A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.

Thigh muscularity and strength in teenage soccer players.

This study examined the thigh muscularity and strength capability in early adolescent soccer players. The cross-sectional areas (CSAs) of the thigh muscles and dynamic strength during knee extension and flexion at 1.05 rad/s were determined twice at an interval of 6 months in 24 male soccer players aged 12-13 years and 11 age- and body height-matched non-athletes. After 6 months, muscle CSA and dynamic strength increased without significant interaction of time and group. Thigh total muscle CSA was not significantly affected by group, but the value relative to either thigh CSA or body mass was higher in soccer players. While knee flexion strength was similar between the 2 groups, knee extension strength was greater in soccer players than in non-athletes, even in terms of strength relative to CSA. The current results indicate that, compared with age- and body height-matched non-athletes, early adolescent soccer players are characterized by higher relative distribution of muscle mass within the thigh and higher knee extension strength relative to the quadriceps CSA. During the growth stage in which body height begins to increase markedly, however, participation in competitive soccer training does not increase the rate of development in thigh muscularity and strength.

A genetic linkage map of the Syrian hamster and localization of cardiomyopathy locus on chromosome 9qa2.1-b1 using RLGS spot-mapping.

The Syrian cardiomyopathic hamster (BIO14.6) has an inherited form of progressive myocardial necrosis and congestive heart failure. Although widely studied as an animal model for human hypertrophic cardiomyopathy, further genetic analysis has been limited by a scarcity of DNA markers. Until now, only six autosomal linkage groups have been described and the number of polymorphic loci was extremely limited. In this study, we applied the restriction landmark genome scanning (RLGS) spot-mapping method to construct a genetic map of the Syrian hamster (Mesocricetus auratus) using 72 back-cross progeny. Although the polymorphic rate is very low (3-7%) between the strains, 531 polymorphic spots/loci were mapped, showing the power of this approach and reasonable applicability to other organisms lacking a well-defined genetic map. Further, the spot markers which flank the cardiomyopathy (cm) locus were cloned to determine the chromosomal location of cm by fluorescent in situ hybridization (FISH) analysis, resulting in the assignment of the locus to the centromeric region of hamster chromosome 9qa2.1-b1. Several candidate genes responsible for hypertrophic cardiomyopathy in humans have been excluded.

The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons.

We have identified a strong candidate cDNA for the mouse reeler gene. This 5 kb transcript encodes a 99.4 kD protein consisting of 881 amino acids and possessing two EGF-like motifs. We assayed two independent mutant alleles--'Jackson reeler', which has a deletion of the entire gene, and 'Orleans reeler' which exhibits a 220 bp deletion in the open reading frame, including the second EGF-like motif and resulting in a frame shift. In situ hybridization reveals that the transcript is detected exclusively in the pioneer neurons which guide neuronal cell migration along the radial array. Our findings offer an explanation for how the reeler mutant phenotype causes a disturbance of the complex architecture of the neuronal network.

Identification of an imprinted U2af binding protein related sequence on mouse chromosome 11 using the RLGS method.

A new imprinted gene has been discovered in mice using the technique of restriction landmark genomic scanning (RLGS) with methylation sensitive enzymes. Eight out of 3,100 strain-specific NotI and BssHII spots were identified as imprinted in reciprocal F1 hybrids. Subsequently, we isolated a genomic clone for one locus on proximal chromosome 11 near the Glns locus, an imprinted region in uniparental disomic mice, and its corresponding cDNA clone. Expression of this transcript from the paternal allele was established using RT-PCR of reciprocal F1-hybrid mice. The amino-acid sequence deduced from the cDNA showed significant homology to the U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit.

Factors associated with self-assessed masticatory ability among community-dwelling elderly Japanese.

