Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan

Background. Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. Methods. ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. Results. Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. Conclusions. EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients (AU)

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Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan.

BACKGROUND: Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. METHODS: ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. RESULTS: Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. CONCLUSIONS: EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients.

Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma.

PURPOSE: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. METHODS: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. RESULTS: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. CONCLUSIONS: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212.

Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma.

PURPOSE: Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma. METHODS: Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015). RESULTS: Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively. CONCLUSION: Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01990859.

Association between eating rate and obesity: a systematic review and meta-analysis.

BACKGROUND: The association between eating rate and obesity has recently been reported. However, the findings remain inconclusive. OBJECTIVES: We undertook a systematic review with a meta-analysis of published epidemiological studies to provide a reliable close estimate of the association between eating rate and obesity. METHODS: A comprehensive search of MEDLINE, EMBASE and CINAHL was conducted to identify studies that reported quantitative estimates for indices of obesity based on the category of eating rate. Interventional studies or studies conducted using children as subjects were excluded. Two independent researchers extracted the data. A summary estimate was calculated using a random-effects model, and subgroup analyses were conducted to identify sources of heterogeneity. RESULTS: Data from 23 published studies were eligible for inclusion. The mean difference in body mass indices (BMIs) between individuals who ate quickly and those who ate slowly was 1.78 kg m(-2) (95% confidence interval (CI), 1.53-2.04 kg m(-2)). The pooled odds ratio of eating quickly on the presence of obesity was 2.15 (95% CI, 1.84-2.51). There was evidence of significant quantitative heterogeneity in the magnitudes of the association across studies (I2=78.4%, P-value for heterogeneity <0.001 for BMI, I2=71.9%, P-value for heterogeneity <0.001 for obesity), which may be partially explained by differences in the type of study population (a weaker association was observed for BMI in diabetic patients). CONCLUSIONS: Eating quickly is positively associated with excess body weight. Further studies are warranted to determine whether interventions to slow the speed of eating are effective for weight control.

Acetaldehyde production by major oral microbes.

OBJECTIVES: To assess acetaldehyde (ACH) production by bacteria constituting the oral microbiota and the inhibitory effects of sugar alcohols on ACH production. MATERIALS AND METHODS: The predominant bacterial components of the salivary microbiota of 166 orally healthy subjects were determined by barcoded pyrosequencing analysis of the 16S rRNA gene. Bacterial ACH production from ethanol or glucose was measured using gas chromatography. In addition, inhibition by four sugars and five sugar alcohols of ACH production was assayed. RESULTS: Forty-one species from 16 genera were selected as predominant and prevalent bacteria based on the following criteria: identification in ≥95% of the subjects, ≥1% of mean relative abundance or ≥5% of maximum relative abundance. All Neisseria species tested produced conspicuous amounts of ACH from ethanol, as did Rothia mucilaginosa, Streptococcus mitis and Prevotella histicola exhibited the ability to produce ACH. In addition, xylitol and sorbitol inhibited ACH production by Neisseria mucosa by more than 90%. CONCLUSIONS: The oral microbiota of orally healthy subjects comprises considerable amounts of bacteria possessing the ability to produce ACH, an oral carcinogen. Consumption of sugar alcohols may regulate ACH production by oral microbes.

Fruit and vegetable intake and mortality from cardiovascular disease in Japan: a 24-year follow-up of the NIPPON DATA80 Study.

BACKGROUND/OBJECTIVES: There have been few studies on the association of fruit and vegetable (FV) intake with cardiovascular disease (CVD) risk in Asian populations where both dietary habits and disease structure are different from western countries. No study in Asia has found its significant association with stroke. We examined associations of FV intake with mortality risk from total CVD, stroke and coronary heart diseases (CHDs) in a representative Japanese sample. METHODS: A total of 9112 participants aged from 24-year follow-up data in the NIPPON DATA80, of which baseline data were obtained in the National Nutrition Survey Japan in 1980, were studied. Dietary data were obtained from 3-day weighing dietary records. Participants were divided into sex-specific quartiles of energy adjusted intake of FV. Multivariate-adjusted hazard ratios (HRs) were calculated between strata of the total of FV intake, fruit intake and vegetable intake. The adjustment included age, sex, smoking, drinking habit and energy adjusted intakes of sodium and some other food groups. RESULTS: Participants with higher FV intake were older, ate more fish, milk and dairy products and soybeans and legumes and ate less meat. Multivariate-adjusted HR (95% confidence interval; P; P for trend) for the highest versus the lowest quartile of the total of FV intake was 0.74 (0.61-0.91; 0.004; 0.003) for total CVD, 0.80 (0.59-1.09; 0.105; 0.036) for stroke and 0.57 (0.37-0.87; 0.010; 0.109) for CHD. CONCLUSIONS: The results showed that higher total intake of FVs was significantly associated with reduced risk of CVD mortality in Japan.

