Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. Many recent studies focused on the interaction between α-synuclein (α-syn) and dopamine in the pathogenesis of PD, and fluorescent anisotropy suggested that the C-terminal region of α-syn may be a target for modification by dopamine. However, it is not well understood why PD-related pathogenesis occurs selectively in dopaminergic neurons. We investigated the interaction between dopamine and α-syn with regard to cytotoxicity. A soluble oligomer was formed by co-incubating α-syn and dopamine in vitro. To clarify the effect of dopamine on α-syn in cells, we generated PC12 cells expressing human α-syn, as well as the α-syn mutants, M116A, Y125D, M127A, S129A, and M116A/M127A, in a tetracycline-inducible manner (PC12-TetOFF-α-syn). Overexpression of wildtype α-syn in catecholaminergic PC12 cells decreased cell viability in long-term cultures, while a competitive inhibitor of tyrosine hydroxylase blocked this vulnerability, suggesting that α-syn-related cytotoxicity is associated with dopamine metabolism. The vulnerabilities of all mutant cell lines were lower than that of wildtype α-syn-expressing cells. Moreover, α-syn containing dopamine-mediated oxidized methionine (Met(O)) was detected in PC12-TetOFF-α-syn. Met(O) was lower in methionine mutant cells, especially in the M127A or M116A/M127A mutants, but also in the Y125D and S129A mutants. Co-incubation of dopamine and the 125YEMPS129 peptide enhanced the production of H2O2, which may oxidize methionine residues and convert them to Met(O). Y125- or S129-lacking peptides did not enhance the dopamine-related production of H2O2. Our results suggest that M127 is the major target for oxidative modification by dopamine, and that Y125 and S129 may act as enhancers of this modification. These results may describe a mechanism of dopaminergic neuron-specific toxicity of α-syn in the pathogenesis of PD.

Background

Although several studies have investigated the relationship between the number of siblings or birth order and childhood overweight, the results are inconsistent. In addition, little is known about the impact of having older or younger siblings on overweight among elementary schoolchildren. The present population-based study investigated the relationship of the number of siblings and birth order with childhood overweight and evaluated the impact of having younger or older siblings on childhood overweight among elementary schoolchildren in Japan.

Methods

Subjects comprised fourth-grade schoolchildren (age, 9–10 years) in Ina Town during 1999–2009. Information about subjects’ sex, age, birth weight, birth order, number of siblings, lifestyle, and parents’ age, height, and weight was collected by a self-administered questionnaire, while measurements of subjects’ height and weight were done at school. Childhood overweight was defined according to age- and sex-specific cut-off points proposed by the International Obesity Task Force. A logistic regression model was used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI) of "number of siblings" or "birth order" for overweight.

Results

Data from 4026 children were analyzed. Only children (OR: 2.13, 95% CI: 1.45-3.14) and youngest children (1.56, 1.13-2.16) significantly increased ORs for overweight compared with middle children. A larger number of siblings decreased the OR for overweight (P for trend < 0.001). Although there was no statistically significant relationship between a larger number of older siblings and overweight, a larger number of younger siblings resulted in a lower OR for overweight (P for trend < 0.001).

Conclusions

Being an only or youngest child was associated with childhood overweight, and having a larger number of younger siblings was negatively associated with overweight. The present study suggests that public health interventions to prevent childhood overweight need to focus on children from these family backgrounds.

Parkinson’s disease is a major neurodegenerative disease involving the selective degeneration of dopaminergic neurons and α-synuclein containing Lewy bodies formation in the substantia nigra. Although α-synuclein is a key molecule for both dopaminergic neuron death and the formation of inclusion bodies, the mechanism of α-synuclein induction of Parkinson’s disease-related pathogenesis is not understood. In the present study, we found that the interaction between dopamine and α-synuclein requires the oxidation of dopamine. Furthermore, we examined the protective effect of chlorogenic acid, a major polyphenol contained in coffee, against α-syn and dopamine-related toxicity. Chlorogenic acid inhibits several DA/α-synuclein-related phenomenon, including the oxidation of dopamine, the interaction of oxidized dopamine with α-synuclein, and the oligomerization of α-synuclein under dopamine existing conditions in vitro. Finally, we showed that the cytoprotective effect against α-synuclein-related toxicity in PC12 cells that can be controlled by the Tet-Off system. Although the induction of α-synuclein in catecholaminergic PC12 cells causes a decrease in cell viability, chlorogenic acid rescued this cytotoxicity significantly in a dose dependent manner. These results suggest that the interaction of oxidized DA with α-synuclein may be a novel therapeutic target for Parkinson’s disease, and polyphenols, including chlorogenic acid, are candidates as protective and preventive agents for Parkinson’s disease onset.

