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Biomedical subjects

R T Bronson

Publications and source records attributed to R T Bronson.

At least 145 records · Page 8Linked to original sources

Purkinje cell degeneration associated with erythroid ankyrin deficiency in nb/nb mice.

Mice homozygous for the nb mutation (Chromosome 8) have a severe hemolytic anemia and develop a psychomotor disorder at 6 mo of age. The nb/nb mice are deficient in erythroid ankyrin (Ank-1) but, until the present study, the role of Ank-1 and of Ank-2 (brain ankyrin) in disease genesis was unknown. In normal erythroid tissues, we show that two major transcripts are expressed from Ank-1, and one of these is also present at high levels in the cerebellum. By in situ hybridization and immunocytochemistry, Ank-1 localizes to the cerebellar Purkinje cells and, to a lesser extent, the granule cells. In nb/nb mice, Ank-1 transcripts are markedly reduced in both erythroid and neural tissue, and nb/nb Purkinje cells and granule cells are nearly devoid of Ank-1. The neurological syndrome appears concurrently with a dramatic loss of Purkinje cells. Ank-2 maps to Chromosome 3 and its expression is unaffected by the nb mutation. We conclude that Ank-1 is specifically required for Purkinje cell stability and, in its absence, Purkinje cell loss and neurological symptoms appear.

Anemia, Hemolytic↗

Murine infection by vesicular stomatitis virus: initial characterization of the H-2d system.

BALB/c mice and congenic H-2Ld-deficient BALB/c-H-2dm2 (dm2) mice were experimentally infected intranasally with isolates of vesicular stomatitis virus (VSV). The survival of infected hosts, viral replication in lungs and brains, and histopathologic in the two mouse strains were compared. In both strains of mice, mortality occurred during the period 7 to 10 days postinfection. However, dm2 mice were relatively resistant to lethal infections. Viral replication occurred at low levels in the lungs of both strains and did not evoke significant pathologic changes. In contrast, viral replication in the brains was much greater; in the BALB/c strain, this was accompanied by more frequent and more severe pathologic changes. In general, mice surviving at day 10 had effectively cleared virus from central nervous system but not respiratory sites. Evidence is presented that viral replication occurs first in the nasal cavity and is transmitted both to the lungs and to the olfactory bulb where focal cytopathology occurs. Virus enters the ventricles, causing encephalitis; necrosis occurs around the ventricles and in the lumbosacral region of the spinal cord. Necrotic lesions were accompanied by mononuclear infiltration. Mice immunized with virus of the same serotype or with a vaccinia virus hybrid encoding the VSV glycoprotein were protected from lethal infection; in contrast, mice immunized with heterotypic virus were susceptible to challenge.

Animals↗

Reduction in rate of occurrence of age related lesions in dietary restricted laboratory mice.

This report describes the results of a study to find differences in the distribution of pathologic lesions between 40% dietary restricted (DR) and ad libitum (AL) fed mice of four genotypes, C57BL/6NNia, DBA/2NNia, B6D2F1NNia and B6C3F1NNia. Representative samples of all organs were studied from 1134 mice killed at 12, 18, 24 and 30 months of age. Approximately half were female, half male. All mice were fed a natural ingredient diet, NIH-31 and were maintained under pathogen free conditions. A total of 135 lesions was observed. The rate of occurrence of each of 35 common lesions is described for each age/genotype/sex in the study. Fifteen lesions are described in detail. Highly significant differences were found between mice of the same age, sex and genotype in the two diet groups in the percent rate of occurrence of total lesions, total tumors, and total lymphoid nodules of various organs. These parameters generally increased with age in both diet groups. For example, of female mice of all genotypes at 24 months, 51% AL and 13% DR mice had tumors. These percentages were 123% and 17% respectively at 30 months. The evidence presented here suggests that total tumors, total lymphoid nodules, total lesions, and absence of lesions are all useful measures of aging, independent of the life span, that reflect the long known effect of dietary restriction on reducing the rate of aging. These parameters, however, only partially reflected the longer life span of hybrid as compared with inbred mice.

Aging↗

Hydrocephalus with hop gait (hyh): a new mutation on chromosome 7 in the mouse.

