IQ is an independent predictor of glycated haemoglobin level in young and middle-aged adults with intellectual disability.

AIMS: Here we examined whether intellectual disability is independently associated with hyperglycaemia. METHODS: We recruited 233 consecutive young and middle-aged adults with intellectual disability. After exclusion of subjects on medication for metabolic diseases or with severe intellectual disability (IQ < 35), 121 subjects were divided by IQ into a group with moderate intellectual disability (35 ≤ IQ ≤ 50), a mild intellectual disability group (51 ≤ IQ ≤ 70) and a borderline group (IQ > 70). RESULTS: HbA1c level was higher in subjects with moderate intellectual disability (42 ± 9 mmol/mol; 6.0 ± 0.8%) than those in the borderline group (36 ± 4 mmol/mol; 5.5 ± 0.3%) and mild intellectual disability group (37 ± 5 mmol/mol; 5.5 ± 0.5%) groups. HbA1c level was correlated with age, BMI, blood pressure, serum triglycerides and IQ in simple linear regression analysis. Multiple regression analysis indicated that IQ, age, BMI and diastolic blood pressure were independent explanatory factors of HbA1c level. CONCLUSIONS: An unfavourable effect of intellectual disability on lifestyle and untoward effect of hyperglycaemia on cognitive function may underlie the association of low IQ with hyperglycaemia.

Dietary patterns and risk of Parkinson's disease: a case-control study in Japan.

BACKGROUND: Nearly all epidemiologic studies examining the association between the risk of Parkinson's disease (PD) and diet have focused on single foods and specific nutrients. However, epidemiologic evidence for the association of dietary pattern with PD, namely the measurement of overall diet by considering the cumulative effects of nutrients is extremely limited. We conducted a hospital-based case-control study in Japan to examine the relationship between dietary patterns and the risk of PD. METHODS: Patients with PD diagnosed using the UK PD Society Brain Bank criteria (n = 249) and controls without neurodegenerative diseases (n = 368) were recruited. At the time of recruitment, dietary intake during the preceding 1 month was assessed using a validated, self-administered diet history questionnaire. Dietary patterns from 33 predefined food groups (energy-adjusted food g/day) were extracted by factor analysis. RESULTS: Three dietary patterns were identified: 'Healthy', 'Western' and 'Light meal' patterns. After adjustment for potential non-dietary confounding factors, the Healthy pattern, characterized by a high intake of vegetables, seaweed, pulses, mushrooms, fruits and fish, was inversely associated with the risk of PD with a border-line significance (P for trend = 0.06). Multivariate Odds ratio (95% confidence intervals) for PD in the highest quartile of the Healthy pattern was 0.54 (0.32-0.92) compared with the lowest quartile. No associations with PD were detected for the other two dietary patterns. CONCLUSION: In this case-control study in Japan, a dietary pattern consisting of high intakes of vegetables, fruits and fish may be associated with a decreased risk of PD.

Dietary intake of antioxidant vitamins and risk of Parkinson's disease: a case-control study in Japan.

BACKGROUND: antioxidant vitamins are expected to protect cells from oxidative damage by neutralizing the effects of reactive oxygen species. However, epidemiological evidence regarding the associations between antioxidant vitamin intake and Parkinson's disease (PD) is limited and inconsistent. We investigated the relationship between dietary intake of selected antioxidant vitamins, vegetables and fruit and the risk of PD in Japan using data from a multicenter hospital-based case-control study. METHODS: included were 249 patients within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, body mass index, dietary intake of cholesterol, alcohol, total dairy products, and coffee and the dietary glycemic index. RESULTS: higher consumption of vitamin E and ß-carotene was significantly associated with a reduced risk of PD after adjustment for confounders under study: the adjusted odds ratio in the highest quartile was 0.45 (95% confidence interval [CI]: 0.25-0.79, P for trend = 0.009) for vitamin E and 0.56 (95% CI: 0.33-0.97, P for trend = 0.03) for ß-carotene. Stratified by sex, such inverse associations were significant only in women. No material relationships were shown between intake of vitamin C, α-carotene, cryptoxanthin, green and yellow vegetables, other vegetables, or fruit and the risk of PD. CONCLUSIONS: higher intake of vitamin E and ß-carotene may be associated with a decreased risk of PD.

