Ayano Takeuchi

Age-Related Amyloid β Deposition in Transgenic Mice Overexpressing Both Alzheimer Mutant Presenilin 1 and Amyloid β Precursor Protein Swedish Mutant Is Not Associated with Global Neuronal Loss

To analyze the relationship between the deposition of amyloid beta peptides (Abeta) and neuronal loss in transgenic models of Alzheimers disease (AD), we examined the frontal neocortex (Fc) and CA1 portion of hippocampus (CA1) in PSAPP mice doubly expressing AD-associated mutant presenilin 1 (PS1) and Swedish-type mutant beta amyloid precursor protein (APPsw) by morphometry of Abeta burden and neuronal counts. Deposition of Abeta was detected as early as 3 months of age in the Fc and CA1 of PSAPP mice and progressed to cover 28.3% of the superior frontal cortex and 18.4% of CA1 at 12 months: approximately 20- (Fc) and approximately 40- (CA1) fold greater deposition than in APPsw mice. There was no significant difference in neuronal counts in either CA1 or the frontal cortex between nontransgenic (non-tg), PS1 transgenic, APPsw, and PSAPP mice at 3 to 12 months of age. In the PSAPP mice, there was disorganization of the neuronal architecture by compact amyloid plaques, and the average number of neurons was 8 to 10% fewer than the other groups (NS, P > 0.10) in CA1 and 2 to 20% fewer in frontal cortex (NS, P = 0.31). There was no loss of total synaptophysin immunoreactivity in the Fc or dentate gyrus molecular layer of the 12-month-old PSAPP mice. Thus, although co-expression of mutant PS1 with Swedish mutant betaAPP leads to marked cortical and limbic Abeta deposition in an age-dependent manner, it does not result in the dramatic neuronal loss in hippocampus and association cortex characteristic of AD.

Amyloid Angiopathy and Variability in Amyloid β Deposition Is Determined by Mutation Position in Presenilin-1-Linked Alzheimer’s Disease

The presenilins (PSs) are components of large molecular complexes that contain beta-catenin and function as gamma-secretase. We report here a striking correlation between amyloid angiopathy and the location of mutation in PS-1 linked Alzheimers disease. The amount of amyloid beta protein, Abeta(42(43)), but not Abeta(40,) deposited in the frontal cortex of the brain is increased in 54 cases of early-onset familial Alzheimers disease, encompassing 25 mutations in the presenilin-1 (PS-1) gene, compared to sporadic Alzheimers disease. The amount of Abeta(40) in PS-1 Alzheimers disease varied according to the copy number of epsilon4 alleles of the Apolipoprotein E gene. Although the amounts of Abeta(40) and Abeta(42(43)) deposited did not correlate with the genetic location of the mutation in a strict linear sense, the histological profile did so vary. Cases with mutations between codon 1 and 200 showed, in frontal cortex, many diffuse plaques, few cored plaques, and mild or moderate amyloid angiopathy. Cases with mutations occurring after codon 200 also showed many diffuse plaques, but the number and size of cored plaques were increased (even when epsilon4 allele was not present) and these were often clustered around blood vessels severely affected by amyloid angiopathy. Similarly, diverging histological profiles, mainly according to the degree of amyloid angiopathy, were seen in the cerebellum. Mutations in the PS-1 gene may therefore alter the topology of the PS-1 protein so as to favor Abeta formation and deposition, generally, but also to facilitate amyloid angiopathy particularly in cases in which the mutation lies beyond codon 200. Finally we report that the amount of Abeta(42(43)) deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.

