Biomedical subjects
Publications and source records attributed to T L Walter.
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Intraperitoneal injection of lipopolysaccharide (LPS) was used to elicit a sublethal, shock-like condition in mice. LPS, 2.5 mg/kg i.p., induced hypothermia, elevated serum TNF-alpha levels and lethality over a 48 h period in male CD-1 mice. The 5-lipoxygenase (LO) inhibitors, WY-50,295 tromethamine and zileuton (100 mg/kg p.o), significantly inhibited hypothermia at 4, 24 and 48 h after LPS. Interestingly, whereas cyclooxygenase (CO) inhibitors (ibuprofen, etodolac, naproxen and tenidap) at 40-80 mg/kg p.o. stimulated hypothermia at 4 h, they significantly reduced the later stages of hypothermia at 24-48 h. Rolipram (PDE-IV inhibitor) and dexamethasone significantly reduced hypothermia at 4-24 h and 1-24 h, respectively. All the anti-inflammatory agents significantly reduced elevated TNF-alpha levels at approximately 70 min post-LPS, except for ibuprofen. In conclusion, these anti-inflammatory standards indicate that LPS-induced shock involves multiple lipid mediators (PG's, LT's and possibly PAF) and secondary cytokine generation. This sublethal model of LPS-induced shock represents a sensitive model for estimating the efficacy of potential drug candidates for the treatment of endotoxic shock.
Kidney function and histopathology were investigated in the adjuvant-induced arthritic rat. Rats injected with Mycobacterium butyricum exhibited symptoms of arthritis (i.e. paw edema and loss of body weight) by day 9 which worsened and included systemic manifestations of the disease on days 16 and 30. Definite signs of kidney dysfunction were observed by day 16 which included elevated urine output and plasma creatinine values and decreased creatinine clearance. By day 30, these parameters were similar to the values obtained from normal rats; however, kidney weights from arthritic rats than those from normal rats. Histopathologic abnormalities observed in the kidneys of arthritic rats on day 30 included tubular lesions consisting of focal basophilia, edema, granular deposits and basement membrane thickening. Changes in the glomerulus included granular deposits with focal glomerulopathy. These findings are the first to clearly demonstrate kidney dysfunction and histopathologic alterations associated with the early expression of the adjuvant-induced disease process in the rat. Our observations in the rat suggest that renal dysfunction in man can be mediated by the inflammatory disease process and is not solely a drug treatment-induced side effect.
Rapamycin (RAPA), a potent immunosuppressive agent that prevents organ graft rejection in animal models of transplantation, possesses a mechanism of action different than that of cyclosporin A and FK-506. In this study, the pharmacological activity of RAPA in a variety of immune and inflammatory models was assessed in order to define better its potential utility as an antiarthritic agent. RAPA inhibited T cell-mediated inflammation in mouse methylated bovine serum albumin-induced delayed-type hypersensitivity (ED40 = 4.7 mg/kg p.o.) and produced oral ED50 of 2.0 mg/kg against developing adjuvant arthritis in rats (3-day dosing schedule) and 9.5 mg/kg in established adjuvant arthritis in rats (daily dosing schedule). In both models of adjuvant arthritis, effects of RAPA were maintained even after cessation of drug dosing. In contrast, after discontinuation of cyclosporin A (5- and 10-mg/kg doses), disease activity returned. RAPA was also effective in another T cell-mediated model, experimental allergic encephalomyelitis (ED50 approximately 5 mg/kg p.o.). At higher doses, RAPA significantly inhibited carrageenan paw edema in rats, a model of acute inflammation (ED40, 56 mg/kg p.o.), without increasing serum corticosterone levels. In this model, doses approximately 10 to 20 times greater than active doses in T cell-mediated models were required. RAPA at 1 to 50 microM did not inhibit in vitro human synovial phospholipase A2 or 5-lipoxygenase and cyclo-oxygenase activity in the human blood leukocyte assay. The total profile of RAPA suggests that it may be effective in the treatment of rheumatoid arthritis, multiple sclerosis and other autoimmune diseases.
Pretreatment with captopril, a kininase II inhibitor, at 10 mg/kg i.p. or s.c., significantly increased the writhing response induced by a minimum effective dose (0.75 mg/kg i.p.) of phenylbenzoquinone (PBQ), by 91-148%. 1,10-Phenanthroline, a carboxypeptidase B inhibitor (2 mg/kg i.p.), in combination with captopril enhanced the algesic effect of PBQ by 309-360%. Captopril also doubled the number of writhes induced by a minimum effective dose of BK (5 micrograms/kg i.p.) in PGE2-pretreated mice. The writhing responses induced by higher doses of PBQ or BK were not affected by these inhibitors. The hyperalgesic effect of BK (1 micrograms) injected into the hindpaw of rats was significantly increased and prolonged by coinjection of captopril (30 micrograms) and 1,10-phenanthroline (30 micrograms) and was prevented by carboxypeptidase B (1 mg). These data indicate that BK plays a role in pain in these models, a role which appears of greatest relevance at threshold algesic stimulation.
Katz (1978) has suggested that mild, fluctuating conductive hearing loss due to middle-ear anomalies may account for the language and attention problems of learning-disabled children. His position was extended here to include autism. Normal, learning-disabled, and autistic children received repeated impedance measures over 5 weeks. A repeated-measures ANOVA of central tendency and variability values led to the conclusions that (1) fluctuating, negative middle-ear pressure greater than normal characterizes both autistic and learning-disabled children, (2) the negative pressure is greater in autistic than in learning-disabled children, and (3) the condition is typically bilateral for autistic children.
Two groups of seven autistic children wore an auditory trainer for an average of 24 minutes per day over two 5-week periods interspersed with 5-week control periods in a time series design. Videotapes were coded for three attentional states (normal, withdrawn, attacking), for verbalization and signing, and for appropriate and acceptable behaviors. Results demonstrated a decrease in time spent withdrawn and increases in signing and in school-appropriate behavior. Results are interpreted as congruent with Katz's theory of reduced attention due to deficits in auditory conductance.