Ovarian reserve may influence the outcome of bone mineral density in patients with long-term use of dienogest.

OBJECTIVE: Long-term administration of dienogest, which is known to have effect on bone mineral density, is frequently done in patients with endometriosis and adenomyosis, but a few studies focused on the bone mineral density changes after finishing the long-term therapy. This study aimed to reveal the factors that adversely affect lumbar bone mineral density. METHOD: Fifty-seven premenopausal women who visited our hospital were diagnosed as either endometriosis or adenomyosis, and they were treated by dienogest for more than 115 weeks (26.5 months). Based on a previous report, bone mineral density changes less than 2% was categorized as the osteopenic group (n = 30), and the others were assigned to the unchanged group (n = 27). Bone mineral density was measured at the lumbar spine using dual-energy X-ray absorptiometry. A representative ovarian reserve marker, endogenous estradiol levels, and follicle-stimulating hormone levels were measured over time and were compared between the osteopenic and unchanged groups. RESULT: Duration of dienogest intake was 59.5 months (osteopenic group) versus 57.5 months (unchanged group). These patients experienced ovarian surgeries in a similar frequency, but the ovarian reserve in osteopenic group was impaired as suggested by the decline of endogenous estradiol level during intake of dienogest compared to that of unchanged group (p = 0.0146). Endogenous follicle-stimulating hormone level between osteopenic group and unchanged group did not reach statistically significant difference, although the osteopenic group showed relatively higher level. CONCLUSION: This study might suggest that decreased ovarian reserve as judged by endogenous estradiol level is a factor that negatively affect bone mineral density, and measurement of endogenous estradiol level during intake of dienogest could have a predictive meaning of future decreased bone mineral density level.

Dairy food, calcium and vitamin D intake in pregnancy, and wheeze and eczema in infants.

The present prospective study examined the association between maternal consumption of dairy products, calcium, and vitamin D during pregnancy and the risk of wheeze and eczema in the infants aged 16-24 months. Subjects were 763 Japanese mother-child pairs. Data on maternal intake during pregnancy were assessed with a diet history questionnaire. Symptoms of wheeze and eczema were based on criteria of the International Study of Asthma and Allergies in Childhood. Higher maternal intake of total dairy products, milk, cheese and calcium during pregnancy was significantly related to a decreased risk of infantile wheeze, but not eczema (adjusted ORs (95% CI) between extreme quartiles were 0.45 (0.25-0.79), 0.50 (0.28-0.87), 0.51 (0.31-0.85), and 0.57 (0.32-0.99), respectively). When maternal vitamin D consumption during pregnancy was categorised into two groups using a cut-off point at the 25th percentile, children whose mothers had consumed > or =4.309 microg x day(-1) had a significantly reduced risk of wheeze and eczema (adjusted ORs (95% CI) were 0.64 (0.43-0.97) and 0.63 (0.41-0.98), respectively). Higher consumption of calcium and dairy foods other than yoghurt during pregnancy may reduce the risk of infantile wheeze. Higher vitamin D intake during pregnancy may be protective against childhood wheeze and eczema.

Consumption of vegetables, fruit, and antioxidants during pregnancy and wheeze and eczema in infants.