Connexin Gene Transfer Preserves Conduction Velocity and Prevents Atrial Fibrillation

Background— Several lines of evidence have suggested that maintenance of atrial fibrillation (AF) depends on reentrant mechanisms. Maintenance of reentry necessitates a sufficiently short refractory period and/or delayed conduction, and AF has been associated with both alterations. Fibrosis, cellular dysfunction, and gap junction protein alterations occur in AF and cause conduction delay. We performed this study to test the hypothesis that gap junction protein overexpression would improve conduction and prevent AF. Methods and Results— Thirty Yorkshire swine were randomized into 2 groups (sinus rhythm and AF), and each group into 3 subgroups: sham-operated control, gene therapy with adenovirus expressing connexin (Cx) 40, and gene therapy with adenovirus expressing Cx43 (n=5 per subgroup). All animals had epicardial gene painting; the AF group had burst atrial pacing. All animals underwent terminal study 7 days after gene transfer. Sinus rhythm animals had strong transgene expression but no atrial conduction changes. In AF animals, controls had reduced and lateralized Cx43 expression, and Cx43 gene transfer restored expression and cellular location to sinus rhythm control levels. In the AF group, both Cx40 and Cx43 gene transfer improved conduction and reduced AF relative to controls. Conclusions— Connexin gene therapy preserved atrial conduction and prevented AF.

Rationale and study design of the Japan environment and children’s study (JECS)

BackgroundThere is global concern over significant threats from a wide variety of environmental hazards to which children face. Large-scale and long-term birth cohort studies are needed for better environmental management based on sound science. The primary objective of the Japan Environment and Children’s Study (JECS), a nation-wide birth cohort study that started its recruitment in January 2011, is to elucidate environmental factors that affect children’s health and development.Methods/DesignApproximately 100,000 expecting mothers who live in designated study areas will be recruited over a 3-year period from January 2011. Participating children will be followed until they reach 13 years of age. Exposure to environmental factors will be assessed by chemical analyses of bio-specimens (blood, cord blood, urine, breast milk, and hair), household environment measurements, and computational simulations using monitoring data (e.g. ambient air quality monitoring) as well as questionnaires. JECS’ priority outcomes include reproduction/pregnancy complications, congenital anomalies, neuropsychiatric disorders, immune system disorders, and metabolic/endocrine system disorders. Genetic factors, socioeconomic status, and lifestyle factors will also be examined as covariates and potential confounders. To maximize representativeness, we adopted provider-mediated community-based recruitment.DiscussionThrough JECS, chemical substances to which children are exposed during the fetal stage or early childhood will be identified. The JECS results will be translated to better risk assessment and management to provide healthy environment for next generations.

Feasibility and validity of the Patient Neurotoxicity Questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02

GoalsThe aim of the study was to determine the feasibility and validity of a newly developed patient-based instrument—the Patient Neurotoxicity Questionnaire (PNQ)—for grading chemotherapy-induced peripheral neuropathy (CIPN).Patients and methodsWe prospectively collected data from 300 female patients who were treated with taxane chemotherapy for primary breast cancer as part of a national multicenter phase III randomized trial (N-SAS BC 02). We evaluated patient compliance with the PNQ and several validation parameters, including concordance between CIPN grades noted by physicians (National Cancer Institute Common Toxicity Criteria) and patients (PNQ), and the concurrent validity and responsiveness of the PNQ versus the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) utilizing data at pre-treatment and before three, five, and seven treatment cycles.Main resultsThe questionnaire completion rate was >90% at all assessments. Evaluation by physicians always resulted in lower neuropathy assessment scores compared with those reported directly by patients (weighted kappa coefficients, 0.02–0.06). Both PNQ sensory and motor scores were significantly correlated with the FACT/GOG-Ntx (r = 0.66 and 0.51, respectively). In the repeated measures analysis of variance model, PNQ grades increased considerably as treatment continued, indicating progressively worsening CIPN over time.ConclusionsThe PNQ has an applicable degree of feasibility and validity, useful for the diagnosis of CIPN as well as for clinical treatment decision-making, where the development of CIPN is a potential treatment-limiting consideration. Physicians underreport and underestimate the severity of CIPN symptoms compared with patients, thereby supporting the importance of assessing patient-reported outcomes using the PNQ.

Validation of the prognostic value of histopathological grading or c-kit mutation in canine cutaneous mast cell tumours: a retrospective cohort study.

