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Lipopolysaccharide (LPS) is a pathogen-associated large molecule responsible for sepsis-related endotoxic shock, and the heart is one of the most common organs adversely affected. LPS is reported to increase serum TNFalpha levels and reduce Per1 and Per2 gene expression. Therefore, in this experiment, we determined the time-dependent effects of LPS on heart rate (HR) and circadian gene expression in the mouse heart and liver. HR of the LPS group was significantly elevated 2 and 8 h after injection compared to the control group. A significant percent increase in HR was observed at ZT6, 12, and 18. LPS increased Tnfalpha mRNA expression in the heart and liver at ZT6, 18, and 24. A time-dependent effect of LPS on reduction of Per1 and Per2 gene expression was also observed in the heart and liver. In order to examine the effect of LPS on cell damage, we examined apoptosis-related gene expression after LPS injection. Bax mRNA expression level of the LPS group was higher than that of the control group 8 and 26 h after injection. On the other hand, Bcl2 mRNA expression level of the LPS group was lower than that of the control group 2 and 26 h after injection. Dexamethasone strongly attenuated the LPS-induced increase of serum TNFalpha without significant change in Per1 and Per2 gene expression in the heart. In conclusion, the present results demonstrated that LPS exerts a time-dependent inhibitory effect on Per1 and Per2 gene expression in the heart and liver. The chronopharmacological lethal effect of LPS may be related to the time-dependent increase of serum TNFalpha level and simultaneously high level of Per2 gene expression in the heart and liver between ZT12-18. Taken together, chronopharmacological effect of LPS may be related to not only sickness behavior syndrome and mortality, but also circadian rhythm systems.

小児期に発症し，16才以後までキャリーオーバーしたIgA腎症37例について，16才以後に尿が正常化した群と尿異常が持続した群に分け，キャリーオーバー関連因子を明らかにするために臨床病理学的検討を行った。 尿正常化群は8例，尿異常持続例は29例であった。発症，発見動機は両群ともchance hematuria and/or proteinuriaが最も多く，発症年令，腎生検時年令，最終観察時年令，男女比，高血圧，肉眼的血尿，腎機能，光顕所見における半月体と尿細管萎縮の頻度，蛍光抗体法所見は両群間で差がなかった。しかし，尿異常持続群では正常化群に比し，高度蛋白尿，糸球体増殖性変化，糸球体硬化，癒着が多く認められた。 以上より，小児期IgA腎症において，高度蛋白尿，強い糸球体増殖性変化，糸球体硬化，癒着が多く認められる症例は成人期にキャリーオーバーする可能性が高いと思われた。

Recent epidemiological changes in patterns of foci of amyotrophic lateral sclerosis (ALS) in the Western Pacific suggest that environmental factors play a contributory role in the pathogenic process of this disorder. In this experimental study on rats, a similar situation of dietary mineral imbalance was created as is found in the soil and drinking water of these ALS foci with a low content of calcium (Ca) and magnesium (Mg) and a high content of aluminum (Al). In groups of rats fed a low Ca diet, low Ca-Mg diet, and low Ca-Mg plus high Al diet, serum Ca levels were found to be lower than those in a group fed a standard diet. Also, serum Mg levels were lower in the groups fed a low Ca-Mg diet and a low Ca-Mg plus high Al diet than in the groups fed a standard diet and only a low Ca diet. There was no significant difference in Mg content of central nervous system (CNS) tissues of groups fed unbalanced and standard diets, except for a significant decrease in Mg content of the spinal cord of rats fed a low Ca-Mg plus high Al diet. Mg content of the lumbar spine and cortical bone decreased in the unbalanced diet groups compared with that of a group fed a standard diet. These findings suggest that under the disturbed bone mineralization induced by unbalanced mineral diets, Mg may be mobilized from bone to maintain the level necessary for vital activity in soft tissues including CNS tissue.

A comparative clinicopathological study was retrospectively performed in 61 children and 51 adults with IgA nephropathy. Hematuria and/or proteinuria as a chance finding was the most common initial clinical sign, being observed in 82.0% of the children and in 52.9% of the adults. At renal biopsy, hypertension and severe proteinuria were found in 9.8 and 33.3% of the adults and in 0 and 14.8% of the children (both p less than 0.05), respectively. Elevations of blood urea nitrogen and serum creatinine were found at this time of biopsy in 21.6 and 9.8% of the adults, but in none of the children (p less than 0.001 and p less than 0.05, respectively). Histologically, focal glomerulosclerosis and tubular atrophy were found in 52.9% of the adults and in 32.8% of the children (p less than 0.05). However, some features of the disease seen in both groups were similar, including the incidences of IgA nephropathy, sex ratio, the mode of onset, incidences of gross hematuria, and high IgA levels in the sera. Furthermore, the relationships between the severity of proteinuria and renal lesions were similar: mesangial proliferation, glomerulosclerosis, and tubular atrophy increased with the degree of the severity of proteinuria. These results suggest that IgA nephropathy is essentially identical in children and adults, although adult patients tend to be further advanced in their disease course at the time of diagnosis, and that focal glomerulosclerosis with tubular atrophy is correlated with deterioration of renal function.