Hydrocephalus with hop gait (hyh) is a new lethal recessive mouse mutation that arose in the C57BL/10J strain at The Jackson Laboratory. It has been mapped to the proximal end of Chromosome 7 close to the Gpi-1 locus. This homozygous mutant is characterized clinically by a domed head and a hopping gait observable at 2 weeks of age and death between 4 and 10 weeks of age. The affected mice have dilated lateral ventricles and a large third ventricular cyst, patent through narrowed rostral cerebral aqueduct, cystic caudal aqueduct and no communication of the aqueduct with the fourth ventricle. The cerebellum has a mild cortical malformation.

Animals↗

Stargazer: a new neurological mutant on chromosome 15 in the mouse with prolonged cortical seizures.

We report here the initial description of the inheritance pattern, linkage mapping, and electroclinical phenotype of a recessive mutation on mouse Chromosome 15, stargazer (stg), that produces epilepsy. The salient epileptic phenotype is a syndrome of spontaneous, prolonged, generalized spike-wave cortical discharges with behavioral arrest. A second, complex, seizure pattern featuring movements during the discharge can also appear. The stg/stg mutant phenotype confirms the general principal that inherited epilepsies sharing similar cortical excitability patterns can be transmitted by single gene loci residing on different chromosomes and provides new evidence that the severity of seizure expression depends on the specific mutant gene affected.

Animals↗

Towards a biomarker of mammalian senescence: carbonic anhydrase III.

Three proteins (D2, D3, D4) have been identified in the male Fischer 344 rat liver that decrease their concentration dramatically to virtually zero during the transition from physiological maturity to senescence. D3 (Mr 28 kDa), absent (or at a very low concentration) from the livers of newborns and females of all ages, reaches at 60 days (sexual maturity) its maximum concentration, which declines almost linearly thereafter. A homologous protein (CNBr peptide map) occurs in the BALB/c mouse under similar conditions. D3 was purified and since its N-terminal is blocked, digested with CNBr. SDS-PAGE-separated peptides were blotted upon Immobilon and sequenced. The partial sequence matches that of rat carbonic anhydrase III. Treatment of senescent rats with 5 alpha-dihydrotestosterone restores D4 completely, yet D2 and D3 only partially, towards their maximum life-time concentration. Thus senescence-related factors (e.g. hepatic androgen receptor) aside from serum testosterone are responsible for the disappearance of the three proteins from the senescent liver.

Aging↗

Adoptive transfer of immune enhancement of experimental ulcerative colitis.

Previous experiments with the carrageenan model for ulcerative colitis have shown that the inflammatory response in guinea pigs can be enhanced by immunization with and subsequent feeding of Bacteroides vulgatus to experimental animals. The present studies showed that only certain strains of B. vulgatus are capable of provoking immune enhancement of ulcerative colitis. Animals were fed carrageenan and various strains of viable B. vulgatus after immunization with a strain of B. vulgatus isolated from a guinea pig with experimentally induced colitis. Histological comparison of immune and nonimmune groups revealed that immune animals which received B. vulgatus from a patient with inflammatory bowel disease had a significantly (P less than 0.025) greater number of histopathological lesions at 21 days than did nonimmune animals. Immune animals receiving B. vulgatus isolated from a clinically normal source did not show any significant difference in disease status when compared to nonimmune animals. Additional experiments showed that adoptive transfer of spleen cells from animals immunized with B. vulgatus to nonimmune recipient animals is effective in transferring the immune enhancement demonstrated in actively immunized animals. Animals which received immune spleen cells with concurrent feeding of B. vulgatus showed a significant (P less than 0.005) increase in inflammation over control groups, in the absence of high titers of circulating antibody. These experiments indicate that B. vulgatus strain-specific factors are important to immune enhancement of experimental disease and also suggest an involvement of the cell-mediated immune system in this model.

Animals↗

Hemagglutinin variants of reovirus type 3 have altered central nervous system tropism.

Variants of the Dearing strain of reovirus type 3 with antigenically altered hemagglutinin proteins are much less neurovirulent than the parental virus. When injected intracerebrally into mice these variants infected a subset of the brain neurons that were infected by the parental virus. When injected intraperitoneally, the variants did not spread to the brain. These results indicate that minor modifications of the reovirus hemagglutinin dramatically alter the ability of the virus to spread into and injure the central nervous system.

Animals↗

Failure of Herpesvirus saimiri to enhance atherogenesis in owl monkeys (Aotus trivirgatus).

