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After stroke, the poorer recovery of motor function of upper extremities compared to other body parts is a longstanding problem. Based on our recent functional MRI evidence on healthy volunteers, this perspective paper proposes systematic hand motor rehabilitation utilizing the plasticity of interhemispheric interaction between motor cortices and following its developmental rule. We first discuss the effectiveness of proprioceptive intervention on the paralyzed (immobile) hand synchronized with voluntary movement of the intact hand to induce muscle activity in the paretic hand. In healthy participants, we show that this bilateral proprioceptive-motor coupling intervention activates the bilateral motor cortices (= bilaterally active mode), facilitates interhemispheric motor-cortical functional connectivity, and augments muscle activity of the passively-moved hand. Next, we propose training both hands to perform different movements, which would be effective for stroke patients who becomes able to manage to move the paretic hand. This bilaterally different movement training may guide the motor cortices into left-right independent mode to improve interhemispheric inhibition and hand dexterity, because we have shown in healthy older adults that this training reactivates motor-cortical interhemispheric inhibition (= left-right independent mode) declined with age, and can improve hand dexterity. Transition of both motor cortices from the bilaterally active mode to the left-right independent mode is a developmental rule of hand motor function and a common feature of motor function recovery after stroke. Hence, incorporating the brain's inherent capacity for spontaneous recovery and adhering to developmental principles may be crucial considerations in designing effective rehabilitation strategies.
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Introduction: Attentional focus is a phenomenon in which shifting the focus of attention alters performance of standing postural control. It can be categorized as internal focus (IF), which directs attention to the body parts, or external focus (EF), which directs attention to the external environment. Although attentional focus that improves standing postural control in younger people exhibits individual dominance, the dominance of attentional focus in standing postural control in older adults remains ambiguous. Therefore, this study aimed to compare the dominance of attentional focus in standing postural control between healthy younger and older adults, a crucial step for understanding the aging process. Methods: The participants performed a standing postural control task under the IF and EF conditions. Based on the condition during which they exhibited superior performance, the participants were divided into two groups: IF-dominant and EF-dominant. The standing postural control performance in each group under the IF and EF conditions was subsequently compared. Results: The results showed that the participants, encompassing both younger and older adults, were divided into the IF-dominant and EF-dominant groups, confirming the dominance of attentional focus. The performance under the EF condition in older adults was also influenced by the dominance of attentional focus. Conclusion: These results highlight the potential importance of intervention methods based on the dominance of attentional focus, providing valuable insights into future research and clinical practice.
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Subjective cognitive complaints (SCCs) are a crucial modifiable risk factor for dementia. There is increasing interest in the association between SCC and sleep disturbance; however, the effects of sleep disturbance on SCC development among community-dwelling elderly individuals in Japan remain unclear. We aimed to cross-sectionally investigate the association between SCC and sleep disturbance, with adjustment for multiple factors related to cognitive decline, among 241 community-dwelling elderly persons without cognitive impairment. The measures were SCCs (Kihon Checklist-Cognitive Function, KCL-CF), sleep disturbance (Japanese version of the Athens Insomnia Scale, AIS-J), general cognitive function (Mini-Mental State Examination), and depressive symptoms (five-item version of the Geriatric Depression Scale [GDS-5]). The following data were collected: sex, age, educational history, whether the participants had visited a medical institution for diseases (hypertension, diabetes, hyperlipidemia, heart disease), and the presence/absence of established risk factors (hearing loss, history of head injury, drinking habits, smoking habits, social isolation, and physical inactivity and activity). Based on the KCL-CF, 96 and 145 participants were considered to have and lack SCCs, respectively. On logistic regression analysis, the AIS-J score and smoking history were significantly associated with SCCs. Our findings suggest that sleep disturbance is associated with SCC development among community-dwelling elderly people in Japan. Evaluating and managing sleep disturbances can be important in preventing SCCs and dementia.
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The severity of allergic asthma is driven by the balance between allergen-specific T regulatory (Treg) and T helper (Th)2 cells. However, it is unclear whether specific subsets of conventional dendritic cells (cDCs) promote the differentiation of these two T cell lineaeges. We have identified a subset of lung resident type 2 cDCs (cDC2s) that display high levels of CD301b and have potent Treg-inducing activity ex vivo. Single cell RNA sequencing and adoptive transfer experiments show that during allergic sensitization, many CD301b+ cDC2s transition in a stepwise manner to CD200+ cDC2s that selectively promote Th2 differentiation. GM-CSF augments the development and maintenance of CD301b+ cDC2s in vivo, and also selectively expands Treg-inducing CD301b+ cDC2s derived from bone marrow. Upon their adoptive transfer to recipient mice, lung-derived CD301b+ cDC2s confer immunological tolerance to inhaled allergens. Thus, GM-CSF maintains lung homeostasis by increasing numbers of Treg-inducing CD301b+ cDC2s.
