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Biomedical subjects

J Clancy

Publications and source records attributed to J Clancy.

At least 19 recordsLinked to original sources
PubMed1996

Subchronic and chronic exposure to d-fenfluramine dose-dependently enhances splenic immune functions in young and old male Fischer-344 rats.

Serotonin (5-HT) has been shown to modulate various arms of the rodent immune system in an age- and sex-dependent fashion. Thus, only young (5-6 months) male and old (21-23 months) female Fischer-344 (F344) rats demonstrated an elevation in ex vivo assessed basal and IL-2 stimulated splenic NK activity as well as CON-A induced T cell proliferation after subchronic (30-44 days) administration of low doses (0.6-1.8 mg/kg per day, p.o.) of the 5-HT releaser and reuptake inhibitor, d-fenfluramine (d-FEN). In the present study when young male F344 rats were administered higher doses of d-FEN (3-9 mg/kg per day, p.o.) for 30-39 days, there was a dose-dependent decrease in basal NK activity which returned to control levels after overnight incubation with IL-2. Further, only the rats receiving 6 mg/kg per day of d-FEN exhibited an elevation (40%) in CON-A mitogenesis compared to controls. When 15-month-old male rats were treated with d-FEN (0.6 mg/kg per day, p.o.) for 8 months, their NK and T cell activities at 23 months were not statistically different from young (7 months old) control animals. Importantly, neither the old rats treated with d-FEN nor the young control animals evidenced splenic or hepatic hypertrophy and lesions. In contrast, the old control animals showed increased NK activity (250%) and decreased T cell mitogenesis (300%) which correlated with a high incidence of splenic pathology. Thus, long-term exposure to d-FEN appears to maintain the NK and T cell arms of the immune system at youthful levels and prophylactically reduce the splenic pathology associated with advancing age. These results suggest that long-term exposure to increased levels of 5-HT may be beneficial to the immune system of the aging male F344 rat.

Aging↗
PubMed1996

Effect of d-fenfluramine on the local immune response to the opportunistic microbial pathogen Candida albicans.

In this study the effects of systemic administration of d-fenfluramine on the local lymphocyte response to Candida albicans was evaluated. Experimental animals were challenged intradermally with Candida albicans and then administered d-fenfluramine (d-FEN 1 mg/kg per day, i.p.) or a balanced salts solution. At successive time intervals, lymphocytes were derived from the draining lymph nodes and from the dermal sites of active microbial challenge. A CD8+ lymphocytosis was observed in all animals challenged with Candida albicans. The CD8+ lymphocytosis was augmented in animals that received d-FEN. Phenotypically, lymph nodes from d-FEN treated animals showed a marked increase in CD3+ and CD8+ lymphocytes, a modest increase in the numbers of NK1.1+ cells and a decrease in Ig+ lymphocytes. Functionally, lymphocytes from the site of active microbial challenge were capable of direct growth inhibition of Candida albicans. The anti-fungal activity was augmented in the animals that received d-FEN. These results suggest that d-FEN augments the local T lymphocyte response to an important microbial pathogen by increasing the number of T lymphocytes draining the site of microbial infection and by increasing the biological activity of the lymphocytes at the site of the infection.

Animals↗
PubMed1996

MgSO4 relaxes porcine airway smooth muscle by reducing Ca2+ entry.

Magnesium sulfate (MgSO4) is used clinically, but its mechanism of action is unknown. To determine whether MgSO4 relaxes airway smooth muscle and to investigate the pathways involved, we compared effects of MgSO4 in porcine tracheal and bronchial muscles contracted with either carbachol or KCl and measured the effects of MgSO4 on the concentration of intracellular free calcium ([Ca2+]i). Lungs were dissected after anesthesia and exsanguination. Tracheal strips and bronchial rings were suspended in tissue baths for measurement of isometric tension in the presence of different concentrations of MgSO4. In separate experiments, tracheal smooth muscle tension and [Ca2+]i were measured simultaneously, using the fluorescent dye fura 2. MgSO4 (1.2, 2.2, 9.2 mM) produced a concentration dependent rightward shift of contraction dose-response curves to KCl but not to carbachol. MgSO4 relaxed trachealis muscles precontracted with KCl or carbachol and simultaneously decreased [Ca2+]i. These findings indicate that MgSO4 directly relaxes airway smooth muscle and that the mechanism involves a decrease in [Ca2+]i. Because initiation and maintenance of contraction during KCl stimulation and maintenance of contraction during carbachol stimulation require Ca2+ entry through voltage-dependent calcium channels, MgSO4-induced relaxation may involve a decrease in Ca2+ entry via these channels.

