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Mutations in optineurin (OPTN) have been identified in a small proportion of sporadic and familial amyotrophic lateral sclerosis (ALS) cases. Recent evidences suggest that OPTN would be involved in not only the pathophysiological mechanisms of motor neuron death of ALS but also myofiber degeneration of sporadic inclusion body myositis. However, the detailed role of OPTN in muscle remains unclear. Initially, we showed that OPTN expression levels were significantly increased in the denervated muscles of mice, suggesting that OPTN may be involved in muscle homeostasis. To reveal the molecular role of OPTN in muscle atrophy, we used cultured C2C12 myotubes treated with tumor necrosis factor-like inducer of apoptosis (TWEAK) as an in vitro model of muscle atrophy. Our data showed that OPTN had no effect on the process of muscle atrophy in this model. On the other hand, we found that myogenic differentiation was affected by OPTN. Immunoblotting analysis showed that OPTN protein levels gradually decreased during C2C12 differentiation. Furthermore, OPTN knockdown inhibited C2C12 differentiation, accompanied by reduction of mRNA and protein expression levels of myogenin and MyoD. These findings suggested that OPTN may have a novel function in muscle homeostasis and play a role in the pathogenesis of neuromuscular diseases.

Background: This study investigated the clinical factors related to hospital-acquired disability (HAD) among 70 patients (median age, 78 years; interquartile range (IQR), 78 - 83) who were hospitalized for heart failure (HF) at Ayase Heart Hospital between December 2019 and October 2020. Methods: HAD was defined as a >= 5-point decrease in Barthel Index (BI) scores from admission to discharge. Twenty-nine HF patients (41%) developed HAD after admission. Results: Compared to the non-HAD group, the HAD group had higher Kihon Checklist scores (14 points (IQR, 11 - 17) vs. 9 points (IQR, 6 - 13); P < 0.01) and prevalence of multi-faceted frailty (90% vs. 29%; P < 0.01), a longer urinary-catheter-placement period (3 days (IQR, 1 - 5] vs. 1 day (IQR, 0 - 2), P < 0.05), less daily number of steps (457 steps (IQR, 301 - 997) vs. 1,692 steps (IQR, 1,227 - 2,418); P < 0.01), and moderate-intensity physical activity time (0 min (IQR, 0 - 2] vs. 1 min (IQR, 0 - 3); P < 0.05). Conclusion: In conclusion, lower physical function and general physical activity and longer urinary-catheter-placement are associated with HAD. Cardiol Res. 2021;12(5):293-301 doi: https://doi.org/10.14740/cr1306

Although sepsis is known to cause functional decline, the prevalence and predictors of hospital-acquired functional decline (HAFD) in patients with sepsis are unclear. The purpose of this study was to investigate the prevalence and predictors of HAFD in patients with sepsis admitted to the ICU. This study is a single-center retrospective observational study from January 2014 to December 2019. We included all consecutive patients with sepsis who received rehabilitation in our ICU. The primary outcome was HAFD, which was defined as a decrease in at least five points of the Barthel index mobility score from prehospital to hospital discharge. We described the prevalence of HAFD and investigated the predictors of HAFD using the multivariate logistic regression analysis adjusting for potential confounders. Among 134 patients, 57 patients (42.5%) had HAFD. The longer time to initial ambulation and lower prehospital walking ability were associated with HAFD (adjusted odds ratio [OR] 1.07; 95% confidence interval [CI], 1.03-1.10 and adjusted OR 0.79; 95% CI, 0.66-0.95, respectively). In conclusion, nearly half of the patients with sepsis who received rehabilitation developed HAFD. Lower functional status prior to hospitalization and the longer time to initial ambulation was associated with HAFD, indicating the potential importance of early ambulation among septic patients in the ICU.

Background Peak oxygen uptake (peak VO2) is known not only as an index of aerobic fitness but also one of an index of life expectancy. Frailty, sarcopenia, and cachexia are associated with a poor prognosis and high mortality. The purpose of this study was to determine the relationships of peak VO2 with the features of sarcopenia, frailty, and cachexia, to provide insight into which might mediate the poor prognosis. Methods The first group of participants was 175 community‐dwelling older Japanese outpatients (58 men and 117 women; mean age 77.6 ± 6.4 years), in whom we assessed the features of sarcopenia, frailty, and cachexia, and measured peak VO2 during cardiopulmonary exercise. To confirm the relationships, we analysed another group of 162 participants (77.3 ± 5.5 years). Results There were significant correlations between peak VO2 and the features of sarcopenia, frailty, and cachexia, with the exception of high sensitivity C‐reactive protein. Multiple linear regression analysis for the prediction of peak VO2 (mL/min) identified following formula: predicted peak VO2 = −11.6 × age (years) + 25.5 × haemoglobin concentration (g/dL) + 114.2 × skeletal muscle mass index (kg/m2) + 8.9 × hand grip strength (kg) + 226.4 × usual walking speed (m/s) − 65.8 × fatiguability (absence 0, presence 1) − 177.4 × chronic heart failure (absence 0, presence 1) + 437.1 (R2 = 0.627, P

Aims Functional decline is associated with worse outcomes in patients with elderly heart failure (HF), but little is known about the prognostic impact of hospital‐acquired disability (HAD) during hospital stay after acute HF. The present study examines the prognostic significance of HAD in the prediction of all‐cause mortality in elderly patients who admitted for acute HF. Methods and results This retrospective study was performed in 1941 elderly patients aged ≥65 years or older from the cardiovascular physiotherapy for acute HF patients in the Tokyo metropolitan area registry and excluded those who died in hospital. HAD was defined as any decline in the Barthel index (BI) before discharge compared with the BI within 1 month before hospital admission. The primary outcome of this study was all‐cause death and HF readmission. A total of 565 (29%) deaths and 789 (41%) HF readmission occurred over a median follow‐up period of 1.7 years. A total of 476 patients (25%) had HAD during hospital stay after acute HF. In multivariable analysis, HAD predicted all‐cause death [hazard ratio (HR): 1.772; 95% confidence interval (CI): 1.450–2.167; P

Arterial stiffness contributes to the development of cardiovascular disease (CVD). However, the relationship between the arterial stiffness and exercise tolerance in CVD patients with preserved ejection fraction (pEF) and those with reduced EF (rEF) is unclear. We enrolled 358 patients who participated in cardiac rehabilitation and underwent cardiopulmonary exercise testing at Juntendo University Hospital. After excluding 195 patients who had undergone open heart surgery and 20 patients with mid-range EF, the patients were divided into pEF (n = 99) and rEF (n = 44) groups. Arterial stiffness was assessed using arterial velocity pulse index (AVI) and arterial pressure volume index (API) at rest. The patients in the pEF group were significantly older and had a higher prevalence of coronary artery disease than the rEF group. The pEF group had significantly lower AVI levels and higher API levels than the rEF group. In the pEF group, the peak oxygen uptake (peak VO2) and the anaerobic threshold was significantly higher than those in the rEF group. The peak VO2 was significantly and negatively correlated with AVI and API in the pEF group (All, P < 0.05), but not in the rEF group. Multivariate linear regression analyses demonstrated that AVI was independently associated with peak VO2 (β = -0.34, P < 0.05) in the pEF group. In conclusion, AVI may be a useful factor for assessing exercise tolerance, particularly in CVD patients with pEF.

