Hyperplastic Areas Research Articles

Intrahepatic bile duct proliferation induced by 4,4′-Diaminodiphenylmethane in rats

Prolonged intoxication with 1000 ppm of 4,4′-diaminodiphenylmethane (DDPM) led to hyperplasia of bile ducts and proliferation of oval cells. Hyperplastic areas gradually regressed and were replaced by fibrous tissue after cessation of DDPM administration. Elevation of γ -glutamic transpeptidase and alkaline phosphatase in serum accompanied the proliferation of bile ductular cells.

Localization of alpha1-fetoprotein and DNA-synthesis in liver cell populations during experimental hepatocarcinogenesis in rats.

AbstractSix‐, 12‐ and 20‐week‐old rats were fed N‐nitrosomorpholine (NNM) at low concentrations (6 mg/kg/day) or high concentrations (20 mg/kg/day) for 6 or 12 weeks. Irrespective of the age of the rats, both NNM schedules resulted in development of hepatomas and during the early stages of hepatoma induction, liver histotoxic patterns depended only on the dose of carcinogen employed. Necrosis of hepatocytes and proliferation of small, oval‐shaped cells occurred when high doses of NNM were applied. Parallel to the proliferation of oval‐shaped cells, resurgence of alpha1‐fetoprotein (AFP) in rat sera was observed and production of this protein was confined to the oval‐shaped cells as shown by immunoperoxidase staining. During proliferation of bile duct epithelium, induced by galactosamine injections, those cells could also stain for AFP, and proliferation of oval‐shaped cells concomitant with intracellular AFP staining resulted from restitution of heavily damaged liver. In pulse‐chase labelling experiments with 3H‐thymidine, oval‐shaped cells were seen in continuous development towards hepatocytes, and distinct areas of hyperplastic appearance occurred. Normal hepatocytes and hyperplastic areas did not stain for AFP. Upon low‐dose feeding of NNM, no cellular AFP and no serum AFP were detected unless hepatoma cells had developed. At the stage of malignant conversion, distinct AFP‐staining nodules were localized which consisted of neoplastic hepatocytes. AFP‐staining and non‐AFP‐staining nodules were seen concomitantly in the same animal. AFP was localized only in neoplastic hepatocytes. Pulse‐labelling experiments with [3H]thymidine showed the proliferative character of hepatoma cells from which the AFP‐staining population in particular was involved. No correlation was found between the presence of AFP and histological grading of hepatomas. The wide range of both serum AFP levels and their rising rates in individual rats indicated the highly heterogeneous character of the induced hepatomas with respect to AFP production.

Beta cell nesidioblastosis

Two patients with severe hypoglycemia since birth are described. In both hyperinsulinism was demonstrated during spontaneous hypoglycemic attacks or could be provoked by various tolerance tests. In case I considerable obesity and psychomotor retardation was present at the age of one year whereas in case II weight gain was normal and development unaffected. Immunofluorescence microscopic and electron microscopic examination of the pancreas after subtotal pancreatectomy revealed diffuse islet cell hyperplasia with nesidioblastosis in case I and β-cell nesidioblastosis in case II. The hyperplastic and nesidioblastotic areas consisted mainly of β-cells. In addition, an accumulation of somatostatin producing cells was observed in case I, and some cells were found with ultrastructural signs of both endocrine and exocrine function. In both cases, pancreatic insulin release was inhibited by a prolonged somatostatin infusion. The results of tolerance tests did not allow a diagnosis of the underlying pancreatic lesion. In case II, leucine-sensitive hypoglycemia detected soon after birth, was present even after subtotal pancreatic resection. Therapeutic trials with diazoxide in case I and a leucine-restricted diet in case II were only of temporary benefit. After subtotal pancreatectomy there was clinical improvement in both cases, but case II still needs a leucine-restricted diet. The familial occurrence of persistent hypoglycemia in both cases suggests that β-cell nesidioblastosis may be a hereditary disorder.

Nature of early appearing, carcinogen-induced liver lesions to iron accumulation.

A technique for induction of iron accumulation in hepatocytes of rats was used to identify early carcinogen-induced lesions by their histochemical absence of iron. Foci of iron-free altered hepatocytes produced by the feeding of N-2-fluorenylacetamide (FAA) for 3 weeks were composed of cells that were replicating when surrounding iron-containing hepatocytes were not, and that responded to a mitotic stimulus when surrounding hepatocytes were inhibited or showed a delayed response. Thus these lesions represented focal hyperplastic overgrowths. The iron-free hyperplastic foci developed into hyperplastic areas that progressed with longer feeding of FAA to form hyperplastic nodules. The lack of iron was a sensitive and reliable marker for hyperplastic lesions, which also permitted their identification in the fresh state. Both early hyperplastic lesions and nodules were often resistant to the necrogenic effects of dimethylnitrosamine, as well as to the antireplicative effect of FAA. The selection of such cells resistant to the toxic effects of carcinogens may be important in the pathogenesis of liver neoplasia.

