Incidence of Hospitalization-Associated Disability in Older Patients With Heart Failure.

BACKGROUND: This study determined the incidence of hospitalization-associated disability (HAD) and its characteristics in older patients with heart failure in Japan.Methods and Results: Ninety-six institutions participated in this nationwide multicenter registry study (J-Proof HF). From December 2020 to March 2022, consecutive heart failure patients aged ≥65 years who were prescribed physical rehabilitation during hospitalization were enrolled. Of the 9,403 patients enrolled (median age 83.0 years, 50.9% male), 3,488 (37.1%) had HAD. Compared with the non-HAD group, the HAD group was older and had higher rates of hypertension, chronic kidney disease, and cerebrovascular disease comorbidity. The HAD group also had a significantly lower Barthel Index score and a significantly higher Kihon checklist score before admission. Of the 9,403 patients, 2,158 (23.0%) had a preadmission Barthel Index score of <85 points. Binomial logistic analysis revealed that age and preadmission Kihon checklist score were associated with HAD in patients with a preadmission Barthel Index score of ≥85, compared with New York Heart Association functional classification and preadmission cognitive decline in those with a Barthel Index score <85. CONCLUSIONS: This nationwide registry survey found that 37.1% of older patients with HF had HAD and that these patients are indicated for convalescent rehabilitation. Further widespread implementation of rehabilitation for older patients with heart failure is expected in Japan.

Dual-MEG interbrain synchronization during turn-taking verbal interactions between mothers and children.

Verbal interaction and imitation are essential for language learning and development in young children. However, it is unclear how mother-child dyads synchronize oscillatory neural activity at the cortical level in turn-based speech interactions. Our study investigated interbrain synchrony in mother-child pairs during a turn-taking paradigm of verbal imitation. A dual-MEG (magnetoencephalography) setup was used to measure brain activity from interactive mother-child pairs simultaneously. Interpersonal neural synchronization was compared between socially interactive and noninteractive tasks (passive listening to pure tones). Interbrain networks showed increased synchronization during the socially interactive compared to noninteractive conditions in the theta and alpha bands. Enhanced interpersonal brain synchrony was observed in the right angular gyrus, right triangular, and left opercular parts of the inferior frontal gyrus. Moreover, these parietal and frontal regions appear to be the cortical hubs exhibiting a high number of interbrain connections. These cortical areas could serve as a neural marker for the interactive component in verbal social communication. The present study is the first to investigate mother-child interbrain neural synchronization during verbal social interactions using a dual-MEG setup. Our results advance our understanding of turn-taking during verbal interaction between mother-child dyads and suggest a role for social "gating" in language learning.

Effect of in-patient cardiac rehabilitation at rehabilitation hospital for cardiology patients: two-center trial.

The effectiveness of cardiac rehabilitation (CR) in patients with cardiovascular disease requiring continuous CR from an acute care hospital to a convalescent rehabilitation hospital is unknown. Therefore, we compared the effect of CR in a rehabilitation hospital for patients with cardiovascular disease with that of those who underwent cardiovascular surgery. Sixty-nine consecutive patients were admitted to two rehabilitation hospitals for CR. Patients were classified by primary disease into two groups: patients with cardiovascular disease (cardiology group, 26 patients) and patients who underwent cardiovascular surgery (surgery group, 43 patients). Clinical information, physical function, cognitive function, activities of daily living (ADL), quality of life (QOL), amount of CR, and length of hospital stay were compared between the two groups. Compared with clinical features, age was significantly higher in the cardiology group (P < 0.001), and the preadmission Barthel index was significantly lower in the cardiology group (P = 0.025). Physical function at the time of transfer was significantly lower in the cardiology group than in the surgery group for the short physical performance battery (P < 0.001), gait speed (P = 0.005), and 6-min walking distance (P = 0.042). No significant difference was found in the amount of CR performed or the length of hospital stay, and no interaction effects were observed in improvements in physical function, exercise tolerance, or QOL. In conclusion, in rehabilitation hospitals, patients with cardiovascular disease were older, had lower preadmission ADL, and had lower a physical function at transfer than those who underwent cardiovascular surgery, but CR improved physical function and QOL to the same extent. The results suggest that the recovery of patients with cardiovascular disease may be similar to those who undergo cardiovascular surgery.

