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Aspirin-exacerbated respiratory disease (AERD) is a complex clinical syndrome characterised by severe asthmatic attack upon treatment with aspirin and/or non-steroidal anti-inflammatory drugs (NSAIDs). Genetic predisposition has been considered as a crucial determinant and candidate genes have concentrated especially on cysteinyl leukotrienes (LTs)- related genes as the inhibitory action of aspirin and NSAIDs on cyclooxygenase activity may cause overproduction of cysteinyl LTs. However, conflicting results have been reported, in parallel with replication studies in different ethnic groups. Thus, future areas of investigations need to focus on comprehensive approaches towards the discovery of other genetic biomarkers. Unfortunately, few papers have been reported about gene polymorphisms in Japanese patients with AERD. Here, we described on our recent genetic investigations on B2ADR, IL-13, IL-17A, CYP2C19, TBXA2R, CRTH2 and HSP70. This review indicates potential genetic biomarkers contributing to the early diagnosis of AERD, which may include CYP2C19 and HSP70 gene polymorphisms, and future validation studies in independent population are required to provide reassurance about our findings

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Aspirin-exacerbated respiratory disease (AERD) is a complex clinical syndrome characterised by severe asthmatic attack upon treatment with aspirin and/or non-steroidal anti-inflammatory drugs (NSAIDs). Genetic predisposition has been considered as a crucial determinant and candidate genes have concentrated especially on cysteinyl leukotrienes (LTs)-related genes as the inhibitory action of aspirin and NSAIDs on cyclooxygenase activity may cause overproduction of cysteinyl LTs. However, conflicting results have been reported, in parallel with replication studies in different ethnic groups. Thus, future areas of investigations need to focus on comprehensive approaches towards the discovery of other genetic biomarkers. Unfortunately, few papers have been reported about gene polymorphisms in Japanese patients with AERD. Here, we described on our recent genetic investigations on B2ADR, IL-13, IL-17A, CYP2C19, TBXA2R, CRTH2 and HSP70. This review indicates potential genetic biomarkers contributing to the early diagnosis of AERD, which may include CYP2C19 and HSP70 gene polymorphisms, and future validation studies in independent population are required to provide reassurance about our findings.

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The present report concerns transient neonatal diabetes mellitus in an extremely preterm infant (gestational age 27 weeks, birth weight 718 g). The patient had intrauterine growth retardation and developed hyperglycaemia on the first day of life. Insulin administration was discontinued on the 89th day of life, which was 1 day before the original due date. This case suggests that (a) insufficient insulin secretion started at least from the second trimester of the pregnancy, and (b) the duration needed for recovery of insulin secretion was not dependent on the maturity.

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Crassulacean acid metabolism (CAM) is one of the photosynthetic pathways regarded as adaptations to water stress in land plants. Little is known about correlations among the level of CAM activity, environment of habitat, life form, and phylogenetic relationship of a plant group from an evolutionary perspective. We examined these relationships in 18 species of Cymbidium (Orchidaceae) because the genus shows distinctive diversification of habitats and life forms. The photosynthetic type was classed into three categories, strong CAM, weak CAM, and C(3) on the basis of CAM activity. CAM expression in Cymbidium was confined to the epiphytic and lithophytic species. Especially, all of these species from tropical to subtropical rainforest exhibited CAM activity. On the other hand, the terrestrial species always exhibited C(3) metabolism irrespective of their varied habitats. Regarding the evolution of photosynthetic characters, weak CAM was the ancestral state in Cymbidium and strong CAM and C(3) metabolism occurred subsequently. The evolution of strong CAM likely enabled Cymbidium to extend to exposed sites in tropical lowland where marked water stress exists. Further, different levels of CAM activity characterized each species and such potential plasticity of CAM may realize the radiation of Cymbidium into sites with different environmental conditions.

