Development of an isogenic human cell trio that models polyglutamine disease.

Polyglutamine (polyQ) diseases are rare autosomal-dominant neurodegenerative diseases associated with the expansion of glutamine-encoding triplet repeats in certain genes. To investigate the functional influence of repeat expansion on disease mechanisms, we applied a biallelic genome-engineering platform that we recently established, called Universal Knock-in System or UKiS, to develop a human cell trio, a set of three isogenic cell lines that are homozygous for two different numbers of repeats (first and second lines) or heterozygous for the two repeat numbers (third line). As an example of a polyQ disease, we chose spinocerebellar ataxia type 2 (SCA2). In a pseudodiploid human cell line, both alleles of the glutamine-encoding triplet repeat in the SCA2-causing gene, ataxin 2 or ATXN2, were first knocked in with a donor sequence encoding both thymidine kinase and either puromycin or blasticidin resistance proteins under dual drug selection. The knocked-in donor alleles were then substituted with a payload having either 22 or 76 triplet repeats in ATXN2 by ganciclovir negative selection. The two-step substitution and subsequent SNP typing and genomic sequencing confirmed that the SCA2-modeling isogenic cell trio was obtained: three clones of 22-repeat homozygotes, two clones of 22/76-repeat heterozygotes and two clones of 76-repeat homozygotes. Finally, RT-PCR and immunoblotting using the obtained clones showed that, consistent with previous observations, glutamine tract expansion reduced transcriptional and translational expression of ATXN2. The cell clones with homozygous long-repeat alleles, which are rarely obtained from patients with SCA2, showed more drastic reduction of ATXN2 expression than the heterozygous clones. This study thus demonstrates the potential of UKiS, which is a beneficial platform for the efficient development of cell models not only for polyQ diseases but also for any other genetic diseases, which may accelerate our deeper understanding of disease mechanisms and cell-based screening for therapeutic drugs.

Biallelic and gene-wide genomic substitution for endogenous intron and retroelement mutagenesis in human cells.

Functional annotation of the vast noncoding landscape of the diploid human genome still remains a major challenge of genomic research. An efficient, scarless, biallelic, and gene-wide mutagenesis approach is needed for direct investigation of the functional significance of endogenous long introns in gene regulation. Here we establish a genome substitution platform, the Universal Knock-in System or UKiS, that meets these requirements. For proof of concept, we first used UKiS on the longest intron of TP53 in the pseudo-diploid cell line HCT116. Complete deletion of the intron, its substitution with mouse and zebrafish syntenic introns, and specific removal of retrotransposon-derived elements (retroelements) were all efficiently and accurately achieved in both alleles, revealing a suppressive role of intronic Alu elements in TP53 expression. We also used UKiS for TP53 intron deletion in human induced pluripotent stem cells without losing their stemness. Furthermore, UKiS enabled biallelic removal of all introns from three human gene loci of ~100 kb and longer to demonstrate that intron requirements for transcriptional activities vary among genes. UKiS is a standard platform with which to pursue the design of noncoding regions for genome writing in human cells.

Association between alanine aminotransferase and all-cause mortality rate: Findings from a study on Japanese community-dwelling individuals.

BACKGROUND: This study examined the relationship between survival prognosis and alanine aminotransferase (ALT), a critical factor contributing to aging-related health and mortality. The research is based on a follow-up study with 6- and 10-year intervals. METHODS: The participants included 1,610 males (63 ± 14 years old) and 2,074 females (65 ± 12 years old) who were part of the Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort). The multivariable-adjusted hazard ratios (HRs) of death between the baseline health checkup and the end of the follow-up periods were estimated using a Cox proportional hazards model, controlling for potential confounding factors. RESULTS: The follow-up survey revealed 180 male deaths (11.2% of male participants) and 146 female deaths (7.0% of female participants). The univariate Cox regression analysis showed a significant increase in the HRs of all-cause mortality with decreasing ALT levels (p < 0.001). Furthermore, compared with individuals with ALT levels of 20-29 IU/L, the multivariable-adjusted HRs (95% confidence interval) for all-cause mortality were 2.73 (1.59-4.70) for those with ALT levels <10 IU/L, 1.45 (1.05-2.00) for those with ALT levels of 10-19 IU/L, and 1.63 (1.05-2.53) for those with ALT levels ≥30 IU/L. CONCLUSIONS: Our findings show that abnormally low ALT levels and high within the normal range were related to all-cause mortality in Japan's community-dwelling individuals. Especially, ALT activity may be an important biomarker for predicting the long-term survival of older adults.

