Biomedical subjects
Publications and source records attributed to A M Jonas.
After exposure to a variant of Citrobacter freundii, suckling and adult mice developed transmissible murine colonic hyperplasia of the same degree of severity. Mucosal hyperplasia was most severe 2 to 3 weeks after inoculation and then regressed. Suckling mice had a high mortality because of secondary inflammatory and erosive changes. Severe hyperplasia was characterized by mitotic activity along the entire crypt column and surface mucosa.
Morphological changes in retinas of aging Fischer 344 rats were characterized. The numbers of photoreceptor cells gradually decreased as rats aged. The outer nuclear layer was 12 cells thick at 3 months, but was reduced to less than 8 cells by 18 months. The decrease of photoreceptor cells was more pronounced in rats housed under a light intensity of 32-ft-c than in rats housed under a light intensity of 1 ft-c. Inner and outer segments of surviving photoreceptor cells were morphologically normal. A new form of retinal degeneration was discovered in aged Fischer rats characterized by selective degeneration of peripheral retina. Degeneration was characterized by severe loss of photoreceptor cells in the far peripheral retina. Microcystoids were found in about 25% ofthe affected retinas, and the loss of photoreceptor cells was followed by proliferation and vascularization of the retinal pigment epithelium and disorganization of retinal structures. The incidence and severity of peripheral retinal degeneration increased with aged and prolonged exposure to comparatively high-intensity light. All Fischer rats ((5/5) housed under light intensity of 32 ft-c developed severe peripheral retinal degeneration by 24 months. Peripheral retinal degeneration was an age-related change but appeared to be exaggerated by ambient light.
The disorder in Wag/Rij rats is a spontaneous, bilateral retinal deneration. It is characterized by an early onset, slowly progressive degeneration of the photoreceptor cells leading to destruction of the retina. Degeneration affects both rod cells and cone cells, and to a lesser degree the cells in the inner nuclear layer. The remarkable alterations in the retinal pigment epithelium during the course of the disease suggest a profound change in metabolism and function of the pigment epithelium and implicate a possibility of interaction between the pigment epithelium and the photoreceptors. Since degenerated cells have also been observed in the inner nuclear layers, there is a possibility that Muller's cells are involved in the retinal degeneration. Controlled experiments have demonstrated that the disease is not induced by light damaging effects of the retina, and initial breeding experiments suggest that the disease is inheritable, probably as an autosomal dominant trait. The retinal degeneration in Wag/Rij rats is a new, unique system and it is a potentially very useful animal model of retinitis pigmentosa.
Pathology, microbiology, and selected serum chemistries were evaluated in 144 male Fischer rats from 4 to 33 mo of age. The rats were reared and maintained under barrier conditions, which successfully excluded the introduction of major infectious disease agents throughout the entire study, including Mycoplasma pulmonis. A wide variety of pathology was found and tabulated, and many lesions were found to increase in severity and incidence with age. There was a high correlation of renal disease severity with increasing age, while alpha-1 globulin and cholesterol increased.
Sialodacryoadenitis virus (SDAV), a coronavirus of rats, evoked both serum neutralization and complement fixation antibody responses when inoculated intranasally in mice. Weanling gnotobiotic CD-1 mice inoculated intranasally with 10(3.0) mean tissue culture infective doses of SDAV remained asymptomatic. Virus was recovered from the nasopharynx, trachea, and lung from day 2 to day 7. Viral antigen was readily detected by indirect immunofluorescence in the lung but rarely in the nasopharynx. Infected mice developed interstitial pneumonia. Susceptible mice contact exposed to experimentally infected mice developed antibody to SDAV. Epizootiological studies indicated that retired breeder mice can have complement-fixing antibody to SDAV and mouse hepatitis virus (MHV) in the absence of MHV infection. These studies show that SDAV is infectious for mice and can be a pathogen for the respiratory system. Thus, SDAV infection of mice may be responsible for spurious seroconversions to MHV.
Transmissible murine colonic hyperplasia, cuased by a variant of Citrobacter freundii (4280). was shown to be modified by diet and by host strain and species. Four different diets fed to mice inoculated with C frundii 4280 were found to have a significant but varying influence on the severity of hyperplasia. Diet also influenced the colonic crypt height of uninoculated, control mice. F344 rats, Syrian hamsters, and NIH Swiss [N:(S)], C57BL/6J, C3H/HeJ, and DBA/2J mice were inoculated with C freundii 4280. Marked strain differences were noted in the mice in mortality and severity of the colonic hyperplasia. The NIH Swiss mice had the greatest and the C57BL/6J mice had the least mucosal hyperplasia. The rats and hamsters did not develop disease or maintain infection after inoculation with the organism. Twenty isolates of Citrobacter from a range of biologic sources were inoculated into susceptible mice, but only mice inoculated with C freundii 4280 developed the disease.
