Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

Challenges faced by older people with dementia during the COVID-19 pandemic as perceived by professionals: a qualitative study with interviews.

BACKGROUND: Previous studies have highlighted a decline in the mental health of older adults over the course of the coronavirus disease 2019 (COVID-19) pandemic. Few studies have determined the possible causes of behavioural and psychological symptoms of dementia during COVID-19 in a comprehensive manner. We aimed to identify the challenges faced by older adults with dementia during the COVID-19 pandemic. METHODS: This study adopted a qualitative approach to understanding the perceptions of healthcare professionals, such as regarding the negative effects of COVID-19 on the mental health of people with dementia. Between January and March 2022, the authors conducted individual in-depth interviews on how COVID-19 affected the stress levels, care, and self-determination of people with dementia. Qualitative data from the individual interviews were data cleansed to ensure the clarity and readability of the transcripts. The qualitative data were then analyzed by inductive manual coding using a qualitative content analysis approach. The grouping process involved reading and comparing individual labels to cluster similar labels into categories and inductively formulate themes. RESULTS: Qualitative analysis extracted 61 different semantic units that were duplicated. Seven categories were inductively extracted using a grouping process. These were further integrated to extract the following four themes: fear of personal protective equipment (PPE), loneliness, dissatisfaction with behavioural restrictions and limitations of video calls, and family interference with service use. DISCUSSION: People with dementia often faced mental distress during the pandemic owing to preventive measures against COVID-19, and a lack of awareness and understanding of such preventive measures worsened their distress. They experienced a severe sense of social isolation and loneliness. Findings also indicated that families tended to ignore the needs of people with dementia and their decisions and opinions regarding healthcare service use.

Investigating the perceptions of career development as the Japanese regional quota medical students and graduates in A prefecture.

Background: There are few reports about the perceptions of the regional quota called Chiikiwaku medical students and graduates. Method: Eighty-four medical students and 41 graduates were enrolled in A prefecture. The questionnaire comprised 22 items scored on a 7-point Likert scale, focusing on perceptions of merit and demerit of Chiikiwaku. The data were collected online. Results: Chiikiwaku students scored higher on an item such as 'regional quotas are a solution to the doctor shortage'. Chiikiwaku graduates felt more burdened than Chiikiwaku students. Conclusion: Our results suggested that the perception of Chiikiwaku was different between Chiikiwaku students and graduates.

Dipeptidyl peptidase-4 disturbs adipocyte differentiation via the negative regulation of the glucagon-like peptide-1/adiponectin-cathepsin K axis in mice under chronic stress conditions.

Exposure to chronic psychosocial stress is a risk factor for metabolic disorders. Because dipeptidyl peptidase-4 (DPP4) and cysteinyl cathepsin K (CTSK) play important roles in human pathobiology, we investigated the role(s) of DPP4 in stress-related adipocyte differentiation, with a focus on the glucagon-like peptide-1 (GLP-1)/adiponectin-CTSK axis in vivo and in vitro. Plasma and inguinal adipose tissue from non-stress wild-type (DPP4+/+), DPP4-knockout (DPP4-/-) and CTSK-knockout (CTSK-/-) mice, and stressed DPP4+/+, DPP4-/-, CTSK-/-, and DPP4+/+ mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/or morphological alterations. On day 14 under chronic stress, stress decreased the weights of adipose tissue and resulted in harmful changes in the plasma levels of DPP4, GLP-1, CTSK, adiponectin, and tumor necrosis factor-α proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-α, GLP-1 receptor, peroxisome proliferator-activated receptor-γ, perilipin2, secreted frizzled-related protein-4, Wnt5α, Wnt11 and ß-catenin proteins and/or mRNAs as well as macrophage infiltration in adipose tissue; these changes were rectified by DPP4 deletion. GLP-1 receptor activation and CTSK deletion mimic the adipose benefits of DPP4 deficiency. In vitro, CTSK silencing and overexpression respectively prevented and facilitated stress serum and oxidative stress-induced adipocyte differentiation accompanied with changes in the levels of pref-1, C/EBP-α, and PPAR-γ in 3T3-L1 cells. Thus, these findings indicated that increased DPP4 plays an essential role in stress-related adipocyte differentiation, possibly through a negative regulation of GLP-1/adiponectin-CTSK axis activation in mice under chronic stress conditions.

Japan-Multimodal Intervention Trial for the Prevention of Dementia: A randomized controlled trial.