Low density lipoprotein cholesterol and all-cause mortality rate: findings from a study on Japanese community-dwelling persons.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) independently impacts aging-related health outcomes and plays a critical role in cardiovascular diseases (CVDs). However, there are limited predictive data on all-cause mortality, especially for the Japanese community population. In this study, it was examined whether LDL-C is related to survival prognosis based on 7 or 10 years of follow-up. METHODS: Participants included 1610 men (63 ± 14 years old) and 2074 women (65 ± 12 years old) who participated in the Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort) and who continued throughout the follow-up periods (follow-up rates: 94.8 and 98.0%). Adjusted relative risk estimates were obtained for all-cause mortality using a basic resident register. The data were analyzed by a Cox regression with the time variable defined as the length between the age at the time of recruitment and that at the end of the study (the age of death or censoring), and risk factors including gender, age, body mass index (BMI), presence of diabetes, lipid levels, renal function, serum uric acid levels, blood pressure, and history of smoking, drinking, and CVD. RESULTS: Of the 3684 participants, 326 (8.8%) were confirmed to be deceased. Of these, 180 were men (11.2% of all men) and 146 were women (7.0% of all women). Lower LDL-C levels, gender (male), older age, BMI under 18.5 kg/m2, and the presence of diabetes were significant predictors for all-cause mortality. Compared with individuals with LDL-C levels of 144 mg/dL or higher, the multivariable-adjusted Hazard ratio (and 95% confidence interval) for all-cause mortality was 2.54 (1.58-4.07) for those with LDL-C levels below 70 mg/dL, 1.71 (1.15-2.54) for those with LDL-C levels between 70 mg/dL and 92 mg/dL, and 1.21 (0.87-1.68) for those with LDL-C levels between 93 mg/dL and 143 mg/dL. This association was particularly significant among participants who were male (P for interaction = 0.039) and had CKD (P for interaction = 0.015). CONCLUSIONS: There is an inverse relationship between LDL-C levels and the risk of all-cause mortality, and this association is statistically significant.

Thigh circumference and handgrip strength are significantly associated with all-cause mortality: findings from a study on Japanese community-dwelling persons.

PURPOSE: In addition to playing a critical role in cardiovascular health, muscle mass and strength independently impact aging-related health outcomes in adults. There are limited predictive data for all-cause mortality, particularly for community-dwelling persons in Japan. This study examined whether handgrip strength (HGS) and thigh circumference are related to survival prognosis based on a 6-year follow-up period. METHODS: Participants were 787 men (aged 69 ± 11 years) and 963 women (aged 69 ± 9 years) who took part in a Nomura cohort study conducted in 2014 and who continued with follow-ups for the subsequent 6 years (follow-up rate: 95.5%). We obtained adjusted relative hazards of all-cause mortality from the basic resident register. The data were subjected to a Cox regression with age as the time variable and gender, age, anthropometric index, smoking habits, drinking habits, exercise habits, cardiovascular history, blood pressure, lipid levels, diabetes, renal function, and serum uric acid as risk factors. RESULTS: Of the 1750 participants, a total of 97 (5.5%) were confirmed to have died, of which 56 were men (7.1% of all male participants), and 41 were women (4.3% of all female participants). The multivariable Cox regression analysis revealed that smaller thigh circumference and lower HGS in men were found to predict 6-year all-cause mortality, but in women only baseline HGS was associated with all-cause mortality. CONCLUSION: Thigh circumference and HGS are useful predictors of death in Japanese community-dwelling men.

Alcohol consumption and serum uric acid are synergistically associated with renal dysfunction among community-dwelling persons.