Background

Studies about the relationship between high-molecular-weight adiponectin (HMW-adn) and anthropometric variables among population-based elementary schoolchildren have been too limited, especially in Japan, where blood collection is not usually performed in the annual health examination at elementary schools. The objective of the present study was to investigate the relationship between HMW-adn and anthropometric variables (body mass index [BMI], percent body fat [%BF], waist circumference [WC], and waist-to-height ratio [WHtR]) among population-based elementary schoolchildren in Japan.

Methods

Subjects comprised all fourth-grade schoolchildren (9 or 10 years of age) in the town of Ina, Saitama Prefecture, Japan during 2005–2008 (N = 1675). After excluding 21 subjects because of refusal to participate or incomplete data, data from a total of 1654 subjects (846 boys and 808 girls) were analyzed. The height, weight, %BF, and WC of each subject were measured, while blood samples were drawn from the subjects to measure adiponectin levels (HMW-adn and total adiponectin). Childhood obesity was determined according to the age- and sex-specific cut-off points proposed by the International Obesity Task Force. Spearman’s correlation coefficients between adiponectin levels and anthropometric variables were calculated for each sex.

Results

The anthropometric variables were negatively correlated with HMW-adn in both boys and girls. Correlation coefficients of HMW-adn with anthropometric variables in the obesity group were consistently higher than those in the non-obesity group among both boys and girls. In addition, only WHtR was significantly correlated with HMW-adn regardless of sex and physique (obesity or non-obesity); the correlation coefficient was -0.386 among boys and -0.543 among girls in the obesity group, while it was -0.124 among boys and -0.081 among girls in the non-obesity group.

Conclusions

HMW-adn was negatively correlated with anthropometric variables, while the correlation coefficients of HMW-adn with anthropometric variables in the obesity group were consistently higher than those in the non-obesity group. Moreover, only WHtR was significantly associated with HMW-adn regardless of sex and physique. The results of this study suggested that it is useful to monitor WHtR as a surrogate for HMW-adn among elementary school students, especially obese children.

Objective

Insulin is recommended as an appropriate treatment in type 2 diabetes patients with suboptimal glycemic control; however, its initiation is often delayed. We therefore conducted the DAWN (Diabetes Attitudes, Wishes and Needs) JAPAN study in an attempt to identify specific patient- and physician-related factors which contribute to delay of insulin initiation among Japanese patients with diabetes. In this report, we explored barriers for physicians which prevent timely insulin initiation.

Methods

The DAWN JAPAN study is a multicenter, questionnaire-based survey, conducted between 2004 and 2005. Participating physicians were categorized as follows based on their expertise: Japan Diabetes Society (JDS) certified specialists (n = 77), JDS-affiliated physicians (n = 30), and non-JDS-affiliated physicians (n = 27). To assess physician barriers to insulin initiation, we have used a newly developed 27- item questionnaire.

Results

The mean age of patients (n = 11,656) treated by participating physicians was 64.1 years. The mean duration of diabetes was 121.6 months, and their mean HbA1c was 7.5%. Insulin was used in 27.4% of total patients. With regard to physician barriers to insulin initiation, the biggest differences in concerns expressed by JDS-certified specialists and non-JDS-affiliated physicians were observed in the following items with statistical significance: “I do not have staff (nurse, pharmacists) who can assist with explanations” (1.3% vs 55.5%, respectively), “I have concerns about the use of insulin therapy in elderly patients” (38.1% vs 81.5%), and “It is difficult to provide guidance and education on insulin injection to patients” (16.9% vs 55.5%). The mean HbA1c at which physicians responded they would recommend insulin to their patients was 8.7%; however, they would reduce this level to 8.2% if they themselves required insulin.

Conclusions

Our results demonstrated that physicians have concerns about insulin use, and suggested that their concerns can lead to delay of insulin initiation.

