Otic cholesteatoma in the sand rat (Psammomys obesus).

To improve treatment of otic cholesteatoma, a model is needed for conduction of experiments. In the search for such a model, we have found cholesteatoma to occur naturally in Psammomys obesus. We present these findings and suggest the fat sand rat as a model for investigating cholesteatoma.

Venoocclusive disease of the liver and phlebectatic peliosis in the golden hamster exposed to dimethylnitrosamine.

The liver of Syrian hamsters was studied after exposure to dimethylnitrosamine (DMN) in drinking water for, respectively, 8, 12 and 16 weeks. One additional group of animals was offered DMN for 8 weeks, but maintained for further 8 weeks after removal of the compound. The changes consisted of a narrowing portal venopathy, probably arising, initially, from toxic pylephlebitis, being followed by widespread subendothelial prolapse of hepatocytes encroaching upon the lumen of terminal hepatic veins, which generally were free of inflammatory fibrosing lesions. The venous lesions were unrelated to malignant processes in the biliary duct system, which occurred after 16 weeks. Dilatation of sinusoids and small venules was associated with the presence of prolapsed hepatocytes around their openings into involved larger veins. At the end of 12 and 16 weeks of continuous ingestion of DMN, but also where the agent was withdrawn already at 8 weeks, phlebectasis and transitional stages in the formation of teleangiactatic type of peliosis were demonstrated, probably resulting from progressively impeded blood flow due to partial occlusion by prolapsed hepatocytes in terminal veins. The mechanism enabling hepatocytes to penetrate the venous wall was not clarified. There was no indication of invasive malignancy. Hepatocyte prolapse appeared more likely to result from some unknown mechanism of benign infiltration, promoted by regenerative stimulation. This may have been initiated by mild persistent ischemia due to the demonstrated portal venopathy. No endothelial hyperplasia was seen at any stage of the experiments thus eliminating the probability of peliosis being a source of vascular neoplasia, which has previously been described following more prolonged exposure to DMN. Certain parallelisms of the experimental results with hepatic vascular lesions in man subjected to drug therapy are discussed.

Capillary ATPase inactivation in early myocardial ischaemia.

The Wachstein-Meisel ATPase reaction can be used in formalin-fixed, postmortem material to demonstrate the microvasculature in the human myocardium. In cases of sudden or rapid cardiac death, the disappearance of enzymatic activity in capillary walls was observed earlier than other light-microscopic signs of damage. This was especially marked in the subendocardial regions. The staining of capillaries was found to be positive again in the varying stages of organization. Fibrotic scars were devoid of staining. The findings besides being of practical value in the diagnosis of early myocardial necrosis, support the theory that loss of capillary metabolic and functional integrity occurs early in ischaemia; it promotes the 'no reflow' phenomenon and may contribute towards myofibre necrosis.

Effects of cycloheximide and tunicamycin on opiate receptor activities in neuroblastoma X glioma NG108-15 hybrid cells.

The molecular mechanism of opiate receptor down-regulation and desensitization was investigated by studying the effects of cycloheximide and tunicamycin on opiate receptor activities in neuroblastoma X glioma NG108-15 hybrid cells. Cycloheximide inhibited [35S]methionine and [3H]-glucosamine incorporation by hybrid cells, while tunicamycin inhibited [3H]glucosamine incorporation only. Exposing hybrid cells to these two agents did not alter the viability of the cell. Treatment of NG108-15 cells with cycloheximide or tunicamycin produced a decrease in [3H]diprenorphine binding dependent on both time and concentrations of inhibitors, with no measurable modification in the ability of etorphine to regulate intracellular cyclic AMP production. Cycloheximide attenuated [3H]-diprenorphine binding by decreasing both the number of sites, Bmax, and the affinity of the receptor, Kd. Tunicamycin treatment produced a decrease in Bmax with no apparent alteration in Kd values. Cycloheximide and tunicamycin did not potentiate the rate or magnitude of etorphine-induced down-regulation or desensitization of opiate receptor in NG108-15 cells. Furthermore, there was an apparent antagonism in cycloheximide action on receptor down-regulation. The reappearance of opiate binding sites after agonist removal was affected by these two inhibitors. Cycloheximide and tunicamycin eliminated the increase in [3H]diprenorphine binding in the chronic etorphine-treated cells after agonist removal. These two inhibitors did not alter the resensitization of hybrid cells to etorphine. Thus, the site of opiate agonist action to induce receptor down-regulation and desensitization is not at the site of protein synthesis or protein glycosylation. These data substantiate previously reported observations that receptor down-regulation and receptor desensitization are two different cellular adaptation processes.

