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BACKGROUND: Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by variants in WRN. The International Registry of Werner Syndrome has identified biallelic pathogenic variants in 179/188 cases of classical WS. In the remaining nine cases, only one heterozygous pathogenic variant has been identified. METHODS: Targeted long-read sequencing (T-LRS) on an Oxford Nanopore platform was used to search for a second pathogenic variant in WRN. Previously, T-LRS was successfully used to identify missing variants and analyse complex rearrangements. RESULTS: We identified a second pathogenic variant in eight of nine unsolved WS cases. In five cases, T-LRS identified intronic splice variants that were confirmed by either RT-PCR or exon trapping to affect splicing; in one case, T-LRS identified a 339 kbp deletion, and in two cases, pathogenic missense variants. Phasing of long reads predicted all newly identified variants were on a different haplotype than the previously known variant. Finally, in one case, RT-PCR previously identified skipping of exon 20; however, T-LRS did not detect a pathogenic DNA sequence variant. CONCLUSION: T-LRS is an effective method for identifying missing pathogenic variants. Although limitations with computational prediction algorithms can hinder the interpretation of variants, T-LRS is particularly effective in identifying intronic variants.
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In this study, we identified a previously uncharacterized skeletal satellite cell-secreted protein, R3h domain containing-like (R3hdml). Expression of R3hdml increases during skeletal muscle development and differentiation in mice. Body weight and skeletal muscle mass of R3hdml knockout (KO) mice are lower compared to control mice. Expression levels of cell cycle-related markers, phosphorylation of Akt, and expression of insulin-like growth factor within the skeletal muscle are reduced in R3hdml KO mice compared to control mice. Expression of R3hdml increases during muscle regeneration in response to cardiotoxin (CTX)-induced muscle injury. Recovery of handgrip strength after CTX injection was significantly impaired in R3hdml KO mice, which is rescued by R3hdml. Our results indicate that R3hdml is required for skeletal muscle development, regeneration, and, in particular, satellite cell proliferation and differentiation.
Subject(s)
Cell Differentiation/genetics , Satellite Cells, Skeletal Muscle/cytology , Satellite Cells, Skeletal Muscle/metabolism , Amino Acid Sequence , Animals , Biomarkers , Cell Proliferation , Gene Expression , Gene Expression Profiling , Mice , Mice, Knockout , Muscle Development/genetics , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/metabolism , MyoD Protein/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Regeneration , Signal TransductionABSTRACT
Many types of cancer cells show a characteristic increase in glycolysis, which is called the "Warburg effect." By screening plant extracts, we identified one that decreases cellular adenosine triphosphate (ATP) levels and suppresses proliferation of malignant melanoma B16F10 cells, but not of noncancerous MEF cells. We showed that its active ingredient is emodin, which showed strong antiproliferative effects on B16F10 cells both in vitro and in vivo. Moreover, we also found that emodin can function as a mitochondrial uncoupler. Consistently, three known mitochondrial uncouplers also displayed potent antiproliferative effects and preferential cellular ATP reduction in B16F10 cells, but not in MEF cells. These uncouplers provoked comparable mitochondrial uncoupling in both cell types, but they manifested dramatically different cellular effects. Namely in MEF cells, these uncouplers induced three to fivefold increases in glycolysis from the basal state, and this compensatory activation appeared to be responsible for the maintenance of cellular ATP levels. In contrast, B16F10 cells treated with the uncouplers showed less than a twofold enhancement of glycolysis, which was not sufficient to compensate for the decrease of ATP production. Together, these results raise the possibility that uncouplers could be effective therapeutic agents specifically for cancer cells with prominent "Warburg effect."
Subject(s)
Adenosine Triphosphate/metabolism , Emodin/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Animals , Cell Line , Cell Proliferation/drug effects , Fallopia japonica/chemistry , Fibroblasts , Glycolysis , Melanoma, Experimental , Mice , Plant Extracts/chemistry , Plant Extracts/pharmacology , Protein Kinase Inhibitors/pharmacology , Rhizome/chemistryABSTRACT
Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.
Subject(s)
Mutation , Werner Syndrome Helicase/genetics , Werner Syndrome/genetics , Age Factors , Animals , Databases, Genetic , Disease Models, Animal , Exons , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Geography , Humans , Japan , Mice , Phenotype , Polymorphism, Genetic , Polymorphism, Single Nucleotide , Registries , Translational Research, Biomedical , Web Browser , Werner Syndrome/diagnosis , Werner Syndrome/epidemiologyABSTRACT
There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to < 6 years), then increased in the later stage [17.3% in ≥ 11 years, p = 0.001 (vs. ≥ 2 to < 6 years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for < 2 years and 17.4 vs. 3.1% for ≥ 2 to < 6 years, p = 0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.
