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Biomedical subjects

E A Kelly

Publications and source records attributed to E A Kelly.

At least 19 recordsLinked to original sources
PubMed1999

Segmental antigen challenge increases fibronectin in bronchoalveolar lavage fluid.

Fibronectin may contribute to asthma pathogenesis by recruitment and activation of inflammatory cells, and by promotion of subepithelial fibrosis. Fibronectin is produced by several types of airway cells, including epithelial cells, fibroblasts, and alveolar macrophages. To test the hypothesis that antigen-induced airway inflammation is associated with increased local generation of fibronectin, segmental bronchoprovocation (SBP) with antigen and saline was performed in 17 atopic patients. Bronchoalveolar lavage (BAL) was performed at 5 min and 48 h after segmental challenge with saline or antigen. Fibronectin concentrations in BAL fluid, measured by enzyme-linked immunosorbent assay (ELISA), increased more than 5-fold 48 h after antigen challenge (65 [47 to 110] versus 407 [240 to 697] ng/ml, median and 25 to 75% interquartiles, p < 0.05). Fibronectin concentrations 48 h after antigen challenge correlated with histamine concentrations 5 min after antigen challenge and numbers of eosinophils, neutrophils, macrophages, and total cells in BAL fluid 48 h after antigen challenge. BAL was more enriched in fibronectin 48 h after challenge than would be predicted solely from increased permeability of plasma proteins. Western blot analysis showed that fibronectin in BAL fluid was largely intact and contained the extra domain-A (ED-A) splice variant of cellular fibronectin, indicative of local production. We conclude that antigen challenge in atopic subjects causes increased production of fibronectin by airway cells and speculate that this response may contribute to airway remodeling in allergic inflammation.

Adult↗
PubMed1998

Eosinophils bind rhinovirus and activate virus-specific T cells.

Episodes of virus-induced exacerbations of asthma are accompanied by increased eosinophils (EOS) in respiratory secretions and evidence of EOS degranulation. Although rhinoviruses (RV) are the viruses most often implicated in exacerbations of asthma in both children and adults, little is known about the immune response to this group of viruses and, in particular, EOS-RV interactions. To define such interactions, we incubated human rhinovirus type 16 (RV16), a serotype using ICAM-1 as a receptor, with EOS purified from PBMC, and measured EOS-RV binding, EOS-mediated Ag presentation and T cell activation, and EOS cell surface marker expression and superoxide production. Significant RV16 binding occurred to EOS that were pretreated with granulocyte-macrophage CSF, and this binding was inhibited by anti-ICAM-1 mAb. EOS also presented viral Ags to RV16-specific T cells, causing T cell proliferation and secretion of IFN-gamma. RV16 induced a significant shift from CD18dim to CD18bright, but did not affect EOS expression of CD54, CD69, or HLA-DR. Finally, RV16 did not induce superoxide production from peripheral blood EOS. These findings suggest that RV16 also binds to airway EOS, which resemble granulocyte-macrophage CSF-treated blood EOS in terms of high expression of ICAM-1. Furthermore, our findings suggest that EOS could participate in RV-induced immune responses through Ag presentation and T cell activation. By activating RV-specific T cells, EOS may play an important role in the initiation of antiviral T cell responses, and these effects could also contribute to enhanced airway inflammation and increased asthma symptoms in susceptible individuals.

Adult↗
PubMed1998

Effect of renal impairment on the pharmacokinetics and tolerability of tiagabine.

PURPOSE: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB). METHODS: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4-6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12 h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB x HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively. RESULTS: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t(1/2)) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 l/h, and from 6.4 to 8.4 h, respectively. CONCLUSIONS: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.

Adult↗
PubMed1997

Rhinovirus-specific T cells recognize both shared and serotype-restricted viral epitopes.

To characterize rhinovirus (RV)-specific T cells, RV16- and RV49-specific CD4 T cells were cloned from peripheral blood, and cytokine secretion and serotype specificity were defined. Each RV-specific clone secreted high levels of interferon-gamma, and several also produced interleukin-4 and -5. To test serotype specificity, each clone was incubated separately with five different RV serotypes. Although 2 of 31 clones proliferated only in response to the virus used in cloning, the rest had significant proliferation in response to 2-5 different serotypes. Thus, RV-specific T cells can be activated by either serotype-specific or shared viral epitopes, raising the possibility that repeated activation of T cells by shared viral determinants in vivo could induce potent recall T cell responses. It is likely that enhanced T cell responses to shared viral epitopes contribute to antiviral activity, airway inflammation, or both.