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [− 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00731-x.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Aim Although it is known that geriatric syndrome is associated with the development of frailty, it is not known whether an amelioration of geriatric syndrome also improves shared risk factors and frailty. Methods In total, 67 community‐dwelling older people (79.6 ± 6.5 years, 49 women) participated in this study (41 were classified as pre‐frail and 26 as frail). We analyzed indices of physical frailty and cognitive depression, exercise tolerance and health‐related quality of life as frailty related indices, and the participants completed a questionnaire regarding common geriatric symptoms (cold extremities, leg edema, breathlessness, urinary incontinence, chronic headache, chronic pain, a sense of numbness, anorexia, constipation, insomnia and skin trouble) using numeric ratings. Frailty was evaluated using the Japanese version of the Cardiovascular Health Study (J‐CHS) criteria. The participants then underwent a far‐infrared low‐temperature sauna (FILTS) program twice a week for 3 months and the above parameters were reassessed. Results After the FILTS program, there were significant differences in usual walking speed, peak oxygen uptake, Geriatric Depression Scale‐15, health‐related quality of life and the severity of several geriatric symptoms. Of the 67 participants, 18 showed improvements in their J‐CHS frailty score, 47 showed no change and two showed reductions. Linear regression analysis showed that the change in the numeric rating of the coldness of extremities (B = −0.105, P = 0.013) and the cumulative numeric rating for geriatric syndromes (B = 0.044, P

Laparoscopic sleeve gastrectomy (LSG) is an important therapeutic option for morbidly obese patients. Although LSG promotes sufficient weight loss, how LSG changes plasma metabolites remains unclear. We assessed changes in plasma metabolite levels after LSG. We collected plasma samples from 15 morbidly obese Japanese patients before and 3 months after LSG. A total of 48 metabolites were quantified using capillary electrophoresis time‐of‐flight mass spectrometry‐based metabolomic profiling. Branched chain amino acids, several essential amino acids, choline, 2‐hydroxybutyric acid, 2‐oxoisovaleric acid and hypoxanthine were significantly decreased after LSG. Tricarboxylic acid cycle metabolites, including citric acid, succinic acid and malic acid, were significantly elevated after LSG. This is the first report to show dynamic alterations in plasma metabolite concentrations, as assessed using capillary electrophoresis time‐of‐flight mass spectrometry, in morbidly obese patients after LSG. Our results might show how LSG helps improve obesity, in part through metabolic status changes, and propose novel therapeutic targets to ameliorate obesity., Dynamic alterations in plasma metabolite concentrations in morbidly obese patients after laparoscopic sleeve gastrectomy.

Aims The kinetics of recovery‐period oxygen uptake (VO2) are affected by the O2 deficit generated during exercise. However, studies using ramp tests (RTs) and constant work rate tests (CT) have differently characterized VO2 responses to increased exercise intensity differently. We used these two types of loading patterns to investigate the effects of low‐intensity, medium‐intensity, and high‐intensity exercises on the half time (T1/2) of recovery‐period VO2 and the mechanism. Methods and results Ten healthy men aged 21.2 ± 0.9 years underwent symptom‐limited cardiopulmonary exercise tests with the ramp protocol to determine their anaerobic threshold. All subjects subsequently underwent three submaximal RT and CT at low, moderate, and high intensities. In all RTs, subjects began exercise by warming up (20 W). In CT, T1/2 was significantly lengthened as exercise intensity increased (CT‐low: 34.0 ± 3.9 s, CT‐moderate: 39.5 ± 3.5 s, CT‐high:44.6 ± 4.2 s; P

Although there are several case reports of progressive multifocal leukoencephalopathy (PML) in multiple myeloma (MM), there are few reports of cases associated with pomalidomide. Here, we report the case of a 69-year-old female who had received 41 cycles of pomalidomide and dexamethasone treatment for relapsed/refractory IgG-κ MM presented with right-hand weakness; she was diagnosed as pomalidomide-associated PML. Fluid-attenuated inversion recovery (FLAIR) on admission showed high signals in the bilateral front-parietal lobe white matter, with multiple punctate lesions in the vicinity of the main lesions. These punctate pattern findings on FLAIR were similar to that of natalizumab-associated PML. Susceptibility weighted imaging (SWI) showed hypointense rims within the cortex at unaffected sites, in the initial stages. Subsequently, the clinical manifestations deteriorated, and the FLAIR images showed new hyperintense white matter lesions at the sites where cortical SWI hypointense rims were detected on the initial MRI examination. Our patient's serial MRI findings suggest that cortical SWI hypointense rims appear prior to the visible demyelinating white matter lesions in patients with PML.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and antisignal recognition particle (SRP) antibodies are frequently associated with immune-mediated necrotizing myopathy (IMNM). However, the difference in clinical manifestations between anti-HMGCR and anti-SRP antibodies is unclear. HMGCR is an essential enzyme for cholesterol biosynthesis and is inhibited by statins that regulate apoptosis of Bcl-2-positive and beta chemokine receptor 4 (CCR4)-positive lymphoma cells. In this study, we aimed to clarify Bcl-2 and CCR4 expressions of lymphocytes in anti-HMGCR antibody-positive IMNM and explore the difference between anti-HMGCR antibody-positive myopathy and other inflammatory myopathies. We retrospectively examined Bcl-2- and CCR4-positive lymphocyte infiltrations in muscle and skin biopsy specimens from 19 anti-HMGCR antibody-positive patients and 75 other idiopathic inflammatory myopathies (IIMs) patients. A higher incidence of Bcl-2- and CCR4-positive lymphocytes was detected in the muscle and skin of anti-HMGCR antibody-positive IMNM patients (p

Background Advanced glycation end-products, indicated by skin autofluorescence (SAF) levels, could be prognostic predictors of all-cause and cardiovascular mortality in patients with diabetes mellitus (DM) and renal disease. However, the clinical usefulness of SAF levels in patients with heart failure (HF) who underwent cardiac rehabilitation (CR) remains unclear. This study aimed to investigate the associations between SAF and MACE risk in patients with HF who underwent CR. Methods This study enrolled 204 consecutive patients with HF who had undergone CR at our university hospital between November 2015 and October 2017. Clinical characteristics and anthropometric data were collected at the beginning of CR. SAF levels were noninvasively measured with an autofluorescence reader. Major adverse cardiovascular event (MACE) was a composite of all-cause mortality and unplanned hospitalization for HF. Follow-up data concerning primary endpoints were collected until November 2017. Results Patients’ mean age was 68.1 years, and 61% were male. Patients were divided into two groups according to the median SAF levels (High and Low SAF groups). Patients in the High SAF group were significantly older, had a higher prevalence of chronic kidney disease, and more frequently had history of coronary artery bypass surgery; however, there were no significant between-group differences in sex, prevalence of DM, left ventricular ejection fraction, and physical function. During a mean follow-up period of 590 days, 18 patients had all-cause mortality and 36 were hospitalized for HF. Kaplan–Meier analysis showed that patients in the high SAF group had a higher incidence of MACE (log-rank P Conclusion SAF levels were significantly associated with the incidence of MACE in patients with HF and may be useful for risk stratification in patients with HF who underwent CR.

