Episodic ataxia type 2 with a novel missense variant (Leu602Arg) in CACNA1A.

Autosomal dominant episodic ataxia type 2 (EA2) is caused by variants in CACNA1A. We examined a 20-year-old male with EA symptoms from a Japanese family with hereditary EA. Cerebellar atrophy was not evident, but single photon emission computed tomography showed cerebellar hypoperfusion. We identified a novel nonsynonymous variant in CACNA1A, NM_001127222.2:c.1805T>G (p.Leu602Arg), which is predicted to be functionally deleterious; therefore, this variant is likely responsible for EA2 in this pedigree.

Case report: Frontotemporal dementia and amyotrophic lateral sclerosis caused by a missense variant (p.Arg89Trp) in the valosin-containing protein gene.

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin-containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non-progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be "damaging" by PolyPhen-2 and "deleterious" using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.

Dermal advanced glycation end-product accumulation is associated with sarcopenia-related measures in middle-aged and older men.

AIMS: Sarcopenia is the age-associated atrophy of muscles, and advanced glycation end-products (AGEs) accumulate in patients with age-associated diseases. We aimed to investigate the relationship between AGE accumulation in the skin and sarcopenia in middle-aged and older Japanese people. MATERIALS AND METHODS: We enrolled 240 participants in this cross-sectional study. The participants consisted of 120 men (mean age 68.8 ± 10.1 years) and 120 women (mean age 67.4 ± 9.0 years). The level of dermal AGE accumulation in the forearms was measured using skin autofluorescence (SAF) and many parameters associated with sarcopenia, including grip strength and thigh muscle cross-sectional area (CSA), were evaluated during medical check-ups at the Ehime University Hospital. RESULTS: Grip strength and thigh muscle CSA were significantly higher in men than women, but mean SAF did not significantly differ between them. There were significant correlations of age, height, C-reactive protein, glycated hemoglobin, grip strength, and thigh muscle CSA with SAF in men, but only age in women. Multivariate analysis showed that SAF was significantly independently associated with low grip strength in men (ß =-0.211, p =0.046). The men were then allocated to four groups according to their grip strength and thigh muscle CSA, and SAF was significantly higher in the lowgrip strength/low-thigh muscle CSA group than in the high-grip strength/high-thigh muscle CSA group (low/low group 2.25 ± 0.37 and high/high group 1.93 ± 0.36, p =0.001). CONCLUSIONS: SAF is associated with sarcopenia-related measures, especially grip strength, in middle-aged and older Japanese men, but not women.

Vascular endothelial dysfunction associated with severity in multiple sclerosis.

BACKGROUND: Impairment of cerebrovascular reactivity (CVR) has been reported in patients with multiple sclerosis (MS). Chronic inflammation and endothelial dysfunction are possible mechanisms underlying this hemodynamic impairment. This study aimed to evaluate CVR and endothelial function in patients with MS and explore their relationships with disease progression using functional sonographic procedures. METHODS: Patients with MS and age-/sex-matched healthy controls were assessed for endothelial function, determined by flow-mediated dilation (FMD), and CVR, measured using the breath-holding index (BHI). RESULTS: Twenty-seven patients with MS and 24 healthy controls were enrolled. FMD was significantly lower in MS subjects than in control subjects (6.0 ± 0.6 vs. 8.6 ± 0.7, p = 0.006); furthermore, BHI was similarly lower in MS than in controls, but insignificant. Remarkably, FMD was significantly lower in secondary progressive MS subjects than in relapse-remitting MS subjects (3.7 ± 1.3 vs. 6.7 ± 0.7, p = 0.045). In addition, FMD was inversely correlated with the disability score as per the expanded disability status scale (R2 = 0.170, p = 0.033) and modified Rankin scale (R2 = 0.187, p = 0.027). CONCLUSION: In patients with MS, endothelial dysfunction was more noticeable than CVR impairment, correlating with the severity and progression of MS.

Casein Hydrolysate Containing Milk-Derived Peptides Reduces Facial Pigmentation Partly by Decreasing Advanced Glycation End Products in the Skin: A Randomized Double-Blind Placebo-Controlled Trial.

Casein hydrolysate has been shown to improve arterial stiffness as estimated by brachial-ankle pulse wave velocity (baPWV) in untreated hypertensive patients. Facial pigmentation is associated with atherosclerosis, both of which are supposed to be modulated by tissue accumulation of advanced glycation end products (AGEs). However, effects of casein hydrolysate on facial pigmentation and AGEs remain largely unknown. This randomized double-blind placebo-controlled trial evaluated whether and how casein hydrolysate improves facial pigmentation in 80 nonhypertensive Japanese patients. Study participants were randomly assigned to receive either active tablets containing casein hydrolysate or placebo for 48 weeks. Facial pigmentation area, baPWV, and skin accumulation levels of AGEs were evaluated by Robo Skin Analyzer RSA50S II, volume-plethysmographic apparatus, and AGE Reader, respectively, at baseline and at the end of the intervention. Treatment with casein hydrolysate, but not placebo significantly reduced triglycerides and facial pigmentation area. There were significant differences of changes in triglycerides, facial pigmentation area, skin accumulation levels of AGEs, and baPWV between the two groups. Furthermore, changes in triglycerides and skin accumulation levels of AGEs were positively and independently associated with those in facial pigmentation area, whereas changes in baPWV were not. This study suggests that casein hydrolysate reduces facial pigmentation area in nonhypertensive participants partly by decreasing skin accumulation levels of AGEs. Clinical-Trials.gov ID: UMIN000027675.