Modification of a melanoma discrimination index derived from hyperspectral data: a clinical trial conducted in 2 centers between March 2011 and December 2013.

BACKGROUND: The morphology of pigmented skin lesions (PSLs) is predominantly a result of varying concentrations and distributions of pigmented molecules such as melanin and hemoglobin. Based on these differences and the fact that their information is contained in cutaneous spectra, a hyperspectral imager (HSI) for pigmented melanoma and a single discrimination index derived from the resultant hyperspectral data are proposed. OBJECTIVE: To develop and evaluate a new discrimination index for melanomas, compared to the previous index. METHODS: A HSI, which is convenient for both patients and clinicians, was newly developed and used in a clinical trial conducted in 2 centers with 80 patients with primary lesions and 17 volunteers between March 2011 and December 2013. There were 24 melanomas and 110 other PSLs. A previously proposed discrimination index was used without modifications. A new index, which emphasized the essential features of melanoma, was proposed, and its performance was examined. For each index, a threshold value was set to minimize the average value of the false positive and false negative fractions. The performances of both indices were compared. RESULTS: The sensitivity and specificity of the old index were 75% and 97%, respectively, while those of the new index were 96% and 87%. CONCLUSION: The new index had a higher sensitivity and adequate specificity, indicating that it is more useful than the old index.

Magnesium intake decreases Type 2 diabetes risk through the improvement of insulin resistance and inflammation: the Hisayama Study.

AIMS: Early studies have shown that magnesium intake decreases the risk of Type 2 diabetes, but the results are still inconsistent. We prospectively examined the association between magnesium intake and incidence of Type 2 diabetes in a general Japanese population. METHODS: A total of 1999 subjects without diabetes aged 40-79 years who underwent a 75-g oral glucose tolerance test were followed up prospectively for a mean of 15.6 years. RESULTS: During the follow-up, 417 subjects developed Type 2 diabetes. The age- and sex-adjusted incidence of Type 2 diabetes significantly decreased with increasing magnesium intake quartile levels (≤ 148.5, 148.6-171.5, 171.6-195.5 and ≥ 195.6 mg/day, P for trend = 0.01). In multivariate analyses, after adjusting for comprehensive risk factors and other dietary factors, the hazard ratio of Type 2 diabetes was 0.67 (95% CI 0.49-0.92; P = 0.01) in the third quartile and 0.63 (95% CI 0.44-0.90; P = 0.01) in the highest quartile compared with the first quartile. In addition, the risk of Type 2 diabetes was 14% lower (P = 0.04) for a 1-sd increment of log-transformed magnesium intake in the multivariate-adjusted model. In stratified analysis, there were statistically significant interactions between magnesium intake and levels of homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein or alcohol intake on the risk of Type 2 diabetes (all P < 0.05). CONCLUSIONS: Our findings suggest that increased magnesium intake was a significant protective factor for the incidence of Type 2 diabetes in the general Japanese population, especially among subjects with insulin resistance, low-grade inflammation and a drinking habit.

Impact of eating rate on obesity and cardiovascular risk factors according to glucose tolerance status: the Fukuoka Diabetes Registry and the Hisayama Study.