This study investigated the relationship between eating behavior and childhood overweight among population-based elementary schoolchildren in Japan. Data was collected from fourth graders (9 or 10 years of age) from Ina Town, Saitama Prefecture, Japan from 1999 to 2009. Information about subjects’ sex, age, and lifestyle, including eating behaviors (eating until full and chewing thoroughly), was obtained using a self-administered questionnaire, and height and weight were measured directly. Overweight was determined according to the definition established by the International Obesity Task Force. Data from 4027 subjects (2079 boys and 1948 girls) were analyzed. Chewing thoroughly was associated with a significantly decreased odds ratio (OR) for being overweight, whereas eating until full significantly increased the OR for being overweight (OR: 1.50, 95% confidence interval: 1.16–1.94) among boys. However, eating until full was not associated with a significantly increased OR for being overweight among the group that reported chewing thoroughly, whereas it was associated with a significantly increased OR for being overweight (2.02, 1.38–2.94) among boys who did not chew thoroughly. In conclusion, eating until full or not chewing thoroughly was associated with being overweight among elementary schoolchildren. Results of this study suggest that chewing thoroughly may be an avenue to explore childhood overweight prevention efforts.

Background

Although the ADA/EASD/IDF International Expert Committee recommends using hemoglobin A1c (HbA1c) to define diabetes, the relation between HbA1c and cardiovascular disease (CVD) has not been thoroughly investigated. We analyzed this relation using clinical data on Japanese individuals with hypercholesterolemia.

Methods

In the large-scale MEGA Study 7832 patients aged 40 to 70 years old with mild-to-moderate hypercholesterolemia without CVD were randomized to diet alone or diet plus pravastatin and followed for >5 years. In the present subanalysis of that study a total of 4002 patients with baseline and follow-up HbA1c data were stratified according to having an average HbA1c during the first year of follow-up <6.0%, 6.0%-<6.5%, or ≥6.5% and their subsequent 5-year incidence rates of CVD compared according to sex, low-density lipoprotein cholesterol (LDL-C), and treatment arm.

Results

Overall, risk of CVD was significantly 2.4 times higher in individuals with HbA1c ≥6.5% versus <6.0%. A similar relation was noted in men and women (hazard ratio [HR], 2.1; p <0.01 and HR, 3.0; p <0.01, respectively) and was regardless of treatment arm (diet alone group: HR, 2.2; p <0.001; diet plus pravastatin group: HR, 1.8; p = 0.02). Spline curves showed a continuous risk increase according to HbA1c level in all subpopulations studied.

Conclusions

In hypercholesterolemic individuals the risk of CVD increases linearly with HbA1c level. This significant contribution by elevated HbA1c to increased CVD is independent of pravastatin therapy, and thus requires appropriate HbA1c management in addition to lipids reduction.

Background

Although the correlation coefficient between body mass index (BMI) and percent body fat (%BF) or waist circumference (WC) has been reported, studies conducted among population-based schoolchildren to date have been limited in Japan, where %BF and WC are not usually measured in annual health examinations at elementary schools or junior high schools. The aim of the present study was to investigate the relationship of BMI to %BF and WC and to examine the influence of gender and obesity on these relationships among Japanese schoolchildren.

Methods

Subjects included 3,750 schoolchildren from the fourth and seventh grade in Ina-town, Saitama Prefecture, Japan between 2004 and 2008. Information about subject's age, sex, height, weight, %BF, and WC was collected from annual physical examinations. %BF was measured with a bipedal biometrical impedance analysis device. Obesity was defined by the following two criteria: the obese definition of the Centers for Disease Control and Prevention, and the definition of obesity for Japanese children. Pearson's correlation coefficients between BMI and %BF or WC were calculated separately for sex.

Results

Among fourth graders, the correlation coefficients between BMI and %BF were 0.74 for boys and 0.97 for girls, whereas those between BMI and WC were 0.94 for boys and 0.90 for girls. Similar results were observed in the analysis of seventh graders. The correlation coefficient between BMI and %BF varied by physique (obese or non-obese), with weaker correlations among the obese regardless of the definition of obesity; most correlation coefficients among obese boys were less than 0.5, whereas most correlations among obese girls were more than 0.7. On the other hand, the correlation coefficients between BMI and WC were more than 0.8 among boys and almost all coefficients were more than 0.7 among girls, regardless of physique.

