Diphenylarsinic acid poisoning from chemical weapons in Kamisu, Japan

We noted a new clinical syndrome with prominent cerebellar symptoms in apartment building residents in Kamisu, Japan. The well that provided drinking water contained diphenylarsinic acid, a degradation product of diphenylcyanoarsine or diphenylchloroarsine, which were developed for use as chemical weapons, inducing severe vomiting and sneezing. Characteristics of diphenylarsinic acid poisoning include brainstem-cerebellar and cerebral symptoms. Mental retardation associated with brain atrophy in magnetic resonance images was evident in some infants. We must be vigilant to prevent or minimize the effects of further diphenylarsinic acid poisoning in Japan or elsewhere.     

Executive dysfunction can explain word-list learning disability in very mild Alzheimer's disease: the Tajiri project

Elderly people with questionable dementia (i.e. a Clinical Dementia Rating (CDR) of 0.5) have been focused on as representing the borderline zone condition between healthy people and dementia patients. Many of them are known to have pathologic traits of very mild Alzheimer's disease (AD). Although they present mild memory disorder, the underlying mechanism has not been fully investigated. Herein is reported the mechanism of learning disability in very mild AD. Eighty-six CDR 0.5 participants and 101 age- and education-matched healthy controls (CDR 0) were randomly selected from a community in the town of Tajiri, Miyagi Prefecture. The word-recall task of the Alzheimer Disease Assessment Scale-Japanese (i.e. learning and recall of 10 words) was administered. The numbers of words recalled in each trial and those never recalled throughout the trials were compared for the two CDR groups. The serial-position function was depicted for three parts (i.e. primary, middle, and recency). The CDR 0.5 group recalled significantly fewer words than the CDR 0 group. The number of never-recalled words was greater in the CDR 0.5 group. A remarkable difference was found in the middle part of the word list. The number of never-recalled words of the CDR 0.5 group was greater in the middle part. The large number of never-recalled words accounted for the poor learning performance of very mild AD participants. The results suggested that very mild AD participants have difficulty in learning and retaining words in the middle part of the word-list because of a functional decline of the central executive system.     

Reduced expression and aberrant localization of p120catenin in human squamous cell carcinoma of the skin

BACKGROUND: p120catenin (p120ctn), a member of the Armadillo protein family, is ubiquitously expressed and binds to classical cadherins together with other catenins to participate in the adherens junction. p120ctn has numerous isoforms generated through extensive splicing and alternative usage of translation initiation codons. Although the involvement of p120ctn in cell growth control has been postulated, little has so far been known about its expression patterns in the skin and epidermal tumors. OBJECTIVE: To identify the isoforms expressed in benign and malignant keratinocytes and to analyze the expression patterns of p120ctn in epidermal tumor specimens. METHODS: HaCaT, DJM-1, BSCC-93, HSC-1, HSC-5 and A431 cells along with normal skin tissue were subjected to RT-PCR to identify the expressed isoforms. For immunofluorescence study, surgical specimens including 29 squamous cell carcinomas (SSCs), 4 basal cell carcinomas (BCCs) and 4 seborrheic keratoses as well as 3 normal skin samples were stained with specific antibodies to detect p120ctn and E-cadherin. RESULTS: RT-PCR revealed that the isoform 3A was predominantly expressed with faint expression of the isoform 4 and that there was no difference in expressed isoforms between the examined cell lines. Immunofluorescent staining indicated that the expression of p120ctn was significantly reduced in all of the examined squamous cell carcinomas and that p120ctn was frequently localized in cytoplasm. In benign tumors and normal samples, p120ctn was properly expressed in cell-cell boundaries. Furthermore, there were several SCCs where E-cadherin continued to be expressed with no expression of p120ctn. CONCLUSION: Reduced expression and aberrant localization of p120ctn are among the most common events during the development and/or progression of SCCs.     

Pharmacogenetic roles of CYP2C19 and CYP2B6 in the metabolism of R- and S-mephobarbital in humans

OBJECTIVES AND METHODS: We assessed the relationship between the metabolism of R- and S-mephobarbital (MPB) and genetic polymorphisms of cytochrome P450 (CYP) 2C19 and CYP2B6. Nine homozygous extensive metabolizers (homo-EMs, 2C19*1/2C19*1) of CYP2C19, ten heterozygous EMs (hetero-EMs, 2C19*1/2C19*2, 2C19*1/2C19*3) and eleven poor metabolizers (PMs, 2C19*2/2C19*2, 2C19*3/2C19*3, 2C19*2/2C19*3) recruited from a Japanese population, received an oral 200 mg-dose of racemic MPB. Blood and urine samples were collected, and R-MPB, S-MPB and the metabolites, phenobarbital (PB) and 4'-hydroxy-MPB, were measured. Each subject was also genotyped for CYP2B6 gene. RESULTS: The mean area under the plasma concentration-time curve (AUC) of R-MPB was 92-fold greater in PMs than in homo-EMs. R/S ratios for AUC of MPB were much higher in PMs than in EMs (homo- and hetero-). The cumulative urinary excretion of 4'-hydroxy-MPB up to 24 h postdose was 21-fold less in PMs than in homo-EMs. The metabolic ratio of AUCPB/(AUCS-MPB + AUCR-MPB) was higher in PMs than in EMs (homo- and hetero-). In addition, this metabolic ratio was lower in the carriers of CYP2B6*6 compared with that in its non-carriers. CONCLUSIONS: Our results indicate that the 4'-hydroxylation of R-MPB is mediated via CYP2C19 and that the rapid 4'-hydroxylation of R-MPB results in a marked difference in the pharmacokinetic profiles between R-MPB and S-MPB in the different CYP2C19 genotypic individuals. In addition, a minor fraction of the interindividual variability in PB formation from MPB may be explainable by the CYP2B6*6 allele.     