AIMS/HYPOTHESIS: Medical nutrition therapy plays a critical role in the prevention and treatment of type 2 diabetes. However, appropriate measures of eating behaviours, such as eating rate, have not yet been clearly established. The aim of the present study was to examine the associations among eating rate, obesity and cardiovascular risk factors. METHODS: A total of 7,275 Japanese individuals aged ≥40 years who had normal fasting glucose levels, impaired fasting glucose or diabetes were divided into four groups according to self-reported eating rate: slow, medium, relatively fast and very fast. The associations between eating rate and various cardiovascular risk factors were investigated cross-sectionally. RESULTS: The proportions of participants who were obese or who had elevated waist circumference levels increased progressively with increases in eating rate (p for trend <0.001), regardless of glucose tolerance status. These associations remained significant after adjustment for potential confounders, namely, age, sex, total energy intake, dietary fibre intake, current smoking, current drinking and regular exercise (p for trend <0.001). Blood pressure and lipid levels also tended to increase in association with eating rate. HbA(1c) rose significantly as eating rate increased, even after multivariate adjustment, including BMI, in diabetic patients on insulin therapy (p = 0.02), whereas fasting plasma glucose did not increase significantly. CONCLUSIONS/INTERPRETATION: Our findings suggest that eating rate is associated with obesity and other cardiovascular risk factors and therefore may be a modifiable risk factor in the management of cardiovascular risk factors and diabetes.

Cut-off values of fasting and post-load plasma glucose and HbA1c for predicting Type 2 diabetes in community-dwelling Japanese subjects: the Hisayama Study.

AIMS: We examined the optimal cut-off values of fasting plasma glucose, 2-h post-load glucose and HbA(1c) for predicting Type 2 diabetes in community-dwelling Japanese subjects. METHODS: A total of 1982 subjects without diabetes aged 40-79 years who underwent a 75-g oral glucose tolerance test were followed prospectively for 14 years by annual health examination. RESULTS: During the follow-up, 295 subjects developed Type 2 diabetes. Compared with the first decile, the crude hazard ratio for incident Type 2 diabetes was significantly higher in the fifth fasting plasma glucose decile [5.4-5.4 mmol/l (97-98 mg/dl)] or higher, in the seventh 2-h post-load glucose decile [6.9-7.2 mmol/l (124-131 mg/dl)] or higher, and in the fifth HbA(1c) decile [34-36 mmol/mol (5.3-5.4%)] or higher. These associations remained substantially unchanged even after adjustment for confounding factors. The receiver operating characteristic curve analysis showed that the optimal cut-off values for predicting Type 2 diabetes were 5.6 mmol/l (101 mg/dl) for fasting plasma glucose, 6.9 mmol/l (124 mg/dl) for 2-h post-load glucose and 37 mmol/mol (5.5%) for HbA(1c). In a stratified analysis, the cut-off values were approximately 5.6 mmol/l (101 mg/dl) for fasting plasma glucose and 37 mmol/mol (5.5%) for HbA(1c), and these values were unchanged over BMI quartile levels, whereas the 2-h post-load glucose cut-off values declined with decreasing BMI levels. CONCLUSIONS: Our findings suggest that the cut-off value for predicting Type 2 diabetes in the Japanese population is 5.6 mmol/l (101 mg/dl) for fasting plasma glucose and 37 mmol/mol (5.5%) for HbA(1c), while the 2-h post-load glucose cut-off value is lower than the diagnostic criterion for impaired glucose tolerance.

Two risk score models for predicting incident Type 2 diabetes in Japan.

AIMS: Risk scoring methods are effective for identifying persons at high risk of Type 2 diabetes mellitus, but such approaches have not yet been established in Japan. METHODS: A total of 1935 subjects of a derivation cohort were followed up for 14 years from 1988 and 1147 subjects of a validation cohort independent of the derivation cohort were followed up for 5 years from 2002. Risk scores were estimated based on the coefficients (ß) of Cox proportional hazards model in the derivation cohort and were verified in the validation cohort. RESULTS: In the derivation cohort, the non-invasive risk model was established using significant risk factors; namely, age, sex, family history of diabetes, abdominal circumference, body mass index, hypertension, regular exercise and current smoking. We also created another scoring risk model by adding fasting plasma glucose levels to the non-invasive model (plus-fasting plasma glucose model). The area under the curve of the non-invasive model was 0.700 and it increased significantly to 0.772 (P < 0.001) in the plus-fasting plasma glucose model. The ability of the non-invasive model to predict Type 2 diabetes was comparable with that of impaired glucose tolerance, and the plus-fasting plasma glucose model was superior to it. The cumulative incidence of Type 2 diabetes was significantly increased with elevating quintiles of the sum scores of both models in the validation cohort (P for trend < 0.001). CONCLUSIONS: We developed two practical risk score models for easily identifying individuals at high risk of incident Type 2 diabetes without an oral glucose tolerance test in the Japanese population.

Melanoma screening system using hyperspectral imager attached to imaging fiberscope.

