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Biomedical subjects

C J Powell

Publications and source records attributed to C J Powell.

35 records · Page 2Linked to original sources
PubMed1991

Shifting necrosis: butylated hydroxytoluene (BHT) and phenobarbital move cocaine-induced hepatic necrosis across the lobule.

Cocaine (60 mg/kg i.p.) caused centrilobular necrosis in the livers of 55% of DBA/2Ha mice. Pretreatment with phenobarbital (PB, 3 x 80 mg/kg i.p.) increased the incidence of necrosis to 70% and shifted this damage to the midzonal region. Pretreatment with butylated hydroxytoluene (BHT, 0.1% in diet) increased the severity of the centrilobular damage and increased the incidence to 90%. Combined treatment with both PB and BHT shifted the site of necrosis to the periportal region of the liver, and induced necrosis in all animals. Microsomal malondialdehyde (MDA) did not reflect the extent of the damage and/or correlate with the site of damage. These results argue against a causal role for lipid peroxidation in the mechanism of cocaine hepatotoxicity, and demonstrate that prior exposure to enzyme-inducing agents can increase sensitivity and dramatically alter the site of cell damage.

Alanine Transaminase↗
PubMed1991

Small-animal model to measure efficacy and immunogenicity of Shigella vaccine strains.

The development of a small-animal model to test the protective efficacy and immunogenicity of a vaccine strain against shigellosis would greatly facilitate the evaluation of potential vaccine candidates. In guinea pigs, the ability of shigellae to invade and multiply within the corneal epithelium, causing keratoconjunctivitis, closely mimics the invasion process in the intestinal epithelium (B. Sereny, Acta Microbiol. Acad. Sci. Hung. 4:367-376, 1957). The serum response of animals recovering from a Shigella keratoconjunctival infection was determined and found to be consistent with that shown by convalescent humans and primates. This model was used to test the efficacy of two vaccine candidates, and the immune response of the guinea pigs to the vaccine strains was examined. Both vaccine strains demonstrated significant protection against challenge by homologous virulent Shigella strains, and the results were comparable with results obtained in trials with monkeys. The guinea pig model also provides a rapid and inexpensive means of evaluating different immunization regimens as well as of testing other variables such as length of protection against disease.

Animals↗
PubMed1991

Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.

The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue.

Animals↗
PubMed1990

Butylated hydroxyanisole (BHA) does not cause forestomach hyperplasia by inhibiting the release of gastric mucus.

High doses of BHA cause hyperplasia and subsequent neoplasia in the rodent forestomach and can inhibit gastric prostaglandin (PG) synthesis in vitro. This paper examines the hypothesis that BHA induced forestomach hyperplasia occurs in response to a reduction of gastric mucus, with consequent irritation of the forestomach. This could result from inhibition of the formation of the PG's which mediate the synthesis and release of protective mucus. Groups of 10 rats received 0 or 2% BHA in the diet for 1 or 3 weeks and a positive control group was fed a diet containing indomethacin (3.5 mg/kg), a potent inhibitor of PG synthesis. After 1 week BHA caused focal erosion and ulceration of the forestomach consistent with an irritant effect, but 2 weeks later the epithelium was healed, thickened and markedly hyperplastic. Histochemical staining for mucus showed that the development of forestomach hyperplasia was associated with increased amounts of gastric and duodenal mucus and increased numbers of serotonergic-cells in the gastric and duodenal epithelium. In contrast, indomethacin caused a marked reduction in both gastric and Brunner's gland mucus. Neither BHA nor indomethacin exerted an effect on one specific type of mucus (viz: neutral, acidic or mixed) in the stomach. These results do not support the hypothesis that forestomach hyperplasia arises from an inhibition of either the synthesis or release of gastric mucus. It is possible that the increased numbers of serotonergic-cells are related to the initial ulcerative, or subsequent hyperplastic response.

Administration, Oral↗
PubMed1988

Tumour formation and insulin secretion by clonal RINm5F cells following repeated subcutaneous transplantation in NEDH rats.