BACKGROUND: Serum uric acid (SUA) is a key risk factor contributing to renal failure, a serious public health problem. However, few studies have examined whether the interactive relationship between alcohol consumption and SUA is independently associated with the estimated glomerular filtration rate (eGFR). METHODS: Our sample comprised 742 men aged 69 ± 11 years (mean ± standard deviation) and 977 women aged 69 ± 10 years from a rural area. We cross-sectionally examined the relationships between the confounding factors of alcohol consumption and SUA with renal function denoted by eGFR estimated using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations modified by a Japanese coefficient. RESULTS: In both genders, eGFR increased with a rise in alcohol consumption. This tendency was more pronounced in participants with hyperuricemia, where SUA was greater than 7.0 mg/dL in men and greater than 6.0 mg/dl in women (men: F = 41.98, p < 0.001; women: F = 41.98, p < 0.001). A multiple linear regression analysis showed that alcohol consumption (men: ß = 0.112, p < 0.001; women: ß = 0.060, p = 0.011) and SUA (men: ß = -0.282, p < 0.001; women: ß = 0.317, p < 0.001) were significantly and independently related to eGFR. Further, the interactive relationship between alcohol consumption and SUA (men: F = 6.388, p < 0.001; women: F = 5.368, p < 0.001) was a significant and independent indicator of eGFR. CONCLUSIONS: These results suggested that alcohol consumption and SUA were synergistically associated with renal dysfunction among community-dwelling persons.

A case of laryngopharyngeal reflux-associated chronic cough: Misinterpretation of treatment efficacy causes diagnostic delay.

A 62-year-old woman presented with a dry cough lasting 18 months. She had previously been examined by multiple doctors, but no abnormalities were observed. Several medications such as rabeprazole and inhaled corticosteroids were administered as test treatments without any improvement. Therefore, the possibility of biological disease, including acid reflux, had been mistakenly ruled out. We examined the sputum gram stain. The result showed phagocyted normal bacterial flora, suggesting aspiration. Laryngoscopy revealed edema of the arytenoid cartilage. The patient was finally diagnosed with laryngopharyngeal reflux and silent aspiration. This case suggested that the ineffectiveness of proton-pump inhibitors cannot always exclude the presence of reflux disease and the usefulness of gram stain examination to detect silent aspiration.

High serum uric acid within the normal range is a useful predictor of hypertension among Japanese community-dwelling elderly women.

BACKGROUND: The risk associated with serum uric acid (SUA) levels when within the normal range is unknown. This study aims to examine whether SUA within the normal range is a predictor of hypertension. METHODS: The subjects comprised 704 men aged 71 ± 9 (mean ± standard deviation) years and 946 women aged 70 ± 8 years recruited for a survey at the community based annual medical check-up. The main outcome was the presence of hypertension (antihypertensive medication and/or having SBP ≥140 mmHg and/or DBP ≥90 mmHg). RESULTS: At baseline, 467 (66.3%) men and 608 (64.3%) women had hypertension. Comparing to lowest quartile in women (SUA-1, uric acid < 4.1 mg/dL), the unadjusted odds ratios (ORs) [95% confidence interval (CI)] for hypertension of SUA-2 (4.1 to 4.7 mg/dL), SUA-3 (4.8 to 5.4 mg/dL), and SUA-4 (≥5.5 mg/dL) were 1.11 (0.78-1.59), 1.75 (1.20-2.55), and 1.89 (1.30-2.77), respectively. These associations were apparent even after adjustments for age, but ORs were attenuated after adjusting for all confounding factors. During a follow-up of 3.0 years, there were 35 (24.0%) hypertension cases in men and 51 (20.8%) in women. In women only, a significant association between increased SUA categories and incidence of hypertension was observed, and the multivariate-ORs (95% (CI) for incident hypertension of SUA-3 (4.5-5.2 mg/dL) and SUA-4 (≥5.3 mg/dL) were 2.23 (0.81-6.11) and 3.84 (1.36-10.8), respectively. CONCLUSIONS: These results suggest that baseline SUA within the normal range could be an important predictor for incidence of hypertension in Japanese community-dwelling elderly women.

