Effect of indomethacin pretreatment on acute mortality in experimental brain injury.

The effect of indomethacin administration on the mortality rate of brain-injured rats was studied in four groups of animals subjected to a level of injury with a fluid-percussion apparatus predetermined to cause 50% mortality (50% lethal dose, or LD50). There were 24 animals in each of the following groups: 1) a control group, on which the LD50 was evaluated; 2) an ethanol-treated group with a mean blood serum level of 0.32 +/- 0.03 gm% (+/- standard error of the mean); 3) an indomethacin-treated group at a dose level of 3 mg/kg body weight administered intraperitoneally 10 to 15 minutes before injury; and 4) an indomethacin/ethanol-treated group. Significant differences in mortality rates were found in these experimental groups; namely, 50%, 58%, 8.3% (p less than 0.005), and 25% (p less than 0.05), respectively. The predetermined LD50 level of a 2.5- to 2.6-atm peak pressure pulse produced immediate apnea in all animals, which was either sustained (Type III), followed by temporary respiratory recovery (Type II), or followed by permanent resumption of breathing (Type I). The most important effect of indomethacin on respiratory function was manifested by a much higher percentage of Type I respiratory responses and a much lower percentage of Type II and III responses (hence a lower mortality rate). There was also a more rapid return to normal breathing in the postapneic period of recovery. Suppression of prostaglandin synthesis and of superoxide anion production at the of trauma may explain, at least in part, these favorable effects of indomethacin.

Epithelialization of the anterior chamber as a complication of penetrating keratoplasty.

Only a few cases of anterior chamber epithelialization after penetrating keratoplasty have been reported, and in most of these the keratoplasty had been preceded by another event that could have been the cause of the process. In the patient whose case we are reporting here, epithelialization of the anterior chamber developed after penetrating keratoplasty.

Fatty liver and kidney syndrome in chickens as an animal model for Reye's syndrome.

Fatty liver and kidney syndrome (FLKS), a naturally occurring but experimentally reproducible disease in chickens, has several clinical, pathological, and biochemical features in common with Reye's syndrome. Because of this, it has been suggested that FLKS may serve as an animal model of Reye's syndrome. We have examined, therefore, various parameters characteristic of Reye's syndrome in chickens affected with FLKS to further delineate the similarities and differences between the two disorders. Plasma glucose concentrations were significantly lower in chickens affected with FLKS which may be caused by the significantly reduced activity of pyruvate carboxylase in all FLKS-affected animals. The activity of propionyl CoA carboxylase was low in only the most severely affected chickens, and beta-methylcrotonyl CoA carboxylase showed no difference when compared with controls. This may be due to variable sensitivities of the three carboxylases to marginal biotin deficiency which occurs with FLKS. Plasma ammonia concentrations and activities of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, however, were not elevated in the affected birds. Histological changes in the liver and kidney were noted in affected chickens, but these changes were not identical with those observed in Reye's syndrome. Although the mechanisms of nitrogen elimination in fowl differ from those in humans, failure to demonstrate hyperammonemia, elevated serum transaminase activities, or similar histological changes in tissues of affected birds indicates that FLKS is not an appropriate model for the study of Reye's syndrome.

Diversity within a human isolate of coxsackie B4: relationship to viral-induced diabetes.

The ability of different strains of a single virus type to produce different pathogenic expressions is well documented within the picornavirus group. Coxsackievirus, group B, type 4 (CB4) has been associated with viral-induced diabetes in man, but expression of its potential to induce diabetes in experimental animals is variable. Evidence is presented here for one of the primary sources of this variability that could explain resulting contradictory reports offered in support or rejection of its diabetogenic potential. C57B1/6 and SWR mice were infected with the Edwards isolate of CB4 (CB4-Edw) and three of its plaque-purified virion "strains." These were designated Edwards isolate-1 (E1), E2, and E3. CB4-Edw, E1, E2, and E3 were serologically similar by infectivity neutralization tests, had identical plaque morphology, and replicated to a similar level in the pancreas. The most profound difference was the level of virus antigen accumulation in the islet cells as determined by immunoperoxidase localization. CB4-Edw had moderate antigen accumulation in most islet cells of SWR mice but was restricted to only a few specific cells within the periphery islets of C57B1/6 mice. Unlike CB4-Edw all three new isolates accumulated antigen in most islet cells of both mouse strains. Virus isolate (strain) E2 showed the most intense accumulation in islet cells. These observations suggest that the Edwards isolate of CB4, like other human isolates of CB4 virus, probably exists as a heterogeneous population of virion strains. The pathogenic consequences and expression of any diabetogenic potential is, therefore, dependent on virus strain selection. This diversity must be considered when evaluating the pathogenic nature of CB4 viruses in experimental animals and the possible role of the viruses in diabetes of man.

