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Biomedical subjects

J Clancy

Publications and source records attributed to J Clancy.

At least 19 recordsLinked to original sources
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

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

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↗
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↗
PubMed1985

Abnormal escape from dexamethasone suppression in agoraphobia with panic attacks.

Patients who met DSM-III criteria for agoraphobia with panic attacks underwent dexamethasone suppression tests (DSTs) before, during, and after treatment with alprazolam or placebo. Similarly, outpatients with major depression were given multiple DSTs as they participated in a study of desmethylimipramine efficacy. The likelihood of an abnormal escape from dexamethasone was similar in the two diagnostic groups; nonsuppression was somewhat more likely among patients with primary depression, but comparisons with agoraphobic groups remained statistically insignificant. These results apparently did not reflect misclassification of primary depression patients as agoraphobics since a history of major depression was not related to the likelihood of nonsuppression within that group. Moreover, change in DST results during treatment reflected clinical change among agoraphobics. After a review of relevant followup and family studies, we conclude that panic disorder and primary depression are separate illnesses and that hypothalamic-pituitary-adrenal axis hyperactivity is an epiphenomenon of both.

Adult↗
PubMed1985

Sublethal fractionated total-body irradiation and donor bone marrow infusion for induction of allograft tolerance.

Tolerance to skin allografts across the strong histocompatibility barrier H-2b to H-2d was achieved with sublethal fractionated total-body irradiation, FTBI, delivered to H-2d mice in 3 doses of 250 rads within 24 hr, followed by transfusion of 3 X 10(7) H-2b donor bone marrow (BM) cells. H-2b skin allografts were applied within 48 hr after the initial radiation. 70% of the mice became long-term (greater than 180-day) survivors with fur-bearing grafts. Marked interexperiment variability in survival rates suggested that infection was the major cause of death in this model and lower weight gain and survival rates for allogenic BM vs. media-treated controls suggested that graft-versus-host disease (GVHD) was also a factor. The observation, however, that long-term survivors (70% of all mice) gained weight and appeared healthy suggested that the GVHD might be self-limiting. Chimeric analysis revealed that approximately 25% of spleen cells were of donor origin, both at short-term (6 weeks) and long-term (greater than 1 year) intervals after tolerance induction. In spite of hematopoietic chimerism, a low incidence of spontaneous tumors, less than 1%, occurred in the long-term survivors.

Actuarial Analysis↗