Reduced integrity of neural pathways from frontal to sensory cortices has been suggested as a potential neurobiological basis of attention-deficit hyperactivity disorder. Neurofeedback has been widely applied to enhance reduced neural pathways in attention-deficit hyperactivity disorder by repeated training on a daily temporal scale. Clinical and model-based studies have demonstrated that fluctuations in neural activity underpin sustained attention deficits in attention-deficit hyperactivity disorder. These aberrant neural fluctuations may be caused by the chaos–chaos intermittency state in frontal-sensory neural systems. Therefore, shifting the neural state from an aberrant chaos–chaos intermittency state to a normal stable state with an optimal external sensory stimulus, termed chaotic resonance, may be applied in neurofeedback for attention-deficit hyperactivity disorder. In this study, we applied a neurofeedback method based on chaotic resonance induced by “reduced region of orbit” feedback signals in the Baghdadi model for attention-deficit hyperactivity disorder. We evaluated the stabilizing effect of reduced region of orbit feedback and its robustness against noise from errors in estimation of neural activity. The effect of chaotic resonance successfully shifted the abnormal chaos-chaos intermittency of neural activity to the intended stable activity. Additionally, evaluation of the influence of noise due to measurement errors revealed that the efficiency of chaotic resonance induced by reduced region of orbit feedback signals was maintained over a range of certain noise strengths. In conclusion, applying chaotic resonance induced by reduced region of orbit feedback signals to neurofeedback methods may provide a promising treatment option for attention-deficit hyperactivity disorder.

The aim of this study was to determine the association between underweight or obese status and hospital- acquired functional decline (HAFD) following cardiovascular surgery. We performed a retrospective, observational, multicenter cohort study of cardiovascular surgery patients between April, 2010, and June, 2017. Body mass index (BMI) was categorized into four classes: underweight group (

Background This study investigated the prevalence of sarcopenia or sarcopenic obesity and their association with frailty and protein-energy wasting (PEW) in hemodialysis patients. Methods The present study enrolled 117 adult hemodialysis patients (35% female, 64 ± 12 years old) from single units of a hemodialysis center. The patients were divided into four groups: normal, obese, sarcopenia, and sarcopenic obesity. Sarcopenia was diagnosed by Asian Working Group for Sarcopenia (AWGS) criteria, and obesity was defined as an extensive percent body fat mass greater than 40% in females and 30% in males. Skeletal muscle mass and percent fat mass were evaluated by multifrequency whole-body bioimpedance electrical analysis after a midweek dialysis session. Handgrip strength and a short physical performance battery (SPPB) were assessed before a dialysis session as indicators of muscle strength and physical performance. Moreover, participants completed the Kihon Checklist and the criteria proposed by the International Society of Renal Nutrition and Metabolism expert panel to classify frailty and PEW. We performed multivariate logistic regression analysis to identify the clinical risk of frailty and PEW in patients with sarcopenia or sarcopenic obesity. Results Forty-six (39.3%) patients were classified as normal; 18 (15.4%), as obese; 35 (29.9%), as having sarcopenia; and 18 (15.4%), as having sarcopenic obesity. The sarcopenia or sarcopenic obesity group had significantly lower handgrip strength than the normal or obesity group (all p < 0.05). In addition, the sarcopenia and sarcopenic obesity groups had significantly lower SPPB scores than the normal group (p < 0.05, respectively). In the multivariate analysis, the sarcopenic obesity group had a significantly higher risk of frailty than the normal group in the multivariate analysis after adjusting for age and gender (OR 4.518, 95%CI 1.218–16.752, p = 0.024). However, sarcopenic obesity was not associated with a higher likelihood of PEW, and sarcopenia imposed a significantly higher risk of PEW (OR 4.272, 95%CI 1.157–15.778, p = 0.029) than that in the normal group after adjusting for confounding factors. Conclusion Sarcopenic obesity was closely associated with frailty compared with the normal condition in HD patients. However, sarcopenic obesity was not associated with a higher likelihood of PEW.

Visual Abstract, Highlights • HMGB1 is a DNA-binding protein associated with nuclear homeostasis and DNA repair. • Decreased nuclear HMGB1 expression is observed in human failing hearts, which is associated with cardiomyocyte hypertrophy and fibrosis. • Cardiac nuclear HMGB1 overexpression ameliorates Ang II–induced pathological cardiac remodeling by inhibiting cardiomyocyte DNA damage and following ataxia telangiectasia mutated activation in mice. • Ataxia telangiectasia mutated inhibitor treatment provided a cardioprotective effect on Ang II–induced cardiac remodeling in mice., Summary High-mobility group box 1 (HMGB1) is a deoxyribonucleic acid (DNA)–binding protein associated with DNA repair. Decreased nuclear HMGB1 expression and increased DNA damage response (DDR) were observed in human failing hearts. DNA damage and DDR as well as cardiac remodeling were suppressed in cardiac-specific HMGB1 overexpression transgenic mice after angiotensin II stimulation as compared with wild-type mice. In vitro, inhibition of HMGB1 increased phosphorylation of extracellular signal-related kinase 1/2 and nuclear factor kappa B, which was rescued by DDR inhibitor treatment. DDR inhibitor treatment provided a cardioprotective effect on angiotensin II–induced cardiac remodeling in mice.

The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.

Alzheimer's disease (AD) is the most common form of dementia and is a progressive neurodegenerative disease that primarily develops in old age. In recent years, it has been reported that early diagnosis of AD and early intervention significantly delays disease progression. Hence, early diagnosis and intervention are emphasized. As a diagnostic index for AD patients, evaluating the complexity of the dependence of the electroencephalography (EEG) signal on the temporal scale of Alzheimer's disease (AD) patients is effective. Multiscale entropy analysis and multifractal analysis have been performed individually, and their usefulness as diagnostic indicators has been confirmed, but the complemental relationship between these analyses, which may enhance diagnostic accuracy, has not been investigated. We hypothesize that combining multiscale entropy and fractal analyses may add another dimension to understanding the alteration of EEG dynamics in AD. In this study, we performed both multiscale entropy and multifractal analyses on EEGs from AD patients and healthy subjects. We found that the classification accuracy was improved using both techniques. These findings suggest that the use of multiscale entropy analysis and multifractal analysis may lead to the development of AD diagnostic tools.

