Vaccine efficacy of transcutaneous immunization with amyloid ß using a dissolving microneedle array in a mouse model of Alzheimer's disease.

Vaccine therapy for Alzheimer's disease (AD) based on the amyloid cascade hypothesis has recently attracted attention for treating AD. Injectable immunization using amyloid ß peptide (Aß) comprising 1-42 amino-acid residues (Aß1-42) as antigens showed therapeutic efficacy in mice; however, the clinical trial of this injected Aß1-42 vaccine was stopped due to the incidence of meningoencephalitis caused by excess activation of Th1 cells infiltrating the brain as a serious adverse reaction. Because recent studies have suggested that transcutaneous immunization (TCI) is likely to elicit Th2-dominant immune responses, TCI is expected to be effective in treating AD without inducing adverse reactions. Previously reported TCI procedures employed complicated and impractical vaccination procedures; therefore, a simple, easy-to-use, and novel TCI approach needs to be established. In this study, we investigated the vaccine efficacy of an Aß1-42-containing TCI using our novel dissolving microneedle array (MicroHyala; MH) against AD. MH-based TCI induced anti-Aß1-42 immune responses by simple and low-invasive application of Aß1-42-containing MH to the skin. Unfortunately, this TCI system resulted in little significant improvement in cognitive function and Th2-dominant immune responses, suggesting the need for further modification.

[Development of social activities-related daily life satisfaction scale for the elderly and evaluation of its reliability and validity].

PURPOSE: The purpose of this study was to develop a Social Activities-Related Daily Life Satisfaction Scale specifically applicable to elderly people in communities and to evaluate its reliability and validity. METHODS: Sixteen items were extracted from an initial pool and assessed for inclusion in the scale by correlation and exploratory factor analyses. To confirm validity, confirmatory factor analysis was conducted and correlation coefficients were calculated. In addition, t-tests were performed in order to generate scores of the subscale related to activity. To prove reliability, Cronbach's coefficient alpha values were calculated. Data for 755 older adults aged 65 to 84 years were obtained from a mail survey in Ichikawa City, Chiba Prefecture. RESULTS: Exploratory factor analyses indicated that four factors, "satisfaction with learning" (four items), "satisfaction with usefulness to others and society" (four items), "satisfaction with health and physical strength" (three items), and "satisfaction with friends" (three items) should be extracted. Confirmatory factor analysis for assessing the 14-item four-factor model showed high goodness of fit indices (GFI = 0.943, AGFI = 0.915, RMSEA = 0.068). Concurrent validity was established by comparing the score of the scale with five external variables (Activity and Daily Life Satisfaction Scale for the Elderly, Life Satisfaction Index K, etc). Student's t-tests revealed that each score of the subscale was positively associated with activity variable. The overall Cronbach's coefficient alpha for the scale was 0.919 and for its four subscales values ranged from 0.814 to 0.887. CONCLUSION: A Social Activities-Related Daily Life Satisfaction Scale was derived consisting of four subscales, "satisfaction with learning", "satisfaction with usefulness to others and society", "satisfaction with health and physical strength", and "satisfaction with friends". The results of the present study suggested that the Social Activities-Related Daily Life Satisfaction Scale has adequate reliability and validity.

Alternative cell death of Apaf1-deficient neural progenitor cells induced by withdrawal of EGF or insulin.