Dietary hepatic cholesterol elevation: effects on coxsackievirus B infection and inflammation.

Mice made hypercholesterolemic (HC) by diet are highly susceptible to coxsackievirus (CV) B5, whereas normal adult animals remain resistant. In attempting to define those dietary-induced physiological changes which contribute to altered resistance, a strong association between accumulation of intrahepatic cholesterol and increased CV B5-induced mortality was demonstrated, with maximum susceptibility to CV coinciding with a 2.5-fold increase in the ratio of hepatic cholesterol to protein. This metabolic imbalance was associated with a lower clearance rate of CV from the blood and liver of C57BL/6 mice, although virus-specific neutralizing antibody production was unaltered. In addition to CV, HC mice were more susceptible to an intravenous inoculation of Listeria monocytogenes in comparison to controls. The macrophage stimulant Corynebacterium parvum failed to increase resistance of HC mice to a high dose of CV B4 and L. monocytogenes and failed to induce the hepatomegaly, splenomegaly, and cellular infiltrate seen in the liver and spleen of normal animals. Furthermore, the peritoneal monocytic infiltrate induced by thioglycolate in normal animals was absent in HC mice. Results from these experiments suggest that decreased resistance to CV in the HC host is attributed to a defect in the nonspecific immune responses of macrophages and monocytes which are of primary importance in resistance to this virus and other infectious agents.

Host factors in Coxsackievirus B4-induced pancreopathy.

The diabetogenic potential of the human isolate, Coxsackievirus B4 (CB4) (Edwards) was studied in three inbred mice strains, SWR/J, DBA/2, and C57BL/6. The mice were infected with this agent and evaluated for mortality, pancreatic histopathology, and glucose tolerance. Results showed that the mortality induced by CB4 in these inbred strains differed considerably. There was no evidence of a correlation between virus-induced mortality and virus-induced pancreopathy. Although CB4 (Edwards) was most lethal to C57BL/6 mice, based on the infecting 50 per cent lethal dose (LD50), this mouse strain developed no pancreatic pathology. The most severe pancreopathy, i.e., acinar necrosis with acute interstitial inflammation and islet atrophy, was observed in SWR/J mice, which had an intermediate susceptibility to virus-induced mortality. DBA/2 mice, which displayed the lowest susceptibility to virus-induced lethality, showed less pancreatic pathology (i.e., acute and chronic interstitial inflammation) than SWR/J mice. IN SWR/J mice, virus-mediated alteration in glucose homeostasis was expressed by an increase in glucose tolerance 7 and 21 days after infection. In contrast, C57BL/6 mice showed a tendency toward chemical diabetes at 21 days postinfection. This study suggests that CB4-induced mortality and pancreatic pathology are independent parameters and do not necessarily determine the glucose tolerance of a given host genotype.

Biphasic development of the postnatal mouse pancreas.

Conventional biochemical and histological methods along with DNA flow-cytometric analysis were used (1) to define development of the mouse pancreas from birth to day 90 and (2) to provide information critical for studies on isolated islets and their component cells. Pancreas development in the mouse followed a biphasic pattern. Phase one extended from birth through day 15 and was dominated by proliferation and growth of endocrine cells as most islets attained adult form by day 15. Phase two, from day 15 through 30, was dominated by proliferation and growth of exocrine cells which became maximal by day 20. These data provide evidence suggesting that the optimum age for islet isolation is toward the end of phase one and before phase two, between days 10 and 15, and the optimum age for isolation of endocrine cells for proliferation and growth in culture is during the early part of phase one before most islets have attained adult form, between days 5 and 9.

The role of host genetics in the pathogenesis of coxsackievirus infection in the pancreas of mice.

The susceptibility of mice to the diabetogenic effect of the M variant of encephalomyocarditis (MEMC) virus is probably inherited as a recissive trait. Three strains of mice that were susceptible to MEMC virus, three strains that were not susceptible to MEMC virus, and three types of F1 hybrid strains were infected with the common human coxsackie virus, group B, type 4 (CB4). They were examined to determine the titer of virus and histochemistry in the pancreas, levels of blood glucose, urinalysis, glucose tolerance, and levels of plasma amylase and insulin. There was a positive correlation between MEMC virus-susceptibility (diabetes-prone) and CB4-induced beta cell degranulation with concurrent hyperinsulemia and hypoglycemia. Also, as for MEMC virus, the titer of CB4 in the pancreas was not genotype-dependent. However, there was an inverse relation between destruction of the exocrine pancreas and the effect on the endocrine pancreas. These results suggest that the genetic factors responsible for the effect of MEMC virus on the endocrine pancreas are also responsive to CB4, and the proposed recessive nature of these factors is maintained for both viruses. In contrast, these factors, which are operatively recessive traits for the effect of CB4 on the endocrine pancreas, appear to be expressed as dominant traits with respect to the exocrine pancreas.