The effects of repeated s.c. transplantation of clonal insulin-secreting RINm5F cells in NEDH rats on tumour morphology, insulin-glucose homeostasis and the function of RINm5F cells re-established in culture were examined after maintenance in vivo for periods of up to 308 days. Transplantation of RINm5F cells for ten consecutive passages consistently produced a single encapsulated vascularized tumour associated with the development in recipient rats of hyperinsulinaemia, hypoglycaemia and eventual neuroglycopenic coma. At the tenth passage, tumour-bearing rats exhibited a markedly enhanced rate of insulin-stimulated glucose uptake by 19 days, with evidence of a large and variable insulin response to i.p. glucose. Survival was 22 +/- 2 days, and resected RINm5F cell tumours exhibited weak immunostaining for insulin in scattered cells, with strands of fibrous tissue separating clusters of tumour cells many of which had distinct polarity. There was no detectable immunostaining for glucagon, somatostatin or pancreatic polypeptide. The insulin content and insulin secretory output of RINm5F cells re-established in culture after 20, 146, 259 or 308 days propagation in vivo were generally enhanced compared with non-passaged RINm5F cells. The magnitude of the effect was not appreciably affected by the duration of maintenance in vivo, but it was critically dependent upon the subsequent period of culture in vitro. Thus, whereas 2-day cultured RINm5F cells from the eighth tumour passage exhibited a greater than 100-fold increment of insulin content and release, with enhanced secretory responsiveness to leucine, arginine, theophylline, K+ (25 mmol/l) or Ca2+ (7.6 mmol/l), RINm5F cells cultured for a further 19 days had almost completely lost the attributes resulting from 259 days of maintenance in vivo. The results indicate substantial enhancement of the functional capabilities of RINm5F cells in vivo, and suggest that the resulting tumours afford a novel model in NEDH rats of responsive trabecular-type insulinomas.

Adenoma, Islet Cell↗
PubMed1987

Defective regulation of insulin release and transmembrane Ca2+ fluxes by human islet cell tumours.

Regulation of insulin release and transmembrane Ca2+ fluxes was examined using pieces of 3 benign medullary-type insulinomas removed from the pancreas of female patients at surgery. Immunocytochemical staining confirmed the presence of insulin-containing cells with no demonstrable glucagon, somatostatin or pancreatic polypeptide. After 3 days of culture in RPMI-1640, tumour pieces released 11-158 mg insulin kg-1 dry wt during acute 60 min incubations with the concomitant uptake of 2-47 mmol 45Ca kg-1 into the intracellular lanthanum-nondisplaceable pool. At 2.56 mM Ca2+, glucose alone or in combination with glyceraldehyde, mannoheptulose or diazoxide did not modify insulin release or 45Ca uptake. Theophylline significantly increased insulin release from 2 tumours with a small stimulatory effect on the third. A depolarising concentration of K+ enhanced insulin release from one tumour but this was not associated with an increase of 45Ca uptake. Calcium antagonists, (verapamil, D-600 and trifluoroperazine) and calcium ionophores (A23187 and Br-X537A) failed to modify insulin release or 45Ca uptake by each of the two tumours tested. Evaluation of 45Ca efflux from one tumour confirmed the unresponsiveness to glucose, K+, verapamil and A23187. Prolonged culture of 2 tumours for up to 16 days was associated with the gradual decline of insulin release to a steady output of 2-15 ng 24 h-1. Addition of verapamil to the cultures inhibited insulin output from one tumour, but mannoheptulose or diazoxide were without effect. The results indicate that inappropriate insulin release from these 3 benign medullary-type insulinomas is associated with disturbances in the regulation of transmembrane Ca2+ fluxes.

Adenoma, Islet Cell↗
PubMed1986

Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas.

Twenty-one days after s.c. subscapular transplantation of a radiation-induced insulinoma, male NEDH rats exhibited hyperinsulinaemia and hypoglycaemia. These features were associated with islet atrophy, degenerative changes in pancreatic A and B cells, and decreases in the pancreatic contents of insulin, glucagon and somatostatin. The immunoreactive glucagon and somatostatin contents of extrapancreatic tissues of insulinoma-bearing rats were unchanged. Surgical resection of the tumour resulted in an immediate fall of plasma insulin, attaining concentrations similar to those of anaesthetised control rats by 10 min. The estimated half-life of insulin was 3.5 min. Hypoglycaemia persisted until 60 min after resection, followed by hyperglycaemia of 1-2 days duration. Glucose tolerance was impaired 1 day after tumour resection despite the coexistence of raised insulin concentrations. Evidence for abnormal pancreatic B cell function was gained by injection of arginine which failed to evoke a plasma insulin response in the resected rats. Two days after resection, plasma glucose and insulin concentrations were similar to those of control rats. Plasma glucose and insulin responses to glucose and arginine were suggestive of tumour recurrence by 12 days. A single large encapsulated tumour was eventually observed in each rat, with resection giving a 17-56 day prolongation of life.

Adenoma, Islet Cell↗
PubMed1986

Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets.

The effect of diet composition on plasma and intestinal concentrations of immunoreactive gastric inhibitory polypeptide (GIP) and intestinal K cell density was examined in obese hyperglycaemic (ob/ob) mice. The mice were reared from 3 to 11 weeks of age on either stock diet, a high fat (HF) cafeteria diet or a high carbohydrate (HC) cafeteria diet. The HF cafeteria diet increased the concentration of GIP in plasma (75%) and in the intestine (118%) and increased the density (54%) of GIP-secreting K cells in the upper jejunum compared with the stock diet. Plasma and intestinal GIP concentrations were not significantly altered by the HC cafeteria diet, although the density of K cells in the upper jejunum was increased (45%). The extent of hyperglycaemia and hyperinsulinaemia in ob/ob mice was not significantly altered by the HF and HC cafeteria diets. The results indicate that an increased amount of dietary fat chronically stimulates the production and secretion of GIP, and enhances intestinal K cell density in ob/ob mice.