Validity Verification of Human Pose-Tracking Algorithms for Gait Analysis Capability.

Two-dimensional (2D) clinical gait analysis systems are more affordable and portable than contemporary three-dimensional (3D) clinical models. Using the Vicon 3D motion capture system as the standard, we evaluated the internal statistics of the Imasen and open-source OpenPose gait measurement systems, both designed for 2D input, to validate their output based on the similarity of results and the legitimacy of their inner statistical processes. We measured time factors, distance factors, and joint angles of the hip and knee joints in the sagittal plane while varying speeds and gaits during level walking in three in-person walking experiments under normal, maximum-speed, and tandem scenarios. The intraclass correlation coefficients of the 2D models were greater than 0.769 for all gait parameters compared with those of Vicon, except for some knee joint angles. The relative agreement was excellent for the time-distance gait parameter and moderate-to-excellent for each gait motion contraction range, except for hip joint angles. The time-distance gait parameter was high for Cronbach's alpha coefficients of 0.899-0.993 but low for 0.298-0.971. Correlation coefficients were greater than 0.571 for time-distance gait parameters but lower for joint angle parameters, particularly hip joint angles. Our study elucidates areas in which to improve 2D models for their widespread clinical application.

Effect of Addition of Tannin Extract from Underutilized Resources on Allergenic Proteins, Color and Textural Properties of Egg White Gels.

Tannins, present in numerous plants, exhibit a binding affinity for proteins. In this study, we aimed to exploit this property to reduce the concentration of allergenic egg white proteins. Tannins were extracted, using hot water, from the lyophilized powder of underutilized resources, such as chestnut inner skin (CIS), young persimmon fruit (YPF), and bayberry leaves (BBLs). These extracts were then incorporated into an egg white solution (EWS) to generate an egg white gel (EWG). Allergen reduction efficacy was assessed using electrophoresis and ELISA. Our findings revealed a substantial reduction in allergenic proteins across all EWGs containing a 50% tannin extract. Notably, CIS and BBL exhibited exceptional efficacy in reducing low allergen levels. The addition of tannin extract resulted in an increase in the total polyphenol content of the EWG, with the order of effectiveness being CIS > YPF > BBL. Minimal color alteration was observed in the BBL-infused EWG compared to the other sources. Additionally, the introduction of tannin extract heightened the hardness stress, with BBL demonstrating the most significant effect, followed by CIS and YPF. In conclusion, incorporating tannin extract during EWG preparation was found to decrease the concentration of allergenic proteins while enhancing antioxidant properties and hardness stress, with BBL being particularly effective in preventing color changes in EWG.

Apolipoprotein E genotype-dependent accumulation of amyloid ß in APP-knock-in mouse model of Alzheimer's disease.

Apolipoprotein E4 (APOE4), the strongest risk factor for late-onset Alzheimer's disease (AD), has been revealed to cause greater accumulation of extracellular amyloid ß (Aß) aggregates than does APOE3 in traditional transgenic mouse models of AD. However, concerns that the overexpression paradigm might have affected the phenotype remain. Amyloid precursor protein (APP)-knock-in (KI) mice, incorporating APP mutations associated with AD development, offer an alternative approach for overproducing pathogenic Aß without needing overexpression of APP. Here, we present the results of comprehensive analyses of pathological and biochemical traits in the brains of APP-KI mice harboring APP-associated familial AD mutations (APPNL-G-F/NL-G-F mice) crossed with human APOE-KI mice. Immunohistochemical and biochemical analyses revealed the APOE genotype-dependent increase in Aß pathology and glial activation, which was evident within 8 months in the mouse model. These results suggested that this mouse model may be valuable for investigating APOE pathobiology within a reasonable experimental time frame. Thus, this model can be considered in investigating the interaction between APOE and Aß in vivo, which may not be addressed appropriately by using other transgenic mouse models.