Subject(s)
AIDS Dementia Complex/drug therapy , AIDS Dementia Complex/physiopathology , Anti-HIV Agents/therapeutic use , AIDS Dementia Complex/diagnosis , AIDS Dementia Complex/psychology , Adult , Age Factors , Antiretroviral Therapy, Highly Active , Female , Humans , Japan , Male , Middle Aged , Multivariate Analysis , Neuropsychological Tests , Prevalence , Prospective Studies , Risk Factors , Time Factors , Viral Load/drug effectsABSTRACT
INTRODUCTION: Increased ankle muscle coactivation during gait is a compensation strategy for enhancing postural stability in patients after stroke. However, no previous studies have demonstrated that increased ankle muscle coactivation influenced ankle joint movements during gait in patients after stroke. PURPOSE: To investigate the relationship between ankle muscle coactivation and ankle joint movements in hemiplegic patients after stroke. METHODS: Seventeen patients after stroke participated. The coactivation index (CoI) at the ankle joint was calculated separately for the first and second double support (DS1 and DS2, respectively) and single support (SS) phases on the paretic and non-paretic sides during gait using surface electromyography. Simultaneously, three-dimensional motion analysis was performed to measure the peak values of the ankle joint angle, moment, and power in the sagittal plane. Ground reaction forces (GRFs) of the anterior and posterior components and centers of pressure (COPs) trajectory ranges and velocities were also measured. RESULTS: The CoI during the SS phase on the paretic side was negatively related to ankle dorsiflexion angle, ankle plantarflexion moment, ankle joint power generation, and COP velocity on the paretic side. Furthermore, the CoI during the DS2 phase on both sides was negatively related to anterior GRF amplitude on each side. CONCLUSION: Increased ankle muscle coactivation is related to decreased ankle joint movement during the SS phase on the paretic side to enhance joint stiffness and compensate for stance limb instability, which may be useful for patients who have paretic instability during the stance phase after stroke.
Subject(s)
Ankle Joint/physiopathology , Ankle/innervation , Gait/physiology , Hemiplegia/etiology , Muscle, Skeletal/physiopathology , Stroke/complications , Aged , Biomechanical Phenomena , Electromyography , Female , Hemiplegia/pathology , Humans , Kinetics , Male , Middle Aged , Motion , Statistics, NonparametricABSTRACT
Loss of motor coordination is one of the main problems for patients after stroke. Muscle synergy is widely accepted as an indicator of motor coordination. Recently, the characteristics of muscle synergy were quantitatively evaluated using nonnegative matrix factorization (NNMF) with surface electromyography. Previous studies have identified that the number and structure of synergies were associated with motor function in patients after stroke. However, most of these studies had a cross-sectional design, and the changes in muscle synergy during recovery process are not clear. In present study, two consecutive measurements were conducted for subacute patients after stroke and the change of number and structure of muscle synergies during gait were determined using NNMF. Results showed that functional change did not rely on number of synergies in patients after subacute stroke. However, the extent of merging of the synergies was negatively associated with an increase in muscle strength and the range of angle at ankle joint. Our results suggest that the neural changes represented by NNMF were related to the longitudinal change of function and gait pattern and that the merging of synergy is an important marker in patients after subacute stroke.
Subject(s)
Hemiplegia/diagnosis , Hemiplegia/physiopathology , Muscle, Skeletal/physiopathology , Recovery of Function/physiology , Stroke/diagnosis , Stroke/physiopathology , Adult , Aged , Aged, 80 and over , Electromyography/methods , Female , Hemiplegia/epidemiology , Humans , Male , Middle Aged , Stroke/epidemiologyABSTRACT
BACKGROUND: This study attempted to assess continued long-term home care by examining patients' independent activities of daily living (ADLs) and caregivers' free time. METHODS: We surveyed the main caregivers of 52 patients with cerebrovascular disease with continuous home care from 1999 to 2010. Survey items were patients' ADLs, the frequency of use of care services, care requirements, and caregiver sense of burden. We compared the survey results between years. RESULTS: ADLs of excretory control, verbal expression, verbal comprehension, and range of activities showed significant deterioration from 1999 to 2010. Patient need for care increased significantly but use of care services did not. Main caregivers were typically spouses who aged together with the patients. Main caregivers rarely changed; occasionally, a son or daughter-in-law became the main caregiver. Patients typically required less than 3 hours of care daily, which did not change over time. Caregivers had significantly more difficulty maintaining their own health in 2010 than 1999. However, they did not identify increases in difficulties with housework or coping with work. They felt that caregiving was a burden but did not indicate that the family relationship had deteriorated. CONCLUSIONS: Regardless of degree of independence of patients' ADLs, caregiver burden was severe. To decrease caregiver burden, it is necessary to use care services, reduce care time, and allow caregivers free time. In addition, it is possible to continue long-term home care by maintaining their relationships.
