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Biomedical subjects

J E Fitzgerald

Publications and source records attributed to J E Fitzgerald.

At least 19 recordsLinked to original sources
PubMed1996

The effect of electrode position in electrocochleography.

This study assessed the effect of needle electrode position on the human cochlear summating potential (SP) obtained by transtympanic electrocochleography (ECochG). Electrocochleography was performed on 10 subjects with large central tympanic membrane perforations with good cochlear function, and in whom a needle electrode could be accurately placed in a series of five pre-determined positions in the middle ear. A comparison of the electrocochleograms revealed a wide scatter of results between different positions in the same patient and between similar positions in different patients. Only when the needle was repositioned at an almost identical recording site in the same subject, was good reproducibility achieved. Such a wide and unpredictable variation in results would suggest great caution is needed when comparing traces obtained using a transtympanic technique which precludes a view of the electrode tip.

Adult↗
PubMed1996

Diffuse panbronchiolitis in the United States.

Diffuse panbronchiolitis (DPB), an important cause of progressive obstructive lung disease in the Far East, represents a distinctive sinobronchial syndrome with typical radiologic and histologic features. We have identified DPB in five citizens of the United States, three with histologic confirmation, who have never traveled to the Far East. There were four men and one woman, whose ages ranged from 46 to 75 yr at the time of diagnosis. All had a prior history of chronic sinusitis and presented with cough, dyspnea, and sputum production. Three were never smokers and two were current smokers. Pulmonary function testing revealed severe airflow limitation (the FEV1 ranging from 22% to 56% of predicted), and overdistention. All patients had high-resolution computed tomographic (HRCT) scans indicating centrilobular nodules with adjoining thickened and dilated bronchioles. In the three patients in whom open lung biopsy was performed, there was bronchiolocentric infiltration of lymphocytes, plasma cells, and foamy macrophages. Three patients remain alive and are being treated with chronic macrolide therapy. The clinical, radiographic, and histologic features of these patients closely resemble those described in Japanese patients. DPB must be considered in the differential diagnosis of sinopulmonary syndromes, bronchiolitis, and cryptic cases of obstructive lung disease among United States citizens, since therapy now offers an improved prognosis.

Aged↗
PubMed1995

Analysis of clonal CD8+ T cell expansions in normal individuals and patients with rheumatoid arthritis.

In the course of studying the circulating TCR repertoire in humans, we noted several individuals with an increase in the percentage of CD8+ T cells expressing a particular V region. In some cases, these CD8 expansions were dramatic, occupying over 40% of the total CD8 repertoire. Using a panel of mAbs to different TCR V regions, we found that over 30% of healthy adults (> 35 years of age) harbor an expansion that alters the peripheral blood CD8 TCR repertoire. A wide range of V regions were expressed by these expansions. Considering that the mAbs used cover only a portion of the V beta repertoire, the data suggest that over 70% of adults are likely to harbor such expansions. Junctional region sequencing showed that the CD8 subset expansions were clonal, and serial studies as long as 4 years showed that they persisted indefinitely. Expansions were not identified in the CD4 population. Discordant expression of one large V beta 6.7+ clone was found in one identical twin set, suggesting the possibility that an environmental exposure is involved in their generation and/or expansion. In one large family, we found five family members with a large CD8 subset expansion. Remarkably similar usage of J beta regions was noted, and two individuals demonstrated V beta 3-expressing clones with homologous CDR3 regions, differing by only one major substitution. The repertoire data from this family suggest that the T cell clones have arisen in response to a common Ag. Studies of patients with rheumatoid arthritis found a significantly increased frequency of circulating CD8 subset expansions that expressed a different V region repertoire compared with the healthy individuals studied. Overall, our results emphasize a frequent alteration in the human CD8 TCR repertoire, most likely related to an environmental exposure, in both healthy individuals and patients with rheumatoid arthritis. The presence of these expansions will be important to consider in any study of human TCR repertoire, and their implication for health and disease will be important to understand.