Hepatotoxic action of CHCl3 was examined biochemically by comparing with those of CCl4 and other related halogenomethanes using normal and phenobarbital (PB)-pretreated animals. In the later stage (24 hr), in mice, PB pretreatment augmented CHCl3-induced liver damage as evidenced by an enhancement of elevation of plasma transaminase activities and a parallel rise in liver triglyceride content. In the earlier stage (1 hr), in normal rats, CCl4 (1.0 ml/kg, i.p.) decreased microsomal glucose-6-phosphatase (G-6-Pase) activity and cytochrome P-450 content, whereas no significant effect was observed with the same dose of CHCl3. PB pretreatment produced a significant loss of both enzymes by CHCl3, and enhanced the loss of cytochrome P-450 induced by CCl4, while G-6-Pase activity was little affected by CCl4 in PB-pretreated rats. Both hepatotoxins increased liver malondialdehyde (MDA) content. Some of these early changes in vivo were reproduced in the lipid peroxidation system in vitro. Diethyldithiocarbamate suppressed various toxic manifestations induced by CHCl3 in PB-pretreated rats, but did not protect against the loss of cytochrome P-450 induced by CHCl3 or CCl4. These results suggest that lipid peroxidation hypothesis proposed for CCl4 hepatotoxicity may be applied to the case of CHCl3 though there exist some qualitatively different characteristics between these hepatotoxins, and that the mechanisms of the loss of microsomal G-6-Pase and cytochrome P-450 by either of these hepatotoxins might be different.

Histopathological changes were studied in renal biopsy specimens from a ten-year-old boy diagnosed as having Alport's hereditary nephritis with the nephrotic syndrome. Biopsy specimens of the kidney showed mild hypercellularity with an increase of mesangial matrix, irregular thickening of the capillary walls in the glomeruli, and numerous clusters of interstitial foam cells by light microscopy. Granular deposits of IgG, IgM, C3 and fibrinogen were seen along the capillaries and partially in the mesangium by immunofluoroscopy. Ultrastructurally, the lesions had various abnormalities of the glomerular basement membrane, including splitting, thinning, disruption, reticulation and irregular thickening. The mesangial matrix was increased and intramembranous deposits were observed. Foam cells were seen among both tubular and interstitial cells.

Influence of codeine on the fine structure of mitochondria in the cells of zona fasciculata of rat adrenal cortex was studied electronmicroscopically. By the administration of codeine in a dose of 40 mg/kg, the number of intramitochondrial vesicles was decreased, the change being diminished during repeated administration of the drug. Withdrawal of codeine reproduced an extensive transformation, while with a re-injection of the drug, a prompt restoration to the pretreated structure was observed. The feasibility of utilizing this transformation as an index of physical dependence liability has been discussed.

Influence of morphine on the transformation of intramitochondrial structure in rat adrenocortical cells and the response of isolated adrenals to ACTH in corticosterone biosynthesis was comparatively studied. Administering morphine 20 mg/kg to rats, the decrease in the sensitivity of cortical cells to ACTH in steroidogenesis was observed to be parallel in time to the onset of transformation of mitochondria while withdrawal of morphine in addicted rats resulted in a similar change. Re-administration of morphine to the withdrawn rats caused nearly complete recovery to the original state within a few hr of both mitochondrial structure and sensitivity to ACTH.

Influences of codeine on the fine structure of zona fasciculata of rat adrenal cortex electron microscopically were studied. The results obtained are as follows. Administering codeine at a dosage of 40mg/kg to normal rats, the honeycombed structures of inner membranes of mitochondria in adrenocortical cells gradually disappeared and the matrix of mitochondria became to less dense. While the deformed structures above-mentioned gradually diminished during the chronic administration of the drug. However, the deformation of inner membranes in mitochondria were produced again in tolerant rats after withdrawal of codeine or treatment of levallorphan, but after the reinjection of codeine, the changes disappeared to the normal state.

Influence of morphine on the fine structure of mitochondria in the cells of zona fasciculata in rat adrenal cortex was studied electronmicroscopically. By the administration of morphine to rats in a dose of 20 mg/kg the specific honeycomb like structure of mitochondria in adrenocortical cells was observed to be transformed from vesicular forms into tubulo-vescicular or tubular ones while the changed structure gradually diminished during repeated administration of the drug. Withdrawal of morphine caused an extensive re-transformation while with a reinjection of the drug a prompt restoration to the pretreated structure was observed. The feasibility of utilizing this transformation as an index of physical dependence liability has been discussed.

Distinct fractional zones of cell membranes in sucrose gradients were obtainable from homogenates of rat liver up to 6 hr (females) and 12 hr (males) following an i.p. injection of CCl4 (0.2 ml/kg body wt.). CCl4 administration to rats caused a marked elevation of NADH-cytochrome c reductase activity in the liver cell membrane. There was a remarkable difference between sexes with respect to time-course of the changes of the enzyme activity, viz., a peak was reached 6 hr after administration in female rats and 12 hr in male rats with normal activity at 6 hr. Neither mitochondrial fractions nor microsomal fractions of rat liver displayed any significant alterations in NADH-cytochrome c reductase activity 6 hr after CCl4 administration.

Influence of morphine on the fine structure of mitochondria in the cell of zona fasciculata of adrenal cortex in mice treated chronically with morphine pellets was studied using the electron microscope. The transformation of mitochondrial structure was observed 12 hours after morphine pellet implantation and the degree of transformation reached a maximum at 48 hours. These changes, however, disappeared within 4 days. On the 4th day after implantation, removal of the pellet or levallorphan challenge resulted in alteration of the mitochondria with evidence of withdrawal syndrome. Reinjection of morphine to the mice immediately after removal of the pellet, however, prevented the appearance of such mitochondrial transformation. Chlorpromazine or sodium pentobarbital did not affect on the transformation of mitochondria.

PTH levels were analysed in sera of patients receiving maintenance hemodialysis, with the vascular type of dementia and orthopedic patients with bone-joint disorders, using PTH assay kits. There were significant interrelationship among all kinds of PTH levels in the hemodialysis patients, but not in patients with the vascular type of dementia and the bone-joint disorders. Renal functions might be responsible for fragmentation of PTH in blood stream. These results suggested that the measurement of PTH levels is needed to examine various kinds of amino-sequence of PTH levels in keeping normal function of kidney.