Keisuke Osakabe

OBJECTIVE: Epilepsy treatment with anti-seizure medications (ASMs) is based on careful assessment of the balance between the likelihood of further seizures and the risk of side effects of treatment. However, there is currently no established biomarker to ascertain seizure control status with ASMs. High-frequency oscillations (HFOs), transient bursts of EEG activity with frequencies beyond 80 Hz, are a new and promising noninvasive epilepsy biomarker. We compared the risk of scalp HFO appearance between pediatric patients with good and poor seizure control by treatment with ASMs. METHODS: A total of 72 epilepsy patients (aged 0-18 years, 39 males) with good and poor seizure control with ASMs participated in this study. We applied a validated automated detector to determine HFO and spike. We calculated the odds ratios (ORs) for scalp HFO and spike appearance according to seizure control status by multiple logistic regression analysis. RESULTS: Scalp HFO was seen more commonly and with a significantly higher detection rate in patients with poor seizure control as compared with patients with good seizure control for both ripple and fast ripple. These significant associations were found for both focal and generalized epilepsy. The ORs for scalp HFO appearance adjusted for confounding factors were significantly higher in patients with poor seizure control compared to those with good seizure control (ripple: OR [95% CI] = 11.91 [2.21-64.30], p = 0.004; fast ripple: 4.98 [1.03-24.09], p = 0.046). There were no significant associations between spike appearance and seizure control status. SIGNIFICANCE: We found an increased risk of scalp HFO appearance in patients with poor seizure control. The results of this study support that scalp HFO is associated with patients having frequent seizures after treatment in both ripple and fast ripple. PLAIN LANGUAGE SUMMARY: This study analyzed scalp high-frequency oscillations and spikes in pediatric patients with various types of epilepsy who were being treated using ASMs. The results showed that an increased risk of scalp HFO appearance was observed in patients with poor seizure control compared to those with good seizure control. These findings were observed in both the ripple (80-250 Hz) and fast ripple (250-500 Hz) bands. The scalp HFO is associated with patients having frequent seizures after treatment in both ripple and fast ripple.

INTRODUCTION: High-frequency oscillation (HFO) in scalp electroencephalography is a promising new noninvasive prognostic epilepsy biomarker, but further data are needed to ascertain the utility of this parameter. The present work investigated the association between epileptic activity and scalp HFO in pediatric patients with various types of epilepsy, using multivariable regression models to correct for possible confounding factors. METHODS: The authors analyzed 97 subjects who were divided into groups with active epilepsy (within 1 year of seizure), seizure-free epilepsy (>1 year without seizure), and nonepilepsy. Regarding the frequency of seizure occurrence as an indicator of epileptic activity, we categorized subjects into four groups (Daily/Weekly, Monthly, Yearly, and Rarely). RESULTS: Multiple linear regression analysis showed that the scalp HFO detection rate was significantly higher in patients with active epilepsy than in those with nonepilepsy (β [95% confidence interval] = 2.77 [1.79-4.29]; P < 0.001). The association between scalp HFO detection rate and frequency of seizure occurrence was highest in the Daily/Weekly group (β [95% confidence interval] = 3.38 [1.57-7.27]; P = 0.002), followed by Monthly and Yearly groups (β [95% confidence interval] = 2.42 [1.02-5.73]; P = 0.046 and 0.36 [0.16-0.83]; P = 0.017). In addition, HFO duration, number of peaks, and number of channels detected were significantly higher in patients with active epilepsy. CONCLUSIONS: Pediatric patients with active epilepsy and high frequency of seizure occurrence exhibited a higher scalp HFO detection rate. These results may help to establish HFO detectable by noninvasive scalp electroencephalography as a biomarker of active epilepsy in pediatric patients.

