Cigarette smoking and progression of kidney dysfunction: a longitudinal cohort study.

INTRODUCTION: Cigarette smoking is one of the most important life-modifiable risk factors for CVD events. The effect on CKD progression caused by smoking remained uncertain, while the effect on CVD had been established. METHOD: The study population included participants from the specific health check and specific health guidance, an annual health check-up for all inhabitants of Japan who were aged between 40 and 74 years. 149,260 subjects (male, 37.1%; female, 62.9%) were included in this analysis. RESULTS: The relationship between smoking status along with new-onset proteinuria and eGFR deterioration more than 15 mL/min/1.73 m2 was examined. Median observation periods were 1427 days [738, 1813] in males and 1437 days [729, 1816] in females. In male participants, the strongest factor upon kidney dysfunction was new-onset proteinuria (1.41 [1.31 1.51], P < 0.001). The second strongest factor on kidney deterioration was smoking (1.24 [1.16 1.31], P < 0.001). In female participants, strongest factor upon kidney dysfunction was smoking (1.27 [1.16-1.39], P < 0.001). The second strongest factor on kidney deterioration was new-onset proteinuria (1.26 [1.17 1.36], P < 0.001). To reveal the relationship of effects from new-onset proteinuria and smoking on the kidney function, the participants were divided into four groups with and without new-onset proteinuria and smoking. The group with both proteinuria and smoking had significantly worst renal prognosis (P for trend < 0.001). CONCLUSION: Large longitudinal observation study revealed smoking has an evil effect on the progression of CKD. This evil effect could be observed in CKD patients with proteinuria as well as in general population without new-onset proteinuria.

Estrogen contributes to the sex difference in the occurrence of senescence-related T cells during the development of visceral adipose tissue inflammation.

It remains unclear whether sex differences exist during the development of visceral adipose tissue (VAT) inflammation associated with obesity. The purpose of this study was to clarify sex differences in the occurrence of senescence-related T cells (CD44high PD-1+ CD4+), which play a key role in the progression of VAT inflammation associated with high-fat diet (HFD)-induced obesity. Phase 1: C57BL/6N mice were fed either a control diet (HFC) or HFD for 5 wk. The area under the curve of the oral glucose-tolerance test (oGTT) was maximal at 15 wk in HFD-fed males and at 21 wk in females. At 17 wk, VAT weights were similar, but an increase in the number of macrophages in the VAT was observed only in HFD-fed males. In addition, the numbers of regulatory and senescence-related T cells were consistently higher in males than in females. Phases 2 and 3: 6-wk-old female mice were randomly divided into sham operation and bilateral ovariectomy (OVX) groups and fed either an HFC or HFD from 7 wk. OVX mice were subjected to 17ß-estradiol releasing or placebo pellet implantation and fed an HFC. Body and VAT weights were higher in the OVX group than in the sham. The number of macrophages did not change in the OVX group with either diet. HFC-fed OVX mice exhibited high senescence-related T cells in the VAT, resembling HFC-fed male mice. This change was abolished by 17ß-estradiol replacement. Thus, we demonstrated different accumulation patterns of VAT immune cells between the sexes, revealing a role for estrogen in the appearance of senescence-related T cells.NEW & NOTEWORTHY The accumulation pattern of adipose tissue differs between the sexes; however, it is unclear whether sex differences exist during the development of adipose tissue inflammation and whether estrogen plays a role. We demonstrated sex differences in immune cells' subpopulation of visceral adipose tissue. The proinflammatory environment appeared earlier in males than in females. In addition, our results suggest that estrogen plays a role in visceral adipose tissue inflammation, particularly by regulating the appearance of senescence-related T cells.

Decline of instrumental activities of daily living is a risk factor for nutritional deterioration in older adults: a prospective cohort study.

BACKGROUND: The association between functional capacity and the subsequent risk of nutritional deterioration is yet to be understood. The purpose of this study was to elucidate the relationship between functional capacity, comprising instrumental activities of daily living (IADL), intellectual activity, and social function, and future decline in nutritional status. METHODS: The current study is a two-year prospective cohort study. A total of 468 community-dwelling older adults without nutritional risks were enrolled. We used the Mini Nutritional Assessment Screening Form. Functional capacity, including IADL, intellectual activity, and social function, was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline. The nutritional status was reassessed at a 2-year follow-up. Risk ratios (RR) of functional capacity for the incidence of nutritional decline were estimated. RESULTS: Low functional capacity was significantly associated with future deterioration of nutritional status (RR 1.12, 95% confidence interval [CI] 1.02-1.25). Of the subdomains of functional capacity, IADL decline (adjusted RR 2.21, 95% CI 1.18-4.13) was an independent risk factor for the incidence of nutritional risk. Intellectual and social activities were not significant. CONCLUSION: Decline in functional capacity, especially IADL, is a risk factor for future deterioration in nutritional status. Further studies are required to elucidate the effect of interventions for IADL decline on maintaining nutritional status in older adults.