Adult attention-deficit/hyperactivity disorder (ADHD) frequently leads to psychological/social dysfunction if unaddressed. Identifying a reliable biomarker would assist the diagnosis of adult ADHD and ensure that adults with ADHD receive treatment. Pupil diameter can reflect inherent neural activity and deficits of attention or arousal characteristic of ADHD. Furthermore, distinct profiles of the complexity and symmetricity of neural activity are associated with some psychiatric disorders. We hypothesized that analysing the relationship between the size, complexity of temporal patterns, and asymmetricity of pupil diameters will help characterize the nervous systems of adults with ADHD and that an identification method combining these features would ease the diagnosis of adult ADHD. To validate this hypothesis, we evaluated the resting state hippus in adult participants with or without ADHD by examining the pupil diameter and its temporal complexity using sample entropy and the asymmetricity of the left and right pupils using transfer entropy. We found that large pupil diameters and low temporal complexity and symmetry were associated with ADHD. Moreover, the combination of these factors by the classifier enhanced the accuracy of ADHD identification. These findings may contribute to the development of tools to diagnose adult ADHD.

Objective The aim of this study was to examine whether preoperative phase angle (PhA) measured by bioelectrical impedance analysis was associated with a hospital-acquired functional decline in older patients undergoing cardiovascular surgery. Methods This was an observational study of prospectively collected data of 114 patients (>65 y of age) with cardiovascular disease who underwent elective cardiovascular surgery between September 2019 and August 2020. Patients were classified into tertiles based on PhA levels. Factors associated with the occurrence of hospital-acquired functional decline (postoperative recovery to preoperative physical function was not possible) were analyzed using univariate and multivariate analyses. Results Patients in the low PhA group were significantly older than those in the middle and high PhA groups; were predominantly women; had higher New York Heart Association cardiovascular and EuroSCORE severity scores; and had significantly lower levels of body mass index, Geriatric Nutritional Risk Index, hemoglobin, and albumin. There was a significant correlation between PhA and nutrition and physical function. The incidence of hospital-acquired functional decline occurred in 26.3% of all patients, with a significantly higher incidence in patients in the low PhA group. Multivariate analysis showed that PhA was extracted as a factor for the hospital-acquired functional decline in all the models. Conclusions PhA was associated with hospital-acquired functional decline in older patients undergoing cardiovascular surgery. PhA is likely to be a comprehensive indicator of physical health that indicates nutritional status, physical function, and geriatric syndrome (frailty/sarcopenia), and is an important predictor of hospital-acquired functional decline in this group of older patients.

Recently, measuring the complexity of body movements during sleep has been proven as an objective biomarker of various psychiatric disorders. Although sleep problems are common in children with autism spectrum disorder (ASD) and might exacerbate ASD symptoms, their objectivity as a biomarker remains to be established. Therefore, details of body movement complexity during sleep as estimated by actigraphy were investigated in typically developing (TD) children and in children with ASD. Several complexity analyses were applied to raw and thresholded data of actigraphy from 17 TD children and 17 children with ASD. Determinism, irregularity and unpredictability, and long-range temporal correlation were examined respectively using the false nearest neighbor (FNN) algorithm, information-theoretic analyses, and detrended fluctuation analysis (DFA). Although the FNN algorithm did not reveal determinism in body movements, surrogate analyses identified the influence of nonlinear processes on the irregularity and long-range temporal correlation of body movements. Additionally, the irregularity and unpredictability of body movements measured by expanded sample entropy were significantly lower in ASD than in TD children up to two hours after sleep onset and at approximately six hours after sleep onset. This difference was found especially for the high-irregularity period. Through this study, we characterized details of the complexity of body movements during sleep and demonstrated the group difference of body movement complexity across TD children and children with ASD. Complexity analyses of body movements during sleep have provided valuable insights into sleep profiles. Body movement complexity might be useful as a biomarker for ASD.

金沢大学理工研究域フロンティア工学系, Background: Electrical muscle stimulation (EMS) is effective for increasing physical function. However, there is no evidence regarding the effects of EMS on muscle mass and physical function in older adults with dementia. The aim of the present study was to quantify the effects of EMS on muscle mass and balance in older adults with dementia. Methods: A total of 32 participants were randomly assigned to an intervention group (n = 16, age = 89.4 ± 4.8 years) and a control group (n = 16, age = 88.1 ± 5.2 years). Participants in the intervention group underwent a general rehabilitation program (20 min for three days/week) and an EMS intervention (23 min for three days/week) for 23 weeks. Participants in the control group underwent general rehabilitation only. The efficacy of EMS was evaluated by lower limb muscle mass, the Berg Balance Scale (BBS), and the functional independence measure (FIM). Results: Muscle mass was significantly increased in the intervention group after 12 weeks (p = 0.008), but average muscle mass in the control group did not change (p = 0.18). Participants in the control group showed a significant decrease in BBS after 12 weeks (p = 0.007), unlike those in the intervention group. Furthermore, there was a strong correlation between the mini-mental state examination (MMSE) results and the change in muscle mass, the BBS, and the FIM in the control group (p < 0.05). Conclusions: These findings suggest that EMS is a useful intervention for increasing muscle mass and maintaining balance function in older adults with dementia., CC BY 4.0

Nervous systems are designed to become extra sensitive to afferent nociceptive stimuli under certain circumstances such as inflammation and nerve injury. How pain hypersensitivity comes about is key issue in the field since it ultimately results in chronic pain. Central sensitization represents enhanced pain sensitivity due to increased neural signaling within the central nervous system (CNS). Particularly, much evidence indicates that underlying mechanism of central sensitization is associated with the change of spinal neurons. Extracellular signal-regulated kinases have received attention as key molecules in central sensitization. Previously, we revealed the isoform-specific function of extracellular signal-regulated kinase 2 (Erk2) in spinal neurons for central sensitization using mice with Cre-loxP-mediated deletion of Erk2 in the CNS. Still, how extracellular signal-regulated kinase 5 (Erk5) in spinal neurons contributes to central sensitization has not been directly tested, nor is the functional relevance of Erk5 and Erk2 known. Here, we show that Erk5 and Erk2 in the CNS play redundant and/or distinct roles in central sensitization, depending on the plasticity context (cell types, pain types, time, etc.). We used male mice with Erk5 deletion specifically in the CNS and found that Erk5 plays important roles in central sensitization in a formalin-induced inflammatory pain model. Deletion of both Erk2 and Erk5 leads to greater attenuation of central sensitization in this model, compared to deletion of either isoform alone. Conversely, Erk2 but not Erk5 plays important roles in central sensitization in neuropathic pain, a type of chronic pain caused by nerve damage. Our results suggest the elaborate mechanisms of Erk signaling in central sensitization.