Primary portal venopathy in the golden hamster treated with low doses of dimethylnitrosamine.

Ingestion of dimethylnitrosamine in a low dose and for a limited period by hamsters resulted in primary intrahepatic pylephlebitis. The process began at 24 h and progressed within 2-4 weeks to narrowing and, eventually, to partial obstruction of the portal bed. The lesions were characterized by endothelial necrosis followed by infiltrations of lymphoid cells extending into the portal tracts. Superficial lesions of terminal hepatic veins and parenchymal changes occurred only after a lapse of, respectively, 2 and 4 weeks when restrictions of portal blood had been assumed. The parenchymal changes consisted of regional regenerative hyperplasia accompanied by subendothelial prolapse of hepatocytes into the wall of terminal veins. The lesions of the portal veins persisted for a prolonged period of time after the exposure to dimethylnitrosamine had ceased. These findings, associated with characteristic histological aspects, suggested secondary immune reaction following the initial toxic pylephlebitis. The possible relevance of the experimental results to understanding the nature of endemic portal venopathy in man is discussed with regard to pathogenesis and etiology.

Dental abnormalities in aging sand rats (Psammomys obesus).

Sand rats transferred from their natural environment to laboratory conditions develop diabetes, cataracts, vertebral lesions, liver tumors, malocclusion and gingival inflammation. In the present study 43 sand rats of different ages were randomly chosen from a colony maintained for 13 years in the laboratory. Macroscopical, microscopical and radiographical examinations of the dental apparatus showed marked abnormalities in animals older than 6 months. The incisors were affected more than molars with an asymmetry between the right and left side of the jaw. Pathological alterations in the incisors included variations in length and curvature, lateral inclination, coronal fractures and pulpal calcifications. The enamel on the buccal aspect of these teeth had a scalloped appearance with corresponding metaplastic changes and folding of the ameloblastic layer. Coronal fractures were also found in molar teeth and were accompanied by marked hypercementosis. These changes are consistent with those reported in rodents with induced hormonal imbalance and may be associated with the diabetic state of aging sand rats. These gerbils are suggested as a model for studying the role of age-related disorders in the pathogenesis of certain dental abnormalities.

Spontaneous uterine neoplasms in the fat sand rat (Psammomys obesus).

Sacrifice of 69 fat sand rats (Psammomys obesus) bred at the Hebrew University--Hadassah Medical School, yielded 19 cases with spontaneous uterine tumours. These consisted of 5 leiomyomas, 3 endometrial polyps, 10 adenofibromas and one possibly malignant mixed mesodermal tumour. The relatively high incidence of adenofibromas histologically resembling the human neoplasm, could make this animal a useful model for further study of Müllerian mixed tumours.

Naturally occurring polypoid hyperplasia and papilloma in gallbladders of the fat sand rat (Psammomys obesus terraesanctae Thomas).

The gallbladders of 256 fat sand rats (131 males and 125 females) seven to 41 months old were studied histologically. None of the sand rats had been used in experimental procedures prior to death. Diffuse polypoid hyperplasia or papilloma of the gallbladder mucosa was found in 49 sand rats. Of these lesions, 45 were present in 126 sand rats in the second half of their lifespan. Neither concretions nor signs of chronic inflammation were seen. Signs of focal epithelial growth activity were seen in either form of lesion. Epithelial hyperplasia was excessive in two gallbladders, and one was diagnosed as carcinoma-in-situ. The papilloma in one sand rat revealed transition to adenocarcinoma, with penetration into the deep layers of the gallbladder. Preneoplastic nodules were found in the liver as frequently as reported previously, but they were unrelated to gallbladder lesions. The unusual high incidence of spontaneous epithelial proliferation in the gallbladder mucosa in sand rats of both sexes through several generations suggests this strain as a model in the experimental study of tumorigenesis in the gallbladder.

The histogenesis of hepatoma occurring spontaneously in a strain of sand rats (Psammomys obesus).

