No abstract

Background-Anisotropic conduction properties may provide a substrate for reentrant arrhythmias. We investigated the age-dependent changes of structural and functional anisotropy in isolated right atria from infant (1 to 2 months), young (6 to 12 months), and old (6 to 10 years) dogs. Methods and Results-The histology of the mapped atrial tissues (a small subepicardial area, 2.8ϫ4.2 mm) was characterized by an age-dependent increase of myofiber width and fat cell infiltration between myofibers. Connexin43 was distributed homogeneously over the entire cell surface in infant dogs, whereas it progressively polarized to the cell termini with increasing age. The activation sequences were analyzed by high-resolution optical mapping using a voltage-sensitive dye. Activation fronts from the pacing site proceeded more rapidly along fiber orientation (longitudinal) than across it (transverse). Infant dogs showed "elliptical" isochrones with a smooth transition between longitudinal and transverse propagation, whereas old dogs had a "square" pattern with a sharp transition. Conduction block occurred predominantly during longitudinal propagation in infant dogs but during transverse propagation in old dogs. The shape of the wave front and the degree of lateral uncoupling seemed to decide the preferential direction of block. A zigzag activation causing an extremely slow transverse conduction was observed only in old dogs. Conclusions-Along with the age-dependent structural anisotropy, the preferential direction of block changed from longitudinal to transverse in association with a change in the wave front configuration. A zigzag propagation based on lateral uncoupling would predispose the elderly to multiple reentry and a higher incidence of atrial fibrillation.

The present study was performed to assess the roles of hepatocellular oxidative damage to DNA and constituents other than DNA in rat liver carcinogenesis caused by a choline‐deficient, l‐amino acid‐defined (CDAA) diet by examining the effects of the antioxidant N, N′‐diphenyl‐p‐phenylenediamine (DPPD). The parameters used for cellular oxidative damage were the level of 8‐hydroxyguanine (8‐OHGua) for DNA and that of 2‐thiobarbituric acid‐reacting substance (TBARS) for constituents other than DNA. A total of 40 male Fischer 344 rats, 6 weeks old, were fed the CDAA diet for 12 weeks with or without DPPD (0.05, 0.10 or 0.20%) or butylated hydroxytoluene (BHT, 0.25%). In the livers of the rats, the numbers and sizes of glutathione S‐transferasc (EC 2.5.1.18) placental form (GSTP)‐ and/or γ‐glutamyltransferase (GGT, EC 2.3.2.2)‐positive lesions and levels of 8‐OHGua and TBARS were determined. The GSTP‐positive lesions of 0.08 mm2 or larger were all stained positively for GGT as well in cross‐sectional area, whereas the smaller lesions were generally negative for GGT. DPPD and BHT reduced the size of the GSTP‐positive lesions without affecting their total numbers. At the same time, they reduced TBARS generation without affecting 8‐OHGua formation in DNA. The present results indicate that oxidative DNA damage (represented by 8‐OHGua formation) and damage to constituents other than DNA (represented by TBARS generation) may play different roles in rat liver carcinogenesis caused by the CDAA diet; the former appears to be involved in the induction of phenotypically altered hepatocyte populations while the latter may be related to the growth of such populations.

Mizoribine has been shown to possess an immunosuppressive action that inhibits the proliferation of lymphocytes selectively by interfering with inosine monophosphate dehydrogenase. Recent studies have demonstrated that mizoribine improves renal tubulointerstitial fibrosis in the rat model of unilateral ureteral obstruction (UUO) by inhibiting the infiltration of macrophages. We, therefore, examined the dose dependency of the suppressive effect of mizoribine on the infiltration of interstitial macrophages and T lymphocytes and the interstitial volume in UUO-treated kidneys. Furthermore, we investigated the expression of osteopontin (OPN), known to be a chemoattractant protein for macrophages, in the renal cortex. In rats with UUO, the interstitial volume was markedly expanded, and macrophage and T lymphocyte infiltration in the interstitium and the expression of OPN in the cortical tubules were greatly increased. Treatment with mizoribine ameliorated the increase in interstitial volume induced by UUO. Interstitial infiltration of macrophages and T lymphocytes was dose dependently suppressed by mizoribine, and the decreased macrophage infiltration was correlated with inhibition of tubular OPN expression. These results suggest that mizoribine has a beneficial effect on several steps contributing to the progression of tubulointerstitial fibrosis caused by obstruction of the ureter.