Association of hospital resource use with comorbidity status and patient age among hip fracture patients in Japan

OBJECTIVES: This study examined the association of resource use with comorbidity status and patient age among hip fracture patients who underwent surgical treatment. DESIGN: We used a database from the Voluntary Hospitals of Japan Quality Indicator Project that involved 10 privately owned leading teaching hospitals in Japan. SETTING: Four of these hospitals in Japan. PARTICIPANTS: We selected 778 operable hip fracture patients aged 65 or older who were admitted to these hospitals between January 1996 and August 2000 (mean age: 80.3 +/- 7.3 years). MEASUREMENTS: A linear mixed model was performed to identify factors associated with the resource use, such as total length of stay (LOS), LOS before surgery, LOS after surgery, total hospital charges, charges for diagnostic examinations, charges for surgery, and length of theater time, among operable hip fracture patients. RESULTS: The mean LOS was 45.9 days, and the mean total hospital charges were US dollars 14,495.0. Results from linear mixed models revealed that higher age was significantly associated with shorter length of theater time (P < 0.01), and that the presence of comorbidity among hip fracture patients was significantly associated with longer total LOS (P < 0.01), longer LOS after surgery (P < 0.001), higher charges for diagnostic examinations (P < 0.001), and shorter length of theater time (P < 0.01). CONCLUSION: These results suggest that the presence of comorbidity among operable hip fracture patients requires greater resource use during their hospital stay, but higher age is not significantly associated with greater resource use at all.     

Occupational class and exposure to job stressors among employed men and women in Japan

BACKGROUND: The relationship between occupational class and exposure to job stressors among employed men and women in Japan remains unclear. METHODS: Data of 16,444 men and 3,078 women were analyzed. The information was obtained from answers to a questionnaire distributed among employees of nine companies in Japan between 1996 and 1998 (average response rate, 85%). The International Standardized Classification of Occupations was used to classify respondents into eight occupational categories. The Job Content Questionnaire was used to measure job demands, job control, worksite support, and job insecurity. The associations between occupational class and job stressors, as well as job strain, were examined controlling for age, education, marital status, chronic medical condition, and personality traits, such as neuroticism and extraversion. RESULTS: Men and women in high-class occupations (e.g., managers and professionals) had significantly greater job control, while job demands and worksite social support were not greatly different among occupations. A clear occupational class gradient in job insecurity was observed in women. A greater prevalence of high job strain was observed in low-class occupations compared to high-class occupations in both men and women. The occupational class gradient in job strain was greater for women. These patterns did not change after controlling for other covariates. CONCLUSION: The present study suggests an occupational class gradient in job strain for employed men and women in Japan. Japanese women workers may have a greater occupational class gradient in job strain and job insecurity than men.     

Development of a novel monoclonal antibody recognizing basal cells of human squamous epithelia

The basal layer of the epithelium is usually thought to contain stem or progenitor cell populations. In order to analyze its biological characteristics, we attempted to produce novel monoclonal antibodies recognizing basal cells of the human esophageal epithelium. Hybridomas were generated from fusions between spleen cells of ddY mice immunized with esophageal epithelial cells (EECs) cultured at low calcium concentrations. A clone, NJ-E-H10, producing a monoclonal antibody (moAb) reacting with basal cells of human esophageal epithelia, was selected for its staining pattern on frozen sections of the epithelia. The immunoreactivities of NJ-E-H10 were detected in the cytoplasm of basal cells predominantly located in the interpapillary zones of the epithelia. In the primary culture of EECs, immunoreactive cells were present at the marginal area of the growing colonies, where EECs extend their cytoplasm and migrate out of the colonies. Immunoelectron microscopy demonstrated the immunoreactivities of the moAb NJ-E-H10 around the intermediate filaments of basal cells, but not on the filaments themselves. In the human skin, NJ-E-H10 positive cells were also observed in the basal layer of the epidermis as well as in keratinocytes in the outer layer of the outer root sheath in hair follicles and myoepitheial cells in the sweat glands. Since the distribution of NJ-E-H10 immunoreactivities differs from that reported by hitherto-known antibodies, the MoAb NJ-E-H10 is considered a new marker for clarifing the biological properties of the basal cell compartment in stratified epithelia.     

