{"title":"Preclinical toxicity study of streptozocin infused into the internal carotid artery of dogs and baboons.","authors":"P M Kanter, G A Bullard, C R West, Z P Pavelic","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Mature male and female dogs (10) and male baboons (4) were each given a single dose of streptozocin (STZ) (1000 mg/m2) by infusion directly into the left internal carotid artery over a two-hour time period. Serial hematology and serum chemistry profiles and physical observations were made, the animals necropsied at varying times after dosage, and the major organs examined histologically. In dogs, severe weight loss, neutrophilia, electrolyte disturbances, decreased liver function, diabetes and decreased serum amylase levels were the major toxicities. In baboons, weight loss, hypoglycemic coma, diabetes, decreased liver function and electrolyte disturbances were observed. While systemic toxicities were severe in both animal species, central nervous system toxicity was minimal. Cerebral toxicities consisting of edema in two dogs, and focal necrosis in one dog were observed histopathologically. No cerebral toxicity occurred in baboons. Based upon these findings, a phase I clinical trial of intra-arterial (internal carotid artery) STZ in patients with primary/metastatic brain tumors would appear feasible.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"5 4","pages":"133-42"},"PeriodicalIF":0.0,"publicationDate":"1990-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13306156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N Azad, R Nayyar, J Tentler, M Cernius, N V Emanuele, L Kirsteins, A M Lawrence
{"title":"Anatomical and functional effects of estrogen-induced prolactinomas on the rat hypothalamus.","authors":"N Azad, R Nayyar, J Tentler, M Cernius, N V Emanuele, L Kirsteins, A M Lawrence","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Although estrogen-induced prolactinomas have been widely studied, little attention has been accorded to local pressure effects of the tumor on the hypothalamus and portal vasculature. To portray the magnitude of this phenomenon, four groups of 12-13-week-old female Fisher 344 rats were studied. Group 1 was an intact control receiving a subcutaneously (SC) placed placebo pellet; group 2 was an ovariectomized control with a SC placed placebo pellet; group 3 was ovariectomized with a 10 mg SC placed diethylstilbestrol (DES) pellet; and group 4 was ovariectomized receiving both 10 mg DES and 10 mg SC placed bromocriptine pellets. Blood samples were obtained at 4 weeks, and the animals were sacrificed at 8 weeks after pellet implantation at which time blood, pituitary and hypothalami were obtained. At 4 weeks serum prolactin levels were similarly and significantly elevated above the control groups in both the DES and DES/bromocriptine groups. By 8 weeks, however, serum prolactin level(s) in the DES-treated animals had tripled from the 4-week value, while levels in the DES/bromocriptine-treated animals were unchanged from the 4-week values. This finding matched the observation that the DES-treated animals had pituitaries 2.5-fold heavier than the DES/bromocriptine animals. The gross and histologic structure of the hypothalami and portal vessels were markedly disrupted in DES-treated rats and much less so in the DES/bromocriptine-treated group. These findings lead us to speculate that the pathogenesis of DES-induced prolactinomas proceeds in two phases: First, there is an early chemical induction phase in which estrogen directly and indirectly stimulates lactotrope proliferation and, second, a mechanical disinhibition phase, where tumor-induced destruction of the hypothalamus and portal vessels unleashes the pituitary from the dopaminergic restraining effects of the hypothalamus.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 4","pages":"237-49"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13755462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Matrix vesicles and calcification of rachitic rat osteoid.","authors":"T F Johnson, D C Morris, H C Anderson","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Tibiae from rachitic weanling rats were studied during healing to examine the mechanism of bone mineralization. Rickets was induced by feeding the animals a low phosphate, low vitamin D diet for five weeks. Calcification was reinstituted in three ways; group I animals received 1.0 ml of NaH2PO4 i.p. and the rachitogenic diet in a darkened room; group II animals were placed in a lighted room and given standard laboratory chow; group III animals were placed in lighted room, given standard laboratory chow and received 1.0 ml of 0.1M NaH2PO4 i.p. Group I healed slowly while II and III were found to heal rapidly and at nearly identical rates. Groups II and III revealed a significantly elevated serum alkaline phosphatase activity and became hyperphosphatemic as the rickets healed suggesting a more vigorous recovery. Ultrastructurally, numerous matrix vesicles were noted in unhealed rachitic bone matrix and these structures acquired mineral upon initiation of healing. Vesicle-associated mineral aggregates increased in size penetrating through and beyond the vesicle membrane and were incorporated into the advancing mineralization front. By 48 hrs. post-healing initiation, the osteoid borders were almost completely mineralized in groups II and III. These observations suggest that in addition to pre-existing mineral, matrix vesicles can also serve as nucleating sites in the osteoid of post-fetal bone.