Adolescent↗
PubMed1995

Relationship of interleukin-1 receptor antagonist to mucosal inflammation in inflammatory bowel disease.

Previous work has suggested that the interleukin-1 (IL-1) receptor antagonist, IL-1ra, may regulate mucosal inflammation in inflammatory bowel disease. The present study assessed the relationship of mucosal IL-1ra levels to histologic severity of inflammation and the related proinflammatory cytokines IL-1 beta and IL-6 in children with inflammatory bowel disease. Colonic biopsy specimens from 29 patients with ulcerative colitis, 27 with Crohn's disease, and 24 noninflammatory control subjects were assayed for IL-1ra, IL-1 beta, and IL-6 by enzyme-linked immunosorbent assay. Histologic activity was graded as none, mild, moderate, or severe. Mucosal IL-1 beta levels, but not IL-1ra levels, were significantly elevated in moderate/severely inflamed biopsies from patients with either ulcerative colitis (p < 0.01) or Crohn's disease (p < 0.001) compared with those with none/mild inflammation. The mucosal molar ratio of IL-1ra/IL-1 beta was significantly lower for moderate/severe inflammation compared with none/mild inflammation for patients with ulcerative colitis (p < 0.05) and Crohn's disease (p < 0.01). The mucosal IL-1ra/IL-1 beta ratio was similar in controls to none/mild inflamed biopsies from subjects with either ulcerative colitis or Crohn's disease. Our observations suggest that increasing mucosal inflammation in inflammatory bowel disease in children is associated with a decrease in the "normal" effective IL-1ra/IL-1 beta ratio in which IL-1ra predominates. The importance of this abnormality to the pathogenesis of inflammatory bowel disease awaits further study.

Adolescent↗
PubMed1995

Localization of interleukin-8 in human gingival tissues.

Periodontitis and gingivitis are chronic inflammatory diseases of the periodontium and adjacent tissues. This site-specific inflammation is characterized by a local infiltration of polymorphonuclear leukocytes and T lymphocytes. Interleukin-8 is a low molecular-weight cytokine that is thought to be responsible for the induction and maintenance of localized inflammation. We hypothesized that locally produced interleukin-8 plays a central role in chronic inflammation of periodontitis by regulating the recruitment and activation of leukocytes in the gingival tissues. To test this hypothesis, we determined whether the interleukin-8 antigen is present locally and is cell-associated. Inflamed and control tissues were analyzed: 1) for the interleukin-8 antigen; 2) by molecular weight; 3) for location; and 4) for the messenger RNA (mRNA) of interleukin-8. The conclusions from these data were that: 1) interleukin-8 antigen and mRNA was elevated in chronically inflamed gingiva; and 2) the major interleukin-8 antigen was detected only in the epithelial cell layer. These results support that interleukin-8 may play a crucial role in the recruitment and activation of neutrophils and T lymphocytes in periodontitis.

Adolescent↗
PubMed1994

TCR expression of activated T cell clones in the lungs of patients with pulmonary sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology in which CD4+ T cells seem to be critically involved. In the lungs of patients with pulmonary disease, CD4+ T cells accumulate in large numbers, and a subset of these cells is activated. By using both quantitative PCR and anti-V beta mAbs, we analyzed the TCR repertoire of total and activated bronchoalveolar lavage T cells, the latter subset being defined by the ability to proliferate in short-term culture supplemented with IL-2. Overall, there was little difference when TCR V beta expression of freshly isolated lung and peripheral blood cells was compared in individual patients. Some individuals did demonstrate a modest increase in a few V beta-expressing subsets. However, after 1 to 2 wk of in vitro growth in IL-2-supplemented media, bronchoalveolar lavage cells from most patients, but not from any healthy individuals, demonstrated a selective expansion of particular V beta-expressing subsets. Interestingly, different V beta-bearing subsets were expanded in different patients. Junctional region sequencing indicated that the proliferating T cells in culture were strikingly oligoclonal and were derived from T cell clones already selectively expanded in vivo. These results provide evidence for a disease process that involves recognition of local Ag(s) by specific subsets of CD4+ T cells. Analysis of the Ag specificity of these IL-2-expanded populations is likely to provide insight into the pathogenesis of this disease.

