Association Between Cerebral Microbleeds and Circulating Levels of Mid-Regional Pro-Adrenomedullin.

BACKGROUND: Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored. OBJECTIVE: We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment. METHODS: In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (< 0.65 nmol/L) or high (≥0.65 nmol/L). RESULTS: The mean MR-proADM level was 0.515±0.127 nmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (p < 0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; p < 0.05). CONCLUSION: High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients.

Daily Consumption of Coffee and Eating Bread at Breakfast Time Is Associated with Lower Visceral Adipose Tissue and with Lower Prevalence of Both Visceral Obesity and Metabolic Syndrome in Japanese Populations: A Cross-Sectional Study.

BACKGROUND: The study aimed to investigate the association between daily consumption of coffee or green tea, with and without habitual bread consumption for breakfast, and components and prevalence of metabolic syndrome in Japanese populations. METHODS: The study population consisted of 3539 participants (1239 males and 2300 females). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression analyses to evaluate the associations of daily coffee and green tea consumption with the prevalence of obesity, visceral obesity, and metabolic syndrome. RESULTS: Coffee consumption was associated with significantly lower proportions of visceral obesity (OR: 0.746, CI: 0.588-0.947) and metabolic syndrome (OR: 0.706, CI: 0.565-0.882). On the other hand, green tea was not associated with visceral obesity (OR: 1.105, CI: 0.885-1.380) or metabolic syndrome (OR: 0.980, CI: 0.796-1.206). The combination of daily drinking coffee and eating bread at breakfast time was associated with significantly lower proportions of obesity (OR: 0.613, CI: 0.500-0.751) (p = 0.911 for interaction), visceral obesity (OR: 0.549, CI: 0.425-0.710) (p = 0.991 for interaction), and metabolic syndrome (OR: 0.586, CI: 0.464-0.741) (p = 0.792 for interaction). CONCLUSION: Coffee consumption was significantly associated with lower visceral adipose tissue and lower proportions of visceral obesity, but the same was not true for green tea consumption. Furthermore, in combination with coffee consumption, the addition of eating bread at breakfast time significantly lowered proportions of visceral obesity and metabolic syndrome, although there was no interaction between coffee and bread.

Growth of cortical bone thickness and trabecular bone density in Japanese children.

BACKGROUND: The acquisition of a high bone density at a young age is a strategy to prevent fractures/falls later in life. We therefore decided to investigate the increases in cortical thickness (CoTh) and trabecular bone density (TBD) of children. METHODS: Subjects comprised 1314 students (678 boys and 636 girls) aged between 12 and 18 years. Lifestyle factors were examined with a self-administered questionnaire (sleep times, exercise habits, and calcium intake). Bone growth was assessed based on CoTh and TBD using an ultrasonic bone densitometer. Height, weight, and body fat percentage were also measured. RESULTS: Increases in CoTh and TBD occurred earlier in girls than in boys. Calcium intake was not sufficient at any of the ages examined, and sleep times were shorter than those recommended by the National Sleep Foundation. Increases in CoTh and TBD occurred subsequent to increases in height. Although increases in CoTh were observed with age in both sexes, TBD increased in boys until the age of 17 years and in girls until the age of 15 years. At 18 years of age, the young adult mean value was greater than 100% for CoTh but lower than 100% for TBD. A multivariate analysis identified age, body mass index (BMI), and exercise as independent positive factors for CoTh, while body fat percentage was an independent negative factor. Age and BMI were independent positive factors for TBD in both sexes, whereas body fat percentage was a positive factor in boys only. CONCLUSIONS: The study found that CoTH and TBD varied with age and differed in increase in boys and girls; related factors of bone increase could also be found. The results of this study may contribute to the acquisition of high bone density in children and adolescents.

Innovative instrumental analysis of heartbeat signals and its clinical application.

A new apparatus has been built that annexes a normal electrocardiograph, ECG, with the aim to enhance its capacity. It adds the normal ECG power to superpose multiple records of ECG altogether and averages out them and, further, makes sophisticated analysis, such as normalizing the peak heights, evaluating the half-line widths of the peaks, or that of the standard deviations of measurements like the inter peak distances. The results of the said calculations have not been obtainable using the former instruments, and are expected to be useful for clinicians.