Malnutrition is an independent predictor of adverse outcomes in patients with acute coronary syndrome. The controlling nutritional (CONUT) score has been applied to assess nutritional status, and has been reported to be associated with poor prognosis in patients with heart failure. However, the prognostic impact of the CONUT score in patients with acute coronary syndrome (ACS) remains to be elucidated. We evaluated the CONUT score in 196 patients with ACS who underwent percutaneous coronary intervention. We divided the patients into four groups according to CONUT score (undernutrition degree: normal, CONUT 0–1 (reference); mild, CONUT 2–4; moderate, CONUT 5–8; severe, CONUT 9–12). The endpoint of the present study was composite events including all-cause death, acute coronary syndrome, target vessel revascularization, and stroke. The median CONUT score was significantly higher in patients with composite events than in those without events (P = 0.0058). Kaplan–Meier analysis revealed that a significantly higher event rate in patients with severe malnutrition (log-rank test, P = 0.0222). In the multivariate Cox proportional hazards analysis, CONUT score was independently associated with composite events after adjustment for confounding factors (adjusted hazard ratio 1.284, 95% confidence interval 1.126–1.457, P = 0.0003). Higher CONUT scores were associated with unfavorable outcomes in patients with ACS. Malnutrition assessed by the CONUT score may provide valuable prognostic information in patients with ACS.

Objectives: In the field of exercise physiology, there has been great interest in exploring circulating microRNAs (miRs) as potential biomarkers. However, it remains to be determined whether circulating miRs reflect cardiorespiratory fitness. The aim of this study was to investigate the association between circulating levels of specific miRs and cardiorespiratory fitness evaluated by cardiopulmonary exercise testing (CPET) after acute myocardial infarction (MI). Methods: Twenty patients who had had an acute MI were included. All patients underwent CPET in the convalescent phase. Quantitative real-time polymerase chain reaction analyses for miR-181 members (a/b/c) and miR-484 were performed to determine the expression levels in the peripheral blood of the included patients and healthy control subjects (n=5). Results: Post-MI patients showed impaired exercise tolerance and ventilatory efficiency in CPET analysis. Compared with controls, circulating levels of miR-181a and 181c were gradually and significantly elevated through the 1st to 7th days after acute MI, whereas miR-181b and miR-484 were not. Circulating miR levels did not correlate with clinical or echocardiographic parameters. However, circulating levels of miR-181c and miR-484 on the 7th day showed significant positive correlations with the anaerobic threshold and peak oxygen consumption from CPET analysis. Moreover, miR-181c levels were inversely associated with the ventilatory inefficiency index. Patients with high exercise capacity after MI showed significantly higher expressions of circulating miR-181c and miR-484 than those with low exercise capacity. Conclusions: The results of this pilot study suggest that circulating levels of miR-181c and miR-484 after acute MI may be predictive biomarkers of post-MI cardiorespiratory fitness.

Bipolar disorder (BD), which involves mood swings between mania and depression, is associated with multiple relapses during long-term treatment and high suicide and morbidity rates. In BD, the circadian rhythms, which are measured by daily mood scores and actigraphic records, are disturbed. Chronotherapy has emerged as a potential treatment for BD because it stabilizes the disturbed circadian rhythms and improves BD symptoms. Concrete treatments include light therapy and combination therapy (light therapy and drugs). However, some patients have difficulty adjusting to light therapy; inappropriate light and duration of treatment increase risks for inducing mixed states and the emergence of conditions, such as hypomania and autonomic hyperactivation. Therefore, it is important to devise methods for optimizing chronotherapy for BD. We aimed to develop feedback signals for the frontal cortex, which were based on the delayed feedback method as one of the chaos control methods, to stabilize the disturbed circadian rhythms of BD. Concrete procedures of this study are indicated as follows: first, circadian rhythms of BD are reproduced using the frontal cortex and hypothalamus neural system, which has been previously proposed. Second, the delayed feedback signal is developed by using bifurcation analysis. Third, the effect of delayed feedback signal is evaluated by index for complexity, and power spectrum under the condition with/without stochastic noise in feedback term. We found that application of the delayed feedback signal to the frontal cortical neural activity induces the periodic state of circadian rhythms from the disturbed complex and is feasible for treating BD. However, when increasing the influence of noise in feedback term, the stabilizing effect is diminished. In conclusion, we developed a stabilizing method for disturbed circadian rhythms of BD using the circadian neural systems. The present study highlights the potential usefulness of the chaos control method for treating BD.

Background: Exercise-based cardiac rehabilitation (CR) improves health-related quality of life and exercise capacity in patients with heart failure (HF). However, CR efficacy in patients with HF who are elderly, frail, or have HF with preserved ejection fraction remains unclear. We examined whether participation in multidisciplinary outpatient CR is associated with long-term survival and rehospitalization in patients with HF, with subgroup analysis by age, sex, comorbidities, frailty, and HF with preserved ejection fraction. Methods: This multicenter retrospective cohort study was performed in patients hospitalized for acute HF at 15 hospitals in Japan, 2007 to 2016. The primary outcome (composite of all-cause mortality and HF rehospitalization after discharge) and secondary outcomes (all-cause mortality and HF rehospitalization) were analyzed in outpatient CR program participants versus nonparticipants. Results: Of the 3277 patients, 26% (862) participated in outpatient CR. After propensity matching for potential confounders, 1592 patients were included (n=796 pairs), of which 511 had composite outcomes (223 [14%] all-cause deaths and 392 [25%] HF rehospitalizations, median 2.4-year follow-up). Hazard ratios associated with CR participation were 0.77 (95% CI, 0.65–0.92) for composite outcome, 0.67 (95% CI, 0.51–0.87) for all-cause mortality, and 0.82 (95% CI, 0.67–0.99) for HF-related rehospitalization. CR participation was also associated with numerically lower rates of composite outcome in patients with HF with preserved ejection fraction or frail patients. Conclusions: Outpatient CR participation was associated with substantial prognostic benefit in a large HF cohort regardless of age, sex, comorbidities, frailty, and HF with preserved ejection fraction.