Interaction between body mass index and serum uric acid in relation to blood pressure in community-dwelling Japanese men.

BACKGROUND: Few data is available on the association between body mass index (BMI), serum uric acid (SUA) levels and blood pressure (BP) categories in the disease continuum, when efforts for its prevention may be applicable. METHODS: We performed a cross-sectional study to examine the association between BMI, SUA and BP in a community-dwelling sample of Japanese men. Individuals not on antihypertensive and uric acid lowering medications, and aged 50 to 90 years [817men aged 66 ± 9 (mean ± standard deviation) years] were recruited for the survey during a community based annual medical check-up. The main outcome was the presence of prehypertension [systolic BP (SBP) 120-139 mmHg and/or diastolic BP (DBP) 80-89 mmHg] and hypertension [SBP ≥ 140 and /or DBP ≥ 90]. RESULTS: In participants with a BMI of < 21.0 kg/m2, increased SUA levels were positively associated with SBP and DBP, but in those with a BMI of ≥ 21.0 kg/m2, increased SUA levels were negatively associated with SBP and DBP. The interaction between BMI and SUA as well as BMI and SUA was a significant and independent determinant for both SBP (ß = - 1.125, p = 0.001) and DBP (ß = - 0.995, p = 0.005). Among participants, the respective prevalence of normotension, prehypertension, and hypertension was 19.5% and 53.7%, and 19.8%. The prevalence of normotension and prehypertension decreased with increasing BMI and the prevalence of hypertension increased with increasing BMI. In participants with a BMI ≥ 21.0 kg/m2, the adjusted-odds ratio of SUA for hypertension was 0.75 (95% CI, 0.59-0.95) compared with normotension and 0.82 (0.70-0.96) compared with prehypertension. In those with a BMI of < 21.0 kg/m2, these associations were not shown. CONCLUSION: BMI may modify the association between SUA and blood pressure status among community-dwelling men.

Alanine Aminotransferase and Total Bilirubin Are Synergistically Associated with Metabolic Syndrome Among Middle-Aged and Elderly Japanese Women.

BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. Alanine aminotransferase (ALT) at high levels and total bilirubin (T-BiL) at low levels were oxidative potentials, but it was uncertain whether ALT and T-BiL had an additive interaction for the risk of MetS. METHODS: From a single community, we recruited 864 women (70 ± 8 years) during their annual health examination. We cross-sectionally investigated whether ALT and T-BiL are associated with MetS and its components based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report. RESULTS: Of these subjects, 415 women (48.0%) had MetS. Participants with MetS had a higher ALT and lower T-BiL level than those without MetS. The adjusted-odds ratios (OR) (95% confidence interval [CI]) for MetS across tertiles of ALT and T-BiL were 1.00, 1.19 (0.78-1.81), and 1.86 (1.24-2.80) and 1.00, 0.96 (0.65-1.43), and 0.54 (0.36-0.81), respectively. When ALT and T-BiL were categorized into three binary characteristics by tertiles of ALT and T-BiL, high T-BiL was associated with decreased risk for MetS in a multivariable model (OR: 0.55, 95% CI: 0.37-0.82), especially among those with 1st tertile ALT. Similarly, high ALT was also associated with increased risk for MetS in a multivariate model (OR: 1.81, 95% CI: 1.20-2.71), especially among those with 2nd & 3rd tertiles of T-BiL. In the formal testing of addictive interaction between ALT and T-BiL for MetS, presence of T-BiL <0.72 mg/dL (1st and 2nd tertile) alone was not associated with increased risk of MetS in a multivariate analysis, and presence of ALT ≥16 IU/L (2nd and 3rd tertile) alone was not associated with increased risk of MetS. CONCLUSIONS: These results suggested that higher ALT and lower T-BiL levels were synergistically associated with MetS, independent of other confounding factors among Japanese women.

Mildly elevated serum total bilirubin is negatively associated with hemoglobin A1c independently of confounding factors among community-dwelling middle-aged and elderly persons.