Oral appliance therapy for obstructive sleep apnea in multiple system atrophy with floppy epiglottis: a case series of three patients.

PURPOSE: A recent study demonstrated that continuous positive airway pressure (CPAP) may exacerbate obstructive sleep apnea (OSA) in patients with multiple system atrophy (MSA) and a floppy epiglottis (FE) as the CPAP promotes downward displacement of the epiglottis into the laryngeal inlet. In this case series, we examined the effectiveness of an oral appliance (OA) for treating OSA in three patients with MSA and an FE. METHODS: Patients with MSA were demonstrated to have an FE on fiberoptic laryngoscopy under sedation using intravenous propofol. The therapeutic intervention was fitting an OA. Polysomnography (PSG) was performed subsequently with the OA in place. RESULTS: In three patients with MSA, some parameters used to assess the severity of OSA improved with an OA. Both apnea-hypopnea index (AHI) and arousal index (ArI) decreased while wearing the OA in two cases while in the third case, apnea index (AI) and cumulative time at peripheral oxygen saturation (SpO2) below 90% (CT90) decreased, but AHI and ArI increased. The only side effects were transient TMJ discomfort, masseter muscle pain, and tooth discomfort. CONCLUSION: OA therapy using a two-piece type mandibular advancement device (MAD) may be a useful treatment intervention for patients with OSA who have MSA and FE.

Corticobasal syndrome mimicking Foix-Chavany-Marie syndrome with suggested 4-repeat tauopathy by tau PET.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative disease diagnosed based on clinical manifestations such as asymmetrical parkinsonism, limb apraxia, and speech and language impairment. The background pathology of CBS is commonly a variety of proteinopathies, but association with cerebrovascular disease has also been reported. Foix-Chavany-Marie syndrome (FCMS) is a rare neurological disorder characterized by facio-pharyngo-glossal diplegia with automatic-voluntary movement dissociation presenting with bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles. FCMS is commonly attributable to stroke. Transactive response DNA binding protein of 43 kD (TDP-43) proteinopathy is also known as the pathological background of FCMS, while the pathological background of the majority of CBS cases consists of diverse tauopathies instead of TDP-43 proteinopathy. In this report, we describe a case mimicking FCMS that was finally diagnosed as CBS with suggested 4-repeat tauopathy. CASE PRESENTATION: A 68-year-old female started experiencing difficulty speaking followed by difficulty writing, and especially texting, several years before her visit. Her impairment had been gradually worsening, and she came to our hospital. On neurological examination, she demonstrated the facial apraxia, frontal lobe dysfunction, and upper motor neuron signs. She presented some characteristics suggestive of FCMS. Her symptoms exhibited rapid progression and myoclonus, parkinsonism, and left-side dominant cortical sensory deficit occurred, resulting in the fulfillment of diagnostic criteria for CBS after 9 months. Tau PET imaging displayed notable ligand uptake in the brainstem, subthalamic nuclei, basal ganglia, and bilateral subcortical frontal lobe, suggesting that her pathological background was 4-repeat tauopathy. As a result of her progressive dysphagia, she became unable to eat and passed away after 12 months. CONCLUSION: We hereby present an atypical case of CBS showing clinical features mimicking FCMS at first presentation. TDP-43 proteinopathy was suspected based on the clinical symptoms in the early stages of the disease; however, the clinical course and imaging findings including tau PET suggested that her pathological background was 4-repeat tauopathy.

V180I genetic Creutzfeldt-Jakob disease: Severe degeneration of the inferior olivary nucleus in an autopsied patient with identification of the M2T prion strain.

Genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation (V180I gCJD) is the most common type of gCJD in Japan, characterized by an older age at onset, slower progression, and moderate to severe cortical degeneration with spongiform changes and sparing of the brainstem and cerebellum. Degeneration of the inferior olivary nucleus (IO) is rarely observed in patients with CJD but is known to occur in fatal familial insomnia (FFI) and MM2-thalamic-type sporadic CJD (sCJD-MM2T) involving type 2 prion protein (M2T prion). Here we report on an 81-year-old Japanese woman who initially developed depressive symptoms followed by progressive cognitive impairment, myoclonus, and hallucinations and died after a clinical course of 23 months. Insomnia was not evident. Genetic analysis of the prion protein (PrP) identified a V180I mutation with methionine/valine heterozygosity at codon 129. Pathologic analysis demonstrated extensive spongiform degeneration, neuronal loss in the cortices, and weak synaptic-type PrP deposition. Except for IO degeneration, the clinicopathologic features and Western blotting PrP band pattern were compatible with those of previously reported V180I gCJD cases. Quantitative analysis revealed that the neuronal density of the IO, especially in the dorsal area, was considerably reduced to the same extent as that of a patient with sCJD-MM2T but preserved in other patients with V180I gCJD and sCJD-MM1 (this patient, 2.3 ± 0.53/mm2 ; a patient with sCJD-MM2T, 4.2 ± 2; a patient with V180I gCJD, 60.5 ± 9.3; and a patient with sCJD-MM1, 84.5 ± 17.9). Use of the protein misfolding cyclic amplification (PMCA) method confirmed the presence of the M2T prion strain, suggesting that the latter might be associated with IO degeneration in V180I gCJD. Autopsy studies are necessary to better understand the nature of CJD, since even if patients present with the common clinical picture, pathologic analysis might provide new insights, as was the case here.

Association between hospital-acquired functional decline and 2-year readmission or mortality after cardiac surgery in older patients: a multicenter, prospective cohort study.

BACKGROUND: Hospital-acquired functional decline (HAFD) is a new predictor of poor prognosis in hospitalized older patients. AIMS: We aimed to assess the impact of HAFD on the prognosis of older cardiac surgical patients 2 years after discharge. METHODS: This multicenter prospective cohort study assessed 293 patients with cardiac disease aged ≥ 65 years who underwent cardiac surgery at 7 Japanese hospitals between June 2017 and June 2018. The primary endpoint was the composite outcome of cardiovascular-related readmission and all-cause mortality 2 years after discharge. HAFD was assessed using the total Short Physical Performance Battery at hospital discharge. RESULTS: The primary outcome was observed in 17.3% of the 254 included patients, and HAFD was significantly associated with the primary outcome. Female sex (hazard ratio [HR], 2.451; 95% confidence interval [CI] 1.232-4.878; P = 0.011), hemoglobin level (HR, 0.839; 95% CI 0.705-0.997; P = 0.046), preoperative frailty (HR, 2.391; 95% CI 1.029-5.556; P = 0.043), and HAFD (HR, 2.589; 95% CI 1.122-5.976; P = 0.026) were independently associated with the primary outcome. The incidence rate of HAFD was 22%, with female sex (odds ratio [OR], 1.912; 95% CI 1.049-3.485; P = 0.034), chronic obstructive pulmonary disease (OR, 3.958; 95% CI 1.413-11.086; P = 0.009), and the time interval (days) between surgery and the start of ambulation (OR, 1.260, 95% CI 1.057-1.502; P = 0.010) identified as significant factors. DISCUSSION: HAFD was found to be an independent prognostic determinant of the primary outcome 2 years after discharge. CONCLUSION: HAFD prevention should be prioritized in the hospital care of older cardiac surgery patients.

Knockdown of optineurin controls C2C12 myoblast differentiation via regulating myogenin and MyoD expressions.

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.

Asymmetric Complexity in a Pupil Control Model With Laterally Imbalanced Neural Activity in the Locus Coeruleus: A Potential Biomarker for Attention-Deficit/Hyperactivity Disorder.