[Association between physical activity and apathy among community-dwelling older adults].

AIM: To determine the association between physical activity and apathy in community-dwelling older adults. METHODS: This was a cross-sectional study. Apathy was assessed using three sub-items from the Geriatric Depression Scale 15 (GDS-3A) on apathy syndrome. Physical activity was measured using a wrist-worn accelerometer. Exercise intensity was classified as sedentary behavior, light-intensity physical activity, or moderate-to-vigorous-intensity physical activity. A logistic regression analysis was used to examine the association between apathy and physical activity for each exercise intensity level. RESULTS: Seven-hundred and eighty-four participants (age 72.7±5.9 years old) were included. Of those, 103 (13.1%) were in the apathy group. A multivariate analysis adjusted for demographic factors revealed that decreased total physical activity (odds ratio [OR] = 0.947, 95% confidence interval [CI] = 0.912-0.984, p = 0.005), light-intensity physical activity (OR = 0.941, 95% CI = 0.899-0.985, p = 0.009), and increased sedentary behavior (OR = 1.002, 95% CI = 1.001-1.003, p = 0.007) were associated with a greater OR of apathy, although moderate-to-vigorous-intensity physical activity was not significant (OR = 0.916, 95% CI = 1.826-1.017, p = 0.100). However, in the final model adjusted for depressive symptoms and functional factors, the association was not found to be significant, and a strong association was observed between depressive symptoms and apathy. CONCLUSION: Physical activity in older adults with apathy symptoms was decreased in this study. However, the associations seemed to be strongly affected by depressive symptoms, and physical activity was not independently associated with apathy.

Relationships between cystatin C- and creatinine-based eGFR in Japanese rural community- dwelling older adults with sarcopenia.

BACKGROUND: Sarcopenia is prevalent in patients with chronic kidney disease (CKD). The indices of physical function, such as grip power and gait speed, decreased according to the decline in the estimated glomerular filtration rate (eGFR). METHODS: We examined the relationships between cystatin C-based GFR (eGFRcys), creatinine-based GFR (eGFRcre), their ratio (eGFRcys/eGFRcre) and sarcopenia in community-dwelling older adults in Japan. This cross-sectional study included 302 men aged 73.9 ± 6.2 years and 647 women aged 72.9 ± 5.8 years from a rural area in Hyogo Prefecture, Japan. eGFRcys and eGFRcre were simultaneously measured, and sarcopenia based on the Asia Working Group for Sarcopenia (AWGS) 2019 criteria was evaluated. RESULTS: eGFRcys and the eGFRcys/eGFRcre ratio were significantly correlated with grip power and gait speed (p < 0.001). The eGFRcys/eGFRcre ratio was also correlated with skeletal muscle mass index (SMI) (p < 0.01). Univariate logistic regression analysis showed eGFRcys and eGFRcys/eGFRcre ratio but not eGFRcre were associated with sarcopenia (p < 0.01). The presence of low eGFRcys (CKDcys) and low eGFRcys/eGFRcre ratio (< 1.0) but not that of low eGFRcre (CKDcre) were associated with sarcopenia (p < 0.01). In the multivariate logistic regression analysis, when the eGFRcys/eGFRcre ratio was added as a covariate to the basic model, it was significantly associated with sarcopenia in women (p < 0.05). Moreover, low eGFRcys/eGFRcre ratio (< 1.0) was associated with a higher risk of sarcopenia in men (p < 0.01). CONCLUSION: In conclusion, CKDcys but not CKDcre is associated with sarcopenia. A lower eGFRcys/eGFRcre ratio may be a practical screening marker of sarcopenia in community-dwelling older adults.

The relationship between bone density and the oral function in older adults: a cross-sectional observational study.