INTRODUCTION: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI). METHODS: Participants aged 65-85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months. RESULTS: Of 531 participants, 406 completed the trial. The between-group difference in composite score changes was 0.047 (95% CI: -0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels. DISCUSSION: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required. HIGHLIGHTS: This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions.

Impacts of "Diabetes Theater," a participative educational workshop for health care professionals, on participants: a patient empowerment perspective.

Introduction: Patient empowerment, as part of patient-centered care, is important in the treatment of diabetes. However, this concept is still not well-understood by healthcare professionals, because it differs substantially from traditional approaches. We developed the "Diabetes Theater" workshop to promote a better understanding of patient empowerment. The present study sought to characterize the learning experience and impact of Diabetes Theater on participants' perceptions regarding patient empowerment. Methods: We analyzed the data using mixed methods. Quantitative data were collected using a questionnaire with a five-item, 11-point Likert scale derived from the Diabetes Attitude Scale. The qualitative component asked the question "If you had to tell your colleagues at work two things you felt or learned at the Diabetes Theater, what would they be?" Quantitative data were analyzed using t tests, and free-text responses were analyzed using Steps for Coding and Theorization. Results: We received 131 responses. Nurses were the most numerous respondents, followed by dietitians, physicians, and pharmacists. Scores for the five items after participation increased in the direction of promoting participants' understanding of and attitudes toward patient empowerment compared to pre-participation. Scores for most questions increased significantly, regardless of the participants' occupation. In their answers to the open-ended questions, participants reported that they had learned about patient empowerment. Discussion: Diabetes Theater appears to be a useful method for healthcare professionals to accurately understand the philosophy of patient empowerment in diabetes.

Drug-related sarcopenia as a secondary sarcopenia.

Sarcopenia has a significant impact on falls, physical function, activities of daily living, and quality of life in older adults, and its prevention and treatment are becoming increasingly important as the global population ages. In addition to primary age-related sarcopenia, activity-related sarcopenia, disease-related sarcopenia, and nutrition-related sarcopenia have been proposed as secondary sarcopenia. Polypharmacy and potentially inappropriate medication based on multiple diseases cause health problems in older patients. In some cases, drugs used for therapeutic or preventive purposes act on skeletal muscle as adverse drug reactions and induce sarcopenia. Although sarcopenia caused by these adverse drug reactions may be more common in older patients, in particular those taking many medications, drug-related sarcopenia has not yet received much attention. This review summarizes drugs that may induce sarcopenia and emphasizes the importance of drug-related sarcopenia as a secondary sarcopenia. Geriatr Gerontol Int 2024; 24: 195-203.

The association between early rehabilitation and ambulatory ability at discharge in patients with hip fractures at acute-phase rehabilitation wards: a survey of the Japan Association of Rehabilitation Database.

This study aimed to examine the effectiveness of early rehabilitation in patients with femoral neck fractures admitted to acute care settings in Japan using the data registered with the Japan Association of Rehabilitation Databases (JARD). We included data for 401 patients (out of 3088 patients) aged ≥ 65 years (85 males, 316 females) from nine hospitals who sustained a femoral neck fracture between July 2005 and September 2015. Using the number of days until surgery or the number of days until the start of rehabilitation or both as the explanatory variables, and the indoor mobility at discharge as the outcome variable, we calculated the adjusted rate ratio (ARR) and 95% confidence interval (CI) using Poisson regression analysis (age, sex, cognitive impairment, concurrent symptoms, and previous history of fracture adjusted as covariates). The ARR for independent walking at the discharge of the early-rehabilitation group (starting rehabilitation within two days after the injury) was significantly higher (ARR: 2.01, 95% CI: 1.34-3.02) than that of the non-early rehabilitation group. These results suggest that early acute-phase rehabilitation after a femoral neck fracture in older patients allows for better ambulatory ability at discharge, regardless of the time to surgery.

[The current role of advance care planning for people with dementia - A narrative review].

Advance care planning (ACP) for people with dementia, as with other diseases, is a necessary process to realize medical treatment and care in the final stage of a person's life. On the other hand, dementia, a disease that is expected to make it difficult for people to make decisions on their own in the future, has a long course, and is characterized by uncertainty regarding the course of the disease, which may also be a limiting factor in the implementation of ACP for people with dementia. On the other hand, the uncertainties may also be a reason for implementing ACP. This paper reviews reports on ACP initiatives for people with dementia from many countries and presents their characteristics, cultural and customary influences, effects, facilitating and inhibiting factors, and recommendations for implementation, with the aim of promoting future ACP initiatives for people with dementia. The aim of the study was to promote future ACP initiatives for people with dementia.

