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Several traditional Japanese medicines including Keigairengyoto (KRT) are used to treat acne vulgaris, but there is no robust evidence of their effectiveness. In this study, we examined the effectiveness and safety of KRT in treating acne vulgaris. An open-label, randomized, parallel control group comparison was conducted with a conventional treatment group (adapalene and topical antibiotics; control group) and a KRT group (control treatment plus KRT). The test drugs were administered for 12 weeks to patients (15 to 64 years, outpatient) with inflammatory acne on their face, and the amount of acne at 2, 4, 8, and 12 weeks was measured. Sixty-four patients were enrolled; 29 patients in each group were included in the analysis. Twenty-eight patients in the control group and 24 patients in the KRT group were included in the efficacy analysis. The number of inflammatory skin rashes at 4 and 8 weeks in the KRT group was significantly decreased compared with the control group. There was no significant difference between the two groups in noninflammatory eruptions and general rashes. There were no serious adverse events in both groups. KRT may be a useful agent in patients with inflammatory acne in combination with conventional treatments. This trial is registered with UMIN 000014831.

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.

A 2 month old boy with Kawasaki disease developed the rare complication of abdominal aortic aneurysm (AAA). He was followed up over 7 years by ultrasonography (2D-ECHO) with and without Doppler flow evaluation, angiography and computed tomography. Calcification was noted 33 months after the onset of the disease but the aneurysm did not decrease in size. 2D-ECHO was adequate for evaluating the size of an aneurysm, but did not show thrombus formation or calcification. Doppler flow studies did not show abnormally high blood flow velocities either at the inflow or outlet of aneurysms, which are indicative of stenosis. On the other hand an abdominal aortogram provided information regarding the luminal shape and abnormalities in flow pattern suggestive of thrombus formation. Fluoroscopy cannot demonstrate calcification in the early stages. Computed tomography (CT) was the imaging method of choice for the evaluation of obstructive or calcific changes; an organizing thrombus was clearly demonstrated and early detection of calcification was possible.

小児期発症のループス腎炎18例 (WHO分類1型1例，II型9例，III型2例，IV型4例，V型2例) に対する治療成績を検討した。18例中，ステロイド剤単独12例，ステロイド剤と免疫抑制剤の併用5例で，他の1例はステロイド剤，免疫抑制剤の投与を行っていない。ステロイド治療に対する反応は良好であり，10年生存率100%，腎生存率100%であった。蛋白尿，血尿の悪化は各々2例，1例にみられたが，他の症例では改善が認められた。血清補体値は全例で改善あるいは正常化し，抗DNA抗体価も全て正常化した。治療後，再生検しえた5例のうち，3例に腎病変の改善を認めた。また，治療中にステロイド中断例が5例あったが，3例が再燃し，うち1例は死亡した。以上より，ループス腎炎では早期診断，早期治療が予後および腎病変の改善に重要であるが，一方，ステロイド維持療法の意義も大きく，治療の中断は予後を著しく悪化させることが明らかとなった。

特発性ネフローゼ症候群におけるキャリーオーバー症例の臨床的検討を行った。小児期に発症し，成人期に至るまで長期観察しえた症例21例中10例 (47.6%) に16歳以後の再発を認めた。うち2例 (9.5%) は20歳以後にも再発の治療を要し，1例 (4.7%) は18歳で血液透析に至った。キャリーオーバー群と長期寛解群との比較検討を行ったが，臨床像，検査所見，ステロイド反応性等には有意な差異は認めなかった。本疾患の予後は良好と思われたが，成人期での再発もあり長期にわたる注意深い経過観察が必要と考えられた。

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。

A 67-year-old man who had necrobiotic xanthogranuloma associated with paraproteinemia is described. He was a human T-lymphotropic virus type 1 (HTLV-1) carrier who had a high titer of circulating anti-HTLV-1 antibodies and neurologic abnormalities that suggested HTLV-1-associated myelopathy. The patient's necrobiotic xanthogranuloma and neurologic symptoms improved after he received four 5-day courses of melphalan, 2 mg/day, and prednisolone, 20 mg/day, at 4-week intervals.

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.

Direct action of CCl4 on rat liver plasma membranes and microsomes was investigated biochemically and morphologically in vitro. Plasma membranes or microsomes were pre-incubated with CCl4, then subjected to enzyme assays and electron microscopic observations. In plasma membranes, Mg++-ATPase lost its activity remarkably corresponding to the amount of CCl4, whereas (Na+-K+)-ATPase remained unaffected. 5′-nucleotidase and leucine aminopeptidase activities decreased to some extent but only with a large amount of CCl4. NADH-cytochrome c reductase activity also decreased, but not NADH-ferricyanide dehydrogenase activity. Some alterations of unit membrane structure and a complete disappearance of hexagonal patterns were observed electron microscopically in CCl4-pretreated plasma membranes. In microsomes, a marked loss of glucose-6-phosphatase activity was detected. NADH-and NADPH-eytochrome c reductase activities also decreased to some extent, whereas NADH-ferricyanide dehydrogenase activity remained unchanged. Some of these results show similar tendencies to those observed with the in vivo administration of CCl4. Thus, alterations of plasma membranes in vivo may indeed be partly due to a direct action of CCl4.

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.