Neutrophil-to-lymphocyte ratio is a predictor of renal dysfunction in Japanese patients with type 2 diabetes.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been widely evaluated as a biomarker in various medical and surgical prognoses, but its usefulness in diabetic kidney disease is not yet known. METHODS: This prospective observational study included outpatients, comprised of 184 men aged 73 ± 11 (mean ± standard deviation) years and 174 women aged 76 ± 10 years at baseline, from a rural hospital. We examined the relationship between baseline NLR calculated by analyzing the differential leukocyte counts in the complete blood count and the 2-year estimated glomerular filtration rate (eGFR) decline rate (i.e. 2-year eGFR-baseline eGFR) ∗100/baseline eGFR. Rapid eGFR decline rate was defined as a value < -25%. RESULTS: Multiple linear regression analysis using rapid eGFR decline rates as objective variables, adjusted for confounding factors as explanatory variables, showed that NLR (ß = 0.138, p = 0.007) as well as presence of antidyslipidemic medication, hemoglobinA1c, and urinary albumin excretion stage were significantly and independently associated with a rapid eGFR decline rate. The multivariate-adjusted odds ratios (95% confidence interval) of the 2nd and 3rd tertiles of baseline NLR for rapid eGFR decline rate were 3.62 (0.70-18.7) and 8.03 (1.54-41.9), respectively. Multivariate-adjusted mean eGFR (95% confidence interval) values after 2 years categorized by tertile of baseline NLR were: 1st, 63.9 (61.8-66.1); 2nd, 60.8 (58.7-62.9); and 3rd, 58.9 (56.8-61.0). CONCLUSIONS: These results suggest that baseline NLR might be a useful biomarker for renal function decline in outpatients with diabetes.

Usefulness of waist-to-height ratio in screening incident hypertension among Japanese community-dwelling middle-aged and elderly individuals.

BACKGROUND: The incidence of hypertension is increasing worldwide and obesity is one of the most significant risk factors. Obesity can be defined by various anthropometric indices such as body mass index (BMI), waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR). This study examined a range of anthropometric indices and their relationships with hypertension. METHODS: This study included 768 men aged 70 ± 10 years and 959 women aged 70 ± 8 years from a rural village. The relationship between anthropometric indices (BMI, WHpR, and WHtR) and hypertension was examined using cross-sectional (baseline, N = 1727) and cohort data (follow-up, N = 419). Receiver operating characteristic (ROC) analysis was used to determine the predictive ability of obesity indices for hypertension in both genders. Logistic regression models were used to evaluate WHtR as a significant predictor of hypertension. RESULTS: In the cross-sectional study, WHtR, BMI, and WHpR showed significant predictive abilities for hypertension in both genders, with WHtR showing the strongest predictive ability. Also, in the cohort study, WHtR showed a significant predictive ability for incident hypertension in both genders, and, for women, BMI as well as WHtR had also predictive ability. In the cross-sectional study, the optimal WHtR cutoff values were 0.53 (sensitivity, 44.3%; specificity, 80.2%) for men and 0.54 (sensitivity, 60.9%; specificity, 68.6%) for women. In the cohort study, the optimal WHtR values were 0.47 (sensitivity, 85.4%; specificity, 39.8%) for men and 0.51 (sensitivity, 66.7%; specificity, 58.2%) for women. CONCLUSIONS: The results suggest that WHtR is a useful screening tool for hypertension among Japanese middle-aged and elderly community-dwelling individuals.

Increased body mass index above the upper normal limit is significantly associated with renal dysfunction among community-dwelling persons.