The objective of this retrospective cohort study was to validate the prognostic value of histological grading of canine cutaneous mast cell tumours (MCTs) according to the Patnaik (grades I-III) and Kiupel (low, high) grading systems, and to confirm the prognostic significance of internal tandem duplications (ITDs) within exon 11 of the c-kit gene (ITD-Exon11). The baseline characteristics and outcome data from 47 dogs diagnosed with cutaneous MCTs were collected and reviewed. Tumours were graded according to both grading systems and the nucleotide sequence of c-kit was evaluated. Results were analyzed to evaluate predictive factors for overall survival (OS) and progression-free survival (PFS). Log-rank tests indicated that dogs with Patnaik grade III MCTs had significantly reduced OS and PFS compared to those with either grade I or II tumours. However, no significant difference in OS or PFS was observed between grade I and II tumours. The dogs with Kiupel high-grade MCTs had significantly shorter OS and PFS than dogs with low-grade MCTs. The presence of ITD-Exon11 was significantly associated with shorter PFS. The result of Cox regression analysis showed that the Kiupel grading system for OS and PFS, and lymph node metastasis for OS, independently predicted prognosis. Kappa statistics confirmed a significantly higher inter-observer consistency for the Kiupel compared to the Patnaik grading system. These findings demonstrate that the Kiupel grading system is a useful prognostic tool for canine cutaneous MCTs in predicting OS and PFS, while the occurrence of ITD-Exon11 appeared to be a useful predictor for PFS.

The Japan Environment and Children's Study (JECS): A Preliminary Report on Selected Characteristics of Approximately 10 000 Pregnant Women Recruited During the First Year of the Study

BACKGROUND The Japan Environment and Childrens Study (JECS) is an ongoing nationwide birth cohort study launched in January 2011. In this progress report, we present data collected in the first year to summarize selected maternal and infant characteristics. METHODS In the 15 Regional Centers located throughout Japan, the expectant mothers were recruited in early pregnancy at obstetric facilities and/or at local government offices issuing pregnancy journals. Self-administered questionnaires were distributed to the women during their first trimester and then again during the second or third trimester to obtain information on demographic factors, physical and mental health, lifestyle, occupation, environmental exposure, dwelling conditions, and socioeconomic status. Information was obtained from medical records in the first trimester and after delivery on medical history, including gravidity and related complications, parity, maternal anthropometry, and infant physical examinations. RESULTS We collected data on a total of 9819 expectant mothers (mean age = 31.0 years) who gave birth during 2011. There were 9635 live births. The selected infant characteristics (singleton births, gestational age at birth, sex, birth weight) in the JECS population were similar to those in national survey data on the Japanese general population. CONCLUSIONS Our final birth data will eventually be used to evaluate the national representativeness of the JECS population. We hope the JECS will provide valuable information on the impact of the environment in which our children live on their health and development.Background The Japan Environment and Children’s Study (JECS) is an ongoing nationwide birth cohort study launched in January 2011. In this progress report, we present data collected in the first year to summarize selected maternal and infant characteristics. Methods In the 15 Regional Centers located throughout Japan, the expectant mothers were recruited in early pregnancy at obstetric facilities and/or at local government offices issuing pregnancy journals. Self-administered questionnaires were distributed to the women during their first trimester and then again during the second or third trimester to obtain information on demographic factors, physical and mental health, lifestyle, occupation, environmental exposure, dwelling conditions, and socioeconomic status. Information was obtained from medical records in the first trimester and after delivery on medical history, including gravidity and related complications, parity, maternal anthropometry, and infant physical examinations. Results We collected data on a total of 9819 expectant mothers (mean age = 31.0 years) who gave birth during 2011. There were 9635 live births. The selected infant characteristics (singleton births, gestational age at birth, sex, birth weight) in the JECS population were similar to those in national survey data on the Japanese general population. Conclusions Our final birth data will eventually be used to evaluate the national representativeness of the JECS population. We hope the JECS will provide valuable information on the impact of the environment in which our children live on their health and development.