UNLABELLED: Self-assessed masticatory ability has been shown to be significantly related to general health among elderly persons. OBJECTIVE: To identify oral factors associated with the self-assessed masticatory ability. BASIC RESEARCH DESIGN: Cross-sectional study. PARTICIPANTS: A total of 736 community-dwelling elderly persons. MAIN OUTCOME MEASURES: Data on background factors and the self-assessed masticatory ability were collected by questionnaire. An intraoral examination examined the pattern of posterior occluding pairs of natural teeth (POPs), the WHO Community Periodontal Index of Treatment Needs (CPI) and denture-related factors such as use of dentures, pain when using dentures and stability and retention of dentures. Chi-squared tests examined the relationships between the self-assessed masticatory ability and the background factors and oral conditions. Ordinal regression models were constructed with the self-assessed masticatory ability as the dependent variable and oral conditions as the principal independent variables, to adjust for the potential confounding variables. RESULTS: Self-assessed impairment of masticatory ability was associated with lost POPs (p < 0.001) and CPI (p = 0.012). In the participants with lost POPs, self-assessed impairment of masticatory ability was associated with not using dentures and pain when using dentures (p < 0.001). In the totally edentulous subjects, impairment of masticatory ability was not associated with stability and retention of dentures (p = 0.070). CONCLUSIONS: Factors affecting self-assessed masticatory ability include the pattern of POPs, periodontal status, denture use and pain when using dentures.

Perceived chewing ability and need for long-term care in the elderly: a 5-year follow-up study.

Increasing need for long-term care in older adults is expected with the ageing of Japan's population. The aim of the present study was to show the relationship between perceived chewing ability and long-term care needs for over 5 years in elderly persons. The chewing ability of 812 elderly persons living independently was evaluated at baseline using self-assessed masticatory ability, and it was classified into one of three categories: ability to chew all foods (good masticatory ability), ability to chew only slightly hard food (fair masticatory ability), and ability to only chew soft or pureed food (poor masticatory ability). Participants' care needs were then followed through Japan's long-term care insurance system for over 5 years. The log-rank test and Cox proportional hazard model were used to examine statistical differences in the frequency of care-needs certification between participants with good and fair or poor masticatory ability. Among participants aged 65-79 years, the frequency of care-needs certification was significantly higher in those with fair or poor masticatory ability than in those with good masticatory ability, and the relative hazard ratio was significantly higher in those with fair or poor masticatory ability than in those with good masticatory ability, after adjusting for age, gender, current employment status, educational background, social interaction, chronic medical conditions and dentition status. These relationships were not found among those aged 80-93 years. Impairment in perceived chewing ability may be associated with higher incidence of certification in Japan's long-term care insurance system among elderly persons aged 65-79.

Nanoscale defect evaluation framework combining real-time transmission electron microscopy and integrated machine learning-particle filter estimation.

Observation of dynamic processes by transmission electron microscopy (TEM) is an attractive technique to experimentally analyze materials' nanoscale phenomena and understand the microstructure-properties relationships in nanoscale. Even if spatial and temporal resolutions of real-time TEM increase significantly, it is still difficult to say that the researchers quantitatively evaluate the dynamic behavior of defects. Images in TEM video are a two-dimensional projection of three-dimensional space phenomena, thus missing information must be existed that makes image's uniquely accurate interpretation challenging. Therefore, even though they are still a clustering high-dimensional data and can be compressed to two-dimensional, conventional statistical methods for analyzing images may not be powerful enough to track nanoscale behavior by removing various artifacts associated with experiment; and automated and unbiased processing tools for such big-data are becoming mission-critical to discover knowledge about unforeseen behavior. We have developed a method to quantitative image analysis framework to resolve these problems, in which machine learning and particle filter estimation are uniquely combined. The quantitative and automated measurement of the dislocation velocity in an Fe-31Mn-3Al-3Si autunitic steel subjected to the tensile deformation was performed to validate the framework, and an intermittent motion of the dislocations was quantitatively analyzed. The framework is successfully classifying, identifying and tracking nanoscale objects; these are not able to be accurately implemented by the conventional mean-path based analysis.

Contribution of trunk muscularity on sprint run.

This study aimed to investigate how the trunk muscularity is related to sprint running performance. In 23 youth soccer players, the cross-sectional images at the mid level of each of L1-L2, L2-L3, L3-L4, L4-L5, and L5-S1 were obtained using magnetic resonance imaging to determine the cross-sectional areas (CSAs) of rectus abdominis, oblique, psoas major, quadratus lumborum and erector spinae muscles. The times taken to sprint over 20 m were measured, and the mean velocity of running was calculated for each of the 2 distances (V (10 m) and V (20 m)) and for the distance from 10 m to 20 m (V (10-20 m)). The CSA values of the 5 slice levels for all muscles except for the quadratus lumborum and those of the 3 slice levels (L1-L2, L2-L3 and L3-L4) for the quadratus lumborum were averaged and expressed relative to the two-third power of body mass (CSA/BM (2/3)). The CSA/BM (2/3) values of the erector spinae and quadratus lumborum were selected as significant contributors to predict V (10 m) ( R(2)=0.450), V (20 m) ( R(2)=0.504) and V (10-20 m) ( R(2)=0.420). The current results indicate that the muscularity of the erector spinae and quadratus lumborum contributes to achieving a high performance in sprint running over distances of less than 20 m.