PURPOSE: Body mass index (BMI) is a simple index of weight-to-height that is commonly used to classify people as underweight, overweight or obesity, and high BMI has been clearly linked to increased risk of illness in adults. However, few studies have examined the significance of upper normal weight as a risk factor for the development of chronic kidney disease (CKD) in the general Japanese population. METHODS: We conducted a prospective cohort study designed as part of the Nomura study. We recruited a random sample of 421 men aged 67 ± 10 (mean ± standard deviation; range 24-95) years and 565 women aged 68 ± 9 (22-84) years during their annual health examination in a single community. We examined the relationship between quartiles of baseline BMI and renal dysfunction after a 3-year evaluation based on estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations modified by the Japanese coefficient. CKD was defined as having dipstick-positive proteinuria (≥ 1 +) or a low eGFR (< 60 mL/min/1.73 m2). RESULTS: Of the 986 participants, a total of 134 (13.6%) participants, including 72 (17.1%) men and 62 (11.0%) women, received a new diagnosis of CKD during the study period, and 25 (9.7%), 19 (8.0%), 47 (19.0%), and 43 (17.8%) diagnoses were received in the BMI-1 (BMI, < 20.7 kg/m2), BMI-2 (BMI, 20.7 to 22.5 kg/m2), BMI-3 (BMI, 22.6 to 24.4 kg/m2), and BMI-4 (BMI ≥ 24.5 kg/m2) groups, respectively. Using BMI-2 as the reference group, the non-adjusted odds ratio (OR) (95% confidence interval) for CKD was 2.70 (1.53-4.75) for BMI-3 and 2.49 (1.40-4.42) for BMI-4, and the multivariable-adjusted OR was 2.52 (1.40-4.56) for BMI-3 and 2.30 (1.26-4.22) for BMI-4. CONCLUSIONS: Increased BMI from upper normal weight is strongly associated with the development of CKD in community-dwelling persons.

Interactive association of baseline and changes in serum uric acid on renal dysfunction among community-dwelling persons.

BACKGROUND: Chronic kidney disease (CKD) is a major public health concern. Baseline serum uric acid (SUA) levels were independently associated with incident renal dysfunction, but whether baseline and changes in SUA produce an interactive effect on renal dysfunction remains unclear. METHODS: The subjects comprised 460 men aged 68 ± 10 (mean ± standard deviation) years and 635 women aged 68 ± 9 years from a rural village. We have found participants who underwent a similar examination 3 years later, and analyzed the relationship between baseline SUA, changes in SUA, and a 3-year follow-up renal function evaluated by estimated glomerular filtration rate (eGFR). RESULTS: A total of 93 (20.2%) men and 76 (12.0%) women had hyperuricemia (men: SUA ≥ 7.0 mg/dL and women: SUA ≥ 6.0 mg/dL) at baseline. Multiple regression analysis using changes in eGFR as objective variable, adjusted for risk factors as explanatory variables, showed that the baseline SUA and changes in SUA were linearly associated with changes in eGFR (ß = ï¼0.115, P < .001 and ß = ï¼0.431, P < .001, respectively). In both normal SUA group and hyperuricemia group, changes in SUA significantly associated with changes in eGFR (ß = ï¼0.473, P < .001 and ß = ï¼0.197, P = .009, respectively). Participants with increased SUA from normal to hyperuricemia group had greater eGFR decline over the follow-up period, and their multivariate-adjusted 3-year follow-up eGFR was significantly lower than in other groups (P < .001). CONCLUSION: Our data demonstrated that baseline and longitudinal changes in SUA were independently and interactively associated with the renal function decline among community-dwelling persons.

Metabolic syndrome is a predictor of decreased renal function among community-dwelling middle-aged and elderly Japanese.