When various biogenic amine modifying drugs were administered to mice which were pretreated with morphine, none of the drugs except atropine and haloperidol altered the usual doubling of the naloxone efficacy which is observed in morphine-pretreated mice. Atropine appeared to decrease the potency of naloxone. Haloperidol, which did not alter naloxone potency in normal mice, further increased the naloxone potency in morphine-pretreated mice. When the biogenic amine modifiers were injected chronically to mice during the development of morphine tolerance, again none of the drugs, except haloperidol and atropine altered the development of tolerance. Haloperidol appeared to enhance and atropine to inhibit the degree of tolerance. These results indicate that it is the alteration in the narcotic-induced enhancement of naloxone potency and not the mere alteration of noloxone potency by various drugs, which can be used as an indicator of the alterations in the development of tolerance.

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.

We report our experience and technique of prefabrication method for cranioplasty, using heat-cured methyl methacrylate (MMA). Recently, an autopolymerizing MMA has been a very popular material for cranioplasty. But an autopolymerizing MMA is so irritable to vital tissue that subgaleal effusion has been frequently noted after cranioplasty. And for a large cranial defect, it is difficult to get a good cosmetic result from the one-stage autopolymerizing MMA method. So, we have used a heat-cured MMA as a material of cranioplasty, and a prosthesis was formed preoperatively using an impression technique. In this method, the subgaleal effusion was markedly decreased and excellent cosmetic result was obtained even to a large cranial defect in a shortened operative time. The histological reactions to the autopolymerizing MMA and the heat-cured MMA were evaluated experimentally embedding each piece of the two materials in the subcutaneous tissue of the rat. The inflammatory reactions including appearance of foreign body giant cells were far less observed in the subcutaneous tissue around the heatcured MMA. This experimental result emphasized the advantage of heat-cured MMA method over autopolymerizing MMA.

The effect of naloxone given at various times after morphine administration on the development of tolerance to and dependence on a single dose of morphine was studied. Naloxone antagonized the analgesic effect of morphine and the development of tolerance to and dependence on morphine, dose dependently. The time course of the development of tolerance to a single dose of morphine almost paralleled that of dependence on morphine but the time course of the disappearance of tolerance did not coincide with that of dependence. When start of the duration of action of morphine was blocked by naloxone for various time intervals, the degree of tolerance to and dependence on morphine was antagonized, time dependently. When the end of the duration of action of morphine was antagonized by naloxone for various time intervals, tolerance and dependence which developed up to that time was completely antagonized by naloxone.

We used a temperature-controlled thermoelectrical method, induced hypotension, and CO2 inhalation to obtain cerebral blood flow (CBF) measurements during surgery for investigation of the state of brain vasoreactivity in subarachnoid hemorrhage patients. The study included 11 patients who underwent 12 operations for ruptured intracranial aneurysms. The CBF data were analyzed to investigate the neurological state, presence or nonpresence of vasospasm, timing of the operation, and outcome of each patient. Autoregulation disturbance, in terms of reaction to hypotension, was consistently seen in patients in poor neurological states, and this disturbance was correlated with poor outcome. This simple monitoring system, used during emergency operations for ruptured aneurysm, was useful in predicting outcome.

A case of ischemic colitis following abdominal aortic aneurysmectomy in a 74-year-old male is reported. The patient was admitted to the hospital with a complaint of severe abdominal pain. A ruptured abdominal aortic aneurysm was suspected, and emergency laparotomy was performed. At the operation a massive hematoma was encountered in the retroperitoneal space caused by rupture of an abdominal aortic aneurysm. Aneurysmectomy was performed uneventfully. The left colon appeared to be viable at the end of the procedure. Three days after the operation he had diarrhea, and the symptoms of bowel ischemia progressed. Colonoscopy on the 7th day after the first operation revealed ischemic colitis. He was treated conservatively for 2 weeks without significant improvement. On the 19th postoperative day uncontrollable massive melena occurred. Emergency laparotomy was carried out again, and resection of the left colon and transverse colostomy were done. The postoperative course after the second operation was uneventful, and the patient is doing well now. Although clinically significant ischemic colitis following aortic reconstruction is rare, colonoscopy after the operation is useful for early recognition of ischemic changes before clinical manifestations.

Spontaneous discharges recorded on the EMG appeared in experimental mice given repeated doses of IDPN according to a time schedule. Spontaneous discharges showing a polyphasic pattern and duration of over 10 ms were considered to be fasciculations. One group of mice, treated with IDPN for 4 weeks became active with an increase in muscle volume 2 months after initiation of experiment; spontaneous discharges were recorded in this group at 3–4 weeks after first IDPN injection and disappeared at 4 months. Histologically, neurogenic muscle atrophy, in terms of group atrophy of muscles, was seen in muscles of mice exhibiting spontaneous discharge patterns. Peripheral nerves showed marked atrophy with degeneration. Dissociation of neurofilaments and other organelles was observed. Axonal swellings, filled with numerous maloriented neurofilaments, were confirmed in the lumbar cord. IDPN given repeatedly to mice at a certain dose causes degeneration of the peripheral nerves and results in neurogenic muscle atrophy.

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.

Morphological changes of liver cell membranes in CCl4-administered rats were observed electronmicroscopically by using mainly a negative staining method. CCl4 caused not only disappearance of elementary particles attached to the surface of cell membranes, but also that of hexagonal subunit patterns (treated with 1 % DOC) in the membranes of tight junction 3–6 hr after administration. Present data indicates that CCl4 primarily affects the plasma membrane rather than endoplasmic reticulum.

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.