Adult↗
PubMed1994

Characterization of circulating interleukin-1 receptor antagonist expression in children with inflammatory bowel disease.

The cytokines IL-1 beta and IL-6 appear to be important in the pathogenesis of inflammatory bowel disease (IBD). Recently, a naturally occurring interleukin-1 receptor antagonist, designated IL-1ra, which inhibits IL-1 beta activity in vitro and in vivo has been described. The purpose of the present study was to assess the circulating levels and relative relationships of IL-1ra, IL-1 beta, and IL-6 in children with IBD of varying severity. Serum/plasma samples were obtained from 32 children with ulcerative colitis, 45 with Crohn's disease, and 24 control patients. Cytokine assays were performed by enzyme-linked immunoassay. IL-1ra levels were significantly elevated in children with ulcerative colitis or Crohn's disease of moderate/severe activity compared to patients with inactive/mild IBD or control subjects (P < 0.001). IL-1 beta was only detectable in the circulation of two subjects with severe colitis (one ulcerative colitis, one Crohn's disease), and both had extremely elevated IL-1ra levels. IL-1ra levels were significantly related to IL-6 levels for patients with IBD (P < 0.00001). Our results suggest that circulating IL-1ra appears in increasing concentrations in children with mounting degrees of disease severity as determined by clinical scoring methods as well as by the level of IL-6. Future work will need to address the clinical and prognostic value of measuring circulating IL-1ra in individuals with inflammatory bowel disease.

Adolescent↗
PubMed1994

Cytokines in experimental otitis media with effusion.

Studies in the authors' laboratory have recently demonstrated the presence of potent inflammatory cytokines such as interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) in human middle ear effusions. The clinical significance of this finding has not been fully elucidated because of the limitations of human studies. We hypothesized that the chinchilla model of otitis media may be an appropriate system with which to study the role of cytokines in otitis media with effusion. To begin to investigate this possibility, 30 chinchillas underwent surgical blockage of the eustachian tube (ET) to promote effusion development. After 2 weeks, examination by otoscopy demonstrated 27 ears to have developed an effusion. Next, all middle ear clefts, in random manner, were either injected with heat-killed Streptococcus pneumoniae 1 x 10(6) in 0.1 mL normal saline, injected with 0.1 mL normal saline alone, or received no injection at all. Middle ear effusions were obtained and analyzed for IL-1 beta and TNF alpha by enzyme-linked immunosorbent assay (ELISA). This study demonstrated a significant correlation between IL-1 beta and the presence of an effusion (P < .001). Additionally, increased TNF alpha levels correlated with bacterial component presence (P < .001), i.e., mean TNF alpha level was 108, 10.8, and 0 pg/mL in bacteria, normal saline, and noninjected ears, respectively. These findings would suggest that cytokine expression may relate to specific pathological conditions and that the chinchilla model for otitis media with effusion (OME) could be used to further explore the role of cytokines in OME.

Animals↗
PubMed1994

Interleukin-8 expression in otitis media.