Both spontaneous (SOS) and 4‐hydroxyaminoquinoline 1‐oxide (4‐HAQO)‐induced osteosarcomas (COS) could be serially transplanted in the subcutaneous back space of syngeneic F344 rats, the success rate becoming 100% within 5 passage generations. Transplanted tumors demonstrated rapid growth and displayed high potential for metastasis to the lung in later generations. Tbus, a 100% lung metastasis rate was observed for SOS after the 20th and for COS after the 14th generation. The histological features of the primary SOS and COS were retained during serial transfer. These model systems should be useful for investigation of the biology of this very important tumor type.

Abstract-Activation of glia has been observed in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis and brain ischemia. Excessive production of nitric oxide (NO), as a consequence of increased inducible NO synthase (iNOS) in glia, contributes to neurodegeneration. Transglutaminase 2 (TG2) is a cross-linking enzyme, which is activated in neurodegenerative diseases such as PD, AD and Huntington's diseases. However, mechanisms contributing to the increased TG activity in neurodegenerative diseases remain to be clarified. In the present study, we examined the expression of TG2 in cultured rat hippocampal astrocytes activated with lipopolysaccharide (LPS), which is generally used for a stimulant of iNOS induction. The expressions of TG2 mRNA and protein were increased by stimulation with LPS in a dose-dependent manner. The LPS-induced TG2 expression was diminished by ammonium pyrrolidine-1-carbodithioate; an inhibitor for nuclear factor (NF)-κB activation, suggesting the factors involved. Both expressions of TG2 and iNOS induced by LPS stimulation were suppressed by an antioxidant, ethyl pyruvate, in a dose-dependent manner. Furthermore, they were also suppressed by cystamine, an inhibitor of TG activity. These results suggest that the level of TG2 expression is regulated by oxidative stress and the activity of TG itself, and that the induction of iNOS and NO production are closely associated with TG2 expression in LPS-stimulated activation of astrocytes.

We macro- and microscopically examined two cases of congenital visceral transposition (situs inversus totalis) in SD rats. We also investigated the possibility of situs inversus in association with immotile-cilia syndrome. The rats had grown normally with no clinical signs of disease. Although all organs including the vascular system were located opposite to the normal position and displayed a mirror image on macroscopic observation, no abnormality was found in any of the organs on microscopic examination. Electron-microscopic observation revealed in neither animal any structural abnormalities of the cilia and flagella, which are one of the diagnostic characterizations of immotile-cilia syndrome. Congenital transposition of the viscera is rare and there are few reports examining complications with situs inversus in rats. This report will be helpful in accumulating information on this condition.

Abstract:Chronic toxicity of diphenyl and its ability to promote carcinogenesis by N-ethyl-N hydroxyethylnitrosamine (EHEN) in the kidney, were studied in Wistar rats.In the study of chronic toxicity, diphenyl at doses of 0, 0.25. and 0.5% was given in the diet to Wistar rats of both sexes for 75 weeks. Diphenyl dose-dependently induced urolithiasis, and stones, accompanied by hematuria. were observed in the kidney, ureter, and urinary bladder as early as 16 weeks after the beginning of the experiment.At the dose of 0.5% of diphenyl, the incidence of stones in the kidney and urinary bladder was 46.2 and 15.4%, respectively, in females and 31.9 and 27.7%, respectively, in males.Kidney stones were black and composed of protein, but urinary bladder stones were yellowish-white and composed of ammonium magnesium phosphate. In the promotion experiment, EHEN, at a dose of 0.1%. was given in the diet for 2 weeks as the initiator of carcinogenesis, and then diphenyl, at doses of 0, 0.125, and 0.5% was supplied in the diet for 34 weeks, to male Wistar rats. Neither doses of diphenyl affected the incidences of dysplastic foci and renal cell tumors induced by EHEN in the kidney.However, 0.5% of diphenyl, in spite of inducing urolithiasis, significantly decreased the mean numbers of both dysplastic foci and renal cell tumors per cm2 of the kidney.These results indicated that diphenyl induced urolithiasis but exhibited rather inhibitory effect on the induction of kidney carcinogenesis by EHEN in rats. (J Toxicol Pathol 2: 41-48, 1989)