Animals↗
PubMed1966

Virulence of Escherichia coli strains for chick embryos.

Powell, Calvin J., Jr. (Walter Reed Army Institute of Research, Washington, D.C.), and Richard A. Finkelstein. Virulence of Escherichia coli strains for chick embryos. J. Bacteriol. 91:1410-1417. 1966.-Fifty-three strains of Escherichia coli, freshly isolated from patients at Children's Hospital, Washington, D.C., were tested for virulence for 13-day chick embryos by allantoic inoculation of serial dilutions of viable cell suspensions. No clear-cut relationship could be demonstrated between inoculum size and response (death of the embryos) which would permit comparisons of virulence based on ld(50) determinations. However, the strains were classified into three groups according to the proportion of embryos which succumbed, regardless of inoculum size. There was no association between enteropathogenicity and embryo virulence, although there was high correlation between hemagglutinative activity for chicken erythrocytes and virulence of strains for embryos. Differences in virulence were not related to ability to multiply in the allantoic cavity nor did bacteremia appear to be essential for death of the embryos. Serial passage in eggs failed to alter virulence. Both the route of inoculation and the age of the embryos had a marked effect on the outcome of challenge with strains of varying virulence. The embryos were most susceptible to challenge by the intravenous route. The susceptibility of younger embryos decreased with increasing embryonic maturity, although some reversal of this trend was noted with 19-day embryos. The toxicity of culture filtrates and filtrates of allantoic fluid from infected embryos seemed to be related to strain virulence, suggesting that elaboration and availability of toxic factors may have an important bearing on the lethality of E. coli strains for chick embryos.

Animals↗
PubMedDate not supplied

Hepatic responses to the administration of high doses of BHT to the rat: their relevance to hepatocarcinogenicity.

Although butylated hydroxytoluene (BHT) is non-mutagenic, at high doses it has recently been associated with an increased incidence of liver tumours in laboratory rodents. To establish whether chronic liver cell injury may be involved in the genesis of these tumours, BHT was administered to rats by orogastric gavage at doses of 0, 25, 250 or 500 mg/kg/day for up to 28 days and also at daily doses of 1000 and 1250 mg BHT/kg for up to 4 days (sublethal doses). The sublethal doses induced centrilobular necrosis within 48 hr, whereas administration of BHT for 7 or 28 days caused dose-related hepatomegaly and at the highest dose level induced progressive periportal hepatocyte necrosis. The periportal lesions were associated with proliferation of bile ducts, persistent fibrous and inflammatory cell reactions, hepatocyte hyperplasia and hepatocellular and nuclear hypertrophy. Biochemical changes consisted of dose-related induction of epoxide hydrolase, dose-related changes in the ratio of cytochrome P-450 isoenzymes and depression of glucose-6-phosphatase. Measurement of BHT demonstrated a dose-related accumulation in fat but not in the liver. Changes in hepatic activating and detoxifying enzyme profiles are implicated both in the mechanism of periportal hepatocyte damage and in the change of site of damage according to the dose and duration of the treatment. The persistent and active nature of the lesions in rats dosed with 500 mg BHT/kg for 28 days, combined with evidence of cell damage at doses equivalent to those associated with hepatic tumours (250 mg BHT/kg), suggests that chronic liver cell damage may be involved in their aetiology. In this and several other studies, there was no evidence that BHT causes liver damage at a dose level of 25 mg/kg/day. As this is several hundred times higher than the normal human intake, it is considered unlikely that BHT poses a threat to human health.

Adipose Tissue↗
PubMedDate not supplied

Expression of the envelope antigen of dengue virus in vaccine strains of Salmonella.

The envelope gene of dengue 4 virus (DEN) was cloned in a plasmid under the control of Escherichia coli expression signals. A clone that expressed 93% of the gene was found to be detrimental to the bacterial host. Another clone which carried only 76% of the E gene was found to be quite stable in vitro as well as in vivo. The killed recombinant bacteria induced antibodies in mice which recognized native DEN virus. Attenuated Salmonella typhimurium (SAL) strains carrying the DEN-E plasmid were tested for their efficacy as orally administered live vaccines. Protective immunization was assessed in a mouse model by immunizing three-week old BALB/c mice followed by challenge with DEN virus. It was found that these young mice were highly susceptible to the carrier SAL strains (M206 and aroA SL3261). Moreover, the SAL-infected mice were more susceptible to DEN virus challenge than control mice, suggesting that the SAL infection caused immunosuppression in these young mice.

Animals↗