BACKGROUND: Various forms of cell death, such as apoptotic, autophagic and non-lysosomal types, are implicated in normal physiological processes. Apoptotic protease activating factor 1 (Apaf1) is an important component of the intrinsic apoptotic pathway. Deficiency of Apaf1 results in an accumulation of neural progenitor cells (NPCs) in the developing central nervous system and thus, in perinatal lethality. A small percentage of the mutant mice, however, are viable and grow to maturity. The occurrence of such normal mutants implicates alternative cell death pathways during neurogenesis. METHODS: NPCs prepared from wild-type or Apaf1-deficient embryos were cultured in growth factor-deprived medium and examined for cell death, caspase activation and morphological alterations. Generation of reactive oxygen species (ROS) and the effects of antioxidants were examined. RESULTS: Wild-type NPCs underwent apoptosis within 24 hours of withdrawal of epidermal growth factor (EGF) or insulin, whereas Apaf1-deficient NPCs underwent cell death but showed no signs of apoptosis. Autophagy was not necessarily accompanied by cell death. Cell death of the Apaf1-deficient NPCs resembled necroptosis-necrosis-like programmed cell death. The necroptosis inhibitor necrostatin-1, however, failed to inhibit the cell death. ROS accumulation was detected in NPCs deprived of growth factors, and an antioxidant partially suppressed the non-apoptotic cell death of Apaf1-deficient NPCs. CONCLUSIONS: These data indicate that after withdrawal EGF or insulin withdrawal, the Apaf1-deficient cells underwent non-apoptotic cell death. ROS generation may partially participate in the cell death. GENERAL SIGNIFICANCE: Non-apoptotic cell death in NPCs may be a compensatory mechanism in the developing CNS of Apaf1-deficient embryos.

[Productive activities and well-being among community-dwelling elderly].

OBJECTIVE: This study examined the association between engagement in productive activities and well-being among community-dwelling elderly. METHODS: Data for 576 older adults were obtained from a mail survey in Osaka City. The productive activities was measured with reference to three domains (paid work, unpaid work at home, and unpaid work outside the home) and the number of productive roles. Well-being was assessed by two measures: life satisfaction (LSIK) and self-rated health. The author used multivariate analyses with each of the two measures of well-being as dependent variables, and each of the productive activities as independent variables. The analyses were conducted separately for men and women, controlling for sociodemographic variables, IADL(instrumental activities of daily living) and social relationships. RESULTS: Multivariate analyses revealed the following findings. Paid work was positively associated with life satisfaction of women and self-rated health of men and women. Unpaid work at home was not significantly associated with life satisfaction or self-rated health for either men or women. However, unpaid work outside the home was related to higher scores for life satisfaction and self-rated health among women. The numbers of productive roles were positively associated with life satisfaction of women and self-rated health of men and women. CONCLUSION: Productive engagement was generally beneficial to older women's well-being except for unpaid work at home. Among men, only paid work out of the three activity domains and the number of productive roles were associated with better self-rated health. Public health policies and programs that bring older women into productive engagement outside the home may thus improve their well-being and generate benefits for communities.

[Effects of social activities on life satisfaction among the elderly: four aspects in men and women].

OBJECTIVE: The current study was performed to examine relationships between different aspects of social activities and life satisfaction among the elderly. This issue was investigated in men and women separately. METHODS: Data for 612 older adults aged 65 to 84 years were obtained from a mail survey in an urban area. Life satisfaction was measured using the LSIK and social activities were assessed by asking respondents their degree of participation in each type of interaction. The focus was on four aspects: personal activities, socially-related activities, learning activities, and job activity. In order to examine relationships between different aspects of social activities and life satisfaction, the author used multiple regression analyses with the four types of social activity level as independent variables. All except job activity were categorized as lower, middle and higher levels, and work was categorized as low and high. Two models of multiple regression were employed. First, each of the four aspects of social activity was entered as an independent variable (Model 1); second, four aspects of social activity were entered as independent variables simultaneously (Model 2). The analyses were conducted separately for men and women, controlling for age, marital status, subjective economic status and IADL (instrumental activities of daily living). RESULTS: (1) The results of the multiple regression analyses (Model 1) were as follows: for both men and women, personal activities were positively associated with life satisfaction. For women, socially-related activities were also positively related to life satisfaction. For both men and women, learning activities and job activity exhibited statistically nonsignificant relationships with life satisfaction. (2) With Model 2, the results were as follows: among men, none of the aspects of social activity was significantly associated with life satisfaction. Among women, only personal activities were positively associated with life satisfaction. CONCLUSION: When all other aspects of social activity, sociodemographic and IADL factors were controlled, older women with higher levels of engagement in personal activities had greater life satisfaction, whereas among men, none of the aspects of social activity was significantly related to life satisfaction.

Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways.

The activation of tumor suppressor p53 induces apoptosis or cell cycle arrest depending on the state and type of cell, but it is not fully understood how these different responses are regulated. Here, we show that Puma and Noxa, the well-known p53-inducible proapoptotic members of the Bcl-2 family, differentially participate in dual pathways of the induction of apoptosis. In normal cells, Puma but not Noxa induces mitochondrial outer membrane permeabilization (MOMP), and this function is mediated in part by a pathway that involves calcium release from the endoplasmic reticulum (ER) and the subsequent caspase activation. However, upon E1A oncoprotein expression, cells also become susceptible to MOMP induction by Noxa, owing to their sensitization to the ER-independent pathway. These findings offer a new insight into differential cellular responses induced by p53, and may have therapeutic implications in cancer.

[Factors associated with social activities among the elderly in a metropolitan area: physical, psychological, and socio-environmental parameters].

OBJECTIVE: The current study examined physical, psychological, and socio-environmental factors related to social activities among the elderly in a metropolitan area. METHODS: Fifteen hundred individuals aged 65 to 84 years were randomly selected in Osaka City. Data for 771 persons (51.4%) were obtained from a mail survey and these for 654 eligible cases were analyzed for level of social activities from four aspects: personal activities, socially-related activities, learning activities, and job activity. In order to examine factors related to social activities, we used logistic regression analyses with each of the four aspects of social activities as dependent variables. Independent variables were socio-demographic, physical, psychological, and socio-environmental variables. RESULTS: Multivariate analyses revealed the following results: no feeling of difficulty in going outdoors, number of friends, sense of collecting information about social activities, and informational social support were positively associated with personal activities. The attitude toward community score, the motivation to live comfortably score, the number of friends, opportunities to be invited to participate, any skill or knowledge, and experience in community activities were positively related to participation in socially-related activities. The attitude toward community score, opportunities to be invited to take part, and sense of collecting information about social activities were also positively associated with learning activities. Furthermore, motivation to active life score, any skill or knowledge, and experience in community activities were positively related to job activity. CONCLUSION: Physical, psychological, and socio-environmental factors as well as socio-demographic factors were found to be associated with social activities among the elderly in a metropolitan area.

ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1.

Accumulation of unfolded proteins induces endoplasmic reticulum (ER) stress. Excessive and prolonged stresses lead cells to apoptosis. However, the precise molecular mechanisms of ER stress-induced apoptosis have not been fully elucidated. We investigated the involvement of the apoptosome in ER stress-induced cell death pathway using mouse embryonic fibroblasts (MEFs) and mice deficient for Apaf-1. Apaf-1-deficient MEFs showed more resistance to ER stress-inducing reagents as compared with wild type cells. Despite comparable induction of ER stress in both wild type and Apaf-1-deficient cells, activation of caspase-3 was only observed in wild type, but not Apaf-1-deficient, MEFs. Under ER stress conditions, BAX translocated to mitochondria and cytochrome c was released from mitochondria. We also demonstrated that caspase-12 was processed downstream of Apaf-1 and caspase-3, and neither overexpression nor knockdown of caspase-12 affected susceptibility of the cells to ER stress-induced cell death. Furthermore, in the kidneys of Apaf-1-deficient mice, apoptosis induced by in vivo administration of tunicamycin was remarkably suppressed as compared with wild type mice. These data collectively demonstrated that Apaf-1 and the mitochondrial pathway of apoptosis play significant roles in ER stress-induced apoptosis.

Coordination of DNA replication and cell division in cyanobacteria Microcystis aeruginosa.

Little is known about the cyanobacterial cell cycle. When either nalidixic acid or hydroxyurea was added to a synchronized culture of Microcystis aeruginosa to block DNA replication, cell division did not occur. Furthermore, transcription of the essential cell division gene, ftsZ was repressed. After DNA replication, ftsZ transcription, as well as cell division, was not affected by hydroxyl urea, suggesting that the DNA replication and cell division of M. aeruginosa are coordinated and that this coordination is partly controlled by ftsZ transcription depending on DNA replication.