A retrospective study was performed to evaluate the potential of a mammalian oncogenic virus, Herpesvirus saimiri, to cause atherosclerosis in owl monkeys (Aotus trivirgatus). This was undertaken since an avian oncogenic herpesvirus, Marek's disease virus, does so in chickens. Data from earlier studies were reviewed and 3 groups of animals were selected. These included 23 animals infected with herpesvirus that died an average of 156 days later with malignant lymphoma; 11 infected an average of 207 days before being killed without lymphoma; and 21 uninfected control animals that died from a variety of diseases. Aortas and hearts from all animals were recovered from storage in formalin and examined for histopathological evidence of atherosclerosis in aortas and coronary arteries. Mild to moderate atherosclerosis characterized by intimal proliferation and the presence of fat droplets was present in 60% of the monkeys and did not differ in occurrence between the groups. Mean intimal thickness did not vary significantly between groups either. A case of naturally-occurring severe atherosclerosis is also reported here. Thus, although this species is susceptible to atherosclerosis, neither the occurrence nor severity of that disease is affected by infection with an oncogenic virus within the time periods studied here.

Animals↗

Enhancement of experimental ulcerative colitis by immunization with Bacteroides vulgatus.

Previous studies with the guinea pig model for ulcerative colitis have shown that the inducing agent, carrageenan, does not provoke ulcerations in germfree guinea pigs, but animals monoassociated with Bacteroides vulgatus develop cecal ulcerations when fed carrageenan. In an effort to define the role of B. vulgatus in this model system, conventional guinea pigs were immunized with B. vulgatus before carrageenan treatment. Immunized animals developed both circulating antibody and positive skin tests for the homologous antigen. A comparison of B. vulgatus-immune and nonimmune carrageenan recipients after 30 days of carrageenan treatment revealed ulcerations of the ceca and large intestine in both groups, but the immune group developed more severe lesions than the nonimmune group. The most severe intestinal lesions were detected in B. vulgatus-immune animals fed both carrageenan and daily doses of viable B. vulgatus. Immune recipients of B. vulgatus alone did not develop ulcerations, but showed histological evidence of intestinal inflammation. Lesions observed in B. vulgatus-immune animals were most severe in the colon and rectum, in contrast to more severe cecal lesions detected in nonimmune carrageenan recipients. Similar experiments with Bacteroides fragilis as an antigen for immunization showed no difference between immune and nonimmune groups. These results suggest that immunization with B. vulgatus enhances the severity of carrageenan-induced colitis.

Animals↗

A retrospective study of infant mortality of cotton-top tamarins (Saguinus oedipus) in captive breeding.

Fifty of 156 (32%) colony bred cotton-top tamarins were stillborn, and 31 (20%) died within the first week after birth. The stillbirth rate was related to litter size and parity in captivity. A higher percent of single births were stillborn (69%) compared to those of twin births (26%) (p less than 0.005). A higher percent of infants born of the first litter in captivity (42%) were stillborn than those of subsequent litters (23%) (p less than 0.025). Stillbirths were not related to season of birth or sex of infant. Survival of live infants was unrelated to season of birth, sex, litter size, or number of litters.

Animals↗

An analysis of the association of gastroenteric lesions with chronic wasting syndrome of marmosets.

Retrospective pathology data from necropsies of 162 marmosets, Saguinus oedipus, were studied to determine the nature of chronic wasting syndrome, a poorly defined entity associated with a high mortality rate in many marmoset colonies. Paraffin sections of the gastroenteric organs of 116 of these marmosets were re-examined in detail; lesions were identified, quantitated, and analyzed with a method of multiple chi-square testing for possible associations between findings. Five distinct disease entities were identified: prosthenorchosis, amebiasis, paramyxovirus disease, sepsis, and chronic colitis. Lesions of several of these often occurred in the same monkey, and all but the first were associated with cachexia. Lesions of chronic colitis were crypt abscesses, mononuclear and polymorphonuclear infiltration of the lamina propria, epithelial cell atypia, karyorrhexis, and lymphoid hyperplasia. The cause of chronic colitis was not identified, nor was any explanation found for weight loss and increased susceptibility to disease.

Animals↗

Pancreatic ectasia in uremic macaques.

Pancreatic ectasia (PE) is a common incidental finding in people dying from uremia. It has been described as dilatation of acini, inspissation of secretions, and proliferation of ductal cells. PE occurred in 17 macaques, 11 of which were known to have been uremic. The lesion was studied by light and electronmicroscopy and histochemistry and by construction of a three-dimensional model of a dilated acinar ductal system from serial semithick Epon sections. Atrophic acinar cells interspersed with clumps of centroacinar cells lined all portions of the system. There was no evidence of ductular proliferation. Fibrillar material was present in the dilated acinar lumens and associated with epithelial cells and leukocytes, but no blockage of the system was demonstrated. The lesion is similar to those induced by a variety of experimental procedures and to the pancreatic lesions of cystic fibrosis.

