Hepatotoxicity of Agents That Enhance Formation of Focal Hepatocellular Proliferative Lesions (Putative Preneoplastic Foci) in a Rapid Rat Liver Bioassay

Hepatotoxicity of Agents That Enhance Formation of Focal HepatocellularProliferative Lesions (Putative Preneoplastic Foci) in a RapidRat Liver Bioassay. WARD, J. M., TSUDA, H., TATEMATSU, M., HAGIWARA,A., AND ITO, N. (1989). Fundam Appl Toxicol. 12., 163–171.The histopathology of hepatic toxicity for 58 chemicals previouslytested in a rapid rat liver bioassay for demonstrating potentialhepatocellular carcinogens and/or tumor promoters was reviewed.Rats received the test diet for 1 week prior to partial hepatectomyand for an additional 5 weeks thereafter at doses near the estimatedmaximally tolerated dose. These rats served as controls forothers receiving initiation by N-nitrosodiethylamine (DEN) andthe test diets. Twenty-two of these chemicals were previouslyfound to enhance the formation of glutathione S-transferase,placental form (GST-P)-positive putative preneoplastic hepatocellularfoci (promoters) following DEN initiation in this rapid bioassay,whereas 36 chemicals did not. Of the agents that promoted GST-P-positivefoci, 14/22 (63.6%) produced toxic hepatocyte lesions whileonly 4/36(11.1%) of the nonpromoters did so at the doses used.Biliary toxicity was found for 7/22 (31.8%) of the promotersand 6/36 (16.7%) of the nonpromoters. Only 2/13 (15%) chemicalsthat inhibited GST-P-positive foci produced hepatic toxicity.Thus, agents that were presumed hepatic tumor promoters characteristicallywere hepatotoxins while nonpromoters of carcinogenesis werenot hepatotoxins in this rapid rat liver bioassay.     

Effects of mineralocorticoid and angiotensin II receptor blockers on proteinuria and glomerular podocyte protein expression in a model of minimal change nephrotic syndrome

Aim: Several proteins constituting the slit diaphragm are considered important for maintaining capillary wall permselectivity. Early intervention with blockers of angiotensin II receptors (AR) and mineralocorticoid receptors (MR) is effective against proteinuria in models of chronic hypertensive and protein‐induced renal damage. However, the effects of AR and/or MR blockers in a model of acute nephrotic syndrome remain unknown. The effects of AR and MR blockers were examined in puromycin aminonucleoside (PAN)‐treated rats. Methods: Six week old male Sprague–Dawley (SD) rats were injected with PAN or vehicle and assigned to groups as follows: vehicle (group C); PAN (group P); PAN followed 3 days later by administration of the MR blocker, eplerenone (group MR), and by the AR blocker, losartan (group AR). Blood pressure and urinary protein excretion were measured and all rats were killed for immunohistochemical investigation on day 14 after PAN administration. Results: Blood pressure did not change throughout the study period. Proteinuria was decreased in groups MR and AR compared with group P (on day 14 after PAN administration, respectively; group P vs AR, P < 0.01; group P vs MR, P < 0.05). Nephrin, podocin and podocalyxin staining was preserved in the glomeruli of groups MR and AR compared with group P. Conclusion: The MR and AR blockers decreased proteinuria in the acute model of nephrotic syndrome with preserved expression of glomerular podocyte protein independently of blood pressure.     

Case of multiple cutaneous granular cell tumors

Granular cell tumor is an uncommon, benign tumor, which mainly occurs on the skin, tongue and oral cavity as a single nodule. Multiple granular cell tumors are rare, with the incidence reported to vary from 7–29% in adult cases of the tumor. We describe a case of multiple cutaneous granular cell tumors in the right lumber and back regions along with a brief review of the published work on multiple cutaneous granular cell tumors.     

Percutaneous central venous catheterization via the great saphenous vein in neonates

In 44 neonates (mean birthweight 1207 g and mean gestational age 30.0 weeks), very small central venous catheters were percutaneously inserted via the great saphenous vein on 46 occasions. Catheter-related complications such as catheter blockages in 17 (37%), edema in a unilateral leg in three (6%), and mechanical disruption in two (4%) were noted. Although two of the neonates were found to have bacteremia and five neonates died, none were catheter related. The optimal length of catheter insertion (Y) from the great saphenous vein at the level of the medial maleollus to the inferior vena cava at T9 and L3 was calculated by regression equations utilizing total body length (X). Radiographs taken with extended and flexed leg postures revealed that the catheter tips were retracted with extension of the lower extremities and the degree of displacement ranged from 1 to 4 (mean 2.7) vertebral levels. Because this movement might cause migration into veins that connect to the inferior vena cava, the catheter tip should be located between T9 and L3, except at the renal vein junction. Percutaneous central venous catheterization via the great saphenous vein is safe and useful. Regression equations provided for rapid estimation of the optimal length of insertion.     