Cathepsin S activity controls chronic stress-induced muscle atrophy and dysfunction in mice.

Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important role in human pathobiology. Given that cathepsin S (CTSS) is upregulated in the stressed vascular and adipose tissues, we investigated whether CTSS participates in chronic stress-induced skeletal muscle mass loss and dysfunction, with a special focus on muscle protein metabolic imbalance and apoptosis. Eight-week-old male wildtype (CTSS+/+) and CTSS-knockout (CTSS-/-) mice were randomly assigned to non-stress and variable-stress groups. CTSS+/+ stressed mice showed significant losses of muscle mass, dysfunction, and fiber area, plus significant mitochondrial damage. In this setting, stressed muscle in CTSS+/+ mice presented harmful alterations in the levels of insulin receptor substrate 2 protein content (IRS-2), phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, and phospho-mammalian target of rapamycin, forkhead box-1, muscle RING-finger protein-1 protein, mitochondrial biogenesis-related peroxisome proliferator-activated receptor-γ coactivator-α, and apoptosis-related B-cell lymphoma 2 and cleaved caspase-3; these alterations were prevented by CTSS deletion. Pharmacological CTSS inhibition mimics its genetic deficiency-mediated muscle benefits. In C2C12 cells, CTSS silencing prevented stressed serum- and oxidative stress-induced IRS-2 protein reduction, loss of the myotube myosin heavy chain content, and apoptosis accompanied by a rectification of investigated molecular harmful changes; these changes were accelerated by CTSS overexpression. These findings demonstrated that CTSS plays a role in IRS-2-related protein anabolism and catabolism and cell apoptosis in stress-induced muscle wasting, suggesting a novel therapeutic strategy for the control of chronic stress-related muscle disease in mice under our experimental conditions by regulating CTSS activity.

Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway.

To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.

Cathepsin S deficiency improves muscle mass loss and dysfunction via the modulation of protein metabolism in mice under pathological stress conditions.

Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non-enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress-related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight-week-old male wildtype (CTSS+/+ ) and CTSS-knockout (CTSS-/- ) mice were randomly assigned to non-stress and variable-stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non-stressed mice, stressed CTSS+/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress-induced harmful changes in the levels of oxidative stress-related (gp91phox and p22phox ,), inflammation-related (SDF-1, CXCR4, IL-1ß, TNF-α, MCP-1, ICAM-1, and VCAM-1), mitochondrial biogenesis-related (PPAR-γ and PGC-1α) genes and/or proteins and protein metabolism-related (p-PI3K, p-Akt, p-FoxO3α, MuRF-1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS-/- mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress-related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress-related muscular diseases.

Effect of drugs on nutritional status and drug-nutrition interactions in older patients.

Older patients are prone to multimorbidity or related polypharmacy, which may cause various adverse drug reactions (ADRs) and a high incidence of drug-related health problems. Although not often noted, ADRs include nutrition-related adverse reactions. Aging, multiple illnesses, mental and psychological problems, declining physical function, and environmental factors can lead to decreased food intake and increased metabolic stress in older people, resulting in energy imbalances that cause malnutrition. ADRs can lead to appetite loss, followed by decreased food intake, which in turn causes malnutrition and deficiencies of various nutrients. However, these nutrition-related ADRs have received less attention. This review article describes drug-nutrition interactions, with a particular focus on older patients. Geriatr Gerontol Int 2023; 23: 465-477.

CTSS Modulates Stress-Related Carotid Artery Thrombosis in a Mouse FeCl3 Model.