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A report of transient neonatal diabetes mellitus in an extremely preterm infant (gestational age 27 weeks, birth weight 718 g). The patient had intrauterine growth retardation and developed hyperglycaemia on the first day of life. Insulin administration was discontinued on the 89th day of life, which was 1 day before the original due date. This case suggests that (a) insufficient insulin secretion started at least from the second trimester of the pregnancy; (b) the duration needed for recovery of insulin secretion was not dependent on the maturity.

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In our country approximately forty people die every year from anaphylaxis caused by hymenoptera stings. Between 1988 and 1996, 48 patients, who had experienced a systemic reaction to hymenoptera sting and were proved to have specific IgE antibodies to wasp, yellow or both (RAST score > or = 2), received rush immunotherapy (RIT) using venom extracts in our hospital. Fifteen patients had re-sting after RIT. Fourteen out of the 15 patients showed only local reaction to the hymenoptera re-sting and one patient had mild generalized symptoms. Although one patient showed mild generalized uriticaria during RIT, no adverse reaction occurred during and after RIT in the other subjects. Follow-up studies on the titers of serum total IgE antibodies and hymenoptera specific IgE and IgG4 antibodies revealed that total and specific IgE antibodies transiently increased one month after RIT and returned to their baseline values by 6 months after RIT, while specific IgG4 antibodies continued to gradually increase up to al least 3 years after RIT. These results demonstrates that RIT is effective in prevention of a systemic reaction to hymenoptera re-sting and an increase in the titer of hymenoptera specific IgG4 antibodies may at least partly explain the efficacy of RIT.

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Cladistic parsimony analyses of rbcL nucleotide sequence data from 171 taxa representing nearly all tribes and subtribes of Orchidaceae are presented here. These analyses divide the family into five primary monophyletic clades: apostasioid, cypripedioid, vanilloid, orchidoid, and epidendroid orchids, arranged in that order. These clades, with the exception of the vanilloids, essentially correspond to currently recognized subfamilies. A distinct subfamily, based upon tribe Vanilleae, is supported for Vanilla and its allies. The general tree topology is, for the most part, congruent with previously published hypotheses of intrafamilial relationships; however, there is no evidence supporting the previously recognized subfamilies Spiranthoideae, Neottioideae, or Vandoideae. Subfamily Spiranthoideae is embedded within a single clade containing members of Orchidoideae and sister to tribe Diurideae. Genera representing tribe Tropideae are placed within the epidendroid clade. Most traditional subtribal units are supported within each clade, but few tribes, as currently circumscribed, are monophyletic. Although powerful in assessing monophyly of clades within the family, in this case rbcL fails to provide strong support for the interrelationships of the subfamilies (i.e., along the spine of the tree). The cladograms presented here should serve as a standard to which future morphological and molecular studies can be compared.

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1. The pharmacokinetics of a novel benzodiazepine partial inverse agonist (S-8510) were studied in the Fischer 344 (F344) rat and B6C3F1 mouse to obtain information for the planning of carcinogenicity studies. Sprague-Dawley (SD) rats were also included for comparison. 2. Clear non-linear elimination of S-8510 was observed after single oral administration of S-8510 in all animals tested (F344 rat, 1-50 mg/kg; SD rat and B6C3F1 mouse, 1-150 mg/kg). 3. Exposure of S-8510 after single oral administration was in the order F344 rat > B6C3F1 mouse > SD rat. 4. Multiple oral administration to F344 rat and B6C3F1 mouse decreased the exposure to S-8510. 5. These results indicate that it is very important to evaluate pharmacological and toxicological studies based on exposure and to be careful in selecting the species and strains of animal used in toxicology studies.