Genetic susceptibility in the neural tube defects induced by ochratoxin A in the genetic arhinencephaly mouse, Pdn/Pdn.

It is well known that ochratoxin A (OTA) induces neural tube defects (NTDs) in mice. In the present study, OTA was administered to the genetic polydactyly/arhinencephaly mouse (Pdn/Pdn) to investigate the synergistic effect between gene and environmental toxin. OTA treatment on day 7.5 of gestation increased NTDs in the Pdn/Pdn mouse. The responsible gene for Pdn/Pdn is Gli3. So, it was speculated that specific susceptibility for OTA in the Pdn/Pdn mouse embryo may be due to the severe depression of Gli3 gene expression. As correlated genes, Gli3, Shh and Fgf8 gene expressions were examined in the Pdn mouse embryo on day 9 of gestation after administration of OTA on day 7.5. No alteration of Shh expression was observed in the non-treated Pdn/Pdn, and OTA-treated +/+ and Pdn/Pdn. Fgf8 signal was observed at the anterior neural ridge (ANR) in the non-treated +/+, and that was elongated in the non-treated Pdn/Pdn, and further elongated and more intensive in the OTA-treated Pdn/Pdn. It was suggested that Fgf8 gene expression was affected by the depression of Gli3, and alteration of Fgf8 gene expression was accelerated by the toxicity of OTA in the Pdn/Pdn.

Exencephaly induction by valproic acid in the genetic polydactyly/arhinencephaly mouse, Pdn/Pdn.

Non-treated homozygous polydactyly/arhinencephaly (Pdn/Pdn) mouse fetuses exhibited exencephaly in 16.7% of cases. Treatment of Pdn/Pdn mice with 350 mg/kg of valproic acid (VPA) on days 8.5 and 9.5 of gestation increased the rate of exencephaly to 66.7%. The responsible gene for the Pdn mouse phenotype has been determined to be Gli3, and the suppression of Gli3 gene expression has been documented in Pdn/Pdn embryos. We investigated how the sonic hedgehog (Shh) and Fgf8 genes, the correlated genes of Gli3, are expressed in the VPA-treated exencephalic Pdn/Pdn embryos on day 10 of gestation, using whole mount in situ hybridization (WISH) and real-time PCR methods. We could not detect any alterations in Shh expression by real-time PCR, or WISH in the non-treated Pdn/Pdn and VPA-treated exencephalic Pdn/Pdn embryos. Altered Fgf8 expression patterns were observed in the commissural plate and dorsal isthmal neuroepithelium in the non-treated Pdn/Pdn embryos. We speculated that the altered expression of Fgf8 might be the result of down-regulation of Gli3 in Pdn/Pdn embryos. Fgf8 gene expression in the commissural plate and dorsal isthmal neuroepithelium exhibits wide or altered signal patterns in the VPA-treated exencephalic Pdn/Pdn embryo. From these findings, it was suggested that down-regulation of Gli3 gene expression induced the altered expression of Fgf8 in the Pdn/Pdn embryos, and that VPA treatment accelerated the alterations of Fgf8 gene expression in the Pdn/Pdn embryos. It was further speculated that altered expression of Fgf8 in the commissural plate may be the fundamental cause of exencephaly, and that the synergistic effect between gene and drug shown in this experiment may explain the differences of sensitivity in the side-effects of the drug.

Sonic hedgehog expression in Gli3 depressed mouse embryo, Pdn/Pdn.