Molecular cloning of a novel variant of the rat soluble guanylate cyclase beta2 subunit.

Soluble guanylate cyclases (sGCs) are heterodimeric enzymes consisting of alpha and beta subunits and catalyze the formation of cGMP from GTP. The beta1 subunit has been characterized in detail, whereas the function and physiological role of the beta2 subunit are poorly understood. In this study, I isolated two distinct cDNA fragments for the beta2 subunit of sGC (beta2a and beta2b) from a rat brain cDNA library by 3' rapid amplification of cDNA ends using degenerate sense primers based on amino acid sequences conserved among membrane-bound guanylate cyclases. The deduced amino acid sequence of beta2a is identical with the corresponding sequence of the previously described beta2 subunit, whereas that of beta2b is C-terminally shorter by 46 amino acids and thus does not contain a consensus sequence for isoprenylation/carboxymethylation. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that both variants are expressed in various tissues, including kidney, liver, and brain. Although the functional significance of the C-terminal region containing the consensus sequence for isoprenylation/carboxymethylation of beta2a remains unclear yet, it is likely that these beta2 subunits play some physiological or pathophysiological role in various tissues.

[Differences in subject needs between nursing home residents' and residential care professional's perspectives].

OBJECTIVE: Considerable attention has been directed toward the quality of nursing home care, with a more recent focus on residents' perspectives concerning bio-psychosocial needs. Several researchers have reported professional and patients' perspectives to be consistently different regarding biopsychosocial needs. The objective of this study was to examine such differences. METHODS: A cross-sectional survey was conducted, with interviews of nursing home residents and a self-administered questionnaire for residential care professions. The data were obtained from 85 matched pairs in 6 nursing homes. The measures for subjective needs of the residents had three dimensions (physical, psychological, and social) covering 8 sub-categories. Analyses of the data offered good evidence of reliability (internal consistency) and content validity. RESULTS: In an agreement statistic analysis using Cohen's kappa, the residents' and care professional perspectives significantly differed regarding subject needs. In another analysis using t-tests, measures for subject needs derived from residential care professionals were consistently greater than those with nursing home residents. This tendency was generally consistent across sub-categories by ADL levels. However, the ranking order for the 7 sub-categories for subject needs was very similar with both raters. CONCLUSION: Assessing nursing home residents' subject needs represents an important and essential component of quality of care. However, needs assessment by the residential care profession is still its infancy and includes failure to consider the residents' perspective. The future research challenge is to find reasons for the gap in subjective thinking between the groups. In addition, researchers can perform a critical function on behalf of nursing home residents when they suggest improvements to the methodology for assessing residential care professionals views on residents' needs.

[Patient with bone metastasis of breast cancer who were improved by weekly DXR/TXT therapy].

The patient was a 57-year-old female with the main complaint of left chest pain and gait disturbance. Multiple bone metastases were observed in the vertebral and pelvic bone. Pathological pressure fracture, stegnosis of the spinal canal and edematous changes in the spinal nerves, especially in the 4th and 5th thoracic vertebrae, were observed. The clinical pathological status was T4cN1M1b, OSS Stage IV. After 4 cycles of weekly doxorubicin (DXR) (20 mg/body)/docetaxel (TXT) (40 mg/body) therapy (day 1, day 8, day 15, 1-week recovery period) were given to the patient, CA15-3 had decreased from 1,200 U/ml to 28 U/ml. The histopathological effect was judged to be Grade 2. Thereafter, ICTP was increased to 12.7 ng/ml and after 2 cycles of the weekly DXR/TXT therapy (day 1, day 8, 2-week recovery period) had been added, the patient was able to walk. MRI of the thoracic vertebrae showed that the foci of bone metastasis had improved 9 months after the treatment with chemotherapeutics, and good PS was maintained. No serious adverse reactions were observed with the weekly DXR/TXT therapy. Therefore, weekly DXR/TXT therapy is considered to be effective in treating patients with bone metastasis.