Subject(s)
Activities of Daily Living , Caregivers/psychology , Cerebrovascular Disorders/therapy , Cost of Illness , Home Nursing , Aged , Aged, 80 and over , Female , Humans , Long-Term Care , Male , Middle Aged , SpousesABSTRACT
[Purpose] The purpose of this study was to assess the relationships between bilateral knee extension strengths and gait performance in subjects with poststroke hemiparesis and to predict gait performance by the paretic and nonparetic knee extension strength. [Subjects and Methods] This was a correlational study in which 238 consecutive inpatients with poststroke hemiparesis were enrolled. Knee extensor muscle strengths in paretic and nonparetic lower limbs were measured with a handheld dynamometer, and the presence or absence of impaired gait was also determined. [Results] The mean strength in the paretic lower limb was 0.90 Nm/kg, and that in the nonparetic lower limb was 1.24 Nm/kg. Discriminant analysis classified the difference between the possibility and impossibility of gait by knee extensor muscle strength (standardized discriminant coefficient: paretic, 1.32; nonparetic, 0.55). Thus, paretic and nonparetic knee extension strengths were integrated in the strength index. A threshold level of 2.0 provided the best balance between positive and negative predictive values for the strength index. [Conclusion] The results indicated that both paretic and nonparetic knee extension strengths were related to gait performance. The strength index deduced from bilateral knee extension strengths may serve as a clinically meaningful index for rehabilitation assessment and training.
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Objectives: Occupational therapy (OT) studies of delirium have attempted to test the effectiveness of interventions to reduce the incidence and duration of delirium. Although some cognitive stimulation appears to be important, appropriate approaches to delirium characterized by cognitive dysfunction remain unclear. This study aimed to determine the incidence and duration of delirium in postoperative cardiovascular surgery patients at the initial time of OT to identify characteristics of patient demographics and cognitive function according to the presence or absence of delirium. Methods: This retrospective study included patients judged to have delirium by the Confusion Assessment Method at the first postoperative OT session (after extubation) in the intensive care unit (ICU). Patient data included age, sex, days until extubation, type of hospitalization, outcome at discharge, Sequential Organ Failure Assessment score and Glasgow Coma Scale (GCS) score at the first OT session, presence or absence of delirium, duration of delirium, and Mini-Mental State Examination-Japanese (MMSE-J) score. The Mann-Whitney U test was used to test differences between the delirium and the non-delirium groups, and a binomial generalized linear model (logistic regression model) with Bayesian estimation was adopted to investigate factors characterizing delirium. Results: A Bayesian logistic regression model with delirium as the dependent variable and "days until extubation" and "spatial orientation" as adjustment variables suggested that "spatial orientation" was a significant factor in delirium. Conclusions: For ICU patients with delirium, the provision of information tailored toward spatial orientation during the first day of OT may improve delirium.
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People living with human immunodeficiency virus (HIV) are at high risk of mental health problems. However, little is known about this risk in HIV-infected patients with hemophilia (HPH) who contracted the virus through blood products. This cross-sectional, observational study assessed patients' mood states and the factors associated with them among Japanese HPH to evaluate the need for psychosocial support. HPH completed self-administered questionnaires (Profile of Mood States [POMS] and General Health Questionnaire-28), neuropsychological tests, and brain magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computerized tomography scans. HIV-infected patients with no hemophilia (HPnH) completed POMS and neuropsychological tests. Socio-demographic characteristics and HIV- and hemophilia-related data were obtained from participants' medical records and interviews. A Mann-Whitney U test and chi-squared analyses were conducted. Fifty-six HPH and 388 HPnH completed the questionnaires and neuropsychological tests. HPH had a significantly lower prevalence of tension-anxiety (HPH, 7%; HPnH, 18%; p = 0.049) and a significantly higher prevalence of low vigor (HPH, 63%; HPnH, 32%; p < 0.001). Low vigor in HPH was significantly associated with impaired executive function (low vigor, 66%; high vigor, 33%; p = 0.019) and a social dysfunction score ≥ 3 (moderate; low vigor, 26%; high vigor, 5%; p = 0.047). Our results highlight the high prevalence of low vigor among HPH, leading to impairments in executive and social functions. Therefore, healthcare workers need to pay attention to the vigor, executive function, and social function of HPH.