The phenotype of the genetic polydactyly/arhinencephaly mouse (Pdn/Pdn) is similar to Greig cephalopolysyndactyly syndrome (GCPS), which is induced by mutation of GLI3. Suppression of Gli3 gene expression has been observed in Pdn/Pdn. Thus, the gene responsible for Pdn/Pdn has been considered to be Gli3. Recently, the mutation point was demarcated, that is, a transposon was inserted into intron 3 of the Gli3 gene in the Pdn mouse. Forward and reverse primers were constructed in intron 3 near the insertion point. A forward primer in the long terminal repeat region of the transposon was also constructed. Now we can discriminate +/+, Pdn/+, Pdn/Pdn embryos from the PCR products. After genotyping of the Pdn embryos, Gli3 and other correlated gene expressions, such as sonic hedgehog (Shh), Bmp-2, Bmp-4, ptc-1, were analyzed by real-time PCR method. Gli3 gene expression in Pdn/Pdn was suppressed to 20-30% of +/+, and that in Pdn/+ was about 60% of +/+ through all the embryonic and neonatal periods examined. As Shh has been considered to be an antagonist of Gli3, Shh expression was analyzed, and a difference among genotypes was observed only on day 9 of gestation. We could not detect any alterations among genotypes in other gene expressions examined. Gli3 and Shh gene expression were also analyzed on day 9 by whole-mount in situ hybridization in the +/+ and Pdn/Pdn embryos. Neuroectoderm was positive by Gli3 probe in +/+ but not in Pdn/Pdn. Notochord, floor plate and prechordal mesoderm were positive by Shh probe both in +/+ and Pdn/Pdn embryos, but ectopic and/or over-expression of Shh were not observed in Pdn/Pdn embryos.

A novel missense mutation of ABCA1 in transmembrane alpha-helix in a Japanese patient with Tangier disease.

Tangier disease (TD) is a hereditary disorder characterized by the severe deficiency or absence of high-density lipoprotein cholesterol (HDL-C). TD is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene, most of which are located in the extracellular loops and nucleotide-binding domains. Here we describe the first case of TD carrying a missense mutation in a transmembrane alpha-helix of ABCA1. A 31-year-old Japanese woman had an extremely low level of HDL-C (1mg/dl) and yellowish tonsillar swelling, leading to the diagnosis of TD. The proband was homozygous for a point mutation of T4978C in exon 37, which results in the substitution of cysteine-1660 to arginine (C1660R) in the 8th transmembrane segment of ABCA1. Her parents, grandmother, and brother were found to be heterozygous for the same mutation. Both peripheral blood leukocytes from the patient and HEK293 cells transfected with T4978C-mutated ABCA1 normally expressed ABCA1 on the plasma membrane and had normal apolipoprotein A-I-binding ability. However, apolipoprotein A-I-mediated efflux of cholesterol and phospholipids was markedly diminished in HEK293 cells transfected with T4978C-mutated ABCA1. These results suggest that this mutant is normally translated and exists as a stable product with normal localization, yet is functionally defective. Cysteine-1660 appears to be a critical residue for cholesterol transport of ABCA1.

The relationship between usual coffee consumption and serum C-reactive protein level in a Japanese female population.

BACKGROUND: Usual coffee consumption may decrease insulin resistance and type 2 diabetes incidence, and reduce cardiovascular disease risk. As a mechanism, coffee-induced lower levels of C-reactive protein (CRP), a marker for the development of these diseases, can be considered. The associations between coffee consumption and CRP should be established by studies on various populations, yet studies in Japanese people, who do not necessarily consume as much coffee daily, are limited. METHODS: In total, 459 community-living Japanese women, aged 23-83 years, were investigated. Clinical data including age, body mass index, blood pressure, HbA(1c), serum high sensitive CRP (hsCRP) and lifestyle habits, such as coffee consumption, were included in the analyses. All analyses were performed in two groups of the population, i.e., age < 60 and > or = 60 years. RESULTS: Significantly lower levels of hsCRP were observed in the group of > or = 1 cup/day than in that of < 1 cup/day in the respective groups of < 60 years (p = 0.001) and > or = 60 years (p < 0.0001). In multiple regression analysis, coffee consumption was significantly, independently and inversely correlated to log-hsCRP in the respective groups of < 60 years (p = 0.017) and > or = 60 years (p < 0.0001). CONCLUSIONS: It was noteworthy that the benefits of coffee consumption, even if > or = 1 cup/day, on serum hsCRP levels were confirmed in Japanese women, following similarly to other ethnic data.