PURPOSE: Metabolic syndrome (MetS) is increasing worldwide with the continuous increase in obesity prevalence. Chronic kidney disease (CKD) is also a major public health problem, but there is controversy over whether baseline MetS is a predictor of decreased renal function among Japanese community-dwelling middle-aged and elderly Japanese. METHODS: We conducted a prospective cohort study designed as part of the Nomura study. We recruited a random sample of 410 men aged 68 ± 8 (mean ± standard deviation; range, 50-95) years and 549 women aged 69 ± 7 (50-84) years during their annual health examination in a single community. We examined the relationship between baseline MetS and renal dysfunction after a 3-year evaluation based on estimated glomerular filtration rate (eGFRCKDEPI) using the CKD-EPI equations modified by the Japan coefficient. CKD was defined as dipstick-positive proteinuria (> or = 1 +) or a low eGFRCKDEPI (< 60 mL/min/1.73 m2). RESULTS: Of the 959 participants, 413 (43.1%) had MetS at baseline. Annual eGFR decline rate was significantly greater in those with MetS than in those without MetS, and the annual eGFR decline rate of < - 1.2 mL/min/1.73 m2/year increased significantly in relation to presence of baseline MetS, especially low HDL cholesterol (HDL-C). Moreover, the incidence rate of CKD after 3 years was 13.5% and increased significantly in relation to presence of baseline MetS, especially its components such as elevated HbA1c. The multivariate-adjusted odd ratio (OR) for CKD in participants with MetS versus those without MetS was 1.55 (0.99-2.43). The multivariate-adjusted ORs for rapid annual eGFR decline rate were significantly high in patients aged ≥ 65 years and presence of medication, regardless of gender and eGFR value. CONCLUSIONS: Low HDL-C and elevated HbA1c levels correlated significantly with eGFR decline in a short period of 3 years. MetS also showed a significant association with eGFR decline. This study suggests the importance of low HDL-C and elevated HbA1c in the effect of MetS on eGFR decline rather than obesity among Japanese community-dwelling middle-aged and elderly Japanese without CKD.

Total bilirubin independently predicts incident metabolic syndrome among community-dwelling women.

BACKGROUND: Metabolic syndrome (MetS) is related to the increased risk of major cardiovascular diseases (CVD). The link between high serum total bilirubin (TBL) is cross-sectionally related to MetS and its components. However, whether serum TBL predicts incidence of MetS and its components remains inconclusive. METHODS: The present study included 893 women aged 70 ±â€¯9 years from a rural village. We examined the relationship between serum TBL and MetS based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report in a cross-sectional (N = 893) and cohort (N = 288) data. RESULTS: In the cross-sectional study, serum TBL (ß = 0.536, p < 0.001) as well as age, alcohol consumption, exercise habits, history of CVD, SUA, GGT, and ALT was significantly and dependently associated with number of MetS components, but in the cohort study serum TBL was not associated with number of MetS components. Compared with the 1st tertile of serum TBL (0.20-0.55 mg/dL), multivariate-adjusted odds ratio (95% confidence interval) for the 2nd -3rd tertiles of serum TBL (0.54-2.00 mg/dL) was 0.70 (0.51-0.95) in the cross-sectional study and 0.41 (0.21-0.81) in the cohort study. CONCLUSIONS: Our data demonstrated an independently negative association between serum TBL and MetS in Japanese community-dwelling women.

Serum uric acid to creatinine ratio is a useful predictor of renal dysfunction among diabetic persons.

BACKGROUND: Serum uric acid (SUA) has been shown to be a predictor of renal disease progression in most but not all studies. This study aims to test whether renal function-normalized SUA {i.e, SUA/creatinine (Cr) ratio} is a predictor of decreased renal function among diabetic patients. METHODS: The subjects comprised 185 men aged 72 ±â€¯11 (mean ±â€¯standard deviation) years and 175 women aged 77 ±â€¯10 years from a rural hospital. We examined the relationship between SUA/creatinine (Cr) ratio and renal function evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation. RESULTS: Annual eGFR decline rate was significantly increased with increased tertile of baseline SUA/Cr ratio (p = 0.011), and prevalence of the rapid progression types (≥3.0 ml/min/1.73 m2/year) was significantly higher in the second and third tertile (≥7,21) of baseline SUA/Cr ratio than the first tertile (<5.86) (p = 0.032). Pearson's correlation coefficient showed that baseline SUA/Cr ratio (r = 0.136, p = 0.012) as well as systolic blood pressure (SBP) and SUA were significantly correlated with annual eGFR decline rate. Multiple regression analysis using annual eGFR decline rate as an objective variable, adjusted for confounding factors as explanatory variables, showed that baseline SUA/Cr ratio (ß = 0.334, p < 0.001) as well as gender and SBP were significantly and independently associated with annual eGFR decline rate. The multivariate-adjusted odds ratios (ORs) (95% confidence interval) of the baseline tertile of the SUA/Cr ratio for rapid progression of annual eGFR decline rate were 1.0, 3.15 (1.66-5.95) and 3.19 (1.57-6.51), respectively. CONCLUSION: Our data demonstrated that baseline SUA/Cr ratio was independently and significantly associated with future renal function decline among diabetic patients.