Self-assessed masticatory ability and hospitalisation costs among the elderly living independently.

The escalating medical costs are a social problem in many countries. Masticatory ability is thought to be related to the general health conditions. The purpose of this study was to show relationships between self-assessed masticatory ability and medical costs among the elderly living independently in community. Data on background factors and self-assessed masticatory ability were collected from 702 Japanese elderly persons by questionnaires. An intra-oral examination was performed to examine the number of remaining teeth. Self-assessed masticatory ability was classified into one of three categories: ability to chew all kinds of food (Good), ability to chew only slightly hard food (Fair) or ability to chew only soft or pureed food (Poor). Data on the annual medical excluding dental costs were obtained from the Japanese National Health Insurance system. The Kruskal-Wallis test was used to examine differences in outpatient costs and hospitalisation costs among the three groups of self-assessed masticatory ability. Univariate unconditional logistic regression models and multivariate logistic regression models were used with medical costs as the dependent variable and self-assessed masticatory ability as the principal independent variable. A significant difference (P=0·039) in hospitalisation costs but not outpatient costs was found among the three groups of self-assessed masticatory ability. The multivariate logistic regression analysis showed that severely impaired masticatory ability (Poor) was significantly related to higher costs of hospitalisation. Self-assessed impairment of masticatory ability may be a significant and independent indicator of higher costs of hospitalisation among community-dwelling elderly persons.

Relationships between perceived chewing ability and muscle strength of the body among the elderly.

The aim of the present study was to elucidate whether self-assessed masticatory ability (masticatory ability) is significantly related to muscle strength of the body evaluated as handgrip strength and skeletal muscle mass of the whole body (kg) (SMM) after adjusting for confounding variables, including, age, gender, height, weight, employment status, type of household, educational background, social interaction, chronic medical conditions, smoking habit, drinking habits and dentition status among the elderly. A total of 381 persons aged 67-74 years were enrolled. Masticatory ability was classified into one of three categories: ability to chew all kinds of food, ability to chew only slightly hard food or ability to chew only soft or pureed food. Handgrip strength was measured, and bioimpedance analysis was used to estimate SMM. One-way analysis of variance and Bonferroni methods were used to examine differences in handgrip strength and SMM among the three groups of masticatory ability. An ordinal regression model was conducted with masticatory ability as the dependent variable and handgrip strength as the principal independent variable. Handgrip strength was significantly lower in those individuals who could chew only soft or pureed food than in those individuals who could chew all kinds of food. No significant difference in SMM was found among the three groups of masticatory ability. Masticatory ability was significantly related to handgrip strength after adjusting for SMM, dentition status and background factors. Chewing ability may be related to muscle strength of the body evaluated as handgrip strength, but not evaluated as SMM.

Associations between self-assessed masticatory ability and higher brain function among the elderly.

Among the elderly, the quality of higher brain function is a contributing factor in performing activities of daily living. The aim of the study is to elucidate, epidemiologically, associations between mastication and higher brain function. A total of 208 community-dwelling elderly persons, aged 70-74 years, were enrolled. Self-assessed masticatory ability (masticatory ability) was classified into one of three categories: ability to chew all kinds of food, ability to chew only slightly hard food, or ability to chew only soft or pureed food. Brain function was assessed by four neuropsychological tests: Raven's Colored Progressive Matrices (RCPM) test, the Verbal Paired Associates 1 (VerPA) task and the Visual Paired Associates 1 task (from the Wechsler Memory Scale Revised Edition), and the Block Design subtest (from the Wechsler Adult Intelligence Scales-Third Edition). Correlations between masticatory ability and each test were examined using Spearman rank correlation coefficients. Multinominal logistic regression models were conducted with the neuropsychological tests as the dependent variables and masticatory ability as the principal independent variable to adjust for age, gender, educational background, social activity, drinking/smoking habits, chronic medical conditions and dental status. Significant correlations were found between the RCPM test, the VerPA task, the Block Design test and masticatory ability. In multinominal logistic regression models, poor masticatory ability was significantly and independently related to the categories under the mean-s.d. points compared with those of the mean ± s.d. ranges for RCPM test and the VerPA task. Significant associations may exist between mastication and higher brain function among the elderly.

