Factors associated with the oral health status of patients with schizophrenia: A cross-sectional study.

BACKGROUND: Oral function deterioration attributed to ageing and medications is one of the main contributory factors of dysphagia. Therefore, oral health management is essential in older patients with schizophrenia. However, no previous studies have evaluated the oral function in patients with schizophrenia. OBJECTIVE: We surveyed patients with schizophrenia to identify factors associated with ageing-related variations in oral function. METHODS: This cross-sectional study included 34 male patients diagnosed with schizophrenia who were hospitalised at a psychiatric hospital between July and September 2021 and underwent a screening examination during dental care. The survey items included basic information, oral hygiene information, oral (oral diadochokinesis [ODK] and tongue pressure), physical function, and nutritional status. Thirty-six male community-dwelling older individuals were included as controls, and their outcomes were compared with those of patients with schizophrenia. RESULTS: Compared with healthy older adults, patients with schizophrenia demonstrated significantly lower teeth numbers, ODK, and calf circumference (CC) (p < .05). Multiple regression analysis revealed that ODK was associated with age and schizophrenia (p < .05). Conversely, tongue pressure was associated with CC (p < .05), suggesting different factors' association with the parameters indicating decreased oral function. CONCLUSIONS: Our study findings suggest that older patients with schizophrenia have decreased tongue pressure and generalised muscle mass, highlighting the need to manage oral function. Interventions for tongue pressure were more strongly associated with muscle mass and could be easier to manage than those with disease-dependent changes in ODK. TRIAL REGISTRATION: Retrospectively registered.

Role of Common Antihypertensives in the Growth of Abdominal Aortic Aneurysm at the Presurgical Stage.

Background: Whether drug therapy slows the growth of abdominal aortic aneurysms (AAAs) in the Japanese population remains unknown. Methods and Results: In a multicenter prospective open-label study, patients with AAA at the presurgical stage (mean [±SD] AAA diameter 3.27±0.58 cm) were randomly assigned to treatment with candesartan (CAN; n=67) or amlodipine (AML; n=64) considering confounding factors (statin use, smoking, age, sex, renal function), with effects of blood pressure control minimized setting a target control level. The primary endpoint was percentage change in AAA diameter over 24 months. Secondary endpoints were changes in circulating biomarkers (high-sensitivity C-reactive protein [hs-CRP], malondialdehyde-low-density lipoprotein, tissue-specific inhibitor of metalloproteinase-1, matrix metalloproteinase [MMP] 2, MMP9, transforming growth factor-ß1, plasma renin activity [PRA], angiotensin II, aldosterone). At 24 months, percentage changes in AAA diameter were comparable between the CAN and AML groups (8.4% [95% CI 6.23-10.59%] and 6.5% [95% CI 3.65-9.43%], respectively; P=0.23]. In subanalyses, AML attenuated AAA growth in patients with comorbid chronic kidney disease (CKD; P=0.04) or systolic blood pressure (SBP) <130 mmHg (P=0.003). AML exhibited a definite trend for slowing AAA growth exclusively in never-smokers (P=0.06). Among circulating surrogate candidates for AAA growth, PRA (P=0.02) and hs-CRP (P=0.001) were lower in the AML group. Conclusions: AML may prevent AAA growth in patients with CKD or lower SBP, associated with a decline in PRA and circulating hs-CRP.

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.

Adipolin protects against renal injury via PPARα-dependent reduction of inflammasome activation.

Although chronic kidney disease (CKD) is a major health problem worldwide, its underlining mechanism is incompletely understood. We previously identified adipolin as an adipokine which provides benefits for cardiometabolic diseases. Here, we investigated the role of adipolin in the development of CKD. Adipolin-deficiency exacerbated urinary albumin excretion, tubulointerstitial fibrosis and oxidative stress of remnant kidneys in mice after subtotal nephrectomy through inflammasome activation. Adipolin positively regulated the production of ketone body, ß-hydroxybutyrate (BHB) and expression of a catalytic enzyme producing BHB, HMGCS2 in the remnant kidney. Treatment of proximal tubular cells with adipolin attenuated inflammasome activation through the PPARα/HMGCS2-dependent pathway. Furthermore, systemic administration of adipolin to wild-type mice with subtotal nephrectomy ameliorated renal injury, and these protective effects of adipolin were diminished in PPARα-deficient mice. Thus, adipolin protects against renal injury by reducing renal inflammasome activation through its ability to induce HMGCS2-dependent ketone body production via PPARα activation.