BACKGROUND: Two previous cohort studies showed inverse relationships between maternal vitamin E and zinc intake during pregnancy and the risk of wheeze and/or asthma in the offspring. We investigated the association between maternal intake of vegetables, fruit, and selected antioxidants during pregnancy and the risk of wheeze and eczema in the offspring aged 16-24 months. METHODS: Subjects were 763 Japanese mother-child pairs. Data on maternal intake during pregnancy were assessed with a diet history questionnaire. Data on symptoms of wheeze and eczema were based on criteria of the International Study of Asthma and Allergies in Childhood. RESULTS: Higher maternal intake of green and yellow vegetables, citrus fruit, and beta-carotene during pregnancy was significantly associated with a reduced risk of eczema, but not wheeze, in the offspring {adjusted odds ratios (ORs) between extreme quartiles [95% confidence intervals (CIs)] = 0.41 (0.24-0.71), 0.53 (0.30-0.93), and 0.52 (0.30-0.89), respectively}. Maternal vitamin E consumption during pregnancy was significantly inversely related to the risk of infantile wheeze, but not eczema [adjusted OR (95% CI) = 0.54 (0.32-0.90)]. No statistically significant exposure-response associations were observed between maternal intake of total vegetables, vegetables other than green and yellow vegetables, total fruit, apples, alpha-carotene, vitamin C, or zinc and the risk of wheeze or eczema in the children. CONCLUSIONS: Higher maternal consumption of green and yellow vegetables, citrus fruit, and beta-carotene during pregnancy may be protective against the development of eczema in the offspring. Higher maternal vitamin E intake during pregnancy may reduce the risk of infantile wheeze.

Active and passive smoking and risk of Parkinson's disease.

OBJECTIVE: To assess the association between active and passive smoking and the risk of Parkinson's disease (PD), a case-control study with 249 PD patients and 369 controls was carried out in Japan. METHODS: Information on smoking was obtained through a self-administered questionnaire. Adjustment was made for age, sex, region of residence, educational level, and occupational exposure. RESULTS: Ever having smoked cigarettes was associated with a reduced risk of PD [adjusted odds ratio = 0.38; 95% confidence interval (CI): 0.24-0.59]. Risk for former smokers was intermediate between the high risk for never smokers and the low risk for current smokers. Adjusted odds ratios for former and current smokers were 0.51 (95% CI: 0.32-0.82) and 0.12 (95% CI: 0.05-0.26), respectively. There was an inverse dose-response gradient with pack-years smoked. No significant association was detected for passive smoking exposure. CONCLUSION: Our results appear to confirm data from previous epidemiological studies.

Insulin secretion and sensitivity before and after surgical treatment for aldosterone-producing adenoma.

AIM: Primary aldosteronism, which is usually caused by an aldosterone-producing tumour, affects glucose metabolism. The effects of this condition on insulin secretion and insulin sensitivity have remained unclear, however. To gain insight into the influence of primary aldosteronism on glucose tolerance, various parameters related to insulin secretion or insulin sensitivity in patients with an aldosterone-producing tumour were comprehensively analyzed. METHODS: To assess 14 patients with an aldosterone-producing tumour, hyperglycaemic and hyperinsulinaemic-euglycaemic clamp tests as well as oral glucose tolerance tests (OGTTs) were performed before and after tumour excision. Time between presurgical analysis and surgery was 27-559 (194±132) days, and 14-142 (51±38) days between surgery and postsurgical analysis. Various parameters related to insulin secretion or sensitivity as determined by OGTT as well as hyperglycaemic and hyperinsulinaemic-euglycaemic clamp analyses were evaluated. RESULTS: Surgical treatment of tumours ameliorated hypokalaemia and reduced plasma aldosterone levels. First and second phases of insulin secretion during the hyperglycaemic clamp, as well as the insulinogenic index and total insulin secretion measured during OGTT, were also improved after surgery. In addition, the insulin sensitivity index determined during the hyperinsulinaemic-euglycaemic clamp was reduced after surgery. CONCLUSION: Primary aldosteronism impairs insulin secretion.

Maternal fat consumption during pregnancy and risk of wheeze and eczema in Japanese infants aged 16-24 months: the Osaka Maternal and Child Health Study.