The morphogenesis of 1, 2-dimethylhydrazine (DMH)-induced lesions in the colon of outbred NIH Swiss mice was determined for up to 5 months of treatment. The effect of hyperplasia on DMH carcinogenesis was also evaluated by introducing a transient hyperplastic stimulus to the colon during the chronic weekly treatment regimen of DMH. The hyperplastic stimulus was a naturally occurring disease of mice, transmissible murine colonic hyperplasia, which is caused by a variant of Citrobacter freundii. In control mice, those not receiving the bacterium, weekly injections of the carcinogen induced neoplastic changes first detectable at two months of treatment in all segments of the colon and in both sexes. The changes increased in frequency and severity with time. Diffuse mucosal hyperpladia and chronic inflammatory and degenerative changes were also associated with DMH after prolonged treatment. The hyperplastic stimulus of C. freundii reduced the latent period for appearance of early DMH tumors, but it had no influence on already established DMH tumors.
The etiology of a transmissable colonic mucosal hyperplasia of mice was investigated. Hyperplasia was produced in mice inoculated with unfiltered colonic suspension from affected mice, but infectivity was lost after passage through a 0.45 mum filter. The etiologic agent was subsequently identified as a variant of Citrobacter freundii. The organism induced colonic mucosal hyperplasia when inoculated into germfree mice, and it was recovered in pure culture from the affected animals.
The criteria for the selection of stocks and strains of laboratory animals were discussed. These include metabolic and environmental factors as well as the presence or introduction of infectious agents. The investigator is now concerned with his experimental animals from conception to death, not just during an experiment. The basis of a health monitoring program to ascertain the health status of incoming animals, to evaluate the status of the environment, and to document the ongoing status of an animal colony was outlined. The facilities of the Yale School of Medicine animal research space were detailed.
A high incidence of keratoconjunctivitis was observed in a closed colony of inbred Lewis/Wistar rats. Clinical signs including blinking, ocular discharge, circumcorneal flush, corneal opacity, ulceration, pannus, hypopyon, and hyphema were observed at about three weeks of age. Acute disease subsided by six weeks of age, but some lesions progressed to low-grade chronic keratitis. Six per cent of affected rats developed megaloglobus, which usually appeared by three weeks of age. Lesions included focal or diffuse interstitial keratitis, corneal ulceration, anterior synechia, and inflammatory exudate in the anterior chamber. A high incidence of lenticular and retinal degeneration was associated with megaloglobus. Most affected rats also had harderian dacryoadenitis. Sialodacryoadenitis virus (SDA) was recovered from nasal washes, but not from affected eyes. Serological evidence indicated that SDA virus infection was widespread in the colony.
The pathogenesis of sialodacryoadenitis was studied in gnotobiotic CD rats inoculated intranasally with the causal virus. Virus replication was detected sequentially in the nasopharynx, tracheobronchial tree, cervical lymph nodes, submaxillary and parotid salivary glands, exorbital gland, and Harderian gland. Acute rhinitis appeared within 2 days after inoculation, and salivary glands had lesions in 4 days. Early changes in salivary and exorbital glands were characterized by necrosis of ductal epithelium, which rapidly progressed to widespread acinar necrosis, marked inflammation, edema and total effacement of glandular architecture. Harderian glands also had massive necrosis of tubuloalveolar units. Repair in all glands was characterized by marked squamous metaplasia of tubuloalveolar units. Repair in all glands was characterized by marked squamous metaplasia of ducts. Neutralizing and complement-fixing antibodies were detected in 7 days, and there was a concomitant decrease in tissue-virus titers. There was no detectable evidence for hematogenous spread of virus or for retrograde infection by way of major salivary ducts.
Conditions for oral transmission of atypical ileal hyperplasia (AIH) in weanling hamsters were established and 22 passages were made. AIH was transmitted by feeding whole cell-free supernatants of ileal homogenates. The etiologic agent(s) was retained by 0.22 mum pore-size filters and was inactivated by chloroform treatment or by heating at 56 degrees C for 30 min. Enteric bacteria from affected animals also induced AIH, but with a lower morbidity and mortality than following inoculation with ileal extracts. Experimentally induced lesions progressed from marked segmental hyperplasia of ileal mucosa to granulomatous inflammation in underlying connective tissue and muscle tunics. Hyperplastic mucosal epithelium penetrated the muscularis mucosa, but metastases were not detected. Serum antibody from exposed animals reacted specifically, by indirect immunofluorescence, with an intracytoplasmic mucosal cell antigen(s) of autologous and homogolous ileal lesions, but antibody did not react with normal ileal mucosa or with unaffected portions of intestine from animals bearing ileal lesions.
The toxic effects of cytembena in beagle dogs and rhesus monkeys were investigated with the drug given as single or daily iv injections in doses ranging from 12.5 to 200 mg/kg/day to dogs and 6.25 to 50 mg/kg/day to monkeys. Renal tubular damage was a major drug- and dose-related finding in both species and was clinically indicated by an accompanying uremia, elevated serum creatinine, and proteinuria. In the kidney, the primary lesion was cellular necrosis and desquamation of the distal tubular epithelium in animals given the lowest toxic doses. More severe but similar histologic changes produced by this drug were further characterized by single dose studies in mice which showed renal mitochondrial swelling and disruption plus generalized cell swelling as progressive, subcellular developments which were well established 24 hours after treatment. Cellular regeneration in the renal tubular epithelium was found in dogs and monkeys retained 6 weeks for observation after treatment, although functional recovery was inconsistent. A toxic effect to lymphoid tissue was an additional finding which is described.