Locus coeruleus (LC) overactivity, especially in the right hemisphere, is a recognized pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and may be related to inattention. LC activity synchronizes with the kinetics of the pupil diameter and reflects neural activity related to cognitive functions such as attention and arousal. Recent studies highlight the importance of the complexity of the temporal patterns of pupil diameter. Moreover, asymmetrical pupil diameter, which correlates with the severity of inattention, impulsivity, and hyperactivity in ADHD, might be attributed to a left-right imbalance in LC activity. We recently constructed a computational model of pupil diameter based on the newly discovered contralateral projection from the LC to the Edinger-Westphal nucleus (EWN), which demonstrated mechanisms for the complex temporal patterns of pupil kinetics; however, it remains unclear how LC overactivity and its asymmetry affect pupil diameter. We hypothesized that a neural model of pupil diameter control featuring left-right differences in LC activity and projections onto two opponent sides may clarify the role of pupil behavior in ADHD studies. Therefore, we developed a pupil diameter control model reflecting LC overactivity in the right hemisphere by incorporating a contralateral projection from the LC to EWN and evaluated the complexity of the temporal patterns of pupil diameter generated by the model. Upon comparisons with experimentally measured pupil diameters in adult patients with ADHD, the parameter region of interest of the neural model was estimated, which was a region in the two-dimensional plot of complexity versus left-side LC baseline activity and that of the right. A region resulting in relatively high right-side complexity, which corresponded to the pathophysiological indexes, was identified. We anticipate that the discovery of lateralization of complexity in pupil diameter fluctuations will facilitate the development of biomarkers for accurate diagnosis of ADHD.

Web Portals for Patients With Chronic Diseases: Scoping Review of the Functional Features and Theoretical Frameworks of Telerehabilitation Platforms.

BACKGROUND: The COVID-19 pandemic has required an increased need for rehabilitation activities applicable to patients with chronic diseases. Telerehabilitation has several advantages, including reducing clinic visits by patients vulnerable to infectious diseases. Digital platforms are often used to assist rehabilitation services for patients in remote settings. Although web portals for medical use have existed for years, the technology in telerehabilitation remains a novel method. OBJECTIVE: This scoping review investigated the functional features and theoretical approaches of web portals developed for telerehabilitation in patients with chronic diseases. METHODS: PubMed and Web of Science were reviewed to identify articles associated with telerehabilitation. Of the 477 nonduplicate articles reviewed, 35 involving 14 portals were retrieved for the scoping review. The functional features, targeted diseases, and theoretical approaches of these portals were studied. RESULTS: The 14 portals targeted patients with chronic obstructive pulmonary disease, cardiovascular, osteoarthritis, multiple sclerosis, cystic fibrosis diseases, and stroke and breast cancer survivors. Monitoring/data tracking and communication functions were the most common, followed by exercise instructions and diary/self-report features. Several theoretical approaches, behavior change techniques, and motivational techniques were found to be utilized. CONCLUSIONS: The web portals could unify and display multiple types of data and effectively provide various types of information. Asynchronous correspondence was more favorable than synchronous, real-time interactions. Data acquisition often required assistance from other digital tools. Various functions with patient-centered principles, behavior change strategies, and motivational techniques were observed for better support shifting to a healthier lifestyle. These findings suggested that web portals for telerehabilitation not only provided entrance into rehabilitation programs but also reinforced participant-centered treatment, adherence to rehabilitation, and lifestyle changes over time.

Laterality of the activation of the vastus lateralis muscle in females with Parkinson's disease during the medication state compared with healthy controls.

The aim of this study was to quantify the laterality of motor unit (MU) activation properties in people with Parkinson's disease (PD) during force production (low- to high-intensity contraction) using high-density surface electromyography (HD-SEMG). Sixteen females with PD (age = 69.9 ± 7.6 years, disease duration = 4.9 ± 5.1 years) and 14 healthy female subjects (age = 68.6 ± 3.6 years) were enrolled in the study and performed submaximal ramp-up contractions during isometric knee extension. HD-SEMG signals were recorded from both vastus lateralis muscles. We calculated the level of heterogeneity in the spatial distribution patterns of the HD-SEMG signals and determined the modified entropy, coefficient of variation of the root mean square (RMS), and correlation coefficient to evaluate MU activation properties. Pearson's correlation coefficients were calculated to examine the relationships between disease severity and the RMS and EMG variables. The RMS value and heterogeneity were significantly higher and lower on the more-affected side in people with PD than on the other side in people with PD or either side in control subjects (p < 0.05). People with PD exhibited the temporal changes of spatial MUs activation properties showed significant laterality when compared to healthy control subjects not only in the low-intensity contractions but also in high-intensity contraction. Moderate-to-strong correlations were observed between disease severity and RMS and EMG variables in people with PD (r > 0.6, p < 0.001). We compared the laterality of MU activation properties between the people with PD and the control subjects. These findings suggest that people with PD have asymmetrical MU activation properties, regardless of the magnitude of force production.