Animals↗
PubMed1995

Antibodies specific for the 70-kDa heat-shock protein parallel the development of acute graft-versus-host disease in (DA x LEW)F1 rats.

Acute GVHD was induced in unirradiated (DA x LEW)F1 rats by the injection of parental DA lymphoid cells. Serum sequentially derived from such animals was found to contain increased levels of antibodies reactive with 70-kDa heat-shock protein (hsp70). Elevated levels of antibody to hsp70 were detected as early as 7 days and were maximal 14 days after the induction of GVHD. These increased levels of antibodies reactive with hsp70 paralleled the onset of the signs and symptoms associated with the development of GVHD. Increased anti-hsp70 reactivity in GVHD sera was associated statistically with increased levels of hsp70-reactive IgM, IgG2a, and IgG2b. In addition, GVHD sera reacted with a 70-kDa protein found within (DA x LEW)F1 lymphoid tissue. These results demonstrate that increased levels of antibodies to hsp70 parallel the onset and development of GVHD in an acute model and are the first to show that antibodies reactive with hsp70 are associated with an ongoing disease process.

Animals↗
PubMed1995

Assays to detect and characterize synthetic agents that inhibit the ErmC methyltransferase.

High throughput chemical file screening with an enzymatic assay to detect inhibitors of the ErmC methyltransferase enzyme from macrolide-lincosamide-streptogramin B (MLSB) resistant pathogenic bacteria identified low molecular weight compounds that had IC50S (50% inhibitory concentration) in the nMolar to microMolar range. These same inhibitors were assessed in vitro for their capacity to inhibit the liver enzyme, cathechol-O-methyltransferase and the prokaryotic enzyme, EcoRI methylase. Selective inhibitors of the ErmC methyltransferase were tested in tertiary assays to determine their minimal inhibitory concentrations (MICs), as single agents and in combination with the macrolide, azithromycin, against strains of pathogenic bacteria expressing MLSB-resistance. Compounds that were active in vitro, alone or in combination with azithromycin, against strains of macrolide-resistant pathogens were tested in a mouse model of infection using an MLSB-resistant strain of Staphylococcus aureus or a macrolide-susceptible strain of Streptococcus pyogenes.

Animals↗
PubMed1995

Phenotypic analysis of pulmonary perivascular mononuclear infiltrates that occur as a direct result of acute lethal graft-versus-host disease describes the onset of interstitial pneumonitis.

We recently determined that the sequential development of interstitial pneumonitis and lymphocytic bronchiolitis/bronchitis occurs as a direct result of acute lethal graft-versus-host disease. Interstitial pneumonitis develops before lymphocytic bronchiolitis/bronchitis primarily from the dissemination of perivascular mononuclear infiltrates. We have used the adult, nonirradiated (DA x LEW) F1 hybrid rat in the absence of chemotherapy, immunosuppression, or overt infection to determine the phenotype of infiltrating perivascular mononuclear cells throughout acute lethal graft-versus-host disease. F1 animals were intravenously injected with 1 x 10(6) DA parental lymphoid cells/g body weight, which produced 100% morbidity and mortality by day 21. Graft-versus-host disease animals were killed on days 3, 7, 10, 14, and 15 to 21 after injection. Whole left lung lobes were frozen, serially sectioned (4 microns), and incubated with a panel of mouse anti-rat monoclonal antibodies. Labeled antibody density was determined by computerized image analysis. Perivascular infiltration was observed first for ED1+, OX8+, and W3/25+ cells, and then OX41+, W3/13+ and OX19/25+ populations. OX6 was expressed in control tissues and at all time points tested. OX12+, OX39+ and MOM/3F12/F2+ cells were not quantifiable. The present study has determined that the process of perivascular infiltration was produced through a biphasic influx of OX6+, T-cell, and macrophage populations.