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BACKGROUND: Androgen deprivation therapy (ADT), administered alone, as combined androgen blockade (CAB) or as ADT plus androgen receptor signalling inhibitors (ARSIs) or ADT plus docetaxel, is the standard treatment for metastatic hormone-naïve prostate cancer (mHNPC) in Japanese real-world practice. OBJECTIVE: To investigate treatment patterns and clinical outcomes in LATITUDE criteria high-risk mHNPC. DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, multicentre, J-ROCK registry study enrolled patients initiating ADT in Japan after May 2019, and categorised them as cohort 1 (ADT or CAB) or cohort 2 (ADT plus ARSIs or docetaxel). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) response, progression-free survival (PFS), time to castrate-resistant prostate cancer (CRPC), overall survival (OS), and safety were evaluated. PFS, time to CRPC, and OS were estimated via the Kaplan-Meier method and between-cohort comparisons via multivariate Cox regression models. RESULTS AND LIMITATIONS: In total, 974 patients were included (cohort 1: 38.1%, cohort 2: 61.9%). CAB was preferred (67.4%) to ADT alone in cohort 1, and abiraterone acetate plus prednisolone was used most frequently in cohort 2 (59.4%). The proportion of patients with ≥50%/≥90% PSA decline or who achieved PSA ≤0.2/≤0.1 ng/ml tended to be higher in cohort 2. PFS (adjusted hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.55), time to CRPC (0.28; 95% CI 0.23-0.36), and OS (0.54; 95% CI 0.35-0.82) were longer in cohort 2. In cohorts 1 and 2, adverse drug reactions of special interest (ADRSIs) occurred in 1.3% and 15.1%, and fatal adverse events occurred in 1.9% and 1.7%, respectively. Limitations included nonrandomised design, varying time since marketing authorisation for ARSIs, and limited safety assessments. CONCLUSIONS: ADT plus ARSIs or docetaxel was used more frequently to treat high-risk mHNPC than standard ADT/CAB and was associated with more favourable clinical outcomes. Although ADRSIs were reported more in cohort 2, the safety profile was considered tolerable. PATIENT SUMMARY: Although many treatment options are available for high-risk metastatic prostate cancer, there are limited reports on real-world clinical experience with different therapies outside of the clinical trial setting. In this study, we compared clinical and safety outcomes with different treatment regimens, using a large series of patients with high-risk metastatic hormone-naïve prostate cancer across Japan. We found that androgen deprivation therapy in combination with newer androgen receptor signalling inhibitors resulted in improved response compared with androgen deprivation therapy alone or in combination with a first-generation antiandrogen.
Subject(s)
Androgen Antagonists , Prostatic Neoplasms , Male , Humans , Aged , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/mortality , Treatment Outcome , Androgen Antagonists/therapeutic use , Middle Aged , Time Factors , Longitudinal Studies , Neoplasm Metastasis , Aged, 80 and over , JapanABSTRACT
AIM: Whether sex differences exist in hereditary progeroid syndromes remains unclear. In this study, we investigated sex differences in patients with Werner syndrome (WS), a model of human aging, using patient data at the time of diagnosis. METHODS: The presence of six cardinal signs in the diagnostic criteria was retrospectively evaluated. RESULTS: We found that the percentage of patients with all cardinal signs was higher in males than in females (54.2% vs. 21.2%). By the age of 40 years, 57.1% of male patients with WS presented with all the cardinal signs, whereas none of the female patients developed all of them. In particular, the frequency of having a high-pitched, hoarse voice, a characteristic of WS, was lower in female patients. The positive and negative predictive values for clinical diagnosis were 100% for males and females, indicating the helpfulness of diagnostic criteria regardless of sex. More female patients than male (86.7% vs. 64%) required genetic testing for their diagnosis because their clinical symptoms were insufficient, suggesting the importance of genetic testing for females even if they do not show typical symptoms of WS. Finally, the frequency of abnormal voice was lower in patients with WS harboring the c.3139-1G > C homozygous mutation. CONCLUSION: These results indicate, for the first time, that there are sex differences in the phenotypes of hereditary progeroid syndromes. The analysis of this mechanism in this human model of aging may lead to the elucidation of sex differences in the various symptoms of normal human aging. Geriatr Gerontol Int 2024; 24: 161-167.