Chronotherapy is a treatment for mood disorders, including major depressive disorder, mania, and bipolar disorder (BD). Neurotransmitters associated with the pathology of mood disorders exhibit circadian rhythms. A functional deficit in the neural circuits related to mood disorders disturbs the circadian rhythm; chronotherapy is an intervention that helps resynchronize the patient's biological clock with the periodic daily cycle, leading to amelioration of symptoms. In previous reports, Hadaeghi et al. proposed a non-linear dynamic model composed of the frontal and sensory cortical neural networks and the hypothalamus to explain the relationship between deficits in neural function in the frontal cortex and the disturbed circadian rhythm/mood transitions in BD (hereinafter referred to as the Hadaeghi model). In this model, neural activity in the frontal and sensory lobes exhibits periodic behavior in the healthy state; while in BD, this neural activity is in a state of chaos-chaos intermittency; this temporal departure from the healthy periodic state disturbs the circadian pacemaker in the hypothalamus. In this study, we propose an intervention based on a feedback method called the "reduced region of orbit" (RRO) method to facilitate the transition of the disturbed frontal cortical neural activity underlying BD to healthy periodic activity. Our simulation was based on the Hadaeghi model. We used an RRO feedback signal based on the return-map structure of the simulated frontal and sensory lobes to induce synchronization with a relatively weak periodic signal corresponding to the healthy condition by applying feedback of appropriate strength. The RRO feedback signal induces chaotic resonance, which facilitates the transition to healthy, periodic frontal neural activity, although this synchronization is restricted to a relatively low frequency of the periodic input signal. Additionally, applying an appropriate strength of the RRO feedback signal lowered the amplitude of the periodic input signal required to induce a synchronous state compared with the periodic signal applied alone. In conclusion, through a chaotic-resonance effect induced by the RRO feedback method, the state of the disturbed frontal neural activity characteristic of BD was transformed into a state close to healthy periodic activity by relatively weak periodic perturbations. Thus, RRO feedback-modulated chronotherapy might be an innovative new type of minimally invasive chronotherapy.

Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro, and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

Introduction In the early development of human infants and toddlers, remarkable changes in brain cortical function for auditory processing have been reported. Knowing the maturational trajectory of auditory cortex responses to human voice in typically developing young children is crucial for identifying voice processing abnormalities in children at risk for neurodevelopmental disorders and language impairment. An early prominent positive component in the cerebral auditory response in newborns has been reported in previous electroencephalography and magnetoencephalography (MEG) studies. However, it is not clear whether this prominent component in infants less than 1 year of age corresponds to the auditory P1m component that has been reported in young children over 2 years of age. Methods To test the hypothesis that the early prominent positive component in infants aged 0 years is an immature manifestation of P1m that we previously reported in children over 2 years of age, we performed a longitudinal MEG study that focused on this early component and examined the maturational changes over three years starting from age 0. Five infants participated in this 3‐year longitudinal study. Results This research revealed that the early prominent component in infants aged 3 month corresponded to the auditory P1m component in young children over 2 years old, which we had previously reported to be related to language development and/or autism spectrum disorders. Conclusion Our data revealed the development of the auditory‐evoked field in the left and right hemispheres from 0‐ to 3‐year‐old children. These results contribute to the elucidation of the development of brain functions in infants., We performed a longitudinal magnetoencephalography (MEG) study that focused on auditory early component. The maturational changes over three years starting from age 0 were examined. Our result revealed that the early prominent component in infants aged 3 month corresponded to the auditory P1m component in young children over 2 years old, which we had previously reported to be related to language development and/or autism spectrum disorders.

Autism spectrum disorders (ASD) are characterized by impaired social cognition and communication. In addition to social impairment, individuals with ASD often have intellectual disability. Intelligence is known to influence the phenotypic presentation of ASD. Nevertheless, the relation between intelligence and social reciprocity in people with ASD remains unclear, especially in childhood. To elucidate this relation, we analyzed 56 typically developing children (35 male, 21 female, aged 60–91 months) and 46 children with ASD (35 male, 11 female, aged 60–98 months) from university and affiliated hospitals. Their cognitive function was evaluated using the Kaufman Assessment Battery for Children. Their social cognition was assessed using the Social Responsiveness Scale. We used linear regression models to ascertain whether the associations between intelligence and social cognition of typically developing children and children with ASD are significantly different. Among the children with ASD, scores on the Kaufman Assessment Battery for Children correlated significantly with social cognition, indicating that higher intelligence is associated with better social cognition. For typically developing children, however, no significant correlation was found. One explanation might be that children with ASD fully use general intelligence for successful learning in social cognition, although extensive use of intelligence might not be necessary for TD children. Alternatively, autistic impairment in social cognition can be compensated by intelligence despite a persistent deficit in social cognition. In either case, when using the SRS as a quantitative phenotype measure for ASD, the influence of intelligence must be considered.

Amyotrophic lateral sclerosis (ALS) primarily affects upper and lower motor neurons. Phosphorylated trans-activation response DNA-binding protein of 43 kDa (TDP-43) inclusion bodies are reportedly a pathological hallmark of sporadic ALS. Here, we present an atypical case of sporadic ALS that progressed very slowly, persisted for 19 years, and clinically appeared to only affect the lower motor neurons; however, upper motor neuron degeneration was detected at autopsy. Furthermore, no inclusion bodies positive for phosphorylated TDP-43, ubiquitin, fused in sarcoma, or superoxide dismutase-1 were detected in the central nervous system. We performed exome-sequencing data analysis but found no genetic disorders. This was therefore an unusual case of lower motor neuron-predominant ALS without TDP-43 pathology or known gene-disease associations. We also reviewed autopsied ALS cases that progressed slowly and had no phosphorylated TDP-43 or ubiquitin-positive inclusions and present the clinicopathological features of such cases. Based on these results, there may be a sporadic ALS subgroup that progresses slowly and shows no accumulation of phosphorylated TDP-43.

Social recognition is the sensitive domains of complex behavior critical for identification, interpretation and storage of socially meaningful information. Social recognition develops throughout childhood and adolescent, and is affected in a wide variety of psychiatric disorders. Recently, new data appeared on the molecular mechanisms of these processes, particularly, the excitatory-inhibitory (E/I) ratio which is modified during development, and then E/I balance is established in the adult brain. While E/I imbalance has been proposed as a mechanism for schizophrenia, it also seems to be the common mechanism in autism spectrum disorder (ASD). In addition, there is a strong suggestion that the oxytocinergic system is related to GABA-mediated E/I control in the context of brain socialization. In this review, we attempt to summarize the underpinning molecular mechanisms of E/I balance and its imbalance, and related biomarkers in the brain in healthiness and pathology. In addition, because there are increasing interest on oxytocin in the social neuroscience field, we will pay intensive attention to the role of oxytocin in maintaining E/I balance from the viewpoint of its effects on improving social impairment in psychiatric diseases, especially in ASD.

Pulse pressure (PP) is a risk factor for cardiovascular diseases and is associated with increased afterload and myocardial oxygen demand. Brain natriuretic peptide (BNP) and heart‐type fatty acid–binding protein (H‐FABP) are known as biomarkers indicating ventricular wall stress and silent myocardial damage. However, the association between PP and ventricular wall stress and silent myocardial damage in the general population is unclear. The authors enrolled 3504 patients who participated in a community‐based annual health check. Serum levels of BNP and H‐FABP were measured as markers of ventricular wall stress and silent myocardial damage. Patients were divided into four groups according to the quartiles of PP. Patients in the highest PP group showed higher serum BNP and H‐FABP levels than that of the other groups. Multivariate logistic analysis showed that high PP was independently associated with ventricular wall stress and silent myocardial damage on the basis of BNP and H‐FABP levels. Compared with systolic blood pressure, diastolic blood pressure, and mean blood pressure, PP was superior in predicting ventricular wall stress and silent myocardial damage evaluated according to BNP and H‐FABP levels, which was reflected by the receiver operating characteristic analysis. Screening of healthy patients revealed that high PP was related to high BNP and H‐FABP levels, suggesting that an asymptomatic general population with high PP may be exposed to ventricular wall stress and myocardial damage and might be susceptible to silent heart failure.