Acute Disease↗
PubMed1994

Interstitial pneumonitis and lymphocytic bronchiolitis/bronchitis as a direct result of acute lethal graft-versus-host disease duplicate the histopathology of lung allograft rejection.

Pulmonary complications are often lethal components of acute graft-vs.-host disease (GVHD). Although interstitial pneumonitis and lymphocytic bronchitis have been implicated as elements of acute GVHD, previous studies have not determined a correlation between the onset of these histopathologies or their contribution to a pulmonary syndrome that may occur as a direct result of acute GVHD. The present study used the adult, nonirradiated (DA x LEW) F1 hybrid rat in the absence of chemotherapy, immunosuppressive drugs, or overt infection to study these aspects of pulmonary pathology during acute GVHD. F1 animals were intravenously injected with 1 x 10(6) DA parental lymphoid cells/g body weight, which produced 100% morbidity and mortality by day 21. Neither syngeneically injected nor noninjected F1 control animals contained any observable or measurable histopathology. In addition, GVHD and control tissues did not contain bacterial, fungal, or CMV contamination as determined by specific tissue and immunohistochemical staining. GVHD animals were killed on days 3, 7, 10, 14, and 15-21 following injection. Whole-lobe tissue sections (4 mu) were stained with H&E, and histologic alterations within predetermined tissue sites were quantified using light-microscopic image analysis. Alveolar septal widths and perivascular infiltrate volume densities were increased significantly above controls by day 7, and reached 2.4- and 2.6-fold increases, respectively, by day 21. These data corroborated the development of an interstitial pneumonitis and lymphocytic bronchiolitis/bronchitis that duplicated the histopathology of lung allograft rejection. The discovery of pulmonary pathology corresponding to lung allograft rejection during acute GVHD in the adult F1 rat implicates the lung as a potential target organ.

Acute Disease↗
PubMed1994

Diminished cytotoxic gene expression in rat cardiac transplants with low-dose cyclosporine/methotrexate combination therapy.

We have previously shown that administration of a combination low-dose cyclosporine (CsA) (1.0 mg/kg/day)/methotrexate (MTX) (450 micrograms/kg/wk) treatment significantly increases the survival of rat cardiac allografts, and may therefore potentially serve as an alternative immunosuppressive therapy designed to promote transplant survival while minimizing high-dose CsA side effects. In contrast to high-dose CsA, low-dose CsA/MTX treatment does not appear to alter IL-2 gene expression, since similar patterns of IL-2 gene transcripts were found in both low-dose CsA/MTX-treated and untreated control allografts on days 1 through 8 posttransplantation (post-tx). The mechanism(s) by which low dose CsA/MTX therapy increases the time of allograft survival remains to be elucidated. The aim of the present study was to determine the effects of low-dose CsA/MTX on the expression of the cytotoxic cytokines, TNF alpha, TNF beta, or lymphotoxin (LT), and the serine proteases HF and C11 (granzymes A and B, respectively) in rat cardiac allografts during rejection. RNA blot analysis showed significant suppression of TNF alpha, LT, HF, and C11 gene expression on days 1 through 8 post-tx in cardiac allografts from low-dose CsA/MTX-treated recipients compared with untreated allograft controls. TNF protein levels in cardiac allografts from low-dose CsA/MTX-treated recipients were also found to be significantly reduced on days 1 through 8 post-tx when compared with time-matched untreated allograft controls (P < or = 0.001). We conclude that low-dose CsA/MTX treatment, while effective in prolonging cardiac transplant survival, appears to act at the mRNA level to downregulate cytotoxic cytokine gene expression. Such trials aimed at evaluating low-dose combination therapy may afford new insight into mechanisms underlying improvement in immunosuppressive treatment.