BACKGROUND: One factor capable of modulating antenatal immune responses is diet. This prospective study examined the association between maternal intake of specific types of fatty acids, cholesterol, fish and meat during pregnancy and the risk of wheeze and eczema in the offspring. METHODS: Subjects were 763 mother-child pairs. Data on maternal intake during pregnancy were assessed with a diet history questionnaire. Data on wheeze and eczema based on criteria of the International Study of Asthma and Allergies in Childhood were obtained from a questionnaire completed by mothers 16-24 months postpartum. RESULTS: Higher maternal intake of alpha-linolenic acid and docosahexaenoic acid during pregnancy was independently associated with a reduced risk of wheeze, but not eczema, in the offspring (adjusted odds ratios (ORs) between extreme quartiles 0.52 (95% CI 0.28 to 0.97) and 0.37 (95% CI 0.15 to 0.91), respectively). Higher maternal intake of n-6 polyunsaturated fatty acids and linoleic acid during pregnancy was independently related to an increased risk of infantile eczema but not wheeze (adjusted ORs 2.25 (95% CI 1.13 to 4.54) and 2.11 (95% CI 1.06 to 4.26), respectively). No significant exposure-response relationships were observed between maternal consumption of total fat, saturated fatty acids, monounsaturated fatty acids, eicosapentaenoic acid, arachidonic acid, cholesterol, meat and fish and the ratio of n-3 to n-6 polyunsaturated fatty acid consumption during pregnancy and infantile wheeze or eczema. CONCLUSIONS: Maternal intake of alpha-linolenic acid and docosahexaenoic acid during pregnancy may be preventive against infantile wheeze. Maternal intake of n-6 polyunsaturated fatty acids, especially linoleic acid, during pregnancy may increase the risk of childhood eczema.

Post-operative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision.

BACKGROUND: The aim of this study was to evaluate the impact of post-operative oral contraceptives (OCs) use on the rate of recurrence after laparoscopic excision of ovarian endometrioma. METHODS: In May 2005, we introduced a 'post-operative OC recommendation' for patients treated with laparoscopic excision of endometrioma. That is, at the time of the operation, we provided each patient with information about OC, known and possible benefits and risks and let her decide whether to take OC. A retrospective cohort study included 87 patients who underwent a laparoscopy after May 2005. The endometrioma recurrence rate at 24 months was compared between those who used OC for the entire follow-up period OC (n = 34) and all of the others (n = 53). We also performed logistic regression analysis to identify variables associated with recurrence. A before-after study included another 224 patients who underwent a laparoscopy before May 2005 and compared the recurrence rate before and after introduction of the 'post-operative OC recommendation'. RESULTS: The recurrence rate in those who used OC for the entire period was significantly lower than in the 'others' group (2.9 versus 35.8%, relative risk 0.082, 95% CI 0.012-0.58, P < 0.001). Post-operative OC was determined as an independent variable associated with lower recurrence (OR 0.054, 95% CI 0.007-0.429, P < 0.001). The overall recurrence rate in patients who underwent laparoscopy after the introduction of the 'post-operative OC recommendation' was significantly lower than that in patients who received laparoscopy before the introduction (18.6 versus 33.1%, relative risk 0.56, 95% CI 0.32-0.97, P < 0.05). CONCLUSIONS: Post-operative OC use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. This information will help in appropriate planning of pre- and post-operative management.

External hip protectors are effective for the elderly with higher-than-average risk factors for hip fractures.

UNLABELLED: In our cluster randomised controlled trial for efficacy of hip protector with 672 ambulatory elderly women, a hip protector was more effective for prevention of hip fractures in residents with fall history (n = 202; hazard ratio (HR), 0.375; 95%CI, 0.14-0.98; p = 0.05) and body-mass index (BMI) < or = 19.0 (n = 206; HR, 0.37; 95%CI, 0.14-0.95; p = 0.04) by a Cox proportional hazards regression model. INTRODUCTION: Hip fractures result from both osteoporosis and falling. A potentially cost-effective method of preventing hip fractures involves the use of hip protectors but recent studies have revealed the uncertain effectiveness of hip protectors even in institutional settings. METHODS: This study was a cluster randomised controlled trial with nursing homes. We randomly assigned 76 homes with 672 ambulatory but frail elderly women. Several risk factors were assessed at baseline and incorporated into a Cox proportional hazards regression model. UMIN Clinical Trials Registry number is UMIN000000467. Research period was between January 2004 and March 2006. RESULTS: In the intervention group, 19 hip fractures occurred (54.0/1,000 person-years), whereas 39 hip fractures occurred in the control group (78.8/1,000 person-years). Hazard ratio of hip fracture in the intervention group was 0.56 (95%CI, 0.31-1.03; p = 0.06) after adjusting for risk factors. In subgroup analysis, hip protectors were more effective for prevention of hip fractures in residents with fall history (n = 202; HR, 0.375; 95%CI, 0.14-0.98; p = 0.05) and BMI < or = 19.0 (n = 206; HR, 0.37; 95%CI, 0.14-0.95; p = 0.04). Overall compliance with use of hip protectors was 79.7%. CONCLUSION: Risk of hip fracture can be reduced by hip protectors among elderly women with fall history and low BMI.