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This study investigated the relationship between subjective grip strength and physical function in community-dwelling older women. Subjective grip strength was assessed using a questionnaire, and physical function and body composition were compared between groups with strong and weak subjective grip strength. Additionally, the two groups were compared in those with mild cognitive impairment (MCI) and those with normal cognitive function, respectively. The results showed significant differences in grip strength (p < 0.001), 30 s chair-stand (CS-30) test (p = 0.039), timed up-and-go (TUG) test (p = 0.027), maximal gait speed (p = 0.029), and skeletal muscle mass (p < 0.001). Older adults with normal cognitive function showed significant differences in grip strength (p < 0.001), quadriceps muscle strength (p < 0.009), one-leg standing time (p = 0.041), CS-30 (p = 0.002), TUG (p = 0.014), gait speed (p = 0.006), and skeletal muscle mass (p = 0.003). Older adults with low subjective grip strength had lower physical function and skeletal muscle mass. However, no items showed significant differences between groups among older adults with MCI. Thus, subjective grip strength is an indicator of an overall decline in physical function and a reduction in skeletal muscle mass in older adults, and cognitive function should be considered when assessing subjective grip strength in older adults.
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The recent increase in the number of frail older adults has led to increased attention being paid to care services in communities such as senior day care centers. Maintaining health-related quality of life (HRQOL) in frail older adults is important for managing long-term care. The purpose of this study was to comprehensively explore the impact of physical, mental, and cognitive factors, particularly central sensitization-related symptoms (CSSs), on the HRQOL among frail older adults in senior day care centers. HRQOL, physical, mental, and cognitive factors, and severity of CSSs were comprehensively measured using validated methods. Correlation and multiple regression analyses were used to examine factors affecting HRQOL among frail older adults in senior day care centers. The results showed that the timed up and go test significantly affected the HRQOL among frail older adults at senior day care centers. Additionally, knee extension muscle strength, number of pain sites, depressive tendencies, and CSS severity showed a significant negative correlation with HRQOL but were not significant influencing factors. This suggests that functional mobility assessments and approaches are important for maintaining and improving the HRQOL in frail older adults at senior day care centers.
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PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.
Subject(s)
Antiemetics , Aprepitant , Carboplatin , Dexamethasone , Nausea , Olanzapine , Vomiting , Humans , Olanzapine/therapeutic use , Olanzapine/administration & dosage , Olanzapine/adverse effects , Male , Carboplatin/adverse effects , Carboplatin/administration & dosage , Nausea/chemically induced , Nausea/prevention & control , Antiemetics/therapeutic use , Antiemetics/administration & dosage , Female , Double-Blind Method , Aged , Vomiting/chemically induced , Vomiting/prevention & control , Middle Aged , Dexamethasone/therapeutic use , Dexamethasone/administration & dosage , Aprepitant/therapeutic use , Aprepitant/administration & dosage , Aged, 80 and over , Drug Therapy, Combination , Adult , Benzodiazepines/adverse effects , Benzodiazepines/administration & dosage , Benzodiazepines/therapeutic use , Antineoplastic Agents/adverse effects , Morpholines/therapeutic use , Morpholines/administration & dosage , Neoplasms/drug therapy , Neurokinin-1 Receptor Antagonists/therapeutic use , Neurokinin-1 Receptor Antagonists/administration & dosageABSTRACT
Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA2, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKß-NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.
Subject(s)
Cell Movement , Dendritic Cells , Homeostasis , Lymph Nodes , Mice, Inbred C57BL , Receptors, CCR7 , Animals , Dendritic Cells/immunology , Dendritic Cells/metabolism , Lymph Nodes/immunology , Lymph Nodes/cytology , Receptors, CCR7/metabolism , Mice , Cell Movement/immunology , Cell Shape , NF-kappa B/metabolism , Mice, Knockout , Signal Transduction/immunology , I-kappa B Kinase/metabolism , Actin-Related Protein 2-3 Complex/metabolismABSTRACT
Movement disorders that stem from neurological conditions such as stroke, cerebral palsy, multiple sclerosis (MS), Parkinson's disease (PD), and spinocerebellar degeneration (SCD) can significantly impair a person's activities of daily living (ADL) [...].