HISTOCHEMICAL DEMONSTRATION OF INCREASED ACTIVITY OF γ-GLUTAMYL TRANSPEPTIDASE IN RAT LIVER DURING HEPATOCARCINOGENESIS

Histochemical demonstration of γ-glutamyl transpeptidase (γ-GTP) during chemically induced hepatocarcinogenesis in the rats was studied. The carcinogens employed were N-OH-FAA (N-hydroxy derivative of N-2-fluorenylacetamide), and aflatoxin B1.In the control rats, activity of γ-GTP was demonstrated in the bile duct cells and occasionally along the bile canaliculi, but was not in the hepatocytes. Proliferating bile duct cells including so-called oval cells and cholangiocarcinoma cells, and hepatocytes of hyperplastic areas and nodules and hepatocellular carcinoma induced by N-OH-FAA with or without aflatoxin B1 revealed positive activity of γ-GTP, histochemically. Only focal demonstration of γ-GTP activity in the hepatocyte was observed in association with a mild hyperplastic change in rats treated with aflatoxin B1 alone.The elevation of γ-GTP activity in serum and liver tissue with appearance of fetal type of its isoenzyme pattern was also demonstrated biochemically and correlated with the histochemical appearance of γ-GTP activity in the liver tissue from the early phase of hepatobiliary carcinogenesis.These results seem to demonstrate carcino-embryonic nature of the induced γ-GTP in the development of cholangiocellular and hepatocellular carcinomas.

Histology and ultrastructure of oat blue dwarf virus infected oats

The oat blue dwarf virus is a small spherical virus (28–30 nm) in diameter and is obligatorily transmitted by the aster leafhopper Macrosteles fascifrons Stål. The virus causes abnormalities in the phloem development of infected plants. Hyperplasia and limited hypertrophy of phloic procambium, in a given procambial strand, begin only after the maturation of the first protophloem sieve-tube element in that particular localized area. The majority of phloem elements produced in hyperplastic areas are parenchymatous, have truncated end walls, and lack sieve plates. Electron-microscopic observations substantiated the hypothesis that the virus was phloem-limited by revealing virus particles only in phloem elements. The greatest accumulation of virus particles was observed in the region between immature and fully vacuolated phloem elements, implicating virus synthesis in immature elements. Crystals of virus particles were often large enough to be seen by light microscopy.

The effect of testosterone and testosterone metabolites on the fine structure of the rat prostate gland in organ culture.

SUMMARY The action of testosterone and its metabolites, dihydrotestosterone and 3β-androstanediol on the fine structure of the rat ventral prostate gland in organ culture was investigated. In intact glands before explantation the epithelial cytoplasm showed a system of membrane-bound ergastoplasmic channels studded with ribosomes, a discrete Golgi body, associated with secretory vacuoles and microvilli projecting into the lumen. In explants grown in non-supplemented medium the epithelium underwent a severe regression. The ergastoplasm collapsed and was fragmented and there was no discrete Golgi body. Microvilli were absent and a number of electron-dense bodies interpreted as lysosomes were scattered throughout the cytoplasm. In explants grown in the presence of testosterone, dihydrotestosterone and 3β-androstanediol the fine structure was similar to that in the intact gland. Ergastoplasm and Golgi apparatus were well maintained, secretory vacuoles could be observed and the microvilli resembled in size and number those of the normal organ. In hyperplastic areas of explants treated with dihydrotestosterone, the maintenance of the ergastoplasm was less complete but the Golgi zone and microvilli were well preserved. In explants treated with testosterone or dihydrotestosterone, nucleolar bodies were observed in many nuclei of epithelium and stroma. The effects of the steroids on the fine structure of the gland confirm those seen at the light microscopic level and support the suggestion that the action of testosterone is mediated through its metabolites.