BACKGROUND: Falls among older adults with a low bone density can lead to a bedridden state. Declining bone density increases the risk of falls resulting fractures in older adults. A person's physical performance is known to be closely related to bone density, and a relationship between the physical performance and the oral function is also known to exist. However, there currently is a lack of evidence regarding the relationship between bone density and the oral function. We assessed the relationship between the bone density and the both the oral function and physical performance among older adults. PATIENTS AND METHODS: 754 older adults aged 65 years or older who independently lived in rural regions and who were not taking any medications for osteoporosis participated. We checked all participants for osteoporosis using an ultrasonic bone density measuring device. Regarding the oral function, we evaluated the following factors: remaining teeth, occlusal support, masticatory performance, occlusal force, and tongue pressure. We also evaluated body mass index (BMI) and skeletal muscle mass Index as clinical characteristics. The normal walking speed, knee extension force and one-leg standing test were evaluated as physical performance. For the statistical analyses, we used the Mann-Whitney U test, chi-square test, the Kruskal-Wallis, and a multiple regression analysis. RESULTS: Eighty-one percent of the females and 58% of the males had osteoporosis or a decreased bone mass. The occlusal force, masticatory performance and the tongue pressure showed significant association with the bone density. The participants physical performance showed a significant association with their bone states except for walking speed. According to a multiple regression analysis, clinical characteristics (sex, age, BMI), one-leg standing and occlusal force showed independent associations with the bone density. It was suggested that the bone density tends to increase if the occlusal force is high and/or the one-leg standing test results are good. CONCLUSIONS: The bone density in the older adults showed a significant relationship not only with clinical characteristics or physical performance, but also with occlusal force. It may also be effective to confirm a good oral function in order to maintain healthy living for older adults.

Prevalence of anti-cyclic citrullinated peptide antibodies in patients with spondyloarthritis: A retrospective study.

OBJECTIVES: Anti-cyclic citrullinated peptide (CCP) antibodies are frequently detected in the sera of patients with rheumatoid arthritis (RA). However, recent studies have revealed a potentially high prevalence rate of these antibodies in patients with other rheumatic disorders, causing confusion while diagnosing RA. Therefore, this study aimed to evaluate the positive rate of anti-CCP antibodies in other chronic arthritis diseases focusing on patients with spondyloarthritis (SpA). METHODS: A total of 109 patients who were diagnosed with SpA at Yukioka Hospital from 1993 to 2018 were included in this retrospective analysis, including patients with ankylosing spondylitis (AS); psoriatic arthritis (PsA); synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO); undifferentiated spondyloarthritis (uSpA); reactive arthritis (ReA); and inflammatory bowel disease-associated SpA (IBD). RESULTS: Overall, 15.3% (16/109) of patients with SpA were positive for anti-CCP antibodies, including 2.3% (1/43) in AS, 23.1% (3/13) in SAPHO, 35.0% (7/20) in PsA, 14.8% (4/27) in uSpA, 0% (0/3) in ReA, and 33.3% (1/3) in IBD. CONCLUSION: PsA patients have a significantly higher prevalence rate of positive anti-CCP antibodies among SpA patients, and the positive rates in SAPHO and uSpA were also high. These findings provide insight into the heterogeneity of SpA with relevance for RA differential diagnosis.

Palmitate induces cardiomyocyte death via inositol requiring enzyme-1 (IRE1)-mediated signaling independent of X-box binding protein 1 (XBP1).

Overloading of the saturated fatty acid (SFA) palmitate induces cardiomyocyte death. The purpose of this study is to elucidate signaling pathways contributing to palmitate-induced cardiomyocyte death. Palmitate-induced cardiomyocyte death was induced in Toll-like receptor 2/4 double-knockdown cardiomyocytes to a similar extent as wild-type cardiomyocytes, while cardiomyocyte death was canceled out by triacsin C, a long-chain acyl-CoA synthetase inhibitor. These results indicated that palmitate induced cytotoxicity after entry and conversion into palmitoyl-CoA. Palmitoyl-CoA is not only degraded by mitochondrial oxidation but also taken up as a component of membrane phospholipids. Palmitate overloading causes cardiomyocyte membrane fatty acid (FA) saturation, which is associated with the activation of endoplasmic reticulum (ER) unfolded protein response (UPR) signaling. We focused on the ER UPR signaling as a possible mechanism of cell death. Palmitate loading activates the UPR signal via membrane FA saturation, but not via unfolded protein overload in the ER since the chemical chaperone 4-phenylbutyrate failed to suppress palmitate-induced ER UPR. The mammalian UPR relies on three ER stress sensors named inositol requiring enzyme-1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Palmitate loading activated only IRE1 and PERK. Knockdown of PERK did not affect palmitate-induced cardiomyocyte death, while knockdown of IRE1 suppressed palmitate-induced cardiomyocyte death. However, knockdown of X-box binding protein 1 (XBP1), the downstream effector of IRE1, did not affect palmitate-induced cardiomyocyte death. These results were validated by pharmacological inhibitor experiments. In conclusion, we identified that palmitate-induced cardiomyocyte death was triggered by IRE1-mediated signaling independent of XBP1.