Animals↗

An analysis of the association of gastroenteric lesions with chronic wasting syndrome of marmosets.

Retrospective pathology data from necropsies of 162 marmosets, Saguinus oedipus, were studied to determine the nature of chronic wasting syndrome, a poorly defined entity associated with a high mortality rate in many marmoset colonies. Paraffin sections of the gastroenteric organs of 116 of these marmosets were re-examined in detail; lesions were identified, quantitated, and analyzed with a method of multiple chi-square testing for possible associations between findings. Five distinct disease entities were identified: prosthenorchosis, amebiasis, paramyxovirus disease, sepsis, and chronic colitis. Lesions of several of these often occurred in the same monkey, and all but the first were associated with cachexia. Lesions of chronic colitis were crypt abscesses, mononuclear and polymorphonuclear infiltration of the lamina propria, epithelial cell atypia, karyorrhexis, and lymphoid hyperplasia. The cause of chronic colitis was not identified, nor was any explanation found for weight loss and increased susceptibility to disease.

Animals↗

Variation in age at death of dogs of different sexes and breeds.

A retrospective study of necropsy data for 2,002 dogs showed that the mean age at death of neutered dogs of both sexes exceeded that of intact dogs, but the differences were not significant. A wide variation in mean age at death of 56 breeds and cross breeds, 3.0 to 9.9 years, was found. This variation was not correlated with mean breed body weight. An attempt was made to explain the variability by finding diseases to which dogs of the short-lived breeds were particularly susceptible. This was not possible in general, since the samples of each breed were small and the total number of diseases from which they died so large. Dogs of long-lived breeds died of diseases appropriate to their age, particularly cancer, 39% of the sample. In the sample as a whole, cancer accounted for 20% of deaths at 5 years and increased to and remained between 40% and 50% from 10 to 16 years of age.

Age Factors↗

Fatal fasting syndrome of obese macaques.

A retrospective study of clinical and pathological data showed that 42 generally obese macaques died after losing approximately 30% of body weight. The mean duration of illness for 29 monkeys whose clinical histories were known was 17 days. All animals had severe fatty change of livers and proximal convoluted renal epithelium. Some also had partial or complete renal tubular atrophy. Other common lesions were pancreatic ectasia, pancreatitis, or focal pancreatic necrosis often with fat necrosis. These lesions constitute fatal fasting syndrome and were the only ones present in 10 cases. Twenty additional fatal lesions were present in six cases; nonfatal ones were present in 14 cases. The most common of the latter were fecal impaction and traumatic lesions from fighting after being recaged in new social groups. Of 15 animals studied clinically, 13 were azotemic. Other clinico-pathologic findings were not contributory. One of 10 rhesus monkeys followed prospectively after being transferred from a single cage to a gang cage, died 74 days later with no lesions apart from those constituting the syndrome. A biopsy survey of 31 clinically normal obese macaques showed that only three had mildly fatty livers. These data suggested that obese macaques becoming anorexic for any reason die from this syndrome when body weight loss is approximately 0.1 kg/day.

Adipose Tissue↗

Ganglioneuropathy in rabbits and a rhesus monkey due to high cumulative doses of doxorubicin.

The effects of long-term administration of doxorubicin in adult rabbits and in a rhesus monkey were studied. Eleven rabbits were given cumulative doses of 2--24 mg/kg over a period of 5--28 weeks. The monkey received a total of 20 mg/kg during a 10-month period. One rabbit exhibited hind leg paresis, but all of the other animals in the study remained clinically free of neurologic signs. Rabbits given less than 12 mg/kg of doxorubicin had only mild degenerative changes in dorsal roots and a few necrotic neurons in the dorsal root ganglia, but these lesions were much more severe in all rabbits when a cumulative dose greater than 16 mg/kg was given. The monkey also had severe ganglioneuropathy, suggesting that primates may also be susceptible to this toxic effect of doxorubicin. Although neurotoxicity has not been observed with the dose schedules of doxorubicin used in clinical practice, the tendency of this drug to damage both postmitotic neural and cardiac cells may provide added understanding of the clinically important doxorubicin cardiomyopathy.

Animals↗