Particle-image velocimetry study of a pediatric ventricular assist device.

Particle-image velocimetry (PIV) was used to visualize the flow within an optically transparent pediatric ventricular assist device (PVAD) under development in our laboratory. The device studied is a diaphragm type pulsatile pump with an ejection volume of 30 ml per beating cycle intended for temporary cardiac assistance as a bridge to transplantation or recovery in children. Of particular interest was the identification of flow patterns, including regions of stagnation and/or strong turbulence that often promote thrombus formation and hemolysis, which can degrade the usefulness of such devices. For this purpose, phase-locked PIV measurements were performed in planes parallel to the diaphragm that drives the flow in the device. The test fluid was seeded with 10 microm polystyrene spheres, and the motion of these particles was used to determine the instantaneous flow velocity distribution in the illumination plane. These measurements revealed that flow velocities up to 1.0 m/s can occur within the PVAD. Phase-averaged velocity fields revealed the fixed vortices that drive the bulk flow within the device, though significant cycle-to-cycle variability was also quite apparent in the instantaneous velocity distributions, most notably during the filling phase. This cycle-to-cycle variability can generate strong turbulence that may contribute to greater hemolysis. Stagnation regions have also been observed between the input and output branches of the prototype, which can increase the likelihood of thrombus formation.

Experimental study on monitoring system of clinical beam purity in multiple-ion beam operation for heavy-ion radiotherapy.

The National Institute of Radiological Sciences has investigated multiple-ion therapy using energetic beams of helium, carbon, oxygen, and neon ions, to improve treatment outcomes of refractory cancer. For this therapy, it is necessary to ensure the helium-ion beam purity to avoid irradiation by unwanted ions. Here, we develop a measurement method for monitoring beam purity. This method can measure the charge number of the ions in a high-purity beam using an ionization chamber and Faraday cup. In addition, it can be used to detect the contamination of the clinical helium-ion beam. We perform beam experiments to evaluate our beam-purity monitoring method and predict that our method is capable of detecting contamination below 1%.

A novel GTP-binding protein, Sar1p, is involved in transport from the endoplasmic reticulum to the Golgi apparatus.

SAR1, a gene that has been isolated as a multicopy suppressor of the yeast ER-Golgi transport mutant sec12, encodes a novel GTP-binding protein. Its nucleotide sequence predicts a 21-kD polypeptide that contains amino acid sequences highly homologous to GTP-binding domains of many ras-related proteins. Gene disruption experiments show that SAR1 is essential for cell growth. To test its function further, SAR1 has been placed under control of the GAL1 promoter and introduced into a haploid cell that had its chromosomal SAR1 copy disrupted. This mutant grows normally in galactose medium but arrests growth 12-15 h after transfer to glucose medium. At the same time, mutant cells accumulate ER precursor forms of a secretory pheromone, alpha-mating factor, and a vacuolar enzyme, carboxypeptidase Y. We propose that Sec12p and Sarlp collaborate in directing ER-Golgi protein transport.

Ultrastructural and biochemical studies on the precursor ribosomal particles isolated from rat liver nucleoli.

Sucrose density gradient analyses of pH 5.5 and pH 7.4 extracts from rat liver nucleoli revealed the presence of two broad peaks of approximately 60S and 80S, and 60S and 80-100S, respectively. Ribonucleoprotein (RNP) particles containing precursor ribosomal RNA in these peaks have been characterized by electron microscopy and RNA analyses. Spherical particles only were found in the 60S peak of the pH 5.5 extract, from which 28S RNA and smaller RNA (23S and 18S RNA) exclusively were extracted. In the broad 80S peak of the pH 5.5 extract, about 60% of the particles were spherical while 30% were rodlike. In the RNA species present there were 28S plus smaller RNA (80%) and 35S RNA (20%). The 60Speak of the pH 7.4 extract contained mainly spherical particles (84%), and the RNA species present was mostly 28S plus smaller RNA (89%). In addition to spherical particles (43%), a number of rodlike (31%) and filamentous molecules (26%) were observed in the heavier side of the 80-100S peak of the pH 7.4 extract, from which 45S (14%), 35S (26%), and 28S and smaller RNA (60%) were extracted. Thus the precursor ribosomal particles containing 45S RNA and 35S RNA appear to be filamentous and rodlike molecules, respectively. Folding of loose ribonucleoprotein filaments into compact, spherical, large subparticles may be part of the maturation process of ribosomal large subparticles, in addition to the so-called sequential cleavage of RNA.