Based on recent studies in the authors' laboratory on the correlation of cytokines and inflammation in otitis media (OM), the authors hypothesized that in chronic otitis media with effusion (COME) interleukin-8 (IL-8) is responsible for 1. the accumulation of leukocytes in the middle ear cleft and 2. in situ leukocyte activation with subsequent tissue damage. Additionally, the authors hypothesized that IL-8 expression is at least in part under the control of interleukin-1 (IL-1) and tumor necrosis factor (TNF). To begin to test this hypothesis, middle ear effusions (MEE) obtained from children ages 2 to 90 months (mean age, 29 months) undergoing tympanostomy tube placement for the presence of these inflammatory cytokines were analyzed. For these studies, IL-8, interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and tumor necrosis factor-beta (TNF-beta) were measured in MEE by radioimmunoassay (RIA) or enzyme-linked immunoassay (ELISA). IL-8, IL-1 beta, TNF-alpha, and TNF-beta were present in 92%, 67%, 77%, and 0% of effusions, respectively. The mean (+/- SEM) values for IL-8, IL-1 beta, and TNF-alpha were 4805 (+/- 913) pg/mg, 4076 (+/- 1510) pg/mg, and 163 (+/- 90) pg/mg. Further analysis indicated that levels of IL-8 correlated with IL-1 beta (R2 = .500, P = .000) and TNF-alpha (R2 = .387, P = .023). Thus the authors' studies clearly demonstrate that IL-8 is consistently present in the MEE of children with COME and is strongly correlated with levels of IL-1 beta and TNF-alpha, both known inducers of IL-8 production. These results support the authors' hypothesis that IL-1 beta, TNF-alpha, and IL-8 are intimately involved in the inflammatory cascade in the middle ear and suggest regulation of these cytokines as possible sites of future therapeutic intervention in otitis media with effusion (OME).

Age Factors↗
PubMed1994

Comparison of body sway analysis techniques. Assessment with subjects standing on a stable surface.

Different analysis methods for the objective measurements of body sway were examined to establish the most sensitive method for identifying changes in stability. Changes between stability with eyes open and eyes closed were used to assess the techniques. Body sway was measured in a group of normal subjects standing on a stable surface using "sway magnetometry," which measures hip movement in the sagittal and coronal planes by magnetic field detectors worn at the waist. The following analysis methods were studied; path length, mean distance from the centre, the area enclosed by the path of movement, and the areas of a convex hull, an ellipse and a circle enclosing the sampled points. The results showed that the path length technique had the smallest inter-subject variability, both with eyes open and eyes closed, and was the only technique whose mean Romberg Coefficient (Eyes Open/Eyes Closed) was more than two standard derivations from 1.0 (0.74 +/- 0.11, mean +/- S.D.), indicating that this technique showed greatest sensitivity for detecting changes in body sway.

Adult↗
PubMed1994

Tissue plasminogen activator activity in human aqueous humor.

PURPOSE: To determine the levels of free plasminogen activator activity in human aqueous humor and to identify the type of activity (i.e., tissue-type t-PA or urokinase-type u-PA) that is responsible. METHODS: Aqueous humor was obtained by a simplified pipette paracentesis before cataract surgery in 31 subjects, ages 57 to 93 years. Levels of plasminogen activator activity were determined using a modified 17-hour specific amidolytic assay. The type of plasminogen activator was investigated in selected samples based on its dependence on soluble fibrin, inhibition by amiloride, and specific antibody blocking. Activity-antigen ratios were compared in seven samples. RESULTS: Plasminogen activator (PA) activity was present in all samples tested. PA activity ranged widely between 0.54 and 26.7 mIU/ml, with a mean value of 10.8 +/- 8.1 mIU/ml. Soluble fibrin, a known stimulator of tissue-type plasminogen activator (t-PA), was required in the assay system. Its absence decreased the measured activity by more than 90%. Amiloride, a known inhibitor of urokinase-type PA, had little or no effect in selected samples tested. The activity was blocked by anti-human t-PA antibodies but not by antibodies against human u-PA, further defining the type of PA responsible for the detected activity. t-PA antigen levels showed less variation among individuals than did activity levels. Antigen-activity ratios ranged between 89 and 552. CONCLUSION: Plasminogen activator activity is present in the human aqueous humor in measurable quantities. The type of PA activity present is almost exclusively t-PA. t-PA activity varies more widely than antigen, as is the case in plasma.

Aged↗
PubMed1993

Adenosine diphosphate stimulates the endothelial release of tissue-type plasminogen activator but not von Willebrand factor from isolated-perfused rat hind limbs.