CYP isoforms involved in the metabolism of clarithromycin in vitro: comparison between the identification from disappearance rate and that from formation rate of metabolites

To clarify whether CYP2C19 is involved in the overall metabolism of clarithromycin (CAM) or not, in vitro studies using human liver microsomes and recombinant CYPs were performed by an approach based on the disappearance rate of parent compound from the incubation mixture. In addition, the results of disappearance rate were compared with those obtained from the formation rates of the major metabolites of CAM, 14-(R)-hydroxy-CAM and N-demethyl-CAM.The intrinsic clearance (CL(int)) values determined from the disappearance of CAM in nine different human liver microsomes were highly correlated with the testosterone 6beta-hydroxylation activity (r=0.957, p<0.001). The CL(int) of CAM was markedly reduced by selective inhibitors of CYP3A4 (ketoconazole and troleandomycin) and by polyclonal antibodies raised against CYP3A4/5 in human liver microsomes. Among the 11 isoforms of recombinant human CYP, only CYP3A4 revealed the metabolic activity for the disappearance of CAM. These results were fairly consistent with those obtained from the conventional approach based on the formation of major metabolites of CAM. Comparison of the kinetic parameters estimated from the disappearance rate of CAM and the formation rates of 14-(R)-hydroxy-CAM and N-demethyl-CAM indicates that N-demethylation and 14-(R)-hydroxylation account for 65% of CL(int) derived from the disappearance of CAM in human liver microsomes.The findings suggest that CYP3A4 plays a predominant role in the overall metabolic clearance of CAM as well as in the formation of 14-(R)-hydroxy-CAM and N-demethyl-CAM. CYP2C19 does not appear to be involved in the overall metabolism of CAM at least in human liver microsomes. A combination of the disappearance rate of a parent compound and the formation rate of metabolites appears to be a useful approach for estimating the percentage contribution of the formation of metabolites to the overall metabolic clearance of a parent compound in vitro.     

How can we improve the quality of health care in Japan? Learning from JCQHC hospital accreditation

The World Health Report 2000 placed Japan first for overall health system attainment: a surprising development considering that, aside from discussing excessive expenditure, health care professionals and the Health Ministry have paid little attention recently to the quality of health care. Japan's free access policy and the universal health care system have actually fostered a very relaxed attitude toward evaluation. Concerned about the possible risks to patient safety, physicians established a volunteer association to promote quality health care issues. Then in 1995, the Japan Council for Quality Health Care (JCQHC) was founded to implement the third party accreditation of hospitals. Concurrent with the formation of the JCQHC, the sharply rising costs of malpractice litigation motivated the authorities and medical facilities to work toward protecting patient safety at different levels. Despite the WHO's positive review, critics maintain that significant inequities still exist in Japanese health care. Examples include, financial inequities between private and public hospitals, and the number and quality of hospitals and physicians between rural and urban areas. To protect patient safety and improve the quality of care, every effort must be made to eliminate inequities in the health care system. JCQHC accreditation is an important tool for furthering these efforts.     

Role of Th2 responses in the development of allergen-induced airway remodelling in a murine model of allergic asthma

(1) To clarify the involvement of Th2 responses in the development of allergen-induced airway remodelling, we investigated the effect of anti-CD4 monoclonal antibody (mAb) and anti-CD8 mAb, and the responses of IL-4 gene-knockout (KO) mice in a murine model of allergic asthma. (2) Mice were immunized twice by intraperitoneal injections of ovalbumin (OA), and exposed to aeroallergen (OA, 1% w v(-1)) for 3 weeks. Twenty-four hours after the final challenge, airway responsiveness to acetylcholine was measured, and bronchoalveolar lavage (BAL) and histological examinations were carried out. (3) Anti-CD4 mAb (1 mg kg(-1)) clearly inhibited allergen-induced increases in airway responsiveness to acetylcholine, the number of eosinophils in BAL fluid, serum OA-specific IgE levels, IL-13 and transforming growth factor-beta1 levels in BAL fluid, and amount of hydroxyproline in the lung by 100, 99, 100, 100, 84, and 60%, respectively. Furthermore, the antibody (1 mg kg(-1)) also attenuated allergen-induced goblet cell hyperplasia in the epithelium and subepithelial fibrosis by 72 and 83%, respectively. In contrast, anti-CD8 mAb (1 mg kg(-1)) showed no effect on each parameter. Furthermore, all these parameters were attenuated in IL-4KO mice by 57, 93, 100, 45, 84 and 60%, and also 72 and 83%, respectively. (4) These findings suggest that Th2 responses play a critical role for the development of allergen-induced airway remodelling, and that the inhibition of Th2 responses, e.g. using anti-CD4 mAb, is a therapeutic approach for the treatment of airway remodelling in asthma.