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Most older adults wish to maintain independence in their familiar communities. However, many experience pain and pain-related disabilities which reduce their health-related quality of life (HRQOL), leading to increased hospitalizations and mortality. This study aimed to determine the impact of physical, mental, and cognitive factors, particularly central sensitization-related symptoms (CSS), on the HRQOL of community-dwelling older adults. A total of 206 participants were included in the analysis, which measured HRQOL, basic attributes, physical functions and body pain, mental factors, cognitive factors, and CSS severity using validated tools. A correlation analysis was used to examine the association between HRQOL and each measure. Furthermore, multiple regression analysis (forced entry method) was performed to identify the factors influencing the HRQOL. The study found that pain intensity and CSS severity significantly influenced the HRQOL among community-dwelling older adults. The higher the pain intensity and CSS severity, the lower their HRQOL. The participants had mild pain and CSS, demonstrating the need to monitor, address, and treat even non-severe issues in community-dwelling older adults. This association, revealed for the first time in this study, suggests that approaches to reduce pain and CSS are important for maintaining and improving the HRQOL of community-dwelling older adults.
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BACKGROUND: Allergic asthma is driven largely by allergen-specific TH2 cells, which develop in regional lymph nodes on the interaction of naive CD4+ T cells with allergen-bearing dendritic cells that migrate from the lung. This migration event is dependent on CCR7 and its chemokine ligand, CCL21. However, is has been unclear whether the other CCR7 ligand, CCL19, has a role in allergic airway disease. OBJECTIVE: This study sought to define the role of CCL19 in TH2 differentiation and allergic airway disease. METHODS: Ccl19-deficient mice were studied in an animal model of allergic asthma. Dendritic cells or fibroblastic reticular cells from wild-type and Ccl19-deficient mice were cultured with naive CD4+ T cells, and cytokine production was measured by ELISA. Recombinant CCL19 was added to CD4+ T-cell cultures, and gene expression was assessed by RNA-sequencing and quantitative PCR. Transcription factor activation was assessed by flow cytometry. RESULTS: Lungs of Ccl19-deficient mice had less allergic airway inflammation, reduced airway hyperresponsiveness, and less IL-4 and IL-13 production compared with lungs of Ccl19-sufficient animals. Naive CD4+ T cells cocultured with Ccl19-deficient dendritic cells or fibroblastic reticular cells produced lower amounts of type 2 cytokines than did T cells cocultured with their wild-type counterparts. Recombinant CCL19 increased phosphorylation of STAT5 and induced expression of genes associated with TH2 cell and IL-2 signaling pathways. CONCLUSIONS: These results reveal a novel, TH2 cell-inducing function of CCL19 in allergic airway disease and suggest that strategies to block this pathway might help to reduce the incidence or severity of allergic asthma.
Subject(s)
Asthma , Hypersensitivity , Animals , Mice , Chemokine CCL19/genetics , Receptors, CCR7 , Ligands , Asthma/genetics , Inflammation/pathology , Lung , Hypersensitivity/metabolism , Allergens/metabolism , Cell Differentiation , Th2 Cells , Dendritic CellsABSTRACT
Mild cognitive impairment (MCI) is associated with a high risk of dementia. Reportedly, 54.6% of older adults with MCI fall into the pre-frailty category. However, it is unclear what differences exist in older adults with regard to their physical, psychological, and functional capacities, which depend on MCI, pre-frailty, or a combination of the two. This study aimed to examine the differences between the association between physical function, psychological function, and functional capacity by examining a combination of MCI and pre-frailty among community-dwelling older Japanese individuals. The participants in the analysis were 236 older people living in the community. They were classified into four groups, as follows: normal, MCI only, pre-frailty only, and pre-frailty/MCI; furthermore, their physical, psychological, and functional capacities were compared. In addition, a multinomial logistic regression analysis was performed using MCI and pre-frailty as dependent variables. No associated factors were identified for MCI only, and a depressive mood was only associated with pre-frailty. When pre-frailty and MCI were combined, knee extension muscle strength, fastest gait speed, the s30 s chair stand test, depressed moods, and the instrumental activities of daily living (IADL) were correlated. Our results suggest that when MCI and pre-frailty are combined, declines in both physical and psychological functions and IADL are likely to occur.