Adenocarcinoma of the pancreas associated with hypoglycemia: case report and review of the literature.

The occurrence of profound hypoglycemia in a patient with metastatic adenocarcinoma of the pancreas is reported. In contrast to the four previously reported cases, no suggestion of excess insulin production was found. Metabolic studies in this patient suggest both increased peripheral glucose utilization and decreased hepatic glucose production as contributing factors which promoted the hypoglycemia.

Suppression of aortic elastic tissue autofluorescence for the detection of viral antigen.

Suppression of aortic elastic tissue autofluorescence was achieved by employing a modification of Verhoeff's elastic tissue staining procedure. Consquently, coxsackievirus B antigen present in the aortic media was detected by conventional fluorescent antibody staining.

Coxsackievirus B cardiopathy and angiopathy in the hypercholesterolemic host.

Studies on the pathogenic potential of the human cardiotropic enterovirus, coxsackievirus B5, show that this agent localizes and replicates in the aorta of mice. Nutritionally-induced hypercholesterolemia leads to an increased replication and persistence of virus in tissues, specifically the aorta. Coxsackievirus B cardiopathy is markedly augmented in the hypercholesterolemic host, resulting in a persistent cardiomyolysis which is not evident in virus-infected animals with normal cholesterol levels. Pathological changes in the aorta become evident only months after the acute infection, and only in hypercholesterolemic animals previously infected with coxsackievirus B5. Our findings of coxsackievirus B-induced angiopathy and cardiopathy in the hypercholesterolemic host extend the known pathogenic range of these human viruses, and further emphasizes their potential as etiological agents of cardiovascular disease.

Pancreatic pseudocyst with massive ascites.

The autopsy finding on a patient with pancreatic ascites are discussed in relation to the cause of the ascites. The findings are consistent with the theory that the ascites is due to peritoneal irritation caused by leaking pancreatic secretions.

Fatal myocarditis associated with acute tonsillitis.

A case of myocarditis, hepatic necrosis, and acute anuria associated with acute tonsillitis was described. The previously reported relation between myocarditis and tonsillitis not of diphtheritic or beta-hemolytic streptococcal origin was discussed, as well as the implications for management.

Infection of hypercholesterolemic mice with Coxsackievirus B.

Adult male mice were made hypercholesterolemic by a diet high in cholesterol, cholic acid, animal fat, and sucrose. After three months on this diet, animals were infected with 5 X 10(9) plaque-forming units of coxsackievirus B5. Control groups consisted of uninfected hypercholesterolemic mice and infected mice maintained on a standard laboratory diet. Infection in the hypercholesterolemic animals was associated with leukopenia, severe fatty metamorphosis and focal necrosis in the liver, cholelithiasis, ileus, cardiomyolysis, and lack of inflammatory response. These mice died within seven to 14 days. Uninfected hypercholesterolemic animals had lesser degrees of fatty liver and cholelithiasis, and all survived. Infected mice maintained on a standard diet also survived. Titers of virus in representative tissues were lower in the hypercholesterolemic than in the normal mice, an indication that replication of virus was not solely responsible for the lethal outcome of the infections. These experiments demonstrate that hypercholesterolemia may alter host defenses against group B coxsackievirus in the mouse.

Susceptibility of mice to group B coxsackie virus is influenced by the diabetic gene.

A positive correlation was found between genetic predisposition to diabetes in the mouse and susceptibility to group B Coxsackie virus in this host. Male mice of the inbred strain C57BL/Ks and the following genetic variants were used; mice homozygous for the autosomal recessive gene for diabetes (db/db), the phenotypically normal heterozygous (db/+), and the normal mice which lacked the diabetic gene (+/+). The mortality response of the +/+ mice to intraperitoneal inoculation with Coxsackie virus B4 differed from the response of the two genetic variants (db/db and db/+) derived from this strain. The db/+ variant was more susceptible to Coxsackie virus B4 than the parental background strain (+/+). The db/db variant was more susceptible than either of the other genotypes. Pathological findings of the pancreas of the three genotypes during the acute stage of infection closely paralleled the genotypically dependent susceptibility of the host.