The acute release of tissue-type plasminogen activator (t-PA) activity and of von Willebrand Factor (vWF) antigen from vascular endothelium was studied ex vivo using the rat hindquarter isolated perfusion model. The release of these proteins has been reported to occur simultaneously in response to a variety of endothelial cell agonists including bradykinin, thrombin and platelet activating factor. It has therefore been suggested that similar endothelial cell pathways and mechanisms are involved in the release of t-PA and vWF in vivo. This paper shows that the releases of t-PA and of vWF are not always closely linked and may depend on the agonist utilized to effect release. In our hands, the bradykinin-induced release of these proteins appears to be essentially identical, but this is not true for adenosine diphosphate (ADP). Rather, ADP is capable of causing the acute release of t-PA without the simultaneous release of vWF in the ex vivo rat hindquarter model. This indicates that the bradykinin- and ADP-induced pathways for t-PA release are probably distinct and that the releases of t-PA and vWF are not as closely linked as previously believed.

Adenosine Diphosphate↗
PubMed1993

Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease.

BACKGROUND: Intestinal and peripheral blood mononuclear cell interleukin 6 (IL-6) production in inflammatory bowel disease might present an increased quantity of IL-6 into the systemic circulation. The aim of the present study was to examine the relationship of circulatory IL-6 to the clinical and laboratory expression of inflammatory bowel disease in children. METHODS: Sera were obtained from 26 children with ulcerative colitis, 49 with Crohn's disease, and 29 control patients. Serum functional IL-6 was measured by a bioassay and antigenic IL-6 by enzyme linked immunosorbent assay. RESULTS: Functional and antigenic serum IL-6 levels were higher in Crohn's disease than in ulcerative colitis or controls (P < 0.0001) and higher in ulcerative colitis than controls (P < 0.04). In Crohn's disease affecting the colon, functional and antigenic serum IL-6 levels were greater than in disease limited to the small bowel (P < 0.002). Increasing disease severity was reflected by increasing antigenic but not functional IL-6 levels in both Crohn's disease (P < 0.001) and ulcerative colitis (P < 0.02). Serum antigenic IL-6 levels were related to acute phase reactants in both diseases (P < 0.001) whereas functional levels were not. CONCLUSIONS: Our results underscore the importance of using both functional and antigenic methodologies in examining the relationship of circulating cytokines to the clinical manifestations of inflammatory bowel disease.

Acute-Phase Proteins↗
PubMed1988

Mucolytic agents and otitis media with effusion.

Middle ear effusion was obtained from children with otitis media with effusion and separated into thick (mucoid) and thin (serous) pools. Both effusion types contained similar amounts of non-dialysable solids. However, the thick effusions contained more mucus glycoprotein than the thin effusions, 25% and 8.2% respectively. Amino acid and carbohydrate analysis of the CsCl purified mucus glycoproteins demonstrated that the glycoprotein from the thick and thin effusions differed in their protein core, those from the thick effusions possessing a higher percentage of serine and threonine, the amino acids to which the sugar side-chains attach. They are also more glycosylated. N-acetyl cysteine and mercaptoethanol caused a fall in the viscosity of solutions of purified middle ear glycoprotein and effusion homogenate. However, longer term incubation caused a rise above the starting viscosity. This effect was concentration-dependent, and was mediated by low molecular weight components in the effusion and not the mucus glycoprotein. S-carboxymethyl cysteine had no effect on the viscosity of either the purified mucus glycoprotein or the effusion homogenate. Therefore, to produce a decrease in effusion viscosity in vivo, the concentration of mucolytic reaching the middle ear and the time it remains there are critical factors.

Amino Acids↗
PubMed1987

Experimental studies on reproduction with the lipid-regulating agent gemfibrozil.