Mycoplasma meleagridis Infection: Development of Air-Sac Lesions in Turkey Poults

SUMMARY The sequential development of lesions in poult air sacs experimentally infected with Mycoplasma meleagridis was studied. Lymphocytic perivascular infiltration occurred early, accompanied by fibrinocellular exudate on the surface of air-sac epithelium. The epithelium became hyperplastic in some areas and underwent necrosis in others. The hyperplastic areas often formed acinar-like structures which coalesced and eventually resulted in separation of air-sac epithelium and exudate. Later in the disease, lymphoid follicles were formed within air-sac tissues, and the exudate became organized. Electron microscopy revealed structures resembling M. meleagridis along the surface of air-sac epithelial cells. It also indicated that the lymphoid follicles resulting from air-sac infections were intimately surrounded by collagen bundles and composed primarily of hemocytoblasts believed to be bursa-dependent cells involved in circulating antibody production.

Differences Between High and Low Breast Tumor Strains of Mice When Ovariectomized at Birth.

ConclusionMarked differences appeared in strains of mice when they were ovariectomized at birth and then examined in later life. The high tumor J AX dba and J AX C3H strains showed stimulated uterus, vagina and mammary glands. The adrenal glands exhibited extensive nodular, hyperplastic areas. All of these organs of the low tumor J AX C57 black strain remained essentially unstimulated. To ascertain whether the above differences are characteristic of all high and low tumor strains, other strains are being studied.

EXPERIMENTAL STUDIES OF THE VIRUS OF INFECTIOUS AVIAN ENCEPHALOMYELITIS

The results of investigations thus far carried out on experimental avian encephalomyelitis indicate that the virus of this newly described disease conforms to the group of definitely established viruses. It was essential to determine its taxonomy since the only prior record of its study (1) defines the infective agent as a virus because the usual cultural attempts failed to reveal a visible microorganism to be identified with it, and because the transmissible agent passed through Seitz and Berkefeld N filters. At the present time such determinants fail completely to satisfy the criteria for defining a virus and their acceptance would lead to the inclusion of certain filtrable microbic agents, difficult to reveal except by special cultural procedures, as viruses (10). The virus of avian encephalomyelitis is distinct from that of equine encephalomyelitis and is clearly a virus sui generis. The striking feature of its properties is its narrow range of host susceptibility-only the avian species are responsive to inoculation; ordinary laboratory animals are apparently resistant, even to large numbers of chicken cerebral infective doses. In addition, it is probable that its size is in the range of that of the equine virus. Studies also reveal that the virus is not easily sedimented by centrifugation (that is, at 5400 R.P.M. for one hour in the angle centrifuge and at 12,000 R.P.M. for one hour in the open air centrifuge) and is resistant to the action of glycerol and to drying. It is readily filtrable through Seitz one and two disc filters, through Berkefeld V and N candles, and is active in dilutions in broth up to 10(-6). It passes through gradocol membranes of 73 mmicro average pore diameter at least (the end-point has not as yet been definitely determined). An attack of the experimental disease leads to development of resistance to reinoculation and of antibodies in the serum. Old birds are reported as being refractory to infection, both in nature and in the laboratory (1, 2). Whether this resistance in mature animals is due to earlier exposure to infection, or to the development of structural or physiological barriers to invasion by the virus, remains still to be determined. Under experimental conditions, the route by which the virus acts uniformly to induce disease is the intracerebral. Yet in certain instances other peripheral ways of inoculation such as the intraperitoneal, subcutaneous, intradermal, intravenous, intramuscular, intrasciatic, may also be effective. Thus far, in limited experiments, feeding, or instilling nasally, or injecting into the vitreous body the infective agent has been ineffective. Whether the viral progression is axonal from peripheral sites is still to be determined; as should be also the question whether it multiplies in any of the organs other than the central nervous tissues. The virus was not detected in the blood during the period of incubation or during the acute phases of the experimental disease. So that unless it is found that other animals harbor the virus, or that still other sources of it exist as yet not disclosed, it is not likely that the disease is disseminated by a blood-sucking insect. The actual portal of entry and the factor in the spread of the disease in nature is still obscure, since the evidence here presented is still too incomplete to elucidate these problems. The pathological lesions induced are of interest. The neuronal reaction resembles that brought about by axonal disturbance (axon reaction, Nissl's or retrograde degeneration). The question may well be asked whether there may not be here an initial injury by the virus to the axonal process of the neuron, which in turn induces the retrograde changes in the cell body. This has as yet to be studied, as well as the possibility of viral progression along an axonal route with or without concurrent multiplication. The significance of the second major lesion in the central nervous system, namely, the generally marked perivascular reaction, is also still to be determined. Finally, the only observable and histopathological change in organs other than the central nervous tissues (in which we have not as yet noted the change) is in the hyperplasia of the normally present lymphoid islands. One is impressed by the prodigious numbers of lymphoid elements surrounding the vessels of the central nervous system and the question here is whether these hyperplastic areas serve as depots to supply the cells for this perivascular reaction.