Antigen-Presenting Cells↗
PubMed1997

Cytokine profiles of stimulated blood lymphocytes in asthmatic and healthy adolescents across the school year.

T cell cytokines play an important role in mediating airway inflammation in asthma. The predominance of a Th2 cytokine profile, particularly interleukin (IL)-4 and IL-5, is associated with the pathogenesis and course of asthma. The aim of this study was to test the hypothesis that a stressful life event alters the pattern of cytokine release in asthmatic individuals. Thirteen healthy controls and 21 asthmatic adolescents gave blood samples three times over a semester: midsemester, during the week of final examinations, and 2-3 weeks after examinations. Interferon-gamma (IFN-gamma), IL-2, IL-4, and IL-5 were measured from supernatants of cells stimulated with PHA/PMA for 24 h. Cells from asthmatic subjects released significantly more IL-5 during the examination and postexamination periods, whereas cells from healthy controls released significantly more IL-2 during the midsemester and examination periods, thereby indicating a bias for a Th2-like pattern in asthmatics and a Th1-like pattern in healthy controls. IL-4 and IL-5 production showed a marked decrease during and after examinations in healthy controls, whereas this decline was absent in asthmatics. The ratios of IFN-gamma:IL-4 and IFN-gamma:IL-5 also revealed significant changes in the profile of cytokine release across the semester. These results indicate differential cytokine responses in asthmatics that may become pronounced during periods of cellular activation.

Adolescent↗
PubMed1997

The immediate and late allergic response to segmental bronchopulmonary provocation in asthma.

The response to antigen is an important factor in the development of airway inflammation. Segmental bronchoprovocation (SBP) with antigen and subsequent bronchoalveolar lavage (BAL) have provided valuable insight into the mechanisms of allergic inflammation. To determine the features of allergic airway response in asthma, 19 subjects with mild asthma underwent antigen SBP in a dose-dependent manner. The amount of antigen used in SBP was 0 (saline), and 1, 5, or 20% of the antigen dose required to drop the FEV1 by 20% (APD20). BAL was done at 5 min and 48 h after SBP. BAL histamine levels increased modestly 5 min after antigen SBP. At 48 h, there was a marked increase in eosinophils and IL-5 concentration even in airway segments where the release of histamine was small. Moreover, eosinophils correlated with IL-5 levels at 48 h (r = 0.63; p < 0.001), but not with BAL histamine concentrations at 5 min. GM-CSF levels did not increase after antigen SBP and did not correlate with eosinophils. These observations indicate that asthmatic subjects can develop a dose-dependent response to antigen SBP that is characterized by a modest increase in histamine immediately after antigen exposure, and marked eosinophilia, which appears proportionately greater than the histamine response and relatively greater than what is seen in allergic nonasthmatic subjects. This feature might be important to the eventual development of airway inflammation in asthma.

Adult↗
PubMed1997

The effect of segmental bronchoprovocation with allergen on airway lymphocyte function.

We hypothesized that allergen-induced airway eosinophilia is linked to activation or recruitment of T cells in the airway and generation of interleukin-5 (IL-5). To evaluate this hypothesis, we performed bronchoscopy with segmental antigen bronchoprovocation in 12 atopic subjects. Bronchoalveolar lavage (BAL) was done 5 min and 48 h after challenge with saline or antigen. Airway cells were isolated and then stimulated ex vivo with a T-cell mitogen, phytohemagglutinin (PHA), and cytokine release was determined. Cells retrieved from the saline-challenged segment secreted principally interferon-gamma (IFN-gamma) and IL-2. In contrast, cells obtained 48 h after allergen challenge secreted high levels of IL-5 and small but increased amounts of IL-4, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although CD4+ T cells were a major source of IL-5, there were no significant changes in the relative proportion of CD4+ cells in response to bronchoprovocation. Additionally, ex vivo secretion of IL-5 by airway cells correlated closely with amounts of IL-5 and eosinophils present in the bronchoalveolar lavage fluid (BALF). These observations suggest that following exposure to allergen, airway T cells are functionally but not phenotypically different from resident airway T cells, and that T cells within the airway contribute to eosinophilic airway inflammation through the secretion of IL-5.