Early detection and proper excision of the primary lesions of melanoma are crucial for reducing melanoma-related deaths. In order to support the early detection of melanoma, melanoma screening systems have been extensively studied and developed. Recently we have proposed a melanoma discrimination index derived from hyperspectral data (HSD) in the visible-near infrared wavelength region. The index represents variegation in spectra over a lesion and works well in discriminating melanoma from other pigmented lesions. However the previous hyperspectral imager did not have an enough allowance for measurement of lesions. To overcome the problem with it, we have developed a hyperspectral imager attached to imaging fiberscope. This equipment has been able to accumulate HSD in a view field of φ40 mm within about 10 seconds, from which the above-mentioned melanoma discrimination index has been calculated. Performance of the system has been studied in nine cases of melanoma and 18 cases of non-melanoma, obtained from patients and volunteers, all of whom were Japanese. The index has achieved a sensitivity of 100 % and a specificity of 94.4 %.

Glucose tolerance status and risk of dementia in the community: the Hisayama study.

OBJECTIVE: We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia. METHODS: A total of 1,017 community-dwelling dementia-free subjects aged ≥60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia. RESULTS: The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95% CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95% CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L, the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L. CONCLUSIONS: Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.

Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study.

OBJECTIVE: The relationship between lipid profiles and Alzheimer disease (AD) pathology at the population level is unclear. We searched for evidence of AD-related pathologic risk of abnormal lipid metabolism. METHODS: This study included brain specimens from a series of 147 autopsies performed between 1998 and 2003 of residents in Hisayama town, Japan (76 men and 71 women), who underwent clinical examinations in 1988. Lipid profiles, such as total cholesterol (TC), triglycerides, and high-density lipoprotein cholesterol (HDLC), were measured in 1988. Low-density lipoprotein cholesterol (LDLC) was calculated using the Friedewald formula. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines (CERAD) and neurofibrillary tangles (NFTs) were assessed according to Braak stage. Associations between each lipid profile and AD pathology were examined by analysis of covariance and logistic regression analyses. RESULTS: Adjusted means of TC, LDLC, TC/HDLC, LDLC/HDLC, and non-HDLC (defined as TC-HDLC) were significantly higher in subjects with NPs, even in sparse to moderate stages (CERAD = 1 or 2), compared to subjects without NPs in multivariate models including APOE ε4 carrier and other confounding factors. The subjects in the highest quartiles of these lipid profiles had significantly higher risks of NPs compared to subjects in the lower respective quartiles, which may suggest a threshold effect. Conversely, there was no relationship between any lipid profile and NFTs. CONCLUSION: The results of this study suggest that dyslipidemia increases the risk of plaque-type pathology.

Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study.

OBJECTIVE: We examined the association between diabetes-related factors and pathology of Alzheimer disease (AD) to evaluate how diabetes affects the pathogenic process of AD. METHODS: This study included specimens from a series of 135 autopsies of residents of the town of Hisayama in Fukuoka prefecture (74 men and 61 women) performed between 1998 and 2003, who underwent a 75-g oral glucose tolerance test in clinical examinations in 1988. We measured diabetes-related factors including fasting glucose, 2-hour post-load plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 1988. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines and neurofibrillary tangles (NFTs) were assessed according to Braak stage. The associations between each factor and AD pathology were examined by analysis of covariance and logistic regression analyses. RESULTS: Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE epsilon4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR. CONCLUSION: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon4.

Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study.

OBJECTIVE: To estimate the incidence and survival rates of total and cause specific dementia in a general Japanese population. METHODS: A total of 828 subjects without dementia, aged 65 years or over, were followed-up prospectively for 17 years. Dementia was subdivided into cause specific subtypes: namely, Alzheimer's disease (AD), vascular dementia (VD), dementia with Lewy bodies (DLB), combined dementia and other types of dementia. During the follow-up, 275 subjects developed dementia; of these, 251 (91.2%) were evaluated morphologically, with 164 subjected to brain autopsy examination and the remaining 87 to neuroimaging. RESULTS: The incidences of total dementia, AD, VD, DLB, combined dementia and other types of dementia were 32.3 (n = 275), 14.6 (124), 9.5 (81), 1.4 (12), 3.8 (33), and 3.1 (16) per 1000 person years, respectively. The incidences of AD, combined dementia and other types of dementia rose with increasing age, particularly after the age of 85 years, but this tendency was not observed for VD or DLB. The survival curve of dementia cases aged 65-89 years was significantly lower than that of age and sex matched controls (10 year survival rate, 13.6% vs 29.3%; hazard ratio 1.67; 95% confidence interval 1.31 to 2.13). The 10 year survival rates were not significantly different among dementia subtypes. CONCLUSIONS: Our findings suggest that the Japanese elderly population has a high risk for the development of dementia, specifically AD and VD, and once dementia is established, the risk of death is considerable.