Physical frailty predicts the development of social frailty: a prospective cohort study.

BACKGROUND: It has not been clarified whether physical frailty symptoms predict social. frailty. The purpose of this study was to elucidate the effect of physical frailty on social frailty, and to determine which domains of physical frailty predict the development of social frailty. METHODS: We employed a two-year prospective cohort study. A total of 342 socially robust community-dwelling older adults were recruited. We used a modified social frailty screening index consisting of four social domains including financial difficulties, living alone, social activity, and contact with neighbors. Physical frailty status was also assessed at baseline. At the two-year follow-up, we assessed the development of social frailty. Social status was assessed using four social subdomains for the primary analysis. Social status was assessed using the two social subdomains of social activity and contact with neighbors, which would be affected by the physical frailty component, for the secondary analysis. The risk ratios (RR) of physical frailty for the development of social frailty were estimated. RESULTS: Although physical frailty symptoms were not a significant risk factor for future development of social frailty as assessed by four social subdomains (adjusted RR 1.39, 95% CI 0.95-2.15), it became significant when development of social frailty was assessed by the two social subdomains (adjusted RR 1.78, 95% CI 1.10-2.88). An analysis using the physical frailty subdomain showed that slow gait speed (adjusted RR 3.41, 95% CI 1.10-10.53) and weakness (adjusted RR 1.06, 95% CI 1.01-1.12) were independent risk factors for development of social frailty as assessed by two social subdomains. CONCLUSIONS: Physical frailty symptoms predict the development of social frailty. Among physical frailty subdomains, gait speed and muscle strength are critical independent risk factors for future decline in the social aspect. The prevention of physical frailty, especially by maintaining gait ability and muscle strength, may be effective for avoiding social frailty.

Basic survey for the prevention of intraoral residual medication in older adults: A pilot study.

OBJECTIVE: This study aimed to assess the relationship between oral hygiene/stomatognathic function and residual intraoral medication in older adults and to identify the oral factors associated with residual oral medication. METHODS: The study included 309 older adults (77 men, 232 women, mean age: 74.1 ± 7.4 years) who were prescribed medications at regular intervals. The following survey items were assessed: overall physical condition, intraoral condition and oral function. Participants prescribed oral medication were classified into groups with and without residual medication in the oral cavity. Statistical analysis was performed using univariate analysis for each of the factors contributing to the presence of residual medication. RESULTS: Only 1.9% of all patients had residual medication, which suggests that older adults in this survey had a low risk of residual intraoral medication. However, greater attention should be given to residual intraoral medication in older adults receiving long-term care. Powdered-form oral medications were more likely to remain in the oral cavity. Older adults with residual medication had a tendency to have less occlusal support, poor tongue hygiene and poor tongue movement. Oral function, particularly functions that are closely related to swallowing, was significantly lower in the residual intraoral medication group when compared to those of the group without residual intraoral medication. CONCLUSIONS: Reduced oral function and powered medication were associated with greater residual intraoral medication in this sample of older Japanese adults.

Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload.