Multidomain Frailty as a Therapeutic Target in Elderly Patients with Heart Failure.

Heart failure and frailty share aging as a strong risk factor. The prevalence of frailty has been shown to be particularly high in elderly patients with heart failure. Moreover, it is important not to confine frailty to physical aspects. Rather, it should be considered to consist of multiple domains, including physical disability, psychiatric disorders, cognitive impairment, depression, and social disconnection. Development of interventions that can improve frailty domains are not well established, although observational studies have evaluated the association of various frailty domains and their prognostic impact. Some interventions, including resistance exercise, functional exercise, and respiratory muscle training have been demonstrated to hold potential for improving physical frailty. In terms of cognitive dysfunction, previous studies have demonstrated that exercise therapy is also effective for cognitive dysfunction. The social domain of frailty is one of the least investigated domains, particularly in patients with heart failure. However, heart failure is also strongly associated with physical frailty and cognitive impairment and has a poor prognosis in old patients. The prevalence of social frailty in elderly patients who need hospitalization due to heart failure is higher than previously thought. Very few studies have tested interventions targeting social frailty. Frailty and heart failure affect each other, and both are becoming increasingly important in society. In this article, we review the physical, cognitive, and social domains of frailty and the possible interventions to improve them in patients with heart failure.

Effects of familiarity on child brain networks when listening to a storybook reading: A magneto-encephalographic study.

Parent-child book reading is important for fostering the development of various lifelong cognitive and social abilities in young children. Despite numerous reports describing the effects of familiarity on shared reading for children, the exact neural basis of the functional network architecture remains unclear. We conducted Magnet-Encephalographic (MEG) experiments using graph theory to elucidate the role of familiarity in shared reading in a child's brain network and to measure the connectivity dynamics of a child while Listening to Storybook Reading (LSBR), which represents the daily activity of shared book reading between the child and caregiver. The LSBR task was performed with normally developing preschool- and school-age children (N = 15) under two conditions: reading by their own mother (familiar condition) vs. an experimenter (unfamiliar condition). We used the phase lag index (PLI), which captures synchronization of MEG signals, to estimate functional connectivity. For the whole brain network topology, an undirected weighted graph was produced using 68 brain regions as nodes and interregional PLI values as edges for five frequency bands. Behavioral data (i.e., the degree of attention and facial expressions) were evaluated from video images of the child's face during the two conditions. Our results showed enhanced widespread functional connectivity in the alpha band during the mother condition. In the mother condition, the whole brain network in the alpha band exhibited topographically high local segregation with high global integration, indicating an increased small-world property. Results of the behavioral analysis revealed that children were more attentive and showed more positive facial expressions in the mother condition than in the experimenter condition. Behavioral data were significantly correlated with graph metrics in the mother condition but not in the experimenter condition. In this study, we identified the neural correlates of a familiarity effect in children's brain connectivity dynamics during LSBR. Furthermore, these familiarity-related brain dynamics were closely linked to the child's behavior. Graph theory applied to MEG data may provide useful insight into the familiarity-related child brain response in a naturalistic setting and its relevance to child attitudes.

Extracellular signal-regulated kinases 2 (Erk2) and Erk5 in the central nervous system differentially contribute to central sensitization in male mice.

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.

Relationship between skin autofluorescence levels and clinical events in patients with heart failure undergoing cardiac rehabilitation.

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 < 0.05). After adjusting for confounding factors, Cox regression multivariate analysis revealed that SAF levels were independently associated with the incidence of MACE (odds ratio, 1.86; 95% confidence interval, 1.08-3.12; P = 0.03). 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.

Radiation effects on atherosclerosis in atomic bomb survivors: a cross-sectional study using structural equation modeling.

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.

Prognostic significance of the controlling nutritional (CONUT) score in patients with acute coronary syndrome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.