Abnormally high glycated hemoglobin (Hb) (HbA1c) is significantly associated with oxidative stress and an increased risk of cardiovascular disease (CVD). Serum total bilirubin (T-B) may have a beneficial role in preventing oxidative changes and be a negative risk factor of CVD. Limited information is available on whether serum T-B is an independent confounding factor of HbA1c. The study subjects were 633 men aged 70 ± 9 (mean ± standard deviation (SD)) years and 878 women aged 70 ± 8 years who were enrolled consecutively from among patients aged ≥40 years through a community-based annual check-up process. We evaluated the relationship between various confounding factors including serum T-B and HbA1c in each gender. Multiple linear regression analysis pertaining to HbA1c showed that in men, serum T-B (ß = -0.139) as well as waist circumference (ß = 0.099), exercise habit (ß = 0.137), systolic blood pressure (SBP) (ß = 0.076), triglycerides (ß = 0.087), and uric acid (ß = -0.123) were significantly and independently associated with HbA1c, and in women, serum T-B (ß = -0.084) as well as body mass index (ß = 0.090), smoking status (ß = -0.077), SBP (ß = 0.117), diastolic blood pressure (DBP) (ß = -0.155), low-density lipoprotein cholesterol (ß = 0.074), prevalence of antidyslipidemic medication (ß = 0.174), and uric acid (ß = 0.090) were also significantly and independently associated with HbA1c. Multivariate-adjusted serum HbA1c levels were significantly high in subjects with the lowest serum T-B levels in both genders. Serum T-B is an independent confounding factor for HbA1c among community-dwelling middle-aged and elderly persons.

Interactive association of serum uric acid and total bilirubin with renal dysfunction among community-dwelling subjects.

PURPOSE: Chronic kidney disease is a major public health concern. Serum uric acid (SUA) at high levels was oxidative stress agents, and total bilirubin (T-BiL) at mildly increased levels was potent antioxidants, but whether SUA and T-BiL produce an additive interaction for the risk of renal dysfunction remains unclear. METHODS: The subjects comprised 567 men aged 71 ± 8 (mean ± standard deviation) years and 853 women aged 70 ± 8 years from a rural village. We examined the relationship between SUA and T-BiL, and renal function was evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation. RESULTS: Stepwise multiple regression analysis using eGFR as an objective variable, adjusted for risk factors as explanatory variables, showed that SUA (ß = -0.358, p < 0.001) as well as age (ß = -0.534, p < 0.001), drinking status (ß = 0.119, p < 0.001), and the presence of antihypertensive medication (ß = -0.058, p = 0.005) were significantly and independently associated with eGFR, but T-BiL was not associated with eGFR. While in the group with the highest tertile of SUA, T-BiL (ß = 0.081, p = 0.032) was significantly and independently associated with eGFR, and in the group with the lowest to middle tertile of SUA, T-BiL was not associated with eGFR. In addition, interaction between SUA and T-BiL (F = 8.512, p = 0.004) as well as age, drinking status, the presence of antihypertensive medication, SUA, and T-BiL was a significant and independent determinant for eGFR. CONCLUSIONS: Our data demonstrated that low T-BiL could be important as a potential risk factor for renal dysfunction in those with high SUA.

Restructuring the Ikeda City school urinary screening system: report of a screening survey.

BACKGROUND: Annual urinary screening is conducted at municipal kindergartens, elementary schools, and junior high schools in Ikeda City, Osaka, Japan (Ikeda City School System), and the results are reviewed by a general physician, but standards for when to recommend specialist referral have not been clear. METHODS: In all children attending the Ikeda City School System in 2012, dipstick urinalysis of a first-morning urine specimen was recommended once or twice, and if a second urinalysis showed proteinuria (≥1+), the urinary protein/creatinine ratio was measured. If this showed ≥0.2 g/g of creatinine (g/gCr), it was recommended that the child be evaluated by a specialist at Ikeda City Hospital. RESULTS: Urinary screening was performed in about 20% (388) of kindergarten, about 90% (5363) of elementary school, and about 86% (2523) of junior high school children living in Ikeda City. Urine samples were obtained from 387, 5349, and 2476 children, respectively. The urinary protein/creatinine ratio was ≥0.2 g/gCr in 13 children, including 1 elementary and 12 junior high children. In these 13 children, chronic nephritic syndrome (CNS) was suspected in 6 junior high school children, and of these, this was a new finding in 5, and renal biopsy was indicated in 3. In Ikeda City, the prevalence of CNS in elementary school children was <0.03%, the prevalence of CNS in junior high school children was 0.29%, and a renal biopsy was indicated in 0.14%. By eliminating the costs associated with assessment of the results by the Ikeda Medical Association, and by directly contracting with the testing company, the expenses paid by Ikeda City for the system itself decreased from 2,508,619 yen to 966,157 yen. CONCLUSIONS: Incorporating the urinary protein/creatinine ratio into the school urinary screening system in the Ikeda City School System and clarifying standards for specialist referral has enabled restructuring of the system so that is efficient and its effectiveness can be assessed.