The Drosophila Ral GTPase regulates developmental cell shape changes through the Jun NH(2)-terminal kinase pathway.

The Ral GTPase is activated by RalGDS, which is one of the effector proteins for Ras. Previous studies have suggested that Ral might function to regulate the cytoskeleton; however, its in vivo function is unknown. We have identified a Drosophila homologue of Ral that is widely expressed during embryogenesis and imaginal disc development. Two mutant Drosophila Ral (DRal) proteins, DRal(G20V) and DRal(S25N), were generated and analyzed for nucleotide binding and GTPase activity. The biochemical analyses demonstrated that DRal(G20V) and DRal(S25N) act as constitutively active and dominant negative mutants, respectively. Overexpression of the wild-type DRal did not cause any visible phenotype, whereas DRal(G20V) and DRal(S25N) mutants caused defects in the development of various tissues including the cuticular surface, which is covered by parallel arrays of polarized structures such as hairs and sensory bristles. The dominant negative DRal protein caused defects in the development of hairs and bristles. These phenotypes were genetically suppressed by loss of function mutations of hemipterous and basket, encoding Drosophila Jun NH(2)-terminal kinase kinase (JNKK) and Jun NH(2)-terminal kinase (JNK), respectively. Expression of the constitutively active DRal protein caused defects in the process of dorsal closure during embryogenesis and inhibited the phosphorylation of JNK in cultured S2 cells. These results indicate that DRal regulates developmental cell shape changes through the JNK pathway.

A novel multiplex PCR assay for Salmonella subspecies identification.

AIM: To develop a novel multiplex polymerase chain reaction (PCR) assay with six primer pairs for Salmonella subspecies identification. METHODS AND RESULTS: Five primer pairs were chosen to detect the genes (fljB, mdcA, gatD, stn and STM4057) responsible for several phenotypic traits or encoding (sub) species-specific regions. A primer pair for invA was added to simultaneously detect Salmonella. The combination of these primer pairs was expected to give unique results to all subspecies, including Salmonella bongori. The multiplex PCR assay was optimized and evaluated with 53 Salmonella strains representing all S. enterica subspecies, S. bongori and five non-Salmonella strains. The multiplex PCR assay revealed that the genotypes were well correlated with the phenotypes in the Salmonella strains tested. The unique band patterns to their subspecies were generated from 94.3% (50/53) of the Salmonella strains, and no product from other strains by the multiplex PCR assay. CONCLUSIONS: The multiplex PCR assay we developed was found to be a rapid, specific and easy to perform method compared with traditional biochemical tests for Salmonella subspecies identification, especially for rapid screening of large numbers of samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The assay will be useful for characterizing Salmonella isolates from reptiles, which belong to various subspecies, and therefore add to the scientific understanding of reptile-associated Salmonellosis.

Breastfeeding and the risk of wheeze and asthma in Japanese infants: the Osaka Maternal and Child Health Study.