Animals↗
PubMed1994

Alcohol content of proprietary mouthwashes.

The use of mouthwashes with high ethanol content has been linked to excess risks of mouth cancer, as have prolonged and frequent use of mouthwashes with lower ethanol contents. Twenty two proprietary mouthwashes available without prescription in Ireland were analysed by gas chromatography and their ethanol contents (w/v) at manufacturers' recommended dilutions for use were calculated. The ethanol contents of diluted mouthwashes ranged from < 0.01-23.40% w/v. 27% had ethanol contents > 10% w/v; 9% had ethanol contents > 20% w/v. As the use of the higher ethanol content mouthwashes may be a possible risk factor for oral cancer in frequent or constant users, we believe that the attention of the statutory regulatory authorities should be drawn to this situation.

Ethanol↗
PubMed1994

Assays to detect and characterize human immunodeficiency virus type 1 (HIV-1) receptor antagonists, compounds that inhibit binding of the HIV-1 surface glycoprotein, gp120, to the CD4 receptor on human T lymphocytes.

Human immunodeficiency virus type 1 infects human helper T lymphocytes by an interaction between gp120, the viral coat protein, and the T-cell receptor CD4. Two microtiter-based immunoassays, an enzyme-linked immunosorbent assay (ELISA) and a particle concentration fluorescence assay, were developed to measure gp120-CD4 binding and were then used to screen a variety of compounds for the inhibition of this interaction. Additional protocols, called "consumption assays," were defined to distinguish inhibitors which functioned by sequestering either gp120 or CD4 to prevent the final effective bimolecular interaction. Monoclonal antibodies of defined specificity and compounds known from other published studies to inhibit gp120-CD4 binding were tested in an attempt to validate the assays used in the study. Once the capacity of these assays to detect known gp120-CD4 inhibitors was confirmed, they were used to screen synthetic agents and fermentation broths for novel compounds that might be used as human immunodeficiency virus receptor antagonists. A 2,4-diaminoquinazoline, CP-101,816-1, was found to inhibit this interaction (50% inhibitory concentration in ELISA, 32.5 micrograms/ml) and to interact more strongly with CD4 than with gp120 in the consumption assays. The identification of a novel inhibitor, a 2,4-diaminoquinazoline, confirmed that such assays are useful for the detection of human immunodeficiency virus type 1 receptor antagonists.

Antibodies, Monoclonal↗
PubMed1994

Immunological and molecular characterization of Helicobacter felis urease.

Urease activity has recently been shown to be an important virulence determinant for Helicobacter pylori, allowing it to survive the low pH of the stomach during colonization. Experimental murine infection with Helicobacter felis is now being used as a model for H. pylori infection to study the effects of vaccines, antibiotics, and urease inhibitors on colonization. However, little information comparing the ureases of H. felis and H. pylori is available. Urease was partially purified from the cell surface of H. felis ATCC 49179 by A-5M agarose chromatography, resulting in an eightfold increase in specific activity over that of crude urease. The apparent Km for urea for the partially purified urease was 0.4 mM, and the enzyme was inhibited in a competitive manner by flurofamide (50% inhibitory concentration = 0.12 microM). Antiserum to whole cells of H. pylori recognized both H. pylori and H. felis urease B subunits. Antiserum raised against H. felis whole cells recognized the large and small autologous urease subunits and the cpn60 heat shock molecule in both H. felis and H. pylori. However, this antiserum showed only a weak reaction with the B subunit of H. pylori urease. Two oligomeric DNA sequences were used as probes to evaluate the relatedness of H. felis and H. pylori urease gene sequences. One 30-mer from the ureA sequence, which had been shown previously to be specific for H. pylori, failed to hybridize to H. felis genomic DNA. A probe to the putative coding sequence for the active site of the H. pylori ureB subunit hybridized at low intensity to a 2.8-kb fragment of BamHI-HindIII-digested H. felis DNA, suggesting that the sequences were homologous but not identical, a result confirmed from the recently published sequences of ureA and ureB from H. felis.