Comprehensive treatment of advanced neuroblastoma involving autologous bone marrow transplant

Encouraging results are reported with high-dose chemotherapy and total body irradiation followed by autologous bone marrow transplantation in the treatment of advanced neuroblastoma. However, relapse remains a significant problem. We used high-dose chemotherapy, surgery, intraoperative radiation and an autologous bone marrow transplant treated in vitro to remove tumor cells followed by 13-cis-retinoic acid to treat 36 children with advanced neuroblastoma. This comprehensive treatment appears to improve the survival rate of patients with advanced neuroblastoma, including those with N-myc amplification and bony involvement. The disease-free survival rate was 66% (95% confidence interval, 49–84%) at 3 years. All patients who received 13-cis-retinoic acid developed cheilitis, but no bone marrow depression occurred in these patients. Five patients developed hemolytic uremic syndrome (HUS) post-transplant. This may have been related to the procedure used for total body irradiation. Patients who had their kidneys shielded during this procedure did not develop this syndrome. Patients who received local irradiation at the primary site showed no evidence of relapse in this region, indicating that such therapy may help to prevent a relapse. These data suggest a high rate of 3 year disease-free survival with this treatment strategy. The nonrandomized nature of the study and use of multiple modalities precludes analysis of the specific contribution of each.     

Persistent production of interferon-gamma (IFN-γ) and IL-12 is essential for the generation of protective immunity against Listeria monocytogenes

IFN-γ and IL-12 are believed to be important in the host defence against Listeria infection in mice. However, the relationship between these two cytokines and generation of protective immunity remains poorly understood. In the present study, it was found that at least 4 days of immunizing infection were required for the generation of protective immunity against L. monocytogenes. Protective immunity was generated only by immunizing infection with virulent strain. Even repeated injections of avirulent strain failed to induce protective immunity. When the immunizing infection was terminated with antibiotics, generation of protective immunity and IFN-γ-producing ability was impaired, while expression of IFN-γ and IL-12 was also impaired. The mutual relationship between IFN-γ and IL-12 in L. monocytogenes infection was analysed in vitro. After neutralization of IL-12, IFN-γ production was completely blocked and IFN-γ expression was also inhibited. In contrast, there was no change of IL-12 expression after neutralization of IFN-γ. Taking all facts into consideration, it may be concluded that persistent production of IFN-γ induced by persistent production of IL-12 during immunizing infection is essential for the generation of protective immunity against L. monocytogenes.     

Correlation between α1–Adrenoceptors in Biopsy Specimens and Endoscopic Color Changes of Human Gastric Ulcer

α₁–Adrenoceptors were measured in the scar tissue (U) and marginal normal mucosa (C) of human gastric ulcers by radio-binding assay using [³H]-prazosin as the ligand. The specific radioactivity binding was calculated for the membrane-rich fractions of the U and C regions along with U/C ratio, and the relationship between the scar color tone and α–adrenoceptor binding levels was studied by conventional endoscopy and pharmacoendoscopy The U/C ratio for red scars (mean: 92.2%) increased as redness decreased. White scars had a mean U/C ratio of 135.6%. For pharmacoendoscopic classes P₁ and P₂, which remained red after spraying epinephrine onto the scar, the mean U/C ratio was 86.8%. For the P₃ class, which turned pale after the application of epinephrine spray, the mean U/C ratio was 172.0%. The recurrence of peptic ulcers is more frequent when red scars ocAcur, assessed by conventional endoscopy, in the P₁ and₂ classes, evaluated by pharmacoendoscopy, than in white scars (P₃ class). As the α₁–adrenoceptor binding of [³H]-prazosin appears to be proportional to the maturity of vasculature tissue, the present data suggest this latter factor plays a key role in the recurrence of gastric ulcers and that pharmacoendoscopy allows for a more accurate prognosis of ulcer relapse than conventional endoscopy     

Multiple glomus tumours: successful treatment with electron beam irradiation

A case is reported of a 23-year-old male with multiple glomus tumours that showed marked involution after he had electron beam therapy.