Epidemiological evidence for an effect of breastfeeding on asthma continues to be inconclusive. The present prospective study examined the relationship between breastfeeding and the risk of wheeze and asthma in Japanese infants. A birth cohort of 763 infants was followed. The first survey during pregnancy and the second survey between 2 and 9 months postpartum collected information on potential confounding factors. Data on breastfeeding, wheeze, and asthma were obtained from questionnaires in the third survey from 16 to 24 months postpartum. Adjustment was made for maternal age, maternal and paternal history of asthma, atopic eczema, and allergic rhinitis, indoor domestic pets (cats, dogs, birds, or hamsters), family income, maternal and paternal education, maternal smoking during pregnancy, baby's sex, baby's older siblings, household smoking in the same room as the infant, and time of delivery before the third survey. By the third survey, the cumulative incidence of wheeze and asthma was 22.1% and 4.3%, respectively. Neither exclusive breastfeeding for 4 months or more nor partial breastfeeding for 6 months or more were materially related to the risk of wheeze. No measurable association was observed between exclusive breastfeeding for 4 months or more and the risk of asthma. Partial breastfeeding for 6 months or more was inversely related to the risk of asthma although the adjusted odds ratio (OR) was not statistically significant. When infants were stratified according to whether there was a negative or positive allergic history in at least 1 parent, a nearly 40% and 60% decrease, respectively, in the ORs were found for exclusive and partial breastfeeding only in infants without a parental allergic history, although the ORs were not statistically significant. The present prospective study showed no statistically significant relationship between breastfeeding duration and the risk of wheeze or asthma in Japanese infants.

Study of audio speakers containing ferrofluid.

This work validates a method for increasing the radial restoring force on the voice coil in audio speakers containing ferrofluid. In addition, a study is made of factors influencing splash loss of the ferrofluid due to shock. Ferrohydrodynamic analysis is employed throughout to model behavior, and predictions are compared to experimental data.

Fat and fish intake and asthma in Japanese women: baseline data from the Osaka Maternal and Child Health Study.

OBJECTIVE: It remains controversial whether the intake of n-3 polyunsaturated fatty acids and fish is preventive against asthma. This cross-sectional study investigated the relationship between fat and fish intake and the prevalence of asthma using baseline data from a prospective study. DESIGN: The subjects were 1002 pregnant Japanese females. A diet history questionnaire was used to assess dietary habits. Current asthma and asthma after age 18 were defined as present if subjects had been treated with medications at some time in the previous 12 months and after reaching the age of 18, respectively. RESULTS: Fish consumption was independently associated with a decreased prevalence of asthma after age 18 and current asthma. A significant inverse relationship was observed between the ratio of n-3 to n-6 polyunsaturated fatty acid intake and the prevalence of current asthma, but not asthma after age 18. Intake of total fat, saturated, monounsaturated, n-3 polyunsaturated and n-6 polyunsaturated fatty acids, cholesterol, meat, eggs or dairy products was not evidently related to either outcome for asthma. CONCLUSION: Our results suggest that fish consumption and the high ratio of n-3 to n-6 polyunsaturated fatty acid intake may be associated with a reduced prevalence of asthma in young female Japanese adults.

Substitution of Ser-17 of pp60c-src: biological and biochemical characterization in chicken embryo fibroblasts.

pp60c-src is phosphorylated mainly on Ser-17 and Tyr-527 in vivo. In this study, we examined the effect of the phosphorylation of Ser-17 on the properties of pp60c-src by introducing Rous sarcoma virus variants carrying pp60c-src in which Ser-17 had been substituted, into chicken embryo fibroblasts. The Ala-17 substitution in wild-type pp60c-src and pp60c-src carrying Phe-527 caused a two- to threefold elevation in the kinase activity in vitro of these proteins; the former variant resulted in no morphological changes of infected cells, whereas the latter variant transformed chicken embryo fibroblasts. Since the substitution of Tyr-527 per se has been reported to activate pp60c-src, these results suggest that the abolishment of the phosphorylation of Ser-17 does not affect noticeably the properties of pp60c-src in chicken embryo fibroblasts.

Opening of mitochondrial K(ATP) channels attenuates the ouabain-induced calcium overload in mitochondria.

