects were investigated. Following a 2 week run-in period, asthmatic subjects were randomly assigned to either placebo (n=11) or theophylline (n=15). Bronchial biopsies were taken at fibre-optic bronchoscopy at the beginning and end of a 6 week period, during which subjects took placebo or theophylline medication at a dose intended to produce therapeutic concentrations. Nine of the placebo subjects and 12 of the theophylline subjects completed the study. Improvement in asthma control was seen in the theophylline-treated group. The mean (SD) theophylline blood level at the end of the study was 10.9 (6.0) microg x mL-1. A significant decrease in interleukin (IL)4 expression from 1.38 to 1.04 cells x mm-2 (<0.05) and a trend to a reduction in IL-5 from 1.29 to 0.48 cells x mm-2 (NS) were seen in biopsies from the theophylline-treated group compared with placebo, although there was no change in mast cell numbers (judged by tryptase expression). A decrease in epithelial CD8+ cells from 2.60 to 0.53 cells x mm-1 of surface (<0.05) was noted. This study shows an anti-inflammatory effect of theophylline in asthmatic bronchi, both in cell numbers and in the expression of IL-4, believed to be an important cytokine in the pathophysiology of asthmatic inflammation. We speculate that theophylline induces downregulation in vivo of cytokine production, accounting for the known inhibitory effect of theophylline on the late asthmatic reaction.

Administration, Inhalation↗
PubMed1995

TNF alpha is localized to nasal mucosal mast cells and is released in acute allergic rhinitis.

Allergic mucosal inflammation is characterized by tissue infiltration with eosinophils, and associated activation of mast cells and T lymphocytes. Tumour necrosis factor (TNF) alpha/cachectin is a candidate cytokine relevant to the pathogenesis of these events through its capacity to upregulate the expression of endothelial cell adhesion molecules, mediate granulocyte chemoattraction, and activate eosinophils, mast cells and T cells. To investigate the presence and localization of TNF alpha in the nasal mucosa in allergic rhinitis, nasal biopsies from perennial rhinitic (n = 13) and non-rhinitic volunteers (n = 11) were embedded in glycol methacrylate and immunostained with a monoclonal antibody directed against TNF alpha, and adjacent 2 microns sections stained for tryptase, CD3 and eosinophil cationic protein. This identified positive immunostaining for TNF alpha in the submucosa of both the rhinitic and normal subjects (median cell counts 13 and 23 cells/mm2 respectively, P = 0.24) with cellular localization to mast cells but not to T-lymphocytes or eosinophils. In a subsequent study of seven atopic subjects, nasal allergen challenge produced increases in lavage levels of histamine and albumin, which was associated with significant release of TNF alpha as early as 2 min post-allergen when compared with the saline control day (P = 0.05). This difference was also apparent when studying the area under the curve both at 30 and 60 min post-challenge t-test (P = 0.015 and 0.02 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

The effects of theophylline on mucosal inflammation in asthmatic airways: biopsy results.

Theophylline, a nonspecific phosphodiesterase inhibitor, has only recently been reconsidered as a potential anti-inflammatory drug. Its ability to inhibit late asthmatic responses has pointed to possible inhibition of mechanisms regulating the influx and activity of inflammatory cells into the airways. Increasing evidence points to an anti-inflammatory action of theophylline at doses lower than those necessary for a bronchodilator effect. Withdrawal of theophylline from regular treatment results in an increase both in CD4+ and CD8+ T-cells in the bronchial mucosa and a concomitant decrease in the blood, suggesting that theophylline prevents T-cell trafficking from blood into the airways. Furthermore, pretreatment with theophylline significantly attenuates the influx of eosinophils into the airways associated with an allergen-induced late asthmatic response. In keeping with these observations, in a double-blind, placebo-controlled trial involving mild to moderately severe atopic asthmatics, treatment with theophylline resulted in a significant reduction in the numbers of epithelial CD8+ T-cells. In addition, the numbers of cells containing cytokines, interleukin 4 and 5 (IL-4 and IL-5), decreased in the theophylline-treated group and increased in the placebo-treated group, with the difference between the changes being significant. It would, therefore, appear that theophylline may contribute to asthma control due to its ability to reduce the suppressor/cytotoxic T-cells and cytokines which are relevant to allergic mucosal responses.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Cerebral toxoplasmosis in childhood and adult HIV infection treated with 1-4 hydroxynaphthoquinone and rapid desensitization with pyrimethamine.

BACKGROUND: We describe a child and an adult infected with the human immunodeficiency virus (HIV) who developed cerebral lesions consistent with toxoplasmosis. A biopsy in the child and IgG ELISA in both patients confirmed the diagnosis of Toxoplasma gondii. The patients were initially treated with pyrimethamine, however, computerized tomography studies (CT scan) revealed progression of a left frontal and temporoparietal lesion. Therapy in the child was changed to pyrimethamine, clindamycin, and azithromycin. Repeat CT scan showed further disease progression and therapy was changed to high-dose pyrimethamine (3 mg/kg/d) and azithromycin. A subsequent CT scan disclosed further radiologic progression with increasing edema. The adult patient developed a maculopapular rash during attempted treatment with pyrimethamine. METHODS: Introduction of 2 (trans-4[4 chlorophenol] cyclohexy[3-hydroxy-1, 4 naphthoquinone] (HNPQ) an experimental antiparasitic compound previously used only in adult HIV clinical trials, was instituted in the child and rapid oral desensitization to pyrimethamine was initiated in the adult patient. RESULTS: HNPQ resulted in resolution of the cerebral lesion in the child and rapid oral desensitization to pyrimethamine produced an excellent clinical response in the adult. To our knowledge, these are the first cases of childhood and adult cerebral toxoplasmosis treated successfully with HNPQ and rapid oral desensitization to pyrimethamine. CONCLUSION: HNPQ and pyrimethamine desensitization should be considered as alternate modes of therapy in patients who become intolerant or fail to respond to traditional therapy for toxoplasmosis.

AIDS-Related Opportunistic Infections↗