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To clarify which process in renal secretion is responsible for the stereoselective renal secretion of organic anions, the renal handling of enantiomers of 5-monomethylsulfamoyl-6,7-dichloro-2, 3-dihydrobenzofuran-2-carboxylic acid (MBCA) was studied by the multiple-indicator dilution method, using isolated perfused rat kidney. After bolus injection of (R)-(+)-[14C]MBCA or (S)-(-)-[14C]MBCA into the renal artery, the outflow patterns for the perfusate and the urinary excretion rate profiles were estimated by statistical moment analysis. AUC values and mean transit times in kidney for the MBCA enantiomers indicated that (R)-(+)-MBCA was excreted much more extensively in urine and that it had a higher affinity for renal tissue than did (S)-(-)-MBCA. A significantly larger intrinsic clearance of secretion for (R)-(+)-MBCA attested to the R-(+)-preferential renal secretion. The uptake rate constant across the basolateral membrane, the ratio of the uptake rate constant to the free fraction in the perfusate, and the intracellular distribution volume were significantly larger for (R)-(+)-MBCA than for (S)-(-)-MBCA, indicating that uptake across the basolateral membrane and intracellular distribution were R-(+)-preferential. However, the mean time across renal epithelial cells for secreted molecules, the single-pass mean residence time in renal epithelial cells, and the rate constant for secretion across the brush-border membrane were not significantly different between enantiomers. The simultaneous presence of (R)-(+)-MBCA decreased the intrinsic clearance of secretion, the ratio of the uptake rate constant to the free fraction in the perfusate, and the intracellular distribution volume for (S)-(-)-[14C]MBCA, although the secretion rate constant, the mean time across renal epithelial cells for secreted molecules, and the single-pass mean residence time in renal epithelial cells were not influenced by (R)-(+)-MBCA, confirming that uptake across the basolateral membrane and intracellular distribution were stereoselective processes.

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Medicinal herbs, Geum japonicum, Syzygium aromaticum, Terminalia chebula, and Rhus javanica, with anti-herpes simplex virus therapeutic activity, inhibited replication of human cytomegalovirus(CMV) and murine CMV(MCMV) in vitro. These anti-CMV activities were examined in an MCMV infection model using immunosuppressed mice. Geum japonicum, Syzygium aromaticum, and Terminalia chebula significantly suppressed MCMV yields in lungs of treated mice compared with water treatment. Efficacy of oral treatment with 750 mg/kg/day of Geum japonicum-extract was similar to that of the intraperitoneal administration with 2 mg/kg/day of ganciclovir in increasing the body weight of infected mice and reducing the virus yield in the lungs. These herbs may be beneficial for the prophylaxis of CMV diseases in immunocompromized patients.

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The metabolic activity and cellularity of adipocytes isolated from the abdominal adipose tissue of normal heifers and heifers with fat necrosis were compared. The basal rate of U-14C glucose incorporation into total lipids in adipocytes from the periphery of the necrotic mass was higher than that in the colonic mesentery of both the affected and normal heifers. In the affected animals. adipocytes from the mesentery of the spiral colon and adipocytes from the periphery of the necrotic mass failed significantly to increase the incorporation of labelled acetate and glucose, respectively, in response to insulin. In the presence of adrenalin, adipocytes from the colonic mesentery and the periphery of the necrotic mass of the affected heifers released more glycerol than adipocytes from the colonic mesentery of normal animals. In addition, the mean diameters of adipocytes from the colonic mesentery and the periphery of the necrotic mass of the affected heifers were significantly greater than those from the colonic mesentery of normal animals. These results indicate that excessive fattiness in abdominal adipose tissue may predispose cattle to fat necrosis.