Base Sequence↗
PubMed1993

Use of low-dose cyclosporine A/methotrexate to prolong rat cardiac allograft survival.

Cyclosporine A (CSA) is the standard immunosuppressive agent used in human cardiac transplantation to prevent rejection; however, adverse side effects have been reported at therapeutic doses. Therefore, a need remains for the implementation of specific therapies designed to achieve transplant success with a minimum of undesirable side effects. The aims of the present study were: (1) to evaluate the efficacy of a low-dose CSA (1.0 mg/kg/day) / methotrexate (MTX) (450 micrograms/kg/week) combination therapy in prolonging rat cardiac allograft survival, and (2) to determine the effects of low-dose CSA/MTX on interleukin-2 (IL-2) gene expression in rat cardiac allografts. The average time to rejection of newborn donor Brown Norway (BN) rat hearts transplanted into the ear pinnae of CSA/MTX-treated adult Lewis recipients, measured by the absence of electrocardiographic (ECG) activity, more than doubled from day 8 post-transplantation (post-tx) to day 18 post-tx when compared to allografts in untreated control recipients (p < or = 0.01). Northern blot analysis demonstrated that IL-2 mRNA transcripts in cardiac allografts treated with low-dose CSA/MTX were detected as early as day 1 post-tx, and at increasing levels as rejection progressed post-tx. When IL-2 gene expression in allografts from CSA/MTX-treated recipients was compared to levels in allografts from untreated recipients, no significant difference in the pattern of IL-2 induction was observed. In contrast, IL-2 mRNA transcripts were not detected post-tx in allografts from recipients treated with high-dose (15 mg/kg/day) CSA or in cardiac isografts. The presence of IL-2 gene transcripts, therefore, appears to be allograft-specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Environmental factors related to the outcome of panic disorder. A seven-year follow-up study.

The purpose of this study was to examine factors related to the outcome of naturalistically treated panic disorder. In order to achieve this we followed up 69 patients 7 years after they had presented at a psychiatric clinic. At follow-up, the patients were generally doing well despite persisting symptoms. Patients who were more severely ill at the time of initial assessment had a worse outcome. These patients had more severe panic and agoraphobic symptoms, had illnesses of longer duration, and more often had histories of major depression. Among the developmental variables examined, separation from a parent by death or divorce was strongly related to poor outcome. Other factors associated with poor outcome included high interpersonal sensitivity, low social class, and unmarried marital status. The findings show that, for this chronic illness, measures of severity and chronicity predict more severe and persisting symptoms. They also indicate that outcome is importantly related to the social environment in which the illness develops and with which it interacts.

Adult↗
PubMed1993

Induction of TNF alpha and TNF beta gene expression in rat cardiac transplants during allograft rejection.

The expression of the cytotoxic cytokines tumor necrosis factor alpha and TNF beta or lymphotoxin (LT) was assessed in rat cardiac transplants during rejection. Newborn rat cardiac grafts placed in adult rat ear pinnae were retrieved on days 1 through 10 posttransplantation; the average time to rejection, assessed by the absence of detectable electrocardiographic activity, was determined to be 7 days. Total cellular RNA and tissue homogenates were prepared from cardiac transplants in order that relative levels of TNF alpha and LT mRNA and TNF protein could be determined. A biphasic pattern of TNF alpha gene expression was consistently seen in cardiac allografts. TNF alpha mRNA transcripts were detected as early as day 2 post-tx, with peak levels appearing on day 3 post-tx. Although transcript levels decreased by day 4, a significant increase appeared again on day 6 post-tx, coincident with the onset of rejection. Similar to TNF alpha gene expression, LT transcripts demonstrated a biphasic pattern of induction. LT mRNA transcripts also reached peak levels on day 3 post-tx, with a second increase in transcript levels coincident with rejection. TNF protein levels in allografts displayed a biphasic pattern, similar to that shown by the cytokine mRNAs. Peak levels of TNF protein were detected on day 3 post-tx, with a second increase again coinciding with rejection. In contrast to TNF expression found in allografts, TNF alpha and LT mRNA transcripts were not detected in isografts on days 1 through 10 post-tx. TNF protein levels in cardiac isografts were consistently at or below the standard limits of detection, and on days 3 through 7 post-tx were significantly reduced (P < or = 0.001) when compared with time-matched allografts. Increased expression of the cytotoxic cytokines TNF alpha and LT, therefore, appears to be allograft-specific and is an early event during rat cardiac allograft rejection. In conclusion, induction of TNF gene expression may be an important early indicator of transplant rejection.