Spontaneous hepatomas and hepatic preneoplastic changes were observed in sand rats (Psammomys obesus) from two colonies. Both colonies originated from 10 sand rats captured in the Judean desert in 1969. At the age of 6 months, and increasing in multiplicity with advancing age, histologic examination revealed nodules containing hepatocytes characterized by hyperbasophilia, accumulation of glycogen, eosinophilic cytoplasm, or a mixture of these cells. In animals over 25 months old hepatocellular carcinoma was diagnosed. The histologic changes described here were reported to be characteristic of chemical hepatomagenesis in rats. No external chemical carcinogen could be demonstrated in our animal colonies, and a hereditary predisposition to tumor formation is presumed. Identity of hepatic carcinogenesis, irrespective of etiology in distantly related rodents, ie, the laboratory rat and the sand rat, which in reality is a gerbil, supports the assumption of the existence of a general law governing hepatic carcinogenesis.

Acute and protracted changes in the liver of Syrian hamsters induced by a single dose of aflatoxin B1. Observations on pathological effects of the solvent (dimethylformamide).

Male Syrian hamsters, 8-10 weeks of age, were treated with a single intraperitoneal injection of crystalline aflatoxin B1 in solution of N -N -Dimethylformamide (DMF). The concentrations of aflatoxin were adjusted to the smallest controllable amount of solvent in relation to the size of the animal (0-5 or 1-0 ml/kg). Treatment with, respectively, 5-0 or 2-5 mg/kg aflatoxin in 1-0 ml/kg DMF was lethal to most animals within one week. However, reduction of the solvent to 0-5 ml/kg, while not eliminating the mortality entirely during the first week, made possible observation of the survivors up to 28 days. Hamsters appear to be more susceptible to DMF poisoning than other species, like rat, guinea-pig and rabbit in which this solvent was used by investigators on the biological effects of aflatoxin. Either dose given of DMF alone was lethal for several animals during the first week of observation and sufficient to produce histological lesions in the liver which were characteristic and clearly different from those induced by aflatoxin during the same period. DMF alone caused centrilobular necrosis which was accompanied by haemosiderosis of liver structures. With a aflatoxin, in addition, periportal and midzonal necrosis of the liver was present. Aflatoxin B1 and B1 and DMF both induce haemorrhagic tendency probably involvement in the coagulation process of the blood. It cannot be decided, however, at present whether this is the result of an indentical mechanism.

Acute cholecystitis and persistent liver necrosis in mice provoked by isothiocyanate.

Two known cholangiotoxic agents, alpha-naphthylisothiocyanate (ANIT) and p-phenylenediisothiocyanate (PDT), were administered in single doses to mice to study their effects on the gallbladder. Both compounds caused maximal bile duct necrosis and periportal hepatocytic necrosis at 24 hours. In contrast, the gallbladders were edematous but not necrotic at 24 hours after treatment. At 48 hours, and in some animals up to four days, severe cholecystitis was present, while bile ducts revealed progressive regeneration. The delay in the onset of gallbladder lesions was assumed to be the result of the toxic agent concentration in gallbladder bile after hepatic bile secretion was suppressed for 24 hours. The lesions provoked by PDT were similar to those induced by ANIT, except for a hemorrhagic component.

Selective testicular lesions resulting from continuous prolonged intake of minimal amounts of ethionine.

A threshold dose of ethionine was determined which, when administered continuously for up to 10 months, produced testicular lesions in rats but did not interfere with body growth and did not produce histologic lesions in the pancreas. In the liver, only mild fatty changes were observed. Interstitial cells of the testis showed hyperplasia at three to four months, followed by dedifferentiation of these cells in the later stages of the experiment. Complete atrophy of tubules was seen in most segments, but even at 8 and 10 months of ethionine ingestion, well-defined segments revealed intact spermatogenesis in all animals. The hypothetical emergence of a mutant ethionine-resistant spermatogonial stem cell is discussed. When ethionine was withdrawn from the diet at 10 months, incomplete regeneration of tubular epithelium was seen two months later, but the interstitial cells remained of the nondifferentiated type. Fatty changes in the liver, comparable to those observed in male ethionine-treated animals only after castration, are likely to have resulted from dedifferentiation of Leydig cells with concomitant testosterone deficiency. Rats receiving smaller doses of ethionine showed fatty change in the liver although no testicular lesions were recognizable. It is possible that ethionine interfered with synthesis of testosterone before testicular lesions could be demonstrated by light microscopy.