Effect of febuxostat on the level of malondialdehyde-modified low-density lipoprotein, an oxidative stress marker: A subanalysis of the PRIZE study.

BACKGROUND: Febuxostat is a selective xanthine oxidase inhibitor that reportedly exhibits antioxidant properties. We previously performed a multicentre, randomized controlled (PRIZE) study for vascular evaluation under uric acid (UA) control by febuxostat to investigate the progression of carotid lesions in asymptomatic hyperuricemic patients with carotid atherosclerosis for 2 years. HYPOTHESIS: The current subanalysis of the PRIZE study aimed to assess the effect of febuxostat on the level of malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidative stress marker. METHODS: We recruited 383 patients (febuxostat group, n = 200; control group, n = 183) from the PRIZE trial for whom MDA-LDL measurements were available. The UA, MDA-LDL, low-density lipoprotein cholesterol (LDL-C) levels, and MDA-LDL/LDL-C ratio were identified, represented as the estimated difference from baseline to 24 months. We also evaluated the relationship between febuxostat dose (10, ≤20 to <40, and ≤40 to ≤60 mg) and changes in the MDA-LDL level, LDL-C level, or MDA-LDL/LDL-C ratios. RESULTS: The estimated change in MDA-LDL/LDL-C ratio from baseline to 24 months was significantly lower in the febuxostat group than in the control group (p = .025), whereas the estimated changes in MDA-LDL (p = .235) and LDL-C (p = .323) levels did not differ between the two groups. No significant correlation existed between the febuxostat doses and the estimated change in the MDA-LDL level (p = .626), LDL-C level (p = .896), or MDA-LDL/LDL-C ratio (p = .747). CONCLUSIONS: Our findings may indicate a possibility that febuxostat can lower the MDA-LDL/LDL-C ratio, a potential marker of atherosclerosis and oxidative stress, in asymptomatic hyperuricemic patients with carotid atherosclerosis. Further studies are required to validate our findings and elucidate the clinical antioxidant effect of febuxostat.

Awareness and Feasibility of Women Chairing Cardiology Sessions in Scientific Meetings: A Nationwide Survey by the Japanese Circulation Society.

Background: Diversity and inclusion remain a concern in the field of cardiology. Female cardiologists have less opportunity to chair sessions in scientific meetings than men. However, cardiologists' awareness and perspectives on feasibility of chairing sessions is poorly understood. Methods and Results: A web-based survey on awareness regarding the commitment of chairing sessions was sent to 14,798 certificated cardiologists registered with the Japanese Circulation Society (JCS). A total of 3,412 valid responses were obtained, such as 523 women and 2,889 men. Female cardiologists exhibited less interest in serving as chairpersons in Japanese and English sessions (71% women vs. 82% men, p < 0.001, 30% women vs. 40% men, p < 0.001). Influencing factors of chair acceptance in Japanese sessions for female cardiologists were being a cardiologist for over 10 years [odds ratio (OR) 1.84, 95% confidence interval (CI) 1.02-3.33], experience studying abroad (OR 3.35, 95% CI 1.93-5.81) and chairing sessions (OR 8.39, 95% CI 5.48-12.9), having a Doctor of Philosophy (OR 2.82, 95% CI 1.09-7.31), presence of 4 or more female cardiovascular specialists in the hospital (OR 1.70, 95% CI 1.10-2.61) and of role models (OR 2.86, 95% CI 1.93-4.24), and awareness of the JCS chairperson's manual (OR 10.7, 95% CI 6.67-17.1). The receiver operating characteristic (ROC) curve revealed that the number of female cardiovascular specialists in a hospital was a more sensitive predictor of chair acceptance among male than female cardiologists. Conclusions: Female cardiologists were less likely to accept chairing sessions compared with male cardiologists and the presence of female cardiovascular specialists positively influenced chair acceptance.

Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice.

AIMS: Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. METHODS AND RESULTS: apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVß3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively. CONCLUSION: These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.

LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia.

In the heart, fatty acid is a major energy substrate to fuel contraction under aerobic conditions. Ischemia downregulates fatty acid metabolism to adapt to the limited oxygen supply, making glucose the preferred substrate. However, the mechanism underlying the myocardial metabolic shift during ischemia remains unknown. Here, we show that lipoprotein lipase (LPL) expression in cardiomyocytes, a principal enzyme that converts triglycerides to free fatty acids and glycerol, increases during myocardial infarction (MI). Cardiomyocyte-specific LPL deficiency enhanced cardiac dysfunction and apoptosis following MI. Deficiency of