Usefulness of waist-to-height ratio in screening incident metabolic syndrome among Japanese community-dwelling elderly individuals.

This study examined a range of anthropometric indices and their relationships with metabolic syndrome (MetS). Despite recommendations that central obesity assessment should be employed as a marker of metabolic health, there is no consensus regarding the protocol for measurement. The present study included 720 men aged 71 ± 8 years and 919 women aged 71 ± 7 years from a rural village. We examined the relationship between anthropometric indices {e.g., body mass index (BMI), waist-to-height ratio (WHtR), waist-to-hip ratio (WHpR)}, and MetS based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report in a cross-sectional (N = 1,639) and cohort (N = 377) data. A receiver operating curve (ROC) analysis was performed to determine the optimal cut-off value and best discriminatory value of each of these anthropometric indices to predict MetS. In the cross-sectional study, WHtR as well as BMI and WHpR showed significantly predictive abilities for MetS in both genders; and WHtR showed the strongest predictive ability for the presence of MetS. Also in the cohort study, WHtR as well as BMI and WHpR showed significantly predictive abilities for incident MetS in both genders, and in men WHtR showed the strongest predictive ability for incident MetS, but in women BMI showed the strongest predictive ability. In the cross-sectional study, the optimal WHtR cutoff values were 0.52 (sensitivity, 71.0%; specificity, 77.9%) for men and 0.53 (sensitivity, 79.8%; specificity, 75.7%) for women. In the cohort study, the optimal WHtR values were 0.50 (sensitivity, 60.7%; specificity, 73.2%) for men and 0.50 (sensitivity, 75.0%; specificity, 56.1%) for women. Increased WHtR was significantly and independently associated with prevalence of MetS in both genders. These results suggest that WHtR is a useful screening tool for determining metabolic risk in Japanese elderly community dwelling individuals.

Association of neutrophil-to-lymphocyte ratio with early renal dysfunction and albuminuria among diabetic patients.

PURPOSE: Neutrophil-to-lymphocyte ratio (NLR) was widely studied as a prognostic marker in various medical and surgical specialties, but its significance in diabetic kidney disease is not yet established. METHODS: The subjects comprised 199 men aged 73 ± 11 (mean ± standard deviation) years and 187 women aged 77 ± 10 years from a rural hospital. We examined the relationship between NLR calculated by analyzing differential leukocyte count in complete blood picture and renal function evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation and urinary albumin excretion (UAE). RESULTS: NLR was negatively related to eGFR and positively related to UAE. Multiple linear regression analysis using eGFR and UAE as an objective variables, adjusted for confounding factors as explanatory variables showed that NLR (ß = - 0.101, p = 0.009) as well as age, body mass index, serum uric acid, and presence of uric acid lowing medication were significantly and independently associated with eGFR, and NLR (ß = 0.113, p = 0.031) as well as prevalence of cardiovascular disease, systolic blood pressure, presence of antihypertensive medication, presence of antilipidemic medication, and eGFR were significantly and independently associated with UAE. The multivariate-adjusted odds ratios (95% confidence interval) of NLR for stage 3a (eGFR < 60 mL/min/1.73 m2), stage 3b (eGFR < 45 mL/min/1.73 m2), and microalbuminuria (UAE ≥ 30 mg/g Cr) were 1.90 (1.02-3.56) and 2.99 (1.28-6.98), and 1.77 (1.04-3.01), respectively. Next, to examine the consistency of the observed association between NLR and eGFR, we performed subgroup analyses. There was a significant interaction (p = 0.006) only between the two groups regarding antihypertensive medication (absence: ß = - 0.272, p < 0.001 and presence: ß = - 0.029, p = 0.564). CONCLUSIONS: Our data suggested that NLR might be important as a potential factor for evaluating patients with a higher degree of albuminuria among diabetic outpatients.