Background: Frailty and sarcopenia are age-related morbid states, and a low body mass index (BMI) is a characteristic of frailty and cachexia. However, no common index for assessing these three muscle wasting states is available, making it difficult to understand the relationship among them. Peak oxygen uptake (peak VO 2 ), an index of life expectancy, may be a useful common index. Therefore, this study aimed to investigate the relationship among sarcopenia, frailty, and cachexia using age, BMI, and peak VO 2 . Methods: Participants were 175 Japanese community dwelling older adults (58 men, 117 women; 77.6 years). We assessed biochemical, physiological, and physical factors, and symptoms associated with frailty, and cachexia. Peak VO 2 was assessed with a cardiopulmonary exercise test. Participants were classified into five groups: robust, pre-frail, frail, sarcopenia, and cachexia. We compared the groups by age, BMI, and peakVO 2 with average values and 95% confidence intervals (CIs). Results: 17% (n=30) of participants were classified as robust, 40% (n=70) as pre-frail, 12% (n=21) as sarcopenia, 25% (n=44) as frail, and 6% (n=10) as cachexia. Significant differences were found in age (robust vs. frail, pre-frail vs. frail), BMI (robust vs. cachexia, pre-frail vs. cachexia, frail vs. cachexia), and peak VO 2 (robust vs. frail, robust vs. cachexia, pre-frail vs. cachexia) with average values and 95% CIs. Three dimensions among age, BMI and peak VO 2 revealed two trajectories (from robust to frailty via pre-frailty, and from robust to cachexia via sarcopenia) among muscle wasting diseases. Conclusions: This study revealed two trajectories among muscle wasting diseases.

Aims The association of vascular dysfunction and amyloid beta deposition attracted attentions for its relationship with cognitive decline. Previous studies show the correlation between the declined cardiac function and the cognitive impairment. In the present study, we analysed the association between cognitive functions and cardiac parameters in community-dwelling people with preserved ejection fraction without heart failure. Methods and results Subjects were 108 Japanese community-dwelling middle-aged and older adults with preserved ejection fraction (25 men and 83 women; mean age 74.7 years). Cardiac functional parameters at rest were assessed with B-type natriuretic peptide and echocardiography. The cardiopulmonary exercise test was used to test these parameters during exercise. Cognitive function was assessed with the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Other indices were assessed biochemically, physiologically, and physically. There were significant correlations between MoCA-J score and age (r = -0.388), peak oxygen uptake (VO2 , r = 0.201), peak VO2 /heart rate (HR, r = 0.243), peak VO2 /weight (r = 0.244), peak metabolic equivalents (r = 0.244), usual walking speed (r = -0.200), and the Timed Up and Go test (r = -0.230). Multiple linear regression analysis showed peak VO2 /HR was an independent determinant of MoCA-J score after adjusting for potential confounders (B = 0.424). After 6 months of exercise training with 64 subjects, we found that the per cent change of peak VO2 /HR was related to the per cent change of MoCA-J score (r = 0.296). Conclusions These results suggested that peak VO2 /HR (an index of stroke volume at peak exercise) might be associated with cognitive impairment based on the vascular cascade hypothesis.

Key Clinical Message Delayed posthypoxic leukoencephalopathy (DPHL), a demyelinating syndrome, can easily be misdiagnosed as a psychiatric condition. Our case study shows that magnetic resonance imaging is highly useful for an early diagnosis of DPHL and that vascular endothelial growth factor might be a supplementary biomarker for the early detection of DPHL.

Objective To determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). Methods We recruited 59 patients with MSA and determined the predictors of a decline in the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. Results The MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. Conclusions Impairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter.

Background The anterior cruciate ligament (ACL) is responsible for braking forward movement of the tibia relative to the femur and for tibial rotation. After ACL injury, this braking performance deteriorates, inducing abnormal joint movement. The purpose of this study was to clarify the effects of controlled abnormal joint movement on the molecular biological response in intra-articular tissues during the acute phase of ACL injury. Methods Eighty-four mature Wistar male rats were randomly assigned to a controlled abnormal movement (CAM) group, an ACL-transection (ACL-T) group, a sham-operated group, or an intact group. The ACL was completely transected at its midportion in the ACL-T and CAM groups, and a nylon suture was used to control abnormal tibial translation in the CAM group. The sham-operated group underwent skin and joint capsule incisions and tibial drilling without ACL transection. Animals were not restricted activity until sacrifice 1, 3, or 5 days after surgery for histological and gene expression assessments. Acute-phase inflammation requires an important balance between degenerative and biosynthetic processes and is controlled by the activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Both types of gene were analyzed in this study. Results The ACL-T and CAM groups exhibited cleavage of the ACL at all time points. However, for the CAM group, the gap in the ligament stump was extremely small, and fibroblast proliferation was observed around the stump. Relative to the ACL-T group, the CAM group demonstrated significantly lower expression of MMP-13 mRNA and a lower MMP-13/TIMP-1 ratio on days 1 and 5 in the ACL, the medial meniscus and the lateral meniscus. The expression of TIMP-1 mRNA was not significantly different between the ACL-T and CAM groups. Conclusions The study results suggested that controlling abnormal movement inhibited the inflammatory reaction in intra-articular tissues after ACL injury. This reaction was down-regulated in intra-articular tissues in the CAM group. Abnormal joint control caused prolonged inflammation and inhibited remodeling during the acute phase of ACL rupture.

Background: Hand grip strength and peak oxygen uptake (VO2) are important components of frailty. However, the relationship between these two variables among community-dwelling elderly people is still unclear. The present study aimed to investigate this relationship. Methods: Participants were 190 Japanese community-dwelling elderly outpatients (61 men and 129 women, mean age 78.0 years). Hand grip strength of participants’ dominant hand was measured using a Smedley-type hand dynamometer. Peak VO2 levels were assessed with a cardiopulmonary exercise test. Skeletal muscle mass index (SMI) and usual walking speed were assessed physiologically and physically. Sample size was calculated using G*Power 3.1.9.2. Results: There were significant correlations between hand grip strength and age (r = −0.22), peak VO2 (r = 0.40), SMI (r = 0.51), and usual walking speed (r = 0.29). There were significant differences in age, peak VO2 and SMI after participants were divided into normal and low hand grip strength groups according to the Asian Working Group for Sarcopenia threshold, whether both sexes were combined or considered separately. Multiple logistic regression analysis showed that peak VO2, SMI and age were independent determinants of hand grip strength after adjusting for potential confounders (Exp(B) = 0.871; 0.475; 1.065). Longitudinal analysis after 6 months of exercise training showed the percentage of change in hand grip strength and peak VO2 were correlated positively (r = 0.22) for 92 participants. Conclusion: Peak VO2 is independently associated with hand grip strength among community-dwelling elderly outpatients.