Development of gas pulsing system for electron cyclotron resonance ion source.

A gas-pulsing system for an electron cyclotron resonance ion source with all permanent magnets (Kei2 source) at NIRS has been developed and tested. The system consists of a small vessel (30 ml) to reserve CH(4) gas and two fast solenoid valves that are installed at both sides of the vessel. They are connected to each other and to the Kei2 source by using a stainless-steel pipe (4 mm inner diameter), where the length of the pipe from the valve to the source is 60 cm and the conductance is 1.2 l/s. From the results of the test, almost 300 e microA for a pulsed (12)C(4+) beam was obtained at a Faraday cup in an extraction-beam channel with a pressure range of 4000 Pa in the vessel. At this time, the valve has an open time of 10 ms and the delay time between the valve open time and the application of microwave power is 100 ms. In experiments, the conversion efficiency for input CH(4) molecules to the quantity of extracted (12)C(4+) ions in one beam pulse was found to be around 3% and the ratio of the total amount of the gas requirement was only 10% compared with the case of continuous gas provided in 3.3 s of repetition in HIMAC.

Multiply charged carbon-ion production for medical application.

Over 3000 cancer patients have already been treated by the heavy-ion medical accelerator in Chiba at the National Institute of Radiological Sciences since 1994. The clinical results have clearly verified the effectiveness and safety of heavy-ion radiotherapy. The most important result has been to establish that the carbon ion is one of the most effective radiations for radiotherapy. The ion source is required to realize a stable beam with the same conditions for daily operation. However, the deposition of carbon ions on the wall of the plasma chamber is normally unavoidable. This causes an "anti-wall-coating effect," i.e., a decreasing of the beam, especially for the higher charge-state ions due to the surface material of the wall. The ion source must be required to produce a sufficiently intense beam under the bad condition. Other problems were solved by improvements and maintenance, and thus we obtained enough reproducibility and stability along with decreased failures. We summarize our over 13 years of experience, and show the scope for further developments.

Application of compact electron cyclotron resonance ion source.

The compact electron cyclotron resonance (ECR) ion source with a permanent magnet configuration (Kei2 source) has been developed at National Institute of Radiological Sciences for a new carbon therapy facility. The Kei2 source was designed for production of C(4+) ions; its performance such as beam intensity and stability has already reached the medical requirements. Therefore, the prototype development of the source for medical use is essentially finished. Recently, we have started a few studies on other applications of the source. One is the production of fullerenes in the ECR plasma and modified fullerenes with various atoms for new materials. A second application is the production of multiply charged ions (not only carbon) for ion implantation. In this paper, some basic experiments for these applications are reported.

Pathophysiological characteristics of non-alcoholic steatohepatitis-like changes in cholesterol-loaded type 2 diabetic rats.

Spontaneously Diabetic Torii (SDT) fatty rats, a new obese diabetic model, reportedly presented with features of non-alcoholic steatohepatitis (NASH) after 32 weeks of age. We tried to accelerate the onset of NASH in SDT fatty rats using dietary cholesterol loading and noticed changes in the blood choline level which is expected to be a NASH biomarker. Body weight and biochemical parameters were measured from 8 to 24 weeks of age. At 16, 20, 24 weeks, pathophysiological analysis of the livers were performed. Hepatic lipids, lipid peroxides, and the expression of mRNA related to triglyceride (TG) synthesis, inflammation, and fibrosis were evaluated at 24 weeks. Hepatic fibrosis was observed in SDT fatty rats fed cholesterol-enriched diets (SDT fatty-Cho) from 16 weeks. Furthermore, hepatic lipids and lipid peroxide were significantly higher in SDT fatty-Cho than SDT fatty rats fed normal diets at 24 weeks. Hepatic mRNA expression related to TG secretion decreased in SDT fatty-Cho, and the mRNA expression related to inflammation and fibrosis increased in SDT fatty-Cho at 24 weeks. Furthermore, SDT fatty-Cho presented with increased plasma choline, similar to human NASH. There were no significant changes in the effects of feeding a cholesterol-enriched diet in Sprague-Dawley rats. SDT fatty-Cho has the potential to become a valuable animal model for NASH associated with type 2 diabetes and obesity.