Subject(s)
Werner Syndrome , Humans , Male , Female , Werner Syndrome/diagnosis , Werner Syndrome/genetics , Retrospective Studies , Sex Characteristics , Werner Syndrome Helicase/genetics , MutationABSTRACT
BACKGROUND: The purpose of this study was to clarify the structural relationship of quality of life (QOL) in survivors of breast cancer, including difficulty in daily life and negative experiences in daily activities, as health-related indicators. METHODS: Participants were survivors of breast cancer for more than 2 years after primary breast cancer surgery and belonged to self-help groups. The assessment used FACT-B (QOL), HADS (anxiety and depression), SOC (sense of coherence), WHODAS 2.0 (difficulties in daily life), and CAOD (negative experiences in daily activities). Bayesian structural equation modeling (BSEM) was performed to analyze the hypothesized model. If the causal model was significant, multiplication of the path coefficient from emotional distress (anxiety and depression) to QOL, and from SOC to emotional distress, was considered a direct effect on QOL, and from SOC to difficulty in daily life, from difficulty in daily life to negative experiences in daily activities, and from negative experiences in daily activities to anxiety and depression were considered indirect effects on QOL. RESULTS: The participants comprised 73 survivors of breast cancer. The goodness of fit of the model in the BSEM was satisfactory. The direct effect was 0.274, and the indirect effect was 0.164. CONCLUSIONS: An additional finding of this study is that coping with difficulty in daily life and negative experiences in daily activities related to QOL may improve QOL.
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BACKGROUND: The link between arterial stiffness and mild cognitive impairment (MCI) in patients on hemodialysis (HD) has been receiving increased attention. The purpose of this study was to investigate the relationship between cognitive function and ankle brachial index (ABI) and toe brachial index (TBI) values in patients on hemodialysis. Of the 100 participants (mean age: 67.9 years; average history of hemodialysis: 7.3 years). Of these, 46.0% had MCI. The MoCA-J scores were significantly higher in the ABI ≥ 1.06 group. However, the MoCA-J scores divided into the two groups according to the TBI cutoff value were not significantly different. In a multiple regression model with the MoCA-J scores as the objective variable, the ABI was a significantly associated factor. This study indicates that a low ABI might be associated with MCI.
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Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans. To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.
Subject(s)
Insulin Resistance , Insulins , Lipodystrophy , Werner Syndrome , Animals , Humans , Werner Syndrome/genetics , Adipogenesis/genetics , Caenorhabditis elegans , Cellular Senescence/genetics , Subcutaneous Fat/metabolism , Inflammation , Sirolimus , MammalsABSTRACT
Background: This study is aimed at verifying a hypothetical model of the structural relationship between the recovery process and difficulties in daily life mediated by occupational dysfunction in severe and persistent mental illness (SPMI). Methods: Community-dwelling participants with SPMI were enrolled in this multicenter cross-sectional study. The Recovery Assessment Scale (RAS), the World Health Organization Disability Assessment Schedule second edition (WHODAS 2.0), and the Classification and Assessment of Occupational Dysfunction (CAOD) were used for assessment. Confirmatory factor analysis, multiple regression analysis, and Bayesian structural equation modelling (BSEM) were determined to analyze the hypothesized model. If the mediation model was significant, the path coefficient from difficulty in daily life to recovery and the multiplication of the path coefficients mediated by occupational dysfunction were considered as each the direct effect and the indirect effect. The goodness of fit in the model was determined by the posterior predictive P value (PPP). Each path coefficient was validated with median and 95% confidence interval (CI). Results: The participants comprised 98 individuals with SPMI. The factor structures of RAS, WHODAS 2.0, and CAOD were confirmed by confirmatory factor analysis to be similar to those of their original studies. Multiple regression analysis showed that the independent variables of RAS were WHODAS 2.0 and CAOD, and that of CAOD was WHODAS 2.0. The goodness of fit of the model in the BSEM was satisfactory with a PPP = 0.27. The standardized path coefficients were, respectively, significant at -0.372 (95% CI: -0.586, -0.141) from "difficulty in daily life" to "recovery" as the direct effect and at -0.322 (95% CI: -0.477, -0.171) mediated by "occupational dysfunction" as the indirect effect. Conclusions: An approach for reducing not only difficulty in daily life but also occupational dysfunction may be an additional strategy of person-centered, recovery-oriented practice in SPMI.