Conclusions

BMI was positively correlated with %BF and WC among Japanese schoolchildren. The correlations could be influenced by obesity as well as by gender. Accordingly, it is essential to consider gender and obesity when using BMI as a surrogate for %BF and WC for epidemiological use.

Objective

To evaluate glycemic variability associated with two different premixed insulin analogue formulations when used in a twice-daily regimen.

Patients and Methods

Subjects comprised type 2 diabetic patients aged 20-79 years, treated with twice daily premixed insulin or insulin analogue formulations. All subjects were hospitalized for 6 days and randomized to receive either Humalog Mix 25 (Mix 25) or Humalog Mix 50 (Mix 50). They were then crossed over to the other arm between day 3 and day 4 of the study. Continuous glucose monitoring (CGM) was performed on all subjects to examine the differences in glycemic variability.

Results

Eleven type 2 diabetic patients were enrolled. No significant difference was found in 24-hour mean glucose values and their SDs, pre-meal glucose values, increases from pre-meal to peak glucose values, or time to peak glucose levels between either group. However, the mean glucose values observed during 0-8 hrs were significantly lower with Mix 25 compared to Mix 50 (128 vs. 147 mg/dL; p = 0.024).

Conclusions

The twice-daily Mix 25 regimen provided superior overnight glycemic control compared to the Mix 50 regimen in Japanese patients with type 2 diabetes. However, both twice-daily regimens with either Mix 25 or Mix 50 provided inadequate post-lunch glycemic control.

Trial Registration

Current Controlled Trials UMIN000001327

Objective

The study examined changes in and relationship between body mass index (BMI), leptin and adiponectin levels over a 3-year period in a pediatric population-based cohort.

Study design

A 3-year prospective cohort study of 268 boys and 251 girls aged 9–10 in Ina, Saitama, Japan.

Results

Median body mass index (BMI) significantly increased from baseline (age 9–10) to follow up (age 12–13) in boys from 17.1 to 18.3 kg/m2 (P < 0.001) and in girls from 16.5 to 18.5 kg/m2 (P < 0.001), respectively. Adiponectin values significantly decreased from baseline to follow up in boys (13.5 to 8.9 μg/ml, respectively) (P < 0.001) and in girls (12.4 to 9.5 μg/ml, respectively) (P < 0.001). Leptin values at follow up significantly decreased from baseline in boys (4.9 to 2.3 ng/dl, respectively) (P < 0.001) and also in girls (5.3 to 5.1 ng/dl, respectively) (P = 0.049).

A relatively strong correlation was seen in BMI (Spearman's correlation coefficient, r = 0.864, P < 0.001 in boys; r = 0.873, P < 0.001 in girls), adiponectin (r = 0.705, P < 0.001 in boys; r = 0.695, P < 0.001 in girls), and leptin (r = 0.449, P < 0.001 in boys; r = 0.610, P < 0.001 in girls) before and after the three-year period.

The ratio of follow up to baseline BMI was negatively correlated with that for adiponectin (r = -0.224, P < 0.001 in boys; r = -0.165, P = 0.001 in girls) and positively correlated with that for leptin (r = 0.518, P < 0.001 in boys; r = 0.609, P < 0.001 in girls).

Conclusion

This study demonstrated that baseline adiponectin, leptin and BMI values measured at ages 9–10 correlated with those measured three years later. However, adiponectin values decreased and leptin values increased in those subjects whose BMI increased during over this period.

Background

The large clinical trials proved that Basal-Bolus (BB) insulin therapy was effective in the prevention of diabetic complications and their progression. However, BB therapy needs multiple insulin injections per a day. In this regard, a biphasic insulin analogue needs only twice-daily injections, and is able to correct postprandial hyperglycemia. Therefore it may achieve the blood glucose control as same as that of BB therapy and prevent the diabetic complications including macroangiopathy.