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 3","pages":"123-32"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13909118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effect of fatty acids and their derivatives on mitochondrial structures.","authors":"A K Singh, Y Yoshida, A J Garvin, I Singh","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Reye's Syndrome (RS) is characterized by encephalopathy, fatty degeneration of viscera and high levels of free fatty acids which are implicated in cellular toxicity. We have examined the effects of octanoic acid (C8:0), palmitic acid (C16:0) and oleic acid (C18:1) on rat liver mitochondrial swelling by spectroscopic and microscopic techniques. Of the fatty acids tested oleic acid had a greater effect than palmitic acid while octanoic acid had no effect. Acyl-CoA derivatives produced greater mitochondrial swelling than either acyl-carnitine or free fatty acids. However, identical amounts of palmitoyl-CoA and oleoyl-CoA were required to produce the same degree of swelling. Addition of carnitine (2mM) to oleoyl-CoA reduced the mitochondrial swelling significantly thus suggesting that the toxicity of the fatty acids may be reduced by conversion to their carnitine derivatives. Twice the concentration of oleoyl-carnitine was required to produce half the maximum swelling as compared to oleoyl-CoA. Ultrastructural profiles of mitochondria treated with oleic acid, oleoyl-CoA and oleoyl-carnitine demonstrated greater swelling with oleoyl-CoA than with oleic acid or oleoyl-carnitine. These results suggest that carnitine may protect the mitochondria from damage by the fatty acids and their acyl-CoA derivatives in Reye's Syndrome.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 1","pages":"9-15"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13916659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Staining of surface antigen on migrating lymphocytes in the chemotaxis membrane. I: Complement C5 attracts helper/inducer T cell much more than suppressor/cytotoxic T cell and NK cell.","authors":"Y Hayashi, A Imaizumi, T Yoshida, M Torisu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We have measured various chemotactic activities for neutrophils (1-3), lymphocytes (4), macrophages (5) and eosinophils (6-11) by the modified Boyden chamber method. In the conventional method, it is necessary to purify the indicator cells in upper chamber because it is impossible to distinguish inflammatory cells on the chemotactic membrane. For example, when we estimate T lymphocyte chemotaxis, we collected nylon-wool nonadherent peripheral blood lymphocytes (PBL) and confirmed their purity by sheep erythrocytes rosette formation assay. Pohajdak et al (12) evaluated NK cell chemotaxis by using large granular lymphocytes (LGL) for indicator cells. LGL fractionation was confirmed by monoclonal antibodies, HNK-1, OKT11, OKT3, OKT4, OKT8, OKM1, and MO2. When we arranged the study to evaluate chemotaxis of lymphocyte subsets which were divided by surface antigens, the conventional method needed a large quantity of PBL for the indicator cells. Moreover, one or two lymphocyte subsets had to be obtained from an identical PBL donor. This was time consuming. So, we tried to identify migrating lymphocytes in the chemotaxis membrane by their surface antigens. In this communication, we report that the staining of surface antigens on migrating lymphocytes in the chemotaxis membrane is effective and useful for evaluation of lymphocyte subset chemotaxis. It prompted us to report the new findings about modification of lymphocyte subset chemotaxis by C5a.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 3","pages":"181-92"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13926687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potential role of Kupffer cells in initiating liver injury during endotoxemia.","authors":"M Katoh, M Torisu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The potential contribution of Kupffer cells (KCs) to endotoxin-induced liver damage was evaluated by measuring the functional changes of KGs [Superoxide (O2-) generation, and chemotaxis (CTx)] isolated from such livers and comparing them with biochemical and histological changes of liver damage. Sublethal doses of endotoxin was daily administered to rats for 4 days. Liver damage was apparent in the rats treated with single administration of endotoxin and the maximal change was observed in the rats treated with endotoxin for 2 days in association with the marked enhancement of O2- release and CTx in vitro by KCs from these animals. However, liver injury decreased in the rats treated with endotoxin for 3 days and the rats treated with endotoxin for 4 days had shown almost no detectable injury. KCs' biological functions also diminished in group treated for 3 and 4 days. In particular, oxidative and chemotactic responses of KCs from rats treated for 4 days significantly decreased, compared with the cells from those treated for only two days. These results indicate that KCs are pivotal in the pathogenesis of liver injury during endotoxemia.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 3","pages":"141-61"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13909121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"In vivo detection of retroviral particles in mice with hybridoma induced ascites.","authors":"A H Bartal, R M Ludatscher, C Lichtig","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Ascites induced by hybridoma cells following their injection into pristane-primed peritoneal cavities of BALB/c mice is often associated with the formation of intra-abdominal tumors related to the transplanted cells. These tumors and adjacent abdominal and extra-abdominal organs were excised and examined by electron microscopy. Clusters of viral particles were seen in nearly all cells composing the hybridoma tumors. The viral particles were usually present in rough ER cisternae of the transplanted tumor cells and at times were observed budding from the cisternal membranes. Individual viral units were doughnut shaped, 80-85 nm in diameter, with two concentric shells of which the outer one was more electron dense. No exogenous viral particles were detected in the peritoneally growing hybridoma cells. All non-tumor tissues examined such as liver, spleen, lung, brain and circulating WBC were free of virus. These findings provide further evidence of viral contamination of hybridomas and demonstrate the mode of persistence of such contamination when cells are placed in-vivo.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13916657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J Jagirdar, A Nonomura, J Patil, A Thor, F Paronetto
