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Biomedical subjects

J Clancy

Publications and source records attributed to J Clancy.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1987

Effect of the mi allele on mast cells, basophils, natural killer cells, and osteoclasts in C57Bl/6J mice.

The osteopetrotic, microphthalmic (mi/mi) mouse lacks functional osteoclasts and has also been reported to be deficient in mast cells and natural-killer (NK) cells. The later deficiencies could be secondary to the osteopetrotic marrow, or a direct result of the mi allele. Therefore, heterozygotes were examined for these cell types, since these mice do not exhibit osteopetrosis. Adult +/mi animals have approximately 50%, and mi/mi animals examined by histologic techniques or tissue histamine levels have 0-10%, of the peritoneal, dermal, and intestinal mast cells compared with that of +/+ animals. Leukocyte histamine, indicative of the number of basophils, demonstrates the same pattern. Histamine content per mast cell in +/+ and +/mi animals is identical. The number of large granular lymphocytes (LGL) in splenic leukocyte preparations from +/mi animals is 50% that of +/+ animals, and these cells are undetectable in preparations from mi/mi mice. NK activity against YAC-1 cells paralleled the number of LGL present. The resorptive response of neonatal calvaria to parathyroid hormone was delayed in the case of cultured +/mi bone compared with that of +/+ bone, but the final rate of calcium release was identical. These data indicate that 1) the presence of one mi allele can affect the development of four distinct cell types, and 2) osteopetrosis alone does not account for the lack of mast cells, basophils, and NK cells in mi/mi mice.

Alleles↗
PubMed1987

Kinetics of mast cell, fibroblast, and epidermal cell proliferation during acute graft-versus-host disease in the neonatal rat.

Acute graft-versus-host disease (GVHD) was induced in newborn Brown-Norway (BN) and DA rats by i.v. injection of 3 X 10(7) Lewis (L) lymph node cells. Control BN and DA rats received syngeneic cells. Rats were injected i.v. with [methyl-3H]thymidine for 1 h before being killed at 1, 2, 4, 5, 6, 8, 10, 11, 12, 13, and 14 days after the cellular inoculum. A piece of ventral abdominal skin was removed. Autoradiography was used to determine cell proliferative activity (labeling index, LI) in mast cells and fibroblasts of the dermis and basal cells of the epidermis. In addition, the number of mast cells per high-power field was determined for all 4 groups of rats: control DA, GVHD-DA, control BN, and GVHD-BN. Only GVHD-BN rats demonstrated extensive dermatitis. The LI of mast cells, fibroblasts, and basal cells decreased in control rats with increasing age. Although there were differences between DA and BN rats, there was a general pattern of increased proliferation of mast cells at early time points of GVHD followed by a decrease to or below control levels. The number of mast cells per high-power field also increased at early time intervals in both the DA and BN GVHD rats, but decreased significantly at later time points. These data confirm previous studies on chronic GVHD which demonstrated a decrease in the number of mast cells in the skin. Fibroblast LI was decreased at day 1 in both DA and BN GVHD rats. In GVHD-DA, fibroblast LI remained depressed while GVHD-BN demonstrated a second peak in LI at day 10 before declining below control levels. The most prominent basal cell response occurred in GVHD-BN between days 6-14 and is probably indicative of an attempted reparative response associated with GVHD dermatitis in this species. These data demonstrate that the activation of mast cells (proliferation and subsequent degranulation) correlates temporally with cell kinetic alterations occurring in the dermis and epidermis during acute GVHD.

Animals↗
PubMed1986

Seizures following the withdrawal of alprazolam.

Seizures were observed following the withdrawal of alprazolam administered in therapeutic dose for 10 weeks. A review of available case reports suggests that seizures, like other withdrawal phenomena, are more apt to occur with short-acting benzodiazepines. To prevent their occurrence these drugs should be discontinued gradually and consideration given to substituting long-acting drugs during the withdrawal period. Physicians should remain alert to the fact that seizures may occur as early as 24 hours after the abrupt withdrawal of short-acting benzodiazepines.

Adult↗
PubMed1986

Reduction in hypochondriasis with treatment of panic disorder.

Hypochondriasis was assessed in 60 patients with panic disorder and agoraphobia using the Illness Behavior Questionnaire. Before treatment, IBQ hypochondriasis scores were similar to those of a group of hypochondriacal psychiatric patients. In patients who improved with treatment, significant reductions in somatic preoccupation, disease phobia, and disease conviction occurred. Hypochondriasis appears to be a prominent feature of panic disorder and agoraphobia, and responds to treatment of the primary conditions. Our findings underscore the importance of providing adequate treatment and thereby avoiding wasteful use of medical resources and alienation of patients from doctors.

Adult↗
PubMed1985

Tritiated imipramine binding to platelets is decreased in patients with agoraphobia.

Controversy exists regarding the relationship between anxiety states and major depression. We studied the binding of tritiated imipramine to platelet membranes in order to determine if patients with agoraphobia and panic attacks differed from depressed subjects or healthy volunteers on this biological parameter. Mean (+/- SD) Bmax and Kd values were significantly lower in patients with agoraphobia and panic attacks (787 +/- 276 fmole/mg protein and 0.35 +/- 0.14 nM, respectively) than in healthy volunteers (1237 +/- 201 fmole/mg protein and 0.71 +/- 0.37 nM, respectively). In addition, patients with agoraphobia and panic attacks had binding parameters that were similar to those of patients with bipolar or familial pure depressive disorder, but significantly lower than those of patients with depressive spectrum or sporadic depressive disorder. These findings have implications for both the nosology and pathophysiology of anxiety disorders.

Adolescent↗