BACKGROUND: Exposure to chronic psychological stress is a risk factor for metabolic cardiovascular disease. Given the important role of lysosomal CTSS (cathepsin S) in human pathobiology, we examined the role of CTSS in stress-related thrombosis, focusing on inflammation, oxidative stress, and apoptosis. METHODS: Six-week-old wild-type mice (CTSS+/+) and CTSS-deficient mice (CTSS-/-) randomly assigned to nonstress and 2-week immobilization stress groups underwent iron chloride3 (FeCl3)-induced carotid thrombosis surgery for morphological and biochemical studies. RESULTS: On day 14 poststress/surgery, stress had increased the lengths and weights of thrombi in the CTSS+/+ mice, plus harmful changes in the levels of PAI-1 (plasminogen activation inhibitor-1), ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 13 motifs), and vWF (von Willebrand factor) and arterial tissue CTSS expression. Compared to the nonstressed CTSS+/+ mice, the stressed CTSS-/- mice had decreased levels of PAI-1, vWF, TNF (tumor necrosis factor)-α, interleukin-1ß, toll-like receptor-4, cleaved-caspase 3, cytochrome c, p16INK4A, gp91phox, p22phox, ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein-1), MyD88 (myeloid differentiation primary response 88), and MMP (matrix metalloproteinase)-2/-9 and increased levels of ADAMTS13, SOD (superoxide dismutase)-1/-2, eNOS (endothelial NO synthase), p-Akt (phospho-protein kinase B), Bcl-2 (B-cell lymphoma-2), p-GSK3α/ß (phospho-glycogen synthase kinases alpha and beta), and p-Erk1/2 (phospho-extracellular signal-regulated kinase 1 and 2) mRNAs and/or proteins. CTSS deletion also reduced the arterial thrombus area and endothelial loss. A pharmacological inhibition of CTSS exerted a vasculoprotective action. In vitro, CTSS silencing and overexpression, respectively, reduced and increased the stressed serum and oxidative stress-induced apoptosis of human umbilical vein endothelial cells, and they altered apoptosis-related proteins. CONCLUSIONS: CTSS inhibition appeared to improve the stress-related thrombosis in mice that underwent FeCl3-induction surgery, possibly by reducing vascular inflammation, oxidative stress, and apoptosis. CTSS could thus become a candidate therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disease.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

Total pain in advanced dementia: a quick literature review.

Objective: This quick literature review aimed to organize information on the detailed components of total pain in older people with advanced dementia in a holistic manner. Materials and Methods: The authors analyzed qualitative data from relevant clinical guidelines or textbooks, focusing on certain types of pain and distress in older people with advanced dementia, followed by an expert panel review by research team members. In the search, the authors defined a person with advanced dementia as having a functional assessment staging tool scale score greater than or equal to six. Results: The model covered a wide variety of pain, from physical pain to dementia-related psychological and spiritual aspects of total pain, including living environment change, stigma, discrimination, lack of communication and understanding, loss of sense of control and dignity, and cultural distress. It also identified physical appearance as an important factor in dying with dignity, as established by existing research on individuals with incurable cancers. Conclusion: The conceptual model of total pain in people with advanced dementia is expected to help turn healthcare professionals' attention to physical, psychological, social, and spiritual contributors to total pain in advanced dementia.

Early-onset Alzheimer Disease Associated With Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. Although recent reports have noted that cognitive impairment is common in NMOSD, little longitudinal information is available on the trajectories of cognitive function in the disease. Here, we report a case of a 55-year-old woman with an 11-year history of NMOSD who visited our memory clinic for progressive memory loss. She was diagnosed with early-onset Alzheimer disease based on amyloid and tau positron emission tomography imaging biomarkers. This is the first report of early-onset Alzheimer disease in a patient with NMOSD. Complications of Alzheimer disease should be considered when patients with NMOSD exhibit rapid cognitive decline. More longitudinal studies of NMOSD with cognitive impairment are needed.

Nutritional Management of Sarcopenia and Frailty-Shift from Metabolic Syndrome to Frailty.

Older adults have physical and metabolic characteristics, and there are many differences in nutritional outcomes from middle-aged adults. In addition, there are many factors that cause malnutrition peculiar to the older adults, which are not seen in middle-aged adults, and it is easy for them to lose weight and become malnourished. Therefore, nutritional management needs to take into account the age of each subject. Uniform nutritional management can even cause poor health outcomes. The concept of frailty, especially phenotype frailty, and sarcopenia, which have been advocated with the aging of the population and the extension of life expectancy around the world, is very important in considering the extension of healthy life expectancy. In other words, in the super-aged society, frailty and sarcopenia have been emphasized as factors of functional decline, physical dysfunction, and the need for long-term care in addition to the well-known diseases such as cardiovascular disease, malignant tumors, and infectious disease. In fact, these two conditions are strongly associated with the increased risk of new disease development, falls, fractures, disability, hospitalization and death in the older adults. These two conditions are primarily associated with malnutrition and decreased dietary protein intake, and may recover to robustness again with appropriate interventions such as nutritional therapy. Therefore, undernutrition measures are more important for prevention of frailty and sarcopenia than measures for obesity against metabolic syndrome in the older adults, especially in the late-stage older people.