Subject(s)
Mental Disorders , Occupational Therapy , Bayes Theorem , Cross-Sectional Studies , Disability Evaluation , Humans , Latent Class AnalysisABSTRACT
OBJECTIVE: CCN3 belongs to the CCN family, which constitutes multifunctional secreted proteins that act as matrix cellular regulators. We investigated the pathophysiological roles of CCN3 in the vessels. METHODS AND RESULTS: We examined the effects of CCN3 on the proliferation and migration of rat vascular smooth muscle cells (VSMC). CCN3 knockout mice were created, and vascular phenotypes and neointimal hyperplasia induced by photochemically induced thrombosis were investigated. CCN3 suppressed the VSMC proliferation induced by fetal bovine serum. The neutralizing antibody for transforming growth factor-beta did not affect the growth inhibitory effect of CCN3. Moreover, CCN3 enhanced the mRNA expression of cyclin-dependent kinase inhibitors, p21 and p15. Gamma secretase inhibitor, an inhibitor of Notch signaling, partially inhibited the enhanced expression of p21 induced by CCN3. CCN3 also inhibited the VSMC migration. Finally, the histopathologic evaluation of the arteries 21 days after the endothelial injury revealed a 6-fold enhancement of neointimal thickening in the null mice compared with the wild-type mice. CONCLUSIONS: CCN3 suppresses neointimal thickening through the inhibition of VSMC migration and proliferation. Our findings indicate the involvement of CCN3 in vascular homeostasis, especially on injury, and the potential usefulness of this molecule in the modulation of atherosclerotic vascular disease.
Subject(s)
Cell Movement , Cell Proliferation , Diabetic Angiopathies/metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Nephroblastoma Overexpressed Protein/metabolism , Thrombosis/metabolism , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Animals , Aorta/metabolism , Aorta/pathology , Cell Cycle , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p15/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetic Angiopathies/pathology , Diabetic Angiopathies/prevention & control , Femoral Artery/metabolism , Femoral Artery/pathology , Genotype , Hyperplasia , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Nephroblastoma Overexpressed Protein/deficiency , Nephroblastoma Overexpressed Protein/genetics , Phenotype , Protease Inhibitors/pharmacology , Rats , Rats, Wistar , Receptors, Notch/metabolism , Recombinant Proteins/metabolism , Signal Transduction , Thrombosis/pathology , Thrombosis/prevention & control , Time Factors , Transfection , Transforming Growth Factor beta/metabolismABSTRACT
Not only in kidney glomerular physiological function but also glomerular pathology especially in diabetic condition, glomerular podocytes play pivotal roles. Therefore, it is important to increase our knowledge about the genes and proteins expressed in podocytes. Recently, we have identified a novel podocyte-expressed gene, R3h domain containing-like (R3hdml) and analyzed its function in vivo as well as in vitro. Transforming growth factor-ß (TGF-ß) signaling regulated the expression of R3hdml. And R3hdml inhibited p38 mitogen-activated protein kinase phosphorylation, which was induced by TGF-ß, leading to the amelioration of podocyte apoptosis. Furthermore, a lack of R3hdml in mice significantly worsened glomerular function in streptozotocin (STZ)-induced diabetes, while overexpression of R3hdml ameliorated albuminuria in STZ-induced diabetes. Our results surmise that the functional analyses of R3hdml may lead to the development of novel therapeutic strategies for diabetic nephropathy in the future. KEY MESSAGES: ⢠A novel podocyte expressed protein R3h domain containing-like was identified. ⢠R3HDML inhibits podocyte apoptosis by inhibiting TGF-ß-mediated p38 MAPK signaling. ⢠Overexpression of R3HDML ameliorates albuminuria in STZ-induced diabetes mice. ⢠R3HDML may prove to be a novel therapeutic strategy for diabetic nephropathy.
Subject(s)
Biomarkers , Glomerular Basement Membrane/metabolism , Podocytes/metabolism , Transforming Growth Factor beta/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Diabetic Nephropathies/etiology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Disease Models, Animal , Disease Susceptibility , Glomerular Basement Membrane/pathology , Mice , Podocytes/pathologyABSTRACT
Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts in vitro. On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.