Serum Uric Acid to Creatinine Ratio Independently Predicts Incident Metabolic Syndrome Among Community-Dwelling Persons.

BACKGROUND: Metabolic syndrome (MetS) is related to the increased risk of major cardiovascular disease. The link between high serum uric acid (SUA) and creatinine (Cr) levels is causally related to MetS and its components. However, whether renal function-normalized SUA [i.e., SUA to Cr ratio (SUA/Cr)] predicts incident MetS and its components remains inconclusive. MATERIALS AND METHODS: We conducted a prospective cohort study designed as part of the Nomura study. The subjects comprised 447 men ages 68 ± 10 years and 625 women ages 68 ± 9 years from a rural village, and 155 (34.7%) men and 310 women (49.6%) had MetS at baseline. We found participants who underwent a similar examination 3 years later and analyzed the relationship between baseline SUA/Cr and incident MetS defined according to the modified criteria of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III). RESULTS: One hundred forty-nine (33.3%) men and 286 (45.8%) women had MetS after a 3-year follow-up. Multiple linear regression analysis was performed to evaluate the contribution of possible confounding factors for MetS. In women only, baseline SUA/Cr, as well as baseline number of MetS and age, was significantly and independently associated with the number of MetS components at follow-up. The multivariable-adjusted odds ratios (95% confidence interval) for incident MetS across three quartiles of baseline SUA/Cr (1st-2nd, 3rd, and 4th) were 1.00, 1.62 (0.97-2.69), and 2.07 (1.20-3.56), respectively. Furthermore, when subjects were stratified by age, estimated glomerular filtration rate (eGFR), and presence of baseline MetS, baseline SUA/Cr was also a significant and independent determinant for incident MetS in women with age ≥60 years, eGFR ≥70 mL/min/1.73 m2, and presence of baseline MetS. CONCLUSIONS: Baseline SUA/Cr was significantly associated with incident MetS among community-dwelling women.

Baseline and changes in serum uric acid independently predict glucose control among community-dwelling women.

BACKGROUND: Elevated serum uric acid (SUA) levels are associated with glucose control. However, whether baseline and changes in SUA predict long-term follow-up glucose control [e.g., glycated hemoglobin (HbA1c)] remains unclear. METHODS: The subjects comprised 393 women aged 71 ± 8 years and 279 men aged 71 ± 10 years from a rural village. We have identified participants who underwent a similar examination 11 years prior, and subjects were divided into four groups based on the tertiles of baseline and changes in SUA, and examined the relationship between baseline and changes in SUA, and glucose control evaluated by follow-up HbA1c after 11-years. RESULTS: In both genders, follow-up SUA were significantly higher in Group 4 (i.e., women: Group 4, baseline SUA ≥ 4.0 mg/dL and changes in SUA ≥ 0.8 mg/dL; men: Group 4, ≥ 5.3 mg/dL and ≥ 0.4 mg/dL) than in the other Groups, but eGFR was significantly lower. Only in women, there were significant differences among the four groups regarding follow-up HbA1c, and follow-up HbA1c was highest in Group 4. In addition, the interaction between baseline and changes in SUA (F = 5.391, p = 0.021) as well as baseline low-density lipoprotein cholesterol (LDL-C) (F = 13.793, p < 0.001), estimated glomerular filtration ratio (F = 10.715, p = 0.001), HbA1c (F = 118.285, p < 0.001), SUA (F = 9.457, p = 0.002), and changes in SUA (F = 7.757, p = 0.006) was a significant and independent determinant of follow-up HbA1c. Multivariate-adjusted follow-up HbA1c (p = 0.002) were significantly higher in Group 4 than the other groups. CONCLUSIONS: These results suggested that combined assessment of baseline and changes in SUA provides increased information for long-term predictive glucose control, independent of other confounding factors in community-dwelling women.