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Hot water extracts of four traditional herbs, Geum japonicum, Syzygium aromaticum, Terminalia chebula and Rhus javanica, which have been shown to have anti-herpes simplex virus (HSV) activity in vivo, were examined for anti-cytomegalovirus (CMV) activity in vitro and in vivo in this study. They inhibited replication of human CMV and murine CMV (MCMV) in vitro. These anti-CMV activities in vivo were examined in an MCMV infection model using immunosuppressed mice. Mice were subcutaneously treated with various doses of cyclosporine, and immunosuppression and MCMV infection were monitored by suppression of antibody production and virus yield in the lung, respectively. Each herbal extract was orally administered to mice treated with 50 mg/kg of cyclosporine from a day before intraperitoneal infection, and the efficacy of herbs was evaluated by the reduction in the virus yield in the lung. Among them Geum japonicum, Syzygium aromaticum, and Terminalia chebula significantly suppressed MCMV yields in lungs of treated mice compared with water treatment. Efficacy of oral treatment with 750 mg/kg per day of Geum japonicum extract was similar to that of the intraperitoneal administration of 2 mg/kg per day of ganciclovir in increasing the body weight of infected mice and reducing the virus yield in the lungs. These herbs may be beneficial for the prophylaxis of CMV diseases in immunocompromised patients.

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The detection of hepatitis C virus (HCV) in blood donors and patients with acute and chronic hepatitis has brought to the fore another virus or viruses which can be transmitted parenterally and induce liver disease. The RNA of a candidate virus designated GB virus C (GBV-C) was determined by the polymerase chain reaction with primers deduced from a helicase-like region in 229 leprous patients in Japan. GBV-C RNA was detected in 12 (5.2%) patients, and HCV RNA in 41 (18%). Three patients were coinfected with GBV-C and HCV. The nine patients infected with GBV-C alone had aminotransferase levels lower than the three patients with the mixed infection or the 38 patients infected with HCV only (P < 0.001). Sequence comparison within 100 base pairs in the helicase-like region suggested that two, three and three patients, respectively, would have been infected with three distinct strains of GBV-C. These results indicate that patients with leprosy are at increased risk for infection not only with HCV, but also with GBV-C, and that the infection with GBV-C alone would not induce hepatic injuries as severe as HCV infection.

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BACKGROUND/METHODS: Markers of hepatitis C virus infection were tested for in 229 patients with leprosy (male 154, female 75) in Japan. RESULTS: Antibody to hepatitis C virus by a second-generation enzyme immunoassay was detected in 68 patients (30%), and RNA of hepatitis C virus in 41 (18%), in prevalence rates much higher (p < 0.001) than those in matched controls (11/923 or 1.2% and 9/923 or 1.0%, respectively). Hepatitis C virus genotypes were II/1b in 37 (90%), III/2a in three (7%) and IV/2b in one (2%), in which II/1b was more frequently (p < 0.003) represented than in hepatitis C virus carriers without leprosy in Japan (520/767 or 68%). The 41 patients with hepatitis C virus viremia had serum transaminase levels significantly higher than those in the other 188 patients without viremia (p < 0.01). CONCLUSIONS: These results indicate that leprous patients confined in institutions are at high risk of hepatitis C virus infection, and that patients infected with hepatitis C virus should be monitored for liver function and placed on interferon therapy whenever required.

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OBJECTIVE: Restoration of stand-up motion in patients with complete paraplegia utilizing multichannel functional electrical stimulation, and analysis of the restored motion. DESIGN: Nonrandomized control trial. SETTING: General community, a referral center, institutional practice, and ambulatory care: PATIENTS: Twelve volunteer samples were used for the collection of normal data. Two complete paraplegics received treatment for the restoration of stand-up motion. MAIN OUTCOME MEASURES: The electromyogram, joint angle, and floor reaction force were investigated during standing-up with arms crossed in front of the chest, and hands-assisted standing-up using parallel bars. The maximum knee joint torque during standing-up without hands-assists was calculated using a three-segment link model. Standing-up motion in complete paraplegics was restored, and then analyzed using the three-dimensional floor reaction force and the hip, knee, and ankle angles. RESULTS: Main muscles used to stand up were the quadriceps, tibialis anterior, and paraspinal muscles. Hands-assists reduced the muscle activity and the vertical floor reaction force. Peak muscle activity was less during hands-assisted standing-up, except for the rectus femoris and the iliopsoas muscle. The maximum knee joint torque during standing-up was 1.6Nm/kg for both knees. Two complete paraplegics were able to stand up smoothly from a wheelchair based on stimulation data obtained from normal subjects. The characteristic pattern during standing-up was knee flexion preceding extension. CONCLUSION: Stand-up motion was restored utilizing electromyogram data and knee joint torque data from normal subjects.