BACKGROUND: The fatty acid (FA) composition of membrane phospholipid reflects at least in part dietary fat composition. Saturated FA (SFA) suppress Sirt1 activity, while monounsaturated FA (MUFA) counteract this effect. OBJECTIVE: We explored a role of Sirt1 in homeostatic control of the fatty acid composition of membrane phospholipid in the presence of SFA overload. METHODS AND RESULTS: Sirt1 deficiency in cardiomyocytes decreased the expression levels of liver X receptor (LXR)-target genes, particularly stearoyl-CoA desaturase-1 (Scd1), a rate-limiting enzyme in the cellular synthesis of MUFA from SFA, increased membrane SFA/MUFA ratio, and worsened left ventricular (LV) diastolic function in mice fed an SFA-rich high fat diet. In cultured cardiomyocytes, Sirt1 knockdown (KD) exacerbated the palmitate overload-induced increase in membrane SFA/MUFA ratio, which was associated with decrease in the expression of LXR-target genes, including Scd1. Forced overexpression of Scd1 in palmitate-overloaded Sirt1KD cardiomyocytes lowered the SFA/MUFA ratio. Nicotinamide mononucleotide (NMN) increased Sirt1 activity and Scd1 expression, thereby lowering membrane SFA/MUFA ratio in palmitate-overloaded cardiomyocytes. These effects of NMN were not observed for Scd1KD cardiomyocytes. LXRα/ßKD exacerbated palmitate overload-induced increase in membrane SFA/MUFA ratio, while LXR agonist T0901317 alleviated it. NMN failed to rescue Scd1 protein expression and membrane SFA/MUFA ratio in palmitate-overloaded LXRα/ßKD cardiomyocytes. The administration of NMN or T0901317 showed a dramatic reversal in membrane SFA/MUFA ratio and LV diastolic function in SFA-rich HFD-fed mice. CONCLUSION: Cardiac Sirt1 counteracted SFA overload-induced decrease in membrane phospholipid unsaturation and diastolic dysfunction via regulating LXR-mediated transcription of the Scd1 gene.

Relationship between oral environment and frailty among older adults dwelling in a rural Japanese community: a cross-sectional observational study.

BACKGROUND: Oral functions are known to decline with aging. However, there is limited evidence that supports the relationship between oral health and frailty. This study aimed to clarify the relationship between oral hygiene conditions, measured by remaining teeth and mucosa, and frailty among elderly people dwelling in a Japanese rural community. METHODS: We surveyed self-reliant elderly individuals aged ≥65 years who were dwelling in the Sasayama-Tamba area of Hyogo, Japan. Frailty was evaluated according to the total score of the Kihon Checklist (KCL). Based on the KCL score, elderly participants were divided into three groups: robust, pre-frail, and frail. The items measured to evaluate oral environment included the number of remaining teeth, denture usage condition, oral hygiene status, dry mouth condition, and salivary bacterial count. For statistical analysis, Fisher's exact test, one-way analysis of variance, and multiple comparison technique were used. RESULTS: Of 308 elderly participants, 203 (65.9%), 85 (27.6%), and 20 (6.5%) belonged to the robust, pre-frail, and frail groups, respectively. The proportion of participants who were judged to have poor hygiene was significantly higher in the frail group than in the other two groups. The bacterial count was significantly smaller in the frail group than in the robust group, and the frail group had fewer number of remaining teeth than the other two groups, suggesting that the number of remaining teeth may be associated with bacterial count. CONCLUSION: In elderly adults, physical frailty may affect the oral hygiene status and condition of the remaining teeth.

Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture.

RATIONALE: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. OBJECTIVE: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. METHODS AND RESULTS: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. CONCLUSIONS: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.

Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.

Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting that cardiac Sirt1 regulates the local complement system during CR.

Lung natural killer cells play a major counter-regulatory role in pulmonary vascular hyperpermeability after myocardial infarction.

RATIONALE: Natural killer (NK) cells are lymphocytes of the innate immune system that play specialized and niche-specific roles in distinct organs. OBJECTIVE: We investigated the possible function of NK cells in the pathogenesis of congestive heart failure after myocardial infarction. METHODS AND RESULTS: Depletion of NK cells from mice had little effect on cytokine expression (tumor necrosis factor-α, interleukin [IL]-6, and IL-1ß), neutrophil and macrophage infiltration into infarcted myocardium, or left ventricular remodeling after myocardial infarction. However, these mice exhibited severe respiratory distress associated with protein-rich, high-permeability alveolar edema accompanied by neutrophil infiltration. In addition, there were 20-fold more NK cells in the mouse lungs than in heart, and these cells were accumulated around the vasculature. CD107a-positive and interferon-γ-positive cell populations were unchanged, whereas IL-10-positive populations increased. Adoptive transfer of NK cells from wild-type mice, but not from IL-10 knockout mice, into the NK cell-depleted mice rescued the respiratory phenotype. IL-1ß-mediated dextran leakage from a lung endothelial cell monolayer was also blocked by coculture with NK cells from wild-type mice but not from IL-10 knockout mice. CONCLUSIONS: This study is the first to identify a critical role for lung NK cells in protecting lung from the development of cardiogenic pulmonary edema after myocardial infarction.

Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart.

Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. (13)C6-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart.

Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.

Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with N(G)-nitro-l-arginine methyl ester completely abrogates CR-induced cardioprotection and increases nuclear sirtuin 1 (Sirt1) expression. However, it remains unclear whether endothelial nitric oxide (NO) synthase (eNOS) plays a role in CR-induced cardioprotection and Sirt1 activation. We subjected eNOS-deficient (eNOS(-/-)) mice to either 3-mo ad libitum (AL) feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia followed by 60-min reperfusion. The degree of myocardial IRI in AL-fed eNOS(-/-) mice was more severe than that in AL-fed wild-type mice. Furthermore, CR did not exert cardioprotection in eNOS(-/-) mice. eNOS(-/-) mice exhibited elevated blood pressure and left ventricular hypertrophy compared with wild-type mice, although they underwent CR. Although nuclear Sir1 content was increased, the increases in cardiac Sirt1 activity with CR was absent in eNOS(-/-) mice. In eNOS(-/-) mice treated with hydralazine, blood pressure and left ventricular weight became comparable with CR-treated wild-type mice. However, CR-induced cardioprotection was not observed. Resveratrol enhanced cardiac Sirt1 activity but failed to mimic CR-induced cardioprotection in eNOS(-/-) mice. Finally, combination therapy with resveratrol and hydralazine attenuated myocardial IRI and reduced infarct size in eNOS(-/-) mice, and their effects were comparable with those observed in CR-treated wild-type mice. These results demonstrate the essential roles of eNOS in the development of CR-induced cardioprotection and Sirt1 activation during CR. The combination of a relatively low dose of resveratrol with an adequate vasodilator therapy might be useful for managing patients with endothelial dysfunction associated with impaired NO bioavailability.

Relationship between the characteristics of Japanese physicians involved in medical care for older adults and their approaches to treating older patients with multimorbidity.

One countermeasure against the increasing prevalence of multimorbidity is the need to provide clinical education and training that considers the characteristics of physicians. We conducted a questionnaire survey to determine the relationship between physicians' characteristics and their approach to treating older patients with multimorbidity. A total of 3300 geriatric specialists and primary care specialists in Japan were enrolled. A 4-point Likert scale was used to score the following items: difficult diseases (43 items), difficult patient backgrounds (14 items), important clinical factors (32 items), and important clinical management (32 items). Exploratory factor analysis was performed to examine the constructs in each of the scales Diseases, Backgrounds, Clinical Factors, and Clinical Management, and group comparisons by physician characteristics were conducted. A total of 778 respondents were included in the analysis. Six factors for Diseases, two factors for Patient Background, four factors for Clinical Factors, and two factors for Clinical Management were explored as patterns. Group comparison between mean scores for each factor and the characteristics of responding physicians showed statistically significant differences in at least one factor for all patterns in terms of years of experience as a physician (26 years or less, 27 years or more), the clinical setting (providing or not providing home medical care), and sex (male or female). Our results suggest a need for clinical education and training that takes into account not only physicians' experience and clinical setting, but also their sex.

Association between Bone Quality and Physical Activity in Community-Dwelling Older Adults.

Bone quality is an essential factor determining bone strength. However, the relationship between physical activity (PA) and bone quality remains unclear. This study aimed to ascertain the relationship between bone quality and PA using a cortical bone quantitative ultrasound device that measures components of bone quality. In this cross-sectional study, bone quality was assessed in community-dwelling older adults by measuring the cortical speed of sound (cSOS) at the mid-tibia using a quantitative ultrasound device. Using a wrist-worn accelerometer, we calculated the daily duration of moderate-to-vigorous physical activity (MVPA) and light physical activity (LPA) based on estimated METs from the accelerometer data, without differentiating between types of activities. A multiple regression analysis was performed to examine the association between PA and the cSOS. The participants' physical activity averaged 42.0 min/day for MVPA and 483.6 min/day for LPA. No significant association was observed between PA and bone quality in either men or women in the crude models. Furthermore, PA was not significantly correlated with the cSOS in the models adjusted for age, body mass index, nutrient intake, number of medications, and kidney disease. This study was a cross-sectional study which focused on the association between bone quality in older adults and their current amount of PA. The cSOS, as a measure of bone quality, was not associated with PA in men or women. Higher amounts of daily PA, as estimated from metabolic equivalents with an accelerometer, may not necessarily maintain or improve bone quality in older adults. This study does not rule out the potential for a positive association between PA levels or types and bone quality in younger or middle-aged individuals. It was specifically targeted at older adults, and its findings should not be generalized to younger populations. Further longitudinal studies are required to better understand the relationship between PA and bone quality.