Transgenic expression of the protein-L-isoaspartyl methyltransferase (PIMT) gene in the brain rescues mice from the fatal epilepsy of PIMT deficiency

Protein-L-isoaspartyl methyltransfearase (PIMT) plays a physiological role in the repair of damaged proteins containing isoaspartyl residues. In previous studies, we showed that PIMT-deficient mice developed a fatal epileptic seizure associated with the accumulation of damaged proteins in the brain. The mutant mice also showed a neurodegenerative pathology in hippocampi and impaired spatial memory. Still undefined, however, is how the accumulation of isoaspartates leads to the death of PIMT-deficient mice. In the present study, we generated PIMT transgenic (Tg) mice to investigate whether the exogenous expression of PIMT could improve the symptoms associated with PIMT deficiency. Rescue experiments showed that Tg expression of PIMT driven by a prion promoter effectively cured the PIMT-deficient mice. Biochemically, a higher expression level of transgene led to the effective repair of damaged proteins in vivo. Although a lower level of expression caused an accumulation of damaged proteins in a partially rescued line, the mice survived. Interestingly, synapsin I, which was extensively modified posttranslationally in PIMT-deficient mice, was specifically repaired in a partially rescued, but symptom-improved, Tg line. Our results suggest that an overall accumulation of damaged proteins does not necessarily lead to a fatal epileptic seizure, whereas certain modifications, such as changes in synapsin I, may play a pivotal pathological role in epilepsy.     

Effects of social support on the mental health of mothers with infants

OBJECTIVE: We surmised that increase in stress in mothers having infants might be due to decline of social support under circumstances where nuclear family households now predominate. The present study was therefore conducted to analyze relations between stress reactions of mothers having infants, their recognition of social support, and negative feelings toward their baby and child care, a major factor in the burden of childcare. METHODS: The subject were 909 mothers having infants in nuclear families who lived in I city in Osaka Prefecture. Health examinations of infants at the ages of 4 months, 1 year and 6 months, and 3 years and 6 months were utilized. Questionnaires titled "Survey on Childcare" were distributed in advance by mail to parents of the infants included in the health examinations and collected at the health examinations. The survey period was August to September 2000. Personal background variables and, psychological investigation items, including mental health in terms of stress reactions, negative feelings toward childcare as a factor in the burden of childcare, and a support network scale were surveyed and analyzed. RESULTS: The mothers with infants were judged to be in a stressful state from the average mental health scores in all groups. Multiparas had significantly higher negative feelings toward childcare scores. Regarding the age groups of children, a significantly decreasing recognition of a support network as well as significantly increasing negative feelings toward childcare were observed with the growth of children. There was a positive correlation between negative feelings toward childcare and stress reactions. The recognition of social support was negatively correlated with stress reactions and negative feelings toward childcare. CONCLUSION: The study revealed that mothers having infants are in a stressful state and that the recognition of stress is related to negative feelings toward childcare and the recognition of a support network. The feeling of sufficient support lowers the level of stress arising from childcare, and facilitates avoiding or coping with problems, thereby promoting mothers' physical and mental health. This is important for continuation and fulfillment of childcare.     

Relationship of normal levels of activity of daily living and daily habits among elderly women at home

PURPOSE: The relationship of activities of daily living (ADL) with daily habits and age was investigated with a focus on the results of measurements of the normal speed (ordinary level: OL) and maximum speed (maximum capacity: MC) in performing items on a functional fitness test. The significance of the measurement of the ordinary level was also discussed. METHODS: The subjects were 69 women, aged 60-90 years old, who participated in a health workshop for the elderly sponsored by a local municipality and who performed at least 4 items on a functional fitness test. Public health nurses asked subjects about habitual life style, subjective health status and degree of satisfaction in daily life. The ADL level was measured using the tests of functional fitness developed by Oida et al and partially revised by ourselves and physical fitness tests (grip strength, sit and reach, and balancing on one leg with opened eyes). OL was measured as the time needed to perform functional fitness items at normal speed, and MC as the time needed when performing these tasks as quickly as possible. RESULTS: All functional fitness items were accomplished significantly faster with MC than OL. Correlation coefficient values between OL and MC were high significant. Age was found to be significantly related to the hand working test (Hand-T) to evaluate dexterity and the rope working test (Rope-T) to evaluate self-care, except with the MC. An analysis of covariance with age as the covariant revealed that, with OL, there were relationships between Hand-T and Rope-T and the item "active at home," and between the zigzag walking (Zigzag-T) and Rope-T and "walking or riding a bicycle to go shopping." With MC, there were relationships between Hand-T and "active at home," and between Zigzag-T and "walking of riding a bicycle to go shopping." Regarding physical capacity, relationships were seen between both hands and "high level of physical fitness" and "walking fast" and grip strength (Left hand), respectively. CONCLUSION: The ADL items measured in the preset study were related to the daily activities of elderly people. As the OL and MC results demonstrated a high correlation and the ADL items related with OL were found to have almost the same link with MC, we conclude that OL is suitable for testing with the advantage of safety. However, we could not explain differences in relationships between measurements and daily activities, pointing to a need for further research. Elderly people must maintain their capacity for ADL to support a good quality of life, and we have demonstrated the utility of measurements that include normal levels of activity as indicators.     