Background: The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) has become a global health problem. NAFLD has few initial symptoms and may be difficult to detect early, so there is need for a minimally invasive early detection marker. We hypothesized that miR-122 and miR-20a levels combined, as the miR-122/miR-20a ratio might detect NAFLD more sensitively. Methods: This study involved 167 participants with low alcohol intake. Those who had an increase in echogenicity of the liver parenchyma and hepato-renal contrast on ultrasonography were classified as the NAFLD group (n = 44), which was further classified into mild (n = 26) and severe (n = 18) groups based on echogenic intensity and hepatic vessel and diaphragm visualization. Participants without fatty liver were included in the normal group, except for those with an abnormal body mass index, glycated hemoglobin, and systolic blood pressure (n = 123) values. Serum miR-122 and miR-20a expression levels in participants were measured by real-time polymerase chain reaction, and the miR-122/miR-20a was calculated. Results: In the NAFLD group, miR-122 expression was significantly higher and the miR-20a was significantly lower than in the normal group, in agreement with previous studies. miR-122/miR-20a was also significantly higher in the NAFLD group. Receiver operating characteristic curve analysis was performed with miR-122/miR-20a as an NAFLD detection marker, and the area under the curve of miR-122/miR-20a was significantly larger than that of miR-122 or miR-20a alone. Conclusions: The miR-122/miR-20a ratio, combined with miR-122 and miR-20a levels, is a useful biomarker to detect NAFLD with high sensitivity.

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) is a global health problem. In recent years, the inhibitory effect of brain-derived neurotrophic factor (BDNF) on diabetes mellitus and fatty liver has been clarified. The purpose of this study was to analyze the relationship between serum BDNF and NAFLD which caused by abnormal metabolism of glucose and lipids. This cross-sectional study involved 429 participants (mean age, 63.5 years: men, 38.5%) with low alcohol intake. Of the participants, those who had an increase in echogenicity of the liver parenchyma and hepato-renal contrast on ultrasonography were classified as the NAFLD group (n = 88), and the others were classified as the normal (n = 341) group. The NAFLD group was further classified into a mild group (n = 60) and a severe group (n = 28) based on the intensity of echogenicity and visualization of the hepatic vessels and diaphragm. Median BDNF levels were higher in the NAFLD group than the normal group (35.5 vs. 42.3 ng/mL, p < 0.01). Furthermore, BDNF levels tended to be associated with the severity of NAFLD (p < 0.01). In addition to the univariate analysis, in the sex- and age-adjusted model, there was a significant association between the BDNF levels and NAFLD severity (p < 0.01). The fully adjusted regression analysis also showed a positive association between the serum BDNF level and NAFLD (p < 0.01). These results suggest that NAFLD patients have a compensatory increase in circulating BDNF levels.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity, metabolic syndrome, and type II diabetes mellitus. Recently, circulating microRNAs (miRNAs) have been proposed as useful disease biomarkers. We examined whether circulating miRNAs, such as miR-20a, miR-27a, and miR-126, were useful biomarkers for NAFLD. We conducted a cross-sectional analysis of 527 subjects aged 39 years or older who had undergone a health examination in the Yakumo Study. Of the residents, 92 were diagnosed with NAFLD using a registered medical sonographer. Serum miR-20a, miR-27a and miR-126 levels were measured by quantitative real-time PCR. We then calculated the odds ratios for serum miRNA level changes according to the severity of NAFLD using normal liver status as the reference group. Serum levels of miR-20a and 27a, but not miR-126, were significantly lower in NAFLD subjects than normal subjects. Serum miR-20a and miR-27a levels were significantly lower in both male and female severe NAFLD subjects. Logistic regression analysis showed a significant relationship between low circulating miR-20a and 27a levels and severe NAFLD. Down-regulated circulating miR-20a and 27a levels were significantly associated with severe NAFLD in the general population. Circulating miR-20a and miR-27a may be useful biomarkers for severe NAFLD.

Purpose It has been demonstrated that circulating microRNA profiles are affected by physiological conditions. Several studies have demonstrated that microRNAs play important roles in the regulation of adiposity. However, few have investigated the relationship between circulating microRNAs and obesity, which has become a major public health problem worldwide. This study investigated the association between circulating microRNAs and obesity in a Japanese population. Methods Obesity parameters, such as subcutaneous and visceral fat adipose tissue, body fat percentage, and body mass index were assessed in a cross-sectional sample of 526 participants who attended health examinations in Yakumo, Japan. In addition, five circulating microRNAs (miR-20a, -21, -27a, -103a, and -320), which are involved in adipocyte proliferation and differentiation, were quantified using real-time polymerase chain reaction amplification. Results We compared the circulating microRNA concentrations in a percentile greater than 75th (high) with below the value (low) of subcutaneous adipose tissue, visceral fat adipose tissue, body mass index, and per cent body fat. For visceral fat adipose tissue, significant decrease in miR-320 expression was observed in high group. Also, for body mass index, significant change of miR-20a, -27a, 103a, and 320 expression level was observed in high group. Multiple linear regression analysis demonstrated that circulating levels of some microRNA such as miR-27a were significantly associated with subcutaneous adipose tissue, visceral fat adipose tissue, and body mass index. Conclusions Our findings support the need for further studies to determine whether such changes are consistent across different populations and whether the identified microRNAs may represent novel biomarkers to predict the susceptibility and progression of obesity-related disorders.