{"title":"ras oncogene p21 expression in hepatocellular carcinoma.","authors":"J Jagirdar, A Nonomura, J Patil, A Thor, F Paronetto","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Aberrant proto-oncogene expression has been implicated in hepatic cell proliferation, transformation and carcinogenesis using a rat model. To investigate the role of ras p21 product expression in human hepatocellular carcinoma (HCC), we have localized ras p21 in formalin fixed, paraffin-embedded normal and abnormal livers utilizing the avidin-biotin peroxidase method and a monoclonal antibody to ras-gene product p21. A semi-quantitative estimate of p21 expression was performed by serial dilutions of primary antibody. While low dilutions of anti-p21 stained normal hepatocytes, higher dilutions failed to react with normal hepatocytes and these dilutions were used for assessment of p21 enhancement. Increased p21 expression of ras oncogene in HCC occurs in fibrolamellar carcinomas and other better differentiated HCC. Tumor dedifferentiation is associated with an attenuation of p21 expression. Liver adjacent to HCC exhibits p21 enhancement, in contrast to liver surrounding metastatic carcinoma, suggesting increased p21 expression in HCC induction.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 1","pages":"37-46"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13693765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J Mandl, G Bánhegyi, T Garzó, K Lapis, F Antoni, Z Schaff
{"title":"Ethanol treatment inhibits the development of diethylnitrosamine-induced tumors in rats.","authors":"J Mandl, G Bánhegyi, T Garzó, K Lapis, F Antoni, Z Schaff","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Effect of ethanol (20% in drinking water) or acetone (1% in drinking water) treatment was investigated on N-diethylnitrosamine (DEN), acetyl-aminofluorene (AAF) and partial hepatectomy (PH) induced hepatic tumors in rats. Simultaneously with the morphological detection of foci and nodules in the liver of the sacrificed rats, the activities of isozymes of cytochrome P450IIE gene subfamily responsible for the oxidation of ethanol or acetone (as aniline hydroxylase) and also the activity of aminopyrine N-demethylase were determined. Nodules could be detected after DEN, AAF and PH treatment with and without combination with acetone, however nodules did not developed in ethanol treated animals even 6 months after the DEN injection. As expected acetone or ethanol selectively increased the activity of aniline hydroxylase without a general induction of P-450 enzymes. It is suggested that the induction of P-450IIE isoenzymes per se is not connected to the preventive effect of ethanol on DEN induced carcinogenesis.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 4","pages":"227-35"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13755461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Characterization of the antigen-reactive T cell line mediating in vivo delayed type hypersensitivity established by antigen-induced interleukin 2.","authors":"K Kobayashi, S Cohen, T Yoshida","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The murine antigen-reactive T cell line has been established by antigen-induced interleukin 2 (IL-2) derived from immunized syngeneic mice. The surface markers of the cells showed Thy 1+, and Lyt 1+2-. The antigen-reactive cells require the presence of IL-2 for continuous proliferation. IL-2 from mouse, rat, or human sources all stimulate the T cell line growth. The T cell mitogen such as concanavalin A and antigen alone do not stimulate cell proliferation of the cells. The cells proliferate antigen-specifically in the presence of both IL-2 and antigen-presenting cells from histocompatible mice. Antigen-specific in vivo delayed type hypersensitivity response is inducible by injection of the T cells into naive syngeneic mice along with IL-2 and antigen. The reactivity of the T cell line found in vitro (proliferation) and in vivo (delayed type hypersensitivity) is highly antigen-specific, because the cells do not respond another antigen used for immunizing mice. The antigen-reactive T cell line produces neither IL-2 nor inhibiting factors such as neutralizing factors against preformed IL-2 activity and IL-2 production inhibiting factors, thus the cells are exclusive IL-2 acceptor. These results suggest that the interaction of antigen-induced IL-2 and IL-2 dependent antigen-reactive T cells may play a significant role in the induction/expression of in vivo delayed type hypersensitivity to specific antigen, because antigen-induced IL-2 is probably only a relevant IL-2 in the immunized mice.</p>","PeriodicalId":73745,"journal":{"name":"Journal of Experimental Pathology","volume":"4 3","pages":"163-79"},"PeriodicalIF":0.0,"publicationDate":"1989-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13926686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}