Methods

In PROBE (Prospective, Randomized, Open, Blinded-Endpoint) design, forty-two type 2 diabetic patients (male: 73.8%, median(inter quartile range) age: 64.5(56.8~71.0)years) with secondary failure of sulfonylurea (SU) were randomly assigned to BB therapy with a thrice-daily insulin aspart and once-daily basal insulin (BB group) or to conventional therapy with a twice-daily biphasic insulin analogue (30 Mix group), and were followed up for 6 months to compare changes in HbA1c, daily glycemic profile, intima-media thickness (IMT) of carotid artery, adiponectin levels, amounts of insulin used, and QOL between the two groups.

Results

After 6 months, HbA1c was significantly reduced in both groups compared to baseline (30 Mix; 9.3(8.1~11.3) → 7.4(6.9~8.7)%, p < 0.01, vs BB;8.9(7.7~10.0) → 6.9(6.2~7.3)%, p < 0.01), with no significant difference between the groups in percentage change in HbA1c (30 Mix; -14.7(-32.5~-7.5)% vs BB -17.8(-30.1~-11.1)%, p = 0.32). There was a significant decrease in daily glycemic profile at all points except dinner time in both groups compared to baseline. There was a significant increase in the amount of insulin used in the 30 Mix group after treatment compared to baseline (30 Mix;0.30(0.17~0.44) → 0.39(0.31~0.42) IU/kg, p = 0.01). There was no significant difference in IMT, BMI, QOL or adiponectin levels in either group compared to baseline.

Conclusion

Both BB and 30 mix group produced comparable reductions in HbA1c in type 2 diabetic patients with secondary failure. There was no significant change in IMT as an indicator of early atherosclerotic changes between the two groups. The basal-bolus insulin therapy may not be necessarily needed if the type 2 diabetic patients have become secondary failure.

Trial registration

Current Controlled Trials number, NCT00348231

Background

Although oxidative stress by accumulation of reactive oxygen species (ROS) in diabetes has become evident, it remains unclear what genes, involved in redox balance, would determine susceptibility for development of atherosclerosis in diabetes. This study evaluated the effect of genetic polymorphism of enzymes producing or responsible for reducing ROS on coronary artery calcification in type 2 diabetes (T2D).

Methods

An index for coronary-arteriosclerosis, coronary artery calcium score (CACS) was evaluated in 91 T2D patients using a multi-slice computed tomography. Patients were genotyped for ROS-scavenging enzymes, Glutathione peroxidase-1 (GPx-1), Catalase, Mn-SOD, Cu/Zn-SOD, as well as SNPs of NADPH oxidase as ROS-promoting elements, genes related to onset of T2D (CAPN10, ADRB3, PPAR gamma, FATP4). Age, blood pressure, BMI, HbA1c, lipid and duration of diabetes were evaluated for a multivariate regression analysis.

Results

CACS with Pro/Leu genotype of the GPx-1 gene was significantly higher than in those with Pro/Pro (744 ± 1,291 vs. 245 ± 399, respectively, p = 0.006). In addition, genotype frequency of Pro/Leu in those with CACS ≥ 1000 was significantly higher than in those with CACS < 1000 (45.5% vs. 18.8%; OR = 3.61, CI = 0.97–13.42; p = 0.045) when tested for deviation from Hardy-Weinberg's equilibrium. Multivariate regression analyses revealed that CACS significantly correlated with GPx-1 genotypes and age.

Conclusion

The presence of Pro197Leu substitution of the GPx-1 gene may play a crucial role in determining genetic susceptibility to coronary-arteriosclerosis in T2D. The mechanism may be associated with a decreased ability to scavenge ROS with the variant GPx-1.

This paper presents survey results of connectivity to the Internet from preventive and environmental medicine-related departments in medical schools and other institutions in Japan and propose means to establish connectivity among them. Of 191 facilities surveyed, 134 (70%) responded by March 31, 1996. The data presented here are from 132 facilities. One hundred seventeen facilities (89%) answered that they were connected to the Internet. More than 80% of them got access to the Internet in the past two years. One hundred three facilities (78%) answered that e-mail was available. Despite the large percentage being connected, only 11 facilities (8%) had their own homepages. However, just 6 months later more than 25 facilities could be found by their own homepages. The Global Health Network (GHNet) has been developed in the USA based upon the concept that the best means to produce improved health is a better surveillance and information system applying the latest telecommunication technology to public health. The GHNet will offer an initial homepage for Preventive and Environmental Medicine related facilities in Japan to promote and establish sustainable connectivity among them.