Objectives: Circulating micro (mi)RNA profiles are influenced by various medical conditions, and miRNAs have been examined as potential biomarkers for cancer, cardiovascular disease, and diabetes. However, few studieshave investigated whether circulating miRNAs and cigarette smoking are correlated. Our aim was to determine theassociation between smoking status and expression of various miRNAs in a Japanese population sample.Methods: We conducted a cross-sectional analysis of 526 subjects (219 men and 307 women) aged 39 years and older who had undergone a health examination at a clinic in Yakumo, Hokkaido in August 2012. We used quantitative real-time polymerase chain reaction to determine serum miRNA expression. We then calculated the odds ratios for elevated serum miRNA levels according to smoking status using never-smokers as the reference group.Results: Expression of lethal (let)-7d, miRNA(miR)-150, miR-192, miR-197 and miR320 was significantly higher in current smokers than in never-smokers. Multivariate logistic regression analyses showed that while current smokers were significantly more likely to have elevated serum levels of miRNA let-7d, miR-21, miR-122, miR-146, miR-150, miR-192, miR-197, and miR320 than never-smokers, former smokers had significantly higher odds of having elevated miR-1, miR-146, miR-150, miR-195, and miR-320 levels in their sera.Conclusions: We found that cigarette smoking is associated with elevated expression of various serum miRNAs. Our results suggest that it is necessary to consider the confounding effect caused by smoking when evaluating expression of serum miRNAs for diagnosing pathological conditions.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a common debilitating condition in many industrialized countries that increases the risk of cardiovascular disease. The aim of this study was to derive a simple and accurate screening tool for the prediction of NAFLD in the Japanese population. METHODS: A total of 945 participants, 279 men and 666 women living in Hokkaido, Japan, were enrolled among residents who attended a health check-up program from 2010 to 2014. Participants with an alcohol consumption > 20 g/day and/or a chronic liver disease, such as chronic hepatitis B, chronic hepatitis C or autoimmune hepatitis, were excluded from this study. Clinical and laboratory data were examined to identify predictive markers of NAFLD. RESULTS: A new predictive index for NAFLD, the NAFLD index, was constructed for men and for women. The NAFLD index for men = -15.5693+0.3264 [BMI] +0.0134 [triglycerides (mg/dl)], and for women = -31.4686+0.3683 [BMI] +2.5699 [albumin (g/dl)] +4.6740[ALT/AST] -0.0379 [HDL cholesterol (mg/dl)]. The AUROC of the NAFLD index for men and for women was 0.87(95% CI 0.88-1.60) and 0.90 (95% CI 0.66-1.02), respectively. The cut-off point of -5.28 for men predicted NAFLD with an accuracy of 82.8%. For women, the cut-off point of -7.65 predicted NAFLD with an accuracy of 87.7%. CONCLUSION: A new index for the non-invasive prediction of NAFLD, the NAFLD index, was constructed using available clinical and laboratory data. This index is a simple screening tool to predict the presence of NAFLD.

黄色肉芽腫性胆嚢炎(XGC)における超音波像および胆嚢動脈波形分析について検討した。超音波検査を施行し、さらに病理組織診断が得られているXGC 30例を対象とした。対照としてXGCと鑑別が困難となる胆嚢癌32例を検討に加えた。B-mode超音波を施行した30例中、胆石は27例に観察した。Power Doppler法を施行した27例中全例の壁肥厚部に胆嚢動脈と思われる血流表示を観察した。胆嚢癌では全例に線状の豊富な血流表示を認め、XGCの血流表示は胆嚢癌と比較するとやや乏しい傾向であった。限局性壁肥厚であった2例を除く28例中27例にて、胆嚢動脈の波形分析を施行可能であった。いずれもXGCは胆嚢癌に比べ有意に低値を示した。PI1.44以上、かつVmax46cm/s以上の場合が胆嚢癌と診断可能となった。PI1.44未満、かつVmax40cm/s未満であれば、XGCと診断可能となった。