Biomedical subjects
Publications and source records attributed to J Clancy.
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.
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.
Explore the source record for details and available documents.
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.
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.
Explore the source record for details and available documents.
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.
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.
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.
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.
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.
A patient who received therapeutic doses of alprazolam for 8 weeks experienced a withdrawal syndrome beginning 18 hours after its abrupt discontinuation. Short-acting and minimally sedating benzodiazepines may have increased potential for withdrawal reactions.
The response to diazepam and propranolol hydrochloride was compared in 21 patients who (with one exception) met DSM-III criteria for panic disorder and agoraphobia. Each drug was administered for two weeks in double-blind fashion according to a crossover design. The response to diazepam was significantly superior on all measures. By observer rating, 18 patients showed at least moderate improvement with diazepam compared with seven receiving propranolol. Panic attacks and phobic symptoms responded to diazepam, but not to propranolol. The results suggest that benzodiazepines constitute effective short-term treatment for these newly defined disorders.
The biologic basis of Graft-Versus-Host Disease (GVHD) is presented as an extremely complex immunopathologic syndrome that involves interaction between many different donor and host cell types. A model of acute lethal GVHD was employed where adult unirradiated (DA X LEW)F1 rats were injected with LEW spleen and lymph node cells. Controls received the same dose of syngeneic cells. At intervals from 2 to 21 days after cell injection, GVHD and control animals were killed and nonadherent cell suspensions prepared from their lymph nodes, spleen and peripheral blood. Cell suspensions were treated with LEW-anti-DA-alloantiserum or normal LEW serum and then analyzed for sIgM+ (B cells), W 3/13+ (T cells), and IgG-Fc receptors (FcR). Evidence is discussed for the selective removal of host cells with the alloantiserum. In addition, the level of naturally cytolytic (NK/NC) cells was assessed by adding GVHD and control nonadherent lymphoid cells to heterologous lymphoma and sarcoma target cells. Evidence is presented that during acute GVHD, in this parental----F1 combination, there is an early increase within most compartments of donor as well as host W 3/13+ and W 3/13+FcR+ cells. NK/NC cells are increased as well at day 7. During middle stages of acute GVHD, host sIgM+ cells predominate. Late-stage acute GVHD rats contain few donor and host W 3/13+, W 3/13+FcR+, and NK/NC cells but many null cells most of which are FcR-. The importance of unraveling the nature of donor- and host-cell interactions occurring during acute GVHD, which result in rats whose lymphoid tissues are severely depleted of all nonadherent lymphoid cells but FcR- null cells, is discussed.
In this study cell proliferation in Peyer's Patches (PP) and the crypts of Lieberkuhn of the follicle-associated ileal epithelium was analyzed during the development of acute lethal graft-versus-host disease (GVHD) in adult rats. In addition, the effect of thymectomy on GVHD-induced lymphoproliferation was determined by analyzing the 3H-thymidine labeling index in neonatally thymectomized-control and thymectomized-GVHD rats. A significant increase in the 3H-thymidine-labeling index was found in interfollicular (days 2-7), dome (days 5-10), and follicular (days 5-12) regions of PP as well as in associated ileal crypts (days 5-12) of GVHD rats as compared with controls. Thymectomy altered the proliferative response in PP of GVHD rats in that incorporation of 3H-thymidine by follicular and interfollicular cells was significantly lower than in sham-thymectomized GVHD controls during the later stages of the disease. The results suggest a possible role for host thymus-dependent cells in stimulation of or participation in cell proliferation within follicular and interfollicular areas of PP.
The results of this study indicate that both cell proliferation and increased synthesis of extracellular matrix protein contribute to hypertrophy of the rat pulmonary trunk during the early development of hypoxia-induced pulmonary hypertension. As determined by autoradiography after 3H-thymidine injection, pulmonary hypertension results in increased labelling in all cell compartments of the pulmonary trunk wall, the most dramatic response occurring in the adventitia following 3 days' hypoxic exposure. Autoradiography also demonstrated differences in the degree of incorporation of 3H-proline into extracellular protein between hypoxic (3 and 21 days) and control rats. The major focus of 3H-proline incorporation shifted from the adventitia at 3 days to the tunica media at 21 days, although incorporation was significantly higher at 3 compared to 21 days in all wall compartments. The patterns of hyperplasia and matrix protein synthesis in the extrapulmonary arteries of the rat, as reported here, are distinctly different from those seen in many large elastic arteries during development of systemic hypertension. For example, the hyperplastic response of arterial vessels follows a similar temporal sequence in pulmonary and systemic hypertension. However, the adventitia is the region of the pulmonary trunk with highest cell proliferation in pulmonary hypertension while the media is most affected by systemic hypertension. The relevance of the changing patterns of cell proliferation and protein synthesis in the wall of the pulmonary trunk of chronically hypoxic rats to the structural and biochemical properties of this vessel during the early development of pulmonary hypertension is discussed.
Explore the source record for details and available documents.