Effects of cacao liquor proanthocyanidins on PhIP-induced mutagenesis in vitro,and in vivo mammary and pancreatic tumorigenesis in female Sprague-Dawley rats

p53 plays an important role in cell-cycle control, as it facilitates DNA repair activities in response to DNA damage. An aberrant cell cycle impairs DNA repair and increases the probability of mutations that lead to carcinogenesis. The p53 codon 72 Arg/Pro polymorphism has been suggested to be associated with susceptibility to tobacco-related cancers, but this association remains controversial. In this hospital-based case-control study of 304 patients newly diagnosed with squamous cell carcinoma of the head and neck (SCCHN) and 333 cancer-free controls, we evaluated the association between this p53 polymorphism and the risk of SCCHN. All subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (+/-5 years), sex and smoking status. Our results suggested that there was no difference in the distributions of p53 codon 72 genotypes between cases and controls (odds ratio (OR)=1.04, 95% confidence interval (CI) 0.75-1.44 for Pro/Pro vs. Arg/Arg and OR=1.01, 95% CI 0.54-1.91 for Arg/Pro vs. Arg/Arg). However, there was evidence that the Pro allele was associated with an early age of onset of SCCHN. The median ages of onset of SCCHN were 59, 56 and 53 years for Arg/Arg, Arg/Pro and Pro/Pro cases, respectively (P=0.151 among three genotypes; P=0.057 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). The median ages at onset of oral cancers were 62, 57 and 51 years for Arg/Arg, Arg/Pro and Pro/Pro, respectively (P=0.091 among three genotypes; P=0.046 for Pro/Pro vs. Arg/Arg; P=0.066 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). While the results suggest that the P53 codon 72 polymorphism may contribute to oral cancer susceptibility, larger studies are needed to confirm these findings.     

A nested case-control study of risk factors for adult T-cell leukemia/lymphoma among human T-cell lymphotropic virus type-I carriers in Japan

Objectives: The purpose of this study was to investigate the serological risk factors for development of adult T-cell leukemia/lymphoma (ATL) among human T-cell lymphotropic virus type-I (HTLV-I) carriers. Methods: A nested case–control study was performed. The source population comprised 23,922 subjects who had either visited the outpatient clinic or who had received annual health check-ups at the K Hospital, Nagasaki, Japan, at least once during 1985–1996 (HTLV-I seroprevalence = 16.1%). Markers of HTLV-I infection were examined in stored sera from 29 incident cases of ATL diagnosed during 1985–1997, and 158 controls matched for sex, birth year, date of sample collection, and HTLV-I seropositivity (median follow-up = 6.4 years). Results: In exact conditional logistic regression analysis, high levels of soluble interleukin-2 receptor ( 500 U/ml) and high HTLV-I antibody titers ( 1024) were independently associated with an increased risk of developing ATL (Odds ratio 20.5, 95% confidence interval (CI) 4.5–194 and 2.9, 95% CI 0.98–9.5, respectively). The results remained essentially unchanged when the subjects were restricted to those whose histories were followed for two years or longer. Conclusions: These findings indicate that high soluble interleukin-2 receptor levels and high HTLV-I antibody titers are strong predictors of ATL among carriers of HTLV-I.     

Semisynthesis of new sarcophine derivatives with chemopreventive activity

The natural cembranolide sarcophine (3) and its lactone ring-opened analogue (10) were oxidized using selenium dioxide under different reaction temperatures to prepare hydroxylated derivatives. Nine new compounds were obtained, six of them targeted hydroxylated derivatives. The determination of regio- and stereochemistry as well as the mechanistic considerations on the selectivity observed in these reactions are discussed on the basis of 2D NMR and molecular modeling. In preliminary in vitro tests on inhibition of EBV-EA activation, compounds 10 and 12-15 have shown higher activity than the known chemopreventive agent sarcophytol A.     