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DNASE1L3, an enzyme highly expressed in DCs, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of antitumor immunity, the foundation of modern antitumor immunotherapy. In this study, we identify DNASE1L3 as a potentially new regulator of antitumor immunity and a tumor suppressor in colon cancer. In humans, DNASE1L3 is downregulated in tumor-infiltrating DCs, and this downregulation is associated with poor patient prognosis and reduced tumor immune cell infiltration in many cancer types. In mice, Dnase1l3 deficiency in the tumor microenvironment enhances tumor formation and growth in several colon cancer models. Notably, the increased tumor formation and growth in Dnase1l3-deficient mice are associated with impaired antitumor immunity, as evidenced by a substantial reduction of cytotoxic T cells and a unique subset of DCs. Consistently, Dnase1l3-deficient DCs directly modulate cytotoxic T cells in vitro. To our knowledge, our study unveils a previously unknown link between DNASE1L3 and antitumor immunity and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anticancer therapy.
Subject(s)
Colonic Neoplasms , Humans , Mice , Animals , Colonic Neoplasms/metabolism , Chromatin/metabolism , Immunotherapy , T-Lymphocytes, Cytotoxic , Tumor Microenvironment , Endodeoxyribonucleases/genetics , Endodeoxyribonucleases/metabolismABSTRACT
This study aimed to investigate abnormalities in inhibitory cortical excitability and motor control during ballistic-targeting movements in individuals with degenerative cerebellar ataxia (DCA). Sixteen participants took part in the study (DCA group [n = 8] and healthy group [n = 8]). The resting motor-threshold and cortical silent period (cSP) were measured in the right-hand muscle using transcranial magnetic stimulation over the left primary motor cortex. Moreover, the performance of the ballistic-targeting task with right wrist movements was measured. The Scale for the Assessment and Rating of Ataxia was used to evaluate the severity of ataxia. The results indicated that the cSP was significantly longer in participants with DCA compared to that in healthy controls. However, there was no correlation between cSP and severity of ataxia. Furthermore, cSP was linked to the ballistic-targeting task performance in healthy participants but not in participants with DCA. These findings suggest that there is excessive activity in the gamma-aminobutyric acid-mediated cortical inhibitory circuit in individuals with DCA. However, this increase in inhibitory activity not only fails to contribute to the control of ballistic-targeting movement but also shows no correlation with the severity of ataxia. These imply that increased excitability in inhibitory cortical circuits in the DCA may not contribute the motor control as much as it does in healthy older adults under limitations associated with a small sample size. The study's results contribute to our understanding of motor control abnormalities in people with DCA and provide potential evidence for further research in this area.
Subject(s)
Cerebellar Ataxia , Cortical Excitability , Humans , Aged , Ataxia , Movement , HandABSTRACT
Introduction: Asthma is a chronic disease of the airways that impairs normal breathing. The etiology of asthma is complex and involves multiple factors, including the environment and genetics, especially the distinct genetic architecture associated with ancestry. Compared to early-onset asthma, little is known about genetic predisposition to late-onset asthma. We investigated the race/ethnicity-specific relationship among genetic variants within the major histocompatibility complex (MHC) region and late-onset asthma in a North Carolina-based multiracial cohort of adults. Methods: We stratified all analyses by self-reported race (i.e., White and Black) and adjusted all regression models for age, sex, and ancestry. We conducted association tests within the MHC region and performed fine-mapping analyses conditioned on the race/ethnicity-specific lead variant using whole-genome sequencing (WGS) data. We applied computational methods to infer human leukocyte antigen (HLA) alleles and residues at amino acid positions. We replicated findings in the UK Biobank. Results: The lead signals, rs9265901 on the 5' end of HLA-B, rs55888430 on HLA-DOB, and rs117953947 on HCG17, were significantly associated with late-onset asthma in all, White, and Black participants, respectively (OR = 1.73, 95%CI: 1.31 to 2.14, p = 3.62 × 10-5; OR = 3.05, 95%CI: 1.86 to 4.98, p = 8.85 × 10-6; OR = 19.5, 95%CI: 4.37 to 87.2, p = 9.97 × 10-5, respectively). For the HLA analysis, HLA-B*40:02 and HLA-DRB1*04:05, HLA-B*40:02, HLA-C*04:01, and HLA-DRB1*04:05, and HLA-DRB1*03:01 and HLA-DQB1 were significantly associated with late-onset asthma in all, White, and Black participants. Conclusion: Multiple genetic variants within the MHC region were significantly associated with late-onset asthma, and the associations were significantly different by race/ethnicity group.