Polymorphism in the sorbin and SH3-domain-containing-1 (SORBS1) gene and the risk of brain infarction in the Japanese population: the Fukuoka Stroke Registry and the Hisayama study.

BACKGROUND AND PURPOSE: Sorbin and SH3-domain-containing-1 (SORBS1) is an important adaptor protein in insulin-signalling pathway, and its genetic polymorphism may regulate the activity of insulin resistance. We investigated the association between the SORBS1 T228A polymorphism and ischaemic stroke. METHODS: Genotyping was achieved by a rapid-cycle PCR and melting curve analysis using fluorescent probes in 1049 incident cases of ischaemic stroke and 1049 age- and sex-matched control subjects recruited from the Hisayama study. RESULTS: The allele distributions of the SORBS1 T228A polymorphism were similar amongst cases and controls. The multivariate-adjusted odds ratio (OR) of the AA genotype for ischaemic stroke was 2.897 (95% CI, 0.907-8.018) compared with the TT genotype. In terms of stroke subtype, there was a trend toward a difference in the AA genotypes for lacunar infarction, compared with the TT genotype (OR = 8.740, P = 0.0510), and combined TT and TA genotypes (OR = 8.768, P = 0.0505). The other polymorphisms genotyped were not associated with any subtypes of ischaemic stroke. T228A polymorphism of SORBS1 was not associated with the prevalence of diabetes. CONCLUSIONS: The AA genotype of SORBS1 T228A polymorphism may play a role in lacunar infarction in the Japanese population.

Serum levels of resistin and adiponectin in women with periodontitis: the Hisayama study.

Resistin and adiponectin, recently discovered adipokines, are secreted from adipose tissue, with postulated opposing functions in insulin resistance and inflammation. More recently, an abundance of resistin was detected in macrophages, which suggests its important role in inflammation. The aim of this study was to clarify circulating serum adipokine levels in women with periodontitis. Thirty-four women with moderate to severe periodontitis and 42 control individuals with healthy gingiva (50- to 59-year-old women) were selected. The serum level of adipokines was analyzed between groups, along with the obesity index, smoking status, and age. Having periodontitis was significantly associated with an increased level of resistin, both in bivariate (OR, 3.0; 95% CI, 1.2-7.6) and multivariate (adjusted OR, 3.1; 95% CI, 1.1-8.6) analyses. The association of periodontitis with a decreased level of adiponectin did not reach statistical significance. It was concluded that an increased serum resistin level in middle-aged Japanese women with periodontitis may affect systemic health.

NAD(P)H oxidase p22phox C242T polymorphism and ischemic stroke in Japan: the Fukuoka Stroke Registry and the Hisayama study.

The C242T polymorphism of p22phox, a component of NAD(P)H oxidase, may have an impact on cardiovascular diseases; however, the association between this polymorphism and brain infarction is not fully understood. Here, we investigate the relationship between the C242T polymorphism and brain infarction in Japan. We recruited 1055 patients with brain infarction and 1055 control subjects. A chi-squared test revealed that the T-allele frequency was lower in patients with cardioembolic infarction (5.6%) than in control subjects (11.0%, P < 0.001); however, allele frequencies in patients with lacunar and atherothrombotic infarction (11.2%) were not significantly different from those in control subjects (11.0%). A multivariate-adjusted conditional logistic regression analysis also revealed no association between CT + TT genotype, and lacunar and atherothrombotic infarction (odds ratio = 0.97, 95% confidence interval: 0.72-1.32). To investigate the functional effects of the C242T polymorphism, we examined superoxide production in COS-7 cells cotransfected with Nox4 and p22phox of each genotype. The superoxide-producing activity in those cells expressing p22phox with the T allele was not significantly different from that in cells expressing p22phox with the C allele. The present results suggest that the p22phox C242T polymorphism may have a protective effect against cardioembolic infarction, but is not related to lacunar and atherothrombotic infarction in Japan.