Induction of different types of uterine adenocarcinomas in Donryu rats due to neonatal exposure to high-dose p-t-octylphenol for different periods

Inappropriate exposure to estrogens in the fetal and/or newborn period can exert irreversible influence, including carcinogenesis on the reproductive system in mammals. The present study was conducted to investigate uterine carcinogenesis in Donryu rats treated neonatally with a high-dose estrogenic compound, p-t-octylphenol (OP) for different exposure periods. Female Donryu rats were subcutaneously administered 100 mg/kg/day OP every other day for the first 5 postnatal days (PNDs 1-5) or the first 2 weeks (PNDs 1-15). They received a single injection of 20 mg/kg N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) into a uterine horn at 11 weeks of age and were examined until 15 months of age. PNDs 1-5 OP-treated rats showed normal development of the female reproductive system, including uterine gland genesis and normal estrous cycling after vaginal opening. The treatment, however, accelerated an earlier occurrence of persistent estrus and increased the number of well differentiated uterine adenocarcinomas as compared with controls. This indicated that PNDs 1-5 OP treatment acts as a delayed modulator of the hypothalamus-pituitary-ovarian hormonal control system and the modulation increased the serum estrogen:progesterone ratio, resulting in induction of uterine tumors. On the contrary, PNDs 1-15 OP treatment demonstrated immediate and irreversible influences on the control system, called 'androgenization', and induced abnormal uterine development manifested by prolonged persistent estrus immediately after vaginal opening and also suppression of uterine gland genesis. In addition, uterine tumor malignancy in morphological and biological property clearly increased in this group although the total number of adenocarcinomas was not increased. The present study provides evidence that neonatal exposure to a high-dose OP enhances uterine carcinogenesis in rats, and the type of uterine tumors is changed by the periods of neonatal exposure to OP, suggesting that the mechanism of uterine tumor development is dependent upon neonatal exposure periods.     

Use of diffusion weighted MRI to predict the occurrence and severity of hemorrhagic transformation in a rabbit model of embolic stroke

Alpha-synuclein is a brain presynaptic protein that is linked to familiar early onset Parkinson's disease and it is also a major component of Lewy bodies in sporadic Parkinson's disease and other neurodegenerative disorders. Alpha-synuclein expression increases in substantia nigra of both MPTP-treated rodents and non-human primates, used as animal models of parkinsonism. Here we describe an increase in alpha-synuclein expression in a human neuroblastoma cell line, SH-SY5Y, caused by 5-100 microM MPP+, the active metabolite of MPTP, which induces apoptosis in SH-SY5Y cells after a 4-day treatment. We also analysed the activation of the MAPK family, which is involved in several cellular responses to toxins and stressing conditions. Parallel to the increase in alpha-synuclein expression we observed activation of MEK1,2 and ERK/MAPK but not of SAPK/JNK or p38 kinase. The inhibition of the ERK/MAPK pathway with U0126, however, did not affect the increase in alpha-synuclein. The highest increase in alpha-synuclein (more than threefold) in 4-day cultures was found in adherent cells treated with low concentrations of MPP+ (5 microM). Inhibition of ERK/MAPK reduced the damage caused by MPP+. We suggest that alpha-synuclein increase and ERK/MAPK activation have a prominent role in the cell mechanisms of rescue and damage, respectively, after MPP+ -treatment.     

A study among related pairs of Japanese patients with familial Behçet's disease: group comparisons by interval of disease onsets

OBJECTIVE: To investigate the relationship between clinical features and the interval between onset of disease in pairs of related Japanese patients with Beh?et's disease (BD). METHODS: Questionnaires were sent to hospitals in which patients with familial occurrence of BD had been treated according to previous nationwide hospital surveys, and to an additional 341 hospitals selected at random. RESULTS: A total of 35 patients (19 male, 16 female) in 17 families (19 related pairs) were reported. The positive rate of HLA-B51 was 60.9% (14/23). The familial pairs were divided into 2 groups, with the mean interval between disease onset between each pair being either < or = 9 years or > or = 10 years. Among the short interval group, the total number of clinical findings and difference in age of onset was significantly larger than the long interval group. The interval between onsets had a high positive correlation with concordance of clinical findings and a high negative correlation with the difference in onset age. Difference in onset age had a higher negative correlation with same sex. Moreover, age difference had a high negative correlation with HLA-B5 (B51). Analysis of data showed that the related pairs with the short interval between onsets had larger difference in onset age and greater concordance of symptoms than the long interval patients. CONCLUSION: Although our findings did not show any direct evidence of an environmental cause in the etiology of BD, we speculate that there may be a multifactorial etiology including genetic factors such as HLA-B51 positivity.