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Introduction: Motor imagery (MI) is a method of imagining movement without actual movement, and its use in combination with motor execution (ME) enhances the effects of motor learning. Neurofeedback (NFB) is another method that promotes the effects of MI. This study aimed to investigate the effects of NFB on combined MI and ME (MIME) training in a standing postural control task. Methods: Sixteen participants were randomly divided into MIME and MIME + NFB groups and performed 10 trials of a postural control task on an unstable board, with nine trials of MI in between. Electroencephalogram was assessed during MI, and the MIME + NFB group received neurofeedback on the degree of MI via auditory stimulation. A postural control task using an unstable board was performed before and after the MIME task, during which postural instability was evaluated. Results: Postural instability was reduced after the MIME task in both groups. In addition, the root mean square, which indicates the sway of the unstable board, was significantly reduced in the MIME + NFB group compared to that in the MIME group. Conclusion: Our results indicate that MIME training is effective for motor learning of standing postural control. Furthermore, when MI and ME are combined, the feedback on the degree of MI enhances the learning effect.
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Robot-assisted activity (RAA) using a communication robot (RAA-CR) has been proposed as a tool for alleviating behavioral and psychological symptoms accompanying dementia (BPSD) in patients with cognitive decline. This study aimed to clarify the effects of differences in cognitive function among older adults on changes in active brain areas induced by RAA-CR. Twenty-nine older adults were divided into a cognitive decline group (n = 11) and a control group (n = 18). The participants individually received a 5-minute RAA session, and their resting EEG activity was measured before and after the session. Brain spatial analysis was performed on recorded EEG data using standardized low-resolution brain electromagnetic tomography. In addition, statistical comparisons of neural activity in the brain were made before and after RAA-CR and between the cognitively impaired and control groups. These results suggest that RAA-CR stimulates neural activity in the region centered on the posterior cingulate gyrus and precuneus in cognitively healthy older adults but does not significantly alter brain neural activity in cognitively impaired older adults. Therefore, modifications to the implementation methods may be necessary to effectively implement RAA-CR in cognitively impaired individuals.
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Attention focus affects performance in postural control while standing, and it is divided into internal focus (IF) and external focus (EF). Each individual has a predominant attention focus, and research has revealed that the dominance of attention focus may be an acquired trait. However, the impact of non-invasive brain stimulation on attention-focus dominance remains unexplored in the current literature. Here, we examined the effect of high-definition transcranial alternating current stimulation (HD-tACS) on θ waves in the anterior cingulate cortex (ACC) on standing postural control tasks in an EF condition for IF- and EF-dominant groups. The effect of θ HD-tACS on the ACC differed between IF- and EF-dominant groups, and θ HD-tACS in the IF-dominant group decreased the performance of standing postural control under the EF condition. The forced activation of the ACC with θ HD-tACS may have conversely reduced the activity of brain regions normally activated by the IF-dominant group. Additionally, the activation of ACC prioritized visual information processing and suppressed the superficial sensory processing that is normally potentially prioritized by the IF-dominant group. These results highlight the importance of changing the type of rehabilitation and sports training tasks to account for the individual's dominance of attention focus.
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Introduction: Neurofeedback (NFB) training and transcranial direct current stimulation (tDCS) have been shown to individually improve motor imagery (MI) abilities. However, the effect of combining both of them with MI has not been verified. Therefore, the aim of this study was to examine the effect of applying tDCS directly before MI with NFB. Methods: Participants were divided into an NFB group (n = 10) that performed MI with NFB and an NFB + tDCS group (n = 10) that received tDCS for 10 min before MI with NFB. Both groups performed 60 MI trials with NFB. The MI task was performed 20 times without NFB before and after training, and µ-event-related desynchronization (ERD) and vividness MI were evaluated. Results: µ-ERD increased significantly in the NFB + tDCS group compared to the NFB group. MI vividness significantly increased before and after training. Discussion: Transcranial direct current stimulation and NFB modulate different processes with respect to MI ability improvement; hence, their combination might further improve MI performance. The results of this study indicate that the combination of NFB and tDCS for MI is more effective in improving MI abilities than applying them individually.