Background Peripheral artery disease (PAD) is an athero-occlusive disease and a known risk factor for cardiovascular events. The controlling nutritional status (CONUT) score and geriatric nutritional risk index (GNRI) are objective tools for evaluating malnutrition and are reportedly associated with poor clinical outcomes in patients with fatal diseases. However, the effect of malnutrition on the clinical outcomes in patients with PAD remains unclear.Methods and Results:We enrolled 357 patients with PAD who underwent endovascular therapy. Malnutrition was diagnosed by CONUT score and GNRI as in previous reports. During a median follow-up period of 1,071 days, there were 67 major adverse cardiovascular and leg events (MACLEs). The CONUT score- and GNRI-based malnutrition statuses were identified in 56% and 46% of the patients, respectively. Proportion of malnutrition increased with advancing Fontaine class. The multivariate Cox proportional hazard regression analysis demonstrated that both the CONUT score- and GNRI-based malnutrition status was an independent predictor of MACLEs. The Kaplan-Meier analysis demonstrated that the MACLE ratio increased with deteriorating malnutrition. Finally, the addition of the CONUT score or GNRI to the known risk factors significantly improved the net reclassification index and integrated discrimination index. Conclusions Malnutrition was common and closely associated with the clinical outcomes in patients with PAD, indicating that it is a novel therapeutic target in the management of these patients.

Objective The “dysconnection hypothesis” has been proposed as a core neural basis for schizophrenia. Although growing neuroimaging-based evidence suggests atypical functional connectivity in patients with schizophrenia, the results are inconsistent and the effects of antipsychotic treatment remain elusive. Methods We performed resting-state electroencephalography (EEG) in 21 drug-naive patients with schizophrenia (14 patients were re-evaluated after administration of antipsychotic treatment) and 31 age-matched healthy control subjects. We estimated functional connectivity, using the phase lag index (PLI), which captures the true synchronization of EEG signals. Results The patients had reduced functional connectivity of the beta band across frontal regions and of the gamma band throughout the scalp when compared to the control subjects. In the schizophrenia group, symptom severity did not seem associated with functional connectivity. Antipsychotic treatment led to no alterations in functional connectivity. Conclusions Synchronous activity within and across brain areas over multiple frequencies reflect the integration of various types of information processing. Our findings of abnormal frequency- and region-specific functional connectivity patterns may provide further insight into the “dysconnection hypothesis” of schizophrenia. Significance The PLI may serve as a useful measure for the characterization and understanding of the intrinsic pathophysiological mechanisms of schizophrenia, and as a reliable biomarker for this disease.

The relationship between motor unit (MU) firing behavior and the severity of neurodegeneration in Parkinson’s disease (PD) is not clear. This study aimed to elucidate the association between degeneration with dopaminergic pathways and MU firing behavior in people with PD. Fourteen females with PD (age, 72.6 ± 7.2 years, disease duration, 3.5 ± 2.1 years) were enrolled in this study. All participants performed a submaximal, isometric knee extension ramp-up contraction from 0% to 80% of their maximal voluntary contraction strength. We used high-density surface electromyography with 64 electrodes to record the muscle activity of the vastus lateralis muscle and decomposed the signals with the convolution kernel compensation technique to extract the signals of individual MUs. We calculated the degree of degeneration of the central lesion-specific binding ratio by dopamine transporter single-photon emission computed tomography. The primary, novel results were as follows: (1) moderate-to-strong correlations were observed between the degree of degeneration of the central lesion and MU firing behavior, (2) a moderate correlation was observed between clinical measures of disease severity and MU firing behavior, and (3) the methods of predicting central nervous system degeneration from MU firing behavior abnormalities had a high detection accuracy with an area under the curve &gt, 0.83. These findings suggest that abnormalities in MU activity can be used to predict central nervous system degeneration following PD.

Liver abnormalities have a strong impact on clinical outcomes in patients with heart failure (HF), and are known as cardio-hepatic syndrome. The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has been developed to identify liver fibrosis in patients with NAFLD. It remains to be determined whether NFS is associated with cardiovascular prognosis in patients with chronic heart failure (CHF). We calculated NFS in 516 patients with CHF admitted to our hospital. The clinical endpoints were deaths due to progressive HF, myocardial infarction, stroke, and sudden cardiac death, and rehospitalization for worsening HF. There were 173 cardiovascular events noted during a median follow-up of 464 days. Patients with cardiovascular events showed a higher NFS as compared with those without. We divided the patients into four groups according to quartiles of NFS. The proportion of New York Heart Association functional class III/IV and serum brain natriuretic peptide levels were increased with increasing NFS. Kaplan-Meier analysis revealed that cardiovascular event rate was increased with increasing NFS in patients with CHF. In multivariate Cox proportional hazards analysis, NFS was independently associated with cardiovascular events after adjustment for confounding factors. Elevated NFS was associated with unfavorable outcomes in patients with CHF. Liver fibrosis assessed by NFS may provide valuable prognostic information in patients with CHF.

Parkinson's disease (PD) related decreases in muscle strength may result from both central and peripheral factors. However, the effect of PD on the neuromuscular system, such as motor unit activation properties, remains unclear. The purpose of the present study was to compare the spatial distribution pattern of electromyographic activity during sustained contractions in healthy subjects and PD patients. Twenty-five female PD patients and 25 healthy age-matched female control subjects performed ramp submaximal contractions during an isometric knee extension from 20% to 80% of the maximal voluntary contraction (MVC). To evaluate alterations in the spatial electromyography (EMG) potential distribution, normalized root mean square (RMS), modified entropy, coefficient of variation, and correlation coefficients were calculated from multi-channel surface electromyography at 10% force increments. The comparison between PD and healthy subjects revealed that, during increased force exertions, PD patients exhibited less change in normalized RMS, modified entropy, coefficient of variation, and pattern of spatial EMG distribution. These data showed that the heterogeneity and the changes in the activation pattern are smaller in the PD patients than in healthy subjects. This finding may be associated with central adaptation and/or peripheral changes in PD patients.

[Purpose] The purpose of this study is to evaluate the applicability of the calf circumference as a tool for screening sarcopenia. [Subjects and Methods] One hundred sixteen community-dwelling elderly females were enrolled. Calf circumference of the dominant leg was measured using a plastic measuring tape. Subjects were divided into 3 groups based on body mass index (BMI); subjects with the values for BMI