We tested whether opening of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels depolarizes mitochondrial membrane potential (DeltaPsi(m)) and thereby prevents the mitochondrial Ca(2+) overload. With the use of a Nipkow disk confocal system, the mitochondrial Ca(2+) concentration ([Ca(2+)](m)) and DeltaPsi(m) in rat ventricular myocytes were measured by loading cells with Rhod-2 and JC-1, respectively. Exposure to ouabain (1 mmol/L) for 30 minutes produced mitochondrial Ca(2+) overload, and the intensity of Rhod-2 fluorescence significantly increased to 173+/-16% of baseline (P<0.001). Treatment of myocytes with the mitoK(ATP) channel opener diazoxide (100 micromol/L) blunted the ouabain-induced mitochondrial Ca(2+) overload (131+/-10% of baseline; P<0.001 versus ouabain). Moreover, diazoxide significantly depolarized the DeltaPsi(m) and reduced the intensity of JC-1 fluorescence during application of ouabain to 89+/-2% of baseline (P<0.05). These effects of diazoxide were blocked by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 micromol/L). These results indicate that opening of mitoK(ATP) channels prevents a mitochondrial Ca(2+) overload in association with DeltaPsi(m) depolarization and thereby protects myocardium against ischemic damage.

ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients.

OBJECTIVE: Methotrexate (MTX) is most widely used for the treatment of rheumatoid arthritis (RA). However, it has certain drawbacks with regard to individual differences in its therapeutic effects as well as the differences in the patients' response to MTX therapy. We investigated whether multi-drug resistance-1 (ABCB1) C3435T, reduced folate carrier-1 (RFC1) G80A, 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) C347G and a 6bp-deletion polymorphism in the 3'-untranslated region of the thymidylase synthase (TYMS) gene are predictive of MTX sensitivity and its adverse effects. METHODS: Patients whose last maintenance dosage of MTX was 6 mg/week or those in whom MTX therapy was changed due to poor response to MTX were regarded as non-responders. The data of 124 RA patients who had received MTX treatment were retrospectively analyzed for polymorphisms in the ABCB1, RFC1, ATIC and TYMS genes, MTX sensitivity and MTX toxicity. RESULTS: There were no significant differences in MTX sensitivity among the genotypes of RFC1, ATIC and TYMS genes. ABCB1 3435TT cases included statistically significantly more non-responders than 3435CC cases according to univariate analysis (crude odds ratio (OR) = 8.91, p = 0.001) and multivariate analysis (adjusted OR = 8.78, p = 0.038). There were no significant differences in MTX toxicity among the genotypes of all the genes. CONCLUSION: These results suggested that the genetic diagnosis of ABCB1 C3435T can be applied to determine MTX sensitivity for the treatment of RA patients. However, further pharmacokinetics studies are required in this regard.

Characterization of the enzymatic activity of hChlR1, a novel human DNA helicase.

Recently, we cloned two highly related human genes, hChlR1 ( DDX11 ) and hChlR2 ( DDX12 ), which appear to be homologs of the Saccharomyces cerevisiae CHL1 gene. Nucleotide sequence analysis suggests that these genes encode new members of the DEAH family of DNA helicases. While the enzymatic activity of CHL1 has not been characterized, the protein is required for the maintenance of high fidelity chromosome segregation in yeast. Here we report that the hChlR1 protein is a novel human DNA helicase. We have expressed and purified hChlR1 using a baculovirus system and analyzed its enzymatic activity. The recombinant hChlR1 protein possesses both ATPase and DNA helicase activities that are strictly dependent on DNA, divalent cations and ATP. These activities are abolished by a single amino acid substitution in the ATP-binding domain. The hChlR1 protein can unwind both DNA/DNA and RNA/DNA substrates. It has a preference for movement in the 5'-->3' direction on short single-stranded DNA templates. However, unlike other DNA helicases, the hChlR1 DNA helicase can translocate along single-stranded DNA in both directions when substrates have a very long single-stranded DNA region. The enzymatic activities of hChlR1 suggest that DNA helicases are required for maintaining the fidelity of chromosome segregation.