Decreased duration of acute upper respiratory tract infections with daily intake of fermented milk: A multicenter, double-blinded, randomized comparative study in users of day care facilities for the elderly population

BACKGROUND There is insufficient evidence of preventive effect of probiotics on upper respiratory tract infections (URTIs) in an elderly population. METHODS We conducted a multicenter, double-blinded, randomized, placebo-controlled parallel group study. Elderly persons had participated who used day care at 4 facilities in Tokyo. We used fermented milks containing Lactobacillus casei strain Shirota (LcS) and placebo drinks as test drinks. RESULTS A total of 154 subjects was analyzed. The number of persons diagnosed with an acute URTIs was almost identical in both groups (LcS: 31, placebo: 32), whereas the number of acute URTIs events (LcS: 68, placebo: 51) and the symptom score (LcS: 425, placebo: 396) were both higher in the LcS group. Permutation tests performed using the total number of acute URTIs infection events/total days of observation and the total symptom score/total days of observation found no statistically significant difference respectively (P values of .89 and .64, respectively). Comparing the mean duration of infection per infection event found a shorter mean duration in the LcS group (LcS: 3.71 days, placebo: 5.40 days), and the difference was statistically significant. CONCLUSION The results suggest that fermented milk containing LcS probably reduces the duration of acute URTIs.

Estimating Mortality Effects of Fine Particulate Matter in Japan: A Comparison of Time-Series and Case-Crossover Analyses

Abstract Small particles can reach alveoli without being trapped in the upper respiratory tract and may have a greater impact on health than larger particles. Given the limited knowledge on health effects of fine particulate matter (PM2.5) in Japan, the short-term effects of PM2.5 on daily mortality using the generalized additive model (GAM), generalized linear model (GLIM), and time-stratified case-crossover analysis were estimated. Daily mortality data were obtained from the Ministry of Health, Labor, and Welfare. Air pollution and meteorological data in 20 areas were obtained from the National Institute for Environmental Studies and the Japan Meteorological Agency, respectively. The three methods were compared, adjusting for meteorological variables and co-pollutants, for area-specific analyses and combined area-specific results using meta-analysis with a random-effects model. Daily mortality for elderly aged 65 and over varied from 0.5 to 127.3 by area. The 24-hr mean concentration of PM2.5 ranged from 11.8 to 22.8 μg/m3. Area-specific analyses revealed regional heterogeneity. Furthermore, combined results showed that a 10-μg/m3 increase in PM2.5 for the single-pollutant model at lag1 was associated with a 0.53, 0.77, and 0.88% increase in all-cause mortality for the GAM, GLIM, and case-crossover analysis, respectively. These findings provide robust evidence for the short-term effects of air pollutants on daily mortality in Japan and suggest that differences in estimates obtained from different statistical models should be considered when multipollutant models are used.

Impact of short-term exposure to fine particulate matter on emergency ambulance dispatches in Japan

Background Evidence of an association between fine particulate matter (PM2.5) and morbidity is limited in Asia. We used a case-crossover design to evaluate the association between short-term exposure to PM2.5 and emergency ambulance dispatches (as a proxy of acute health outcomes), and to calculate the extent to which a 10 μg/m3 decrease in PM2.5 concentrations would reduce the number of ambulance dispatches. Methods We used data on emergency ambulance dispatches in Fukuoka City, Japan between 2005 and 2010. Emergency ambulance services are publicly funded and cover the entire city. After excluding ambulance dispatches related to external injuries and pregnancy/childbirth, we analysed data on the remaining 176 123 dispatches. We also collected records of daily concentrations of PM2.5 from one ambient air pollution monitoring station. ORs per 10 μg/m3 increase in PM2.5 were estimated using conditional logistic regression controlled for ambient temperature and relative humidity. Results During the study period, the average daily concentration of PM2.5 was 20.3 μg/m3. Exposure to PM2.5 was associated with emergency ambulance dispatches in general (lag0–1; OR=1.008 (95% CI 1.002 to 1.014)) and with dispatches due to respiratory diseases (lag0–1; OR=1.027 (1.007 to 1.048)). No association was observed for dispatches due to cardiovascular diseases. We estimated that a 10 μg/m3 decrease in PM2.5 concentrations would have led to approximately 260 (estimated range=70–460) fewer ambulance dispatches in Fukuoka for 2012. Conclusions Providing further evidence on the short-term health effects of PM2.5 exposure, we found that exposure was associated with an increased number of emergency ambulance dispatches. The effect was, however, relatively small.