Animals↗
PubMed1992

Generalized anxiety disorder vs. panic disorder. Distinguishing characteristics and patterns of comorbidity.

In order to examine the validity of the distinction between generalized anxiety disorder (GAD) and panic disorder (PD) we compared 41 subjects with GAD and 71 subjects with PD. The GAD subjects had never had panic attacks. In contrast to the symptom profile in PD subjects suggestive of autonomic hyperactivity, GAD subjects had a symptom pattern indicative of central nervous system hyperarousal. Also, subjects with GAD had an earlier, more gradual onset of illness. In terms of coexisting syndromes, GAD subjects more often had simple phobias, whereas PD subjects more commonly reported depersonalization and agoraphobia. GAD subjects more frequently had first-degree relatives with GAD, whereas PD subjects more frequently had relatives with PD. A variety of measures indicated that our GAD subjects had a milder illness than those with PD. Also, fewer GAD subjects gave histories of major depression than did PD subjects. Among GAD subjects, coexisting major depression was associated with simple phobia and thyroid disorders and among PD subjects, comorbid depression was associated with social phobia and hypertension. Our findings indicate that the separation of GAD from PD is a valid one. They also indicate that, within disorders, unique patterns of comorbidity may exist that are important both clinically and theoretically.

Adult↗
PubMed1992

Which infusate do I need? Physiological basis of fluid therapy.

A variety of infusates are used, and it is important that the consequences of overinfusion are understood. Infusates are used to expand the intravascular volume or to influence solute composition of body fluids. Choice of infusate depends upon the underlying physiological disturbances. The basis of infusate choice, the actions of frequently-used infusates and the consequences are outlined.

Body Fluid Compartments↗
PubMed1991

Effects of subchronic d-fenfluramine on splenic immune functions in young and old male and female Fischer 344 rats.

The present study was designed to demonstrate age- and sex-related differences in immune functions, and to determine whether subchronic elevations in serotonin (5-HT) availability in vivo would alter immune functions assessed subsequently in vitro. Male and female F344 rats (5 and 21 months of age) were administered the 5-HT releaser and reuptake inhibitor, d-fenfluramine (d-Fen), in their drinking water for 30-38 days then killed. The young animals received a higher dose (1.8 mg/kg/day) of d-Fen than the old rats (0.6 mg/kg/day) in order to compensate for age-related decreases in drug biotransformation and clearance. Brain and spleen d-Fen and metabolite concentrations, however, were considerably higher in the young than in the old rats. d-Fen treatment did not affect body weight or fluid intake. Although substantial sex differences in immune function were not discerned, age-related decreases were observed in absolute splenic cellularity, recombinant interleukin-2 (rIL-2) stimulated natural killer (NK) cytotoxicity, LPS stimulated B-cell mitogenesis, and in the level of Ox19 (CD5) positive cells. d-Fen caused an increase in absolute spleen weight and a decrease in absolute splenic cellularity only in the old rats of both sexes. Spleen cells from young male and old female rats receiving d-Fen had relatively more large granular lymphocytes and enhanced baseline and rIL-2 activated killing of YAC-1 cells than their vehicle matched or opposite sex counterparts. The drug also increased Con A-induced T-cell proliferation in young males and LPS induced B-cell proliferation in old females. d-Fen decreased Ox39 (CD25) levels by 19%, but did not affect any of the other phenotypes examined. The results suggest that 5-HT has a selective stimulatory effect on young male and old female NK activity, and that old female rats are more sensitive to the immunological effects of d-Fen than old male rats.

Adjuvants, Immunologic↗