Adult↗
PubMed1996

Rhinovirus produces nonspecific activation of lymphocytes through a monocyte-dependent mechanism.

There is evidence that rhinovirus (RV) infections are frequent causes of increased asthmatic symptoms and can specifically enhance allergic inflammation in the airway. To further define effects of RV infection on cellular immunity, we have begun to develop in vitro models for study. When human PBMC were incubated with 35S-labeled RV16, specific binding via ICAM-1 on monocytes was observed. Incubation of PBMC with RV also led to a dose-related increase in the expression of the early activation marker CD69 on 30 to 70% of T cells. The RV16-induced increases in CD69 were blocked by anti-ICAM-1 mAb, and were not elicited by UV-inactivated (noninfectious) virus. The degree of CD69 enhancement correlated with the number of monocytes in mixtures of PBMC, did not occur in monocyte-depleted cultures, and was mediated by one or more soluble factor(s). RV also induced secretion of IFN-gamma from both peripheral blood T cells and NK cells, and IFN-gamma mRNA was greatest in T cells that were CD69+. Finally, supernatant from RV-activated CD3+CD69+ cells had biologic activity that promoted eosinophil survival in vitro; this RV16-associated activity was blocked when co-incubations were performed with IFN-gamma mAbs. These observations suggest that RV nonspecifically activates a large proportion of T cells through a monocyte-dependent mechanism. Such changes in vivo could enhance airway inflammation, and this may include effects on inflammatory cells in the airways of allergic individuals.

Adult↗
PubMed1995

A method for interactive medical instruction utilizing the World Wide Web.

We describe the implementation of interactive medical teaching programs in radiology and histology which utilize the Internet's World Wide Web (WWW). The WWW standard hypertext interface allows for simple navigation between related documents but does not provide a method for student tracking or question queries. Electronic forms, a recent feature of the WWW, provide the means to present question documents to remote clients and track student performance. A feature of our approach is dynamic creation of HTML documents based upon interaction with database applications. The approach allows multiple simultaneous, yet asynchronous interactions by geographically dispersed students upon the same instructional database and is scalable, providing the capability for multiple image/document servers. The security of the database is assured given that it is not accessible through the Internet.

Computer Communication Networks↗
PubMed1994

An Internet primer: resources and responsibilities.

The ease with which individuals can access the Internet and with which institutions can make information available on the Internet explains the exponential growth of this national resource. Once one accomplishes the difficult task of installing network services and establishing an ongoing mechanism for their support, it is relatively simple to use software systems such as those described in this article to gainfully traverse the Internet for a wide range of professional activities. But, as we have discussed, every step of the process, from simple naming conventions to organizations and ongoing maintenance of network-based information services, should proceed only after careful consideration of a network growing hourly in complexity. Despite the power of the technology available on one's desktop, one can often be frustrated by the small decisions: what is my colleague's email address? How can I most effectively find relevant information on home health care software? How should I organize a gopher server? When is WAIS preferable to Gopher or W3? Who will help me learn more? The process comes full circle back to academic medical institutions. The usefulness of the Internet hinges upon the policies these institutions create to aid the organization and dissemination of medical information, and in the means they use to make their constituents aware of the pitfalls and potentials of various technologies.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer Communication Networks↗
PubMed1994

The obstetrician and the extremely immature fetus (24-26 weeks): outcome to 5 years of age.