Gemfibrozil, a new lipid-regulating agent, was evaluated in rats and rabbits for effects on various phases of the reproduction process. In teratology studies groups of pregnant rats and rabbits received gemfibrozil at doses up to 200 mg/kg during organogenesis (rat, Days 6-15; rabbit, days 6-18). For peri- and postnatal studies, groups of pregnant rats were given 92 or 331 mg/kg from Day 15 of gestation through weaning. In fertility studies groups of sexually mature male rats were given 93 or 326 mg/kg of gemfibrozil for 61 days and females were given 94 or 318 mg/kg for 15 days prior to mating within treatment groups. Drug administration continued in females through gestation and weaning of the F1 offspring. In subsequent fertility experiments, treated male rats were mated with untreated females and treated females were cohabitated with untreated males. Gemfibrozil did not elicit a teratogenic response in either rats or rabbits up to doses that resulted in maternal toxicity. Reduced pup weights during the neonatal and weaning periods in the female fertility study as well as in the perinatal-postnatal study were the only apparent drug effect. Treatment of female rats prior to mating had no significant effects on general reproductive parameters. Male rats given doses of about 300 mg/kg/day showed inconsistent and equivocal lower rates of fertility relative to the concurrent controls. No adverse effects were seen in the reproductive performance of offspring of gemfibrozil-treated male rats.

Animals↗
PubMed1986

Preclinical toxicity of the new antineoplastic agent, ametantrone acetate, in mice and dogs.

Ametantrone acetate (anthracenedione diacetate, NSC 287513) is an experimental antineoplastic agent with activity against a comprehensive panel of solid transplantable tumors in mice and dogs were carried out to establish tolerable levels. In mice, LD10, LD50 and LD90 values were respectively, 26, 35 and 47 mg kg-1 28 days following single intravenous injection and 22, 67 and 206 mg kg-1 14 days after single intraperitoneal injection. Hemorrhage and necrosis of the small intestine occurred in intercurrent deaths. A 5-day, consecutive intraperitoneal dosing study yielded 28 day, LD10, LD50 and LD90 values of 18, 21 and 26 mg kg-1, respectively, in mice. Bone marrow hypoplasia, lymphoid depletion and focal cardiac changes were observed in animals which died during the 28-day postdose observation period. In dogs, single intravenous injections repeated twice at intervals of 3-8 weeks resulted in leukopenia and thrombocytopenia at a dose of 2.71 mg kg-1 and decreased myeloid: erythroid ratios at a dose of 0.68 mg kg-1. Five consecutive daily intravenous injections in dogs of 0.7 mg kg-1 induced significant clinical and laboratory signs of toxicity but 0.35 mg kg-1 day-1 was tolerated. In dogs, bone marrow, lymphoid tissue and gastro-intestinal tract in both sexes and gonads in the males were target organs for toxicity. Clinical signs and clinical laboratory abnormalities abated in surviving mice and dogs. The spectrum of tissue changes induced by ametantrone was qualitatively similar to that elicited with other intercalating agents.

Animals↗
PubMed1986

Teratogenesis of calcium valproate in rabbits.

The calcium salt of valproic acid (Valontin) has been proposed for use in the treatment of absence, myoclonic, and tonic clonic seizures of the primarily generalized type. The present study was conducted to determine the teratogenic potential of calcium valproate in rabbits. Groups of 20 Dutch-belted rabbits were given oral doses of 50, 150, or 350 mg/kg on days 6-18 of gestation. A reference group was given 350 mg/kg sodium valproate and control groups were untreated or given vehicle alone. Animals were observed daily and body weights were recorded on gestation days 0, 6, 13, 18, and 30. Litter and fetal parameters were evaluated following uterotomies on day 30. No drug-related clinical signs or deaths occurred. Postimplantation loss and the incidence of malformed vertebrae and ribs, rudimentary or absent pollices, and extra vertebrae and ribs were increased at 350 mg/kg with both calcium and sodium salts of valproic acid. At the 150-mg/kg dose level, calcium valproate markedly increased the incidence of supernumerary ribs. No teratogenic or embryotoxic effects were seen with calcium valproate at 50 mg/kg. These data indicate that the sodium and calcium salts of valproic acid exhibit teratogenic potential in rabbits.

Abnormalities, Drug-Induced↗