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We investigated the effects of YM264, a specific platelet-activating factor (PAF) antagonist, on the airway hyperresponsiveness (AH) and the late asthmatic response (LAR) of guinea pigs that were sensitized by exposure to aerosolized ovalbumin (OA). Respiratory resistance (Rrs) was determined by the oscillation technique. Airway responsiveness was evaluated by administering a dose of histamine at which the Rrs reached 200% of the baseline value (H200). Animals were administered 1 or 3 mg/kg of YM264 orally 30 min before and again at 3 h after exposure to OA. YM264 significantly suppressed AH 24 h after and 5 days after the exposure. YM264 also suppressed the development of the LAR and accumulation of eosinophils and neutrophils in the tracheal mucosa of guinea pigs. These observations suggest that PAF is involved in the AH and the development of the LAR in asthma. PAF antagonists may play a beneficial role in the treatment of asthma.

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Our previous study in activity sensitized guinea pigs demonstrated an LAR-like increase in respiratory resistance (Rrs) at 3 to 9 hr after PAF inhalation. The result suggested possible involvement of the priming effect of active sensitization and PAF. Mean while, thromboxane A2 (TXA2) is known to be induced by PAF. The present study investigated the involvement of TXA2 in the guinea pig LAR model with a new TXA2 receptor antagonist, BAY u3405. One hr after BAY u3405 administration to guinea pigs sensitized by ovalbumin, the Rrs following inhalation of PAF was subsequently determined. Infiltration of inflammatory cells in the airway tissue 9 hr after PAF inhalation was also observed. While a re-increase in Rrs was found in all the cases in the control group, the re-increase in Rrs was inhibited significantly in the BAY u3405 administration group, 4 to 9 hr after PAF inhalation. The numbers of eosinophils and lymphocytes in the airway tissue were significantly decreased in the BAY u3405 administration group, as compared with the control group. From these results, the possibility is suggested that TXA2 and its direct effect on the airway and the migration-enhancing effect on eosinophils and T lymphocytes, as well as PFA, are involved in the development of LAR by PAF.

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Penciclovir has potent antiviral activity against varicella-zoster virus (VZV). We have characterized the inhibitory effects of penciclovir and acyclovir on the plaque formation of cell-free VZV and cross-resistance of acyclovir-resistant VZV to penciclovir. The apparent effective concentration for 50% plaque reduction (EC50) of penciclovir determined on the third day was significantly lower than that determined on the fourth or fifth day. The size of plaques was smaller in the presence of penciclovir than in the presence of acyclovir. The effective concentrations for 50% reduction of the number of infected cells per plaque were 1.40 and 5.00 micrograms/ml for penciclovir and acyclovir, respectively. Thus penciclovir suppressed spread of infection within developing plaques more efficiently than acyclovir. Five acyclovir-resistant VZV strains with altered DNA polymerase selected by acyclovir were examined for cross-resistance to penciclovir. They were 11- to 18-fold more resistant to ACV than the parent strain, but only 4- to 5-fold more resistant to PCV. Penciclovir-triphosphate carrying the 3'-hydroxyl group of 2'-deoxyribose might have better affinity to the altered viral DNA polymerase than acyclovir-triphosphate without the 3'-hydroxyl group.

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Bioflavonoids, extracted from flower petals, were examined for their growth inhibitory effect on cells in culture. They were found to significantly suppress the growth of the cultured cells. Anthocyanins tended to show greater inhibitory effect than other flavonoids. Commercially synthesized or purified aglycones of flavonoids were also studied for their suppression of tumor cells. The anthocyanins were more effective than other flavonoid aglycones, although the aglycones were easily inactivated under the culture conditions.

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