The aims of this study were to determine the outcome to 5 years of age for fetuses 24-26 weeks of gestational age from the obstetric viewpoint, and to determine if their outcome has improved over time. Consecutive fetuses with gestational ages from 24-26 weeks born at the Royal Women's Hospital, Melbourne, during 2 separate eras, Era 1 (1977-1982; n = 198) and Era 2 (1985-1987; n = 128) were studied and their outcome to 5 years of age determined. Fetuses referred with lethal malformations or clearly dead before the onset of labour were excluded. The stillbirth rates were similar in both eras (Era 1 23.7%, Era 2 21.9%), but the proportion of survivors to 5 years of age was much higher in Era 2 (Era 1 19.7%, Era 2 30.5%, X2 = 5.0, p < 0.03; odds ratio 1.80; 95% confidence interval [CI] 1.07 to 3.04). Overall, both the proportion and the absolute number of severely disabled children fell over time; 4 children survived with severe sensorineural disability in the 5 1/4 years of Era 1, but only one child in the 3 years of Era 2. From the obstetric viewpoint, only 1.5% of total births survived with a severe sensorineural disability, no higher than the rate expected for children born at term. Fetuses born at 24-26 weeks of gestational age need not contribute disproportionately to the number of severely disabled children in the community; furthermore, their outcome is improving over time. From the obstetrician's viewpoint, survival chances rather than sensorineural outcome should dominate decision-making at these extremely preterm gestations.

Cerebral Palsy↗
PubMed1993

Sensorineural outcome at 2 years for survivors of erythroblastosis treated with fetal intravascular transfusions.

OBJECTIVE: To determine the sensorineural outcome at 2 years of age in a complete cohort of survivors of fetal intravascular transfusions. METHODS: From March 1984 to May 1990, 38 of 52 consecutive fetuses (73%) suffering from severe erythroblastosis survived attempted intravascular transfusions at the Royal Women's Hospital, Melbourne. At 2 years of age, corrected for prematurity where appropriate, the survivors had a psychological assessment, including the mental developmental index of the Bayley scales, and a standardized neurodevelopmental examination. RESULTS: Only one transfused child had a severe sensorineural disability, with severe developmental delay and multiple minor motor seizures. Another child was moderately disabled with spastic hemiplegia. In neither case were complications of an intravascular transfusion the likely explanation for the disability. Only one other child had a mental developmental index in the suspect range. The remaining 35 children (92.1%) had no sensorineural disability. The overall rate of sensorineural impairments and disabilities was lower in the group transfused than in previous reports of survivors of intraperitoneal transfusions. The mean mental developmental index was significantly higher in the transfused group than in a control group of normal birth weight children. CONCLUSION: Children who survive fetal intravascular transfusions compare favorably not only with other high-risk survivors, but also with low-risk children.

Blood Transfusion, Intrauterine↗
PubMed1993

Cognition, school performance, and behavior in very low birth weight and normal birth weight children at 8 years of age: a longitudinal study.

Cognition, school performance, and behavior were assessed at 8 years of age in 132 very low birth weight (VLBW) children free of major sensorineural impairments, and the results were contrasted with a randomly selected control group of normal birth weight (NBW) children. Considering their fragile beginnings, the majority of VLBW children were developing normally and were reading and performing in most academic and social areas as well as the NBW children. However, VLBW children were significantly inferior to NBW children on tests of cognition, including tests of intelligence and visual memory, and on teacher's reports of motor skills and initiative. In addition, proportionally more VLBW children (20.5%) than NBW children (5.9%) were reported by their parents to be not coping at school.

Brain Damage, Chronic↗
PubMed1992

Improvement in outcome for very low birthweight children: apparent or real?

OBJECTIVE: To determine whether improvement in the survival rate of infants with a birthweight of less than 1501 g was accompanied by an increase in the rate of neurological impairment or disability among the survivors. DESIGN, SETTING AND PATIENTS: Two cohorts of consecutive very low birthweight infants (birthweight less than 1501 g) in one tertiary perinatal centre were followed prospectively to eight years of age; for both cohorts, comparison groups of children of birthweight more than 1501 g were randomly selected from hospital births. INTERVENTIONS: The first cohort was born before the introduction of assisted ventilation (1966-1970), the second after assisted ventilation was well established (1980-1982). MAIN OUTCOME MEASURES: Comparisons between cohorts, at eight years of age, of the survival rates and the rates of severe sensorineural impairments and disabilities. RESULTS: The survival rate for very low birthweight infants to eight years of age almost doubled between these cohorts, from 37.1% to 67.8% (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.5-4.7; chi 2 = 57.6; P much less than 0.0001). The biggest gain was the increase in non-disabled survivors at eight years of age, from 52.6% in the first cohort to 80.8% in the second cohort (OR, 3.5; 95% CI, 2.2-5.7; chi 2 = 26.7; P less than 0.0001). Furthermore, the rate of severe disabilities in survivors fell substantially, from 13.6% to 4.1% (OR, 0.31; 95% CI, 0.14-0.69; chi 2 = 8.3; P less than 0.01). Of specific impairments, the rate of severe sensorineural deafness fell substantially (3.2% to 0%: OR, 0.14, 95% CI, 0.02-0.81; chi 2 = 4.8; P less than 0.05), as did the rate of severe intellectual impairment (13.0% to 2.7%: OR, 0.25; 95% CI, 0.11-0.57; chi 2 = 10.7; P less than 0.002). Only the rate of cerebral palsy increased, but not significantly (2.6% to 6.8%; OR, 2.6; 95% CI, 0.89-7.6; chi 2 = 3.0). CONCLUSIONS: It has been possible to improve the survival rate of very low birthweight infants over time without increasing the number of severely disabled survivors. Whether the long-term outcome for these infants is continuing to improve with more recent advances in perinatal care remains to be determined.

Cerebral Palsy↗
PubMed1992

Audiologic assessment of extremely low birth weight infants: a preliminary report.

The aim of this study was to assess all relevant aspects of auditory function, including acuity and perception, of a cohort of extremely low birth weight (< 1000 g) children who survived to 8 years of age; 42 of the 59 consecutive survivors born over a 4-year period from January 1, 1977, had a full auditory assessment. Of the 42 children, 4 (9.5%) had a sensorineural hearing impairment, 5 (11.9%) had a conductive hearing impairment, 24 (57.1%) had figure/ground differentiation problems, and 20 (47.6%) had a short-term auditory memory problem. The 4 children with sensorineural hearing impairments had had significantly higher maximum concentrations of bilirubin in the newborn period (median 167 mumol/L vs 138 mumol/L and had required more intensive care; at 8 years of age they were significantly disadvantaged in verbal ability. The 5 children with conductive hearing impairments were not significantly different on any perinatal or other 8-year outcome variables. The proportion with figure/ground differentiation problems (57.1%) was significantly higher than in a normative population (11.7%, chi 2 = 24.2). Extremely low birth weight children with figure/ground differentiation problems were more likely to be restless in the classroom (45.0% [9/20]) than those without these problems (16.7% [2/12]), but the difference was not statistically significant (chi 2 = 2.7). Children with short-term auditory memory problems had significantly higher maximum bilirubin concentrations in the newborn period (median 152 mumol/L vs 137.5 mumol/L). At 8 years of age they had significantly reduced intelligence and reading ability.(ABSTRACT TRUNCATED AT 250 WORDS)

Audiometry↗
PubMed1992

Changing obstetric practice and 2-year outcome of the fetus of birth weight under 1000 g.

The aim of this study was to assess the outcome up to 2 years of age for the fetus of birth weight 500-999 g, over time and in association with changes in obstetric care. Two consecutive cohorts of infants of birth weight 500-999 g were compared from two eras, 1977-1982 and 1985-1987, and their outcome up to 2 years of age was determined with particular emphasis on the effect of various obstetric interventions at the time of birth, such as cesarean delivery, electronic fetal monitoring, antenatal steroid therapy, and tocolytic therapy. The outcome to 2 years was analyzed by logistic function regression to adjust for imbalances in confounding perinatal variables. In the latter era, the survival rate to 2 years increased significantly by almost 50%, and only 7% of the survivors were severely disabled. The rates of delivery by cesarean and of electronic fetal monitoring both increased significantly in the latter era, but neither was associated with the improved outcome. The only variable associated with an improved outcome that was amenable to obstetric intervention at the time of birth was antenatal steroid therapy, which was used equally in both eras. The obstetrician may aid the fetus of birth weight 500-999 g by giving the mother steroids to accelerate fetal lung maturity, but cesarean cannot be recommended as the routine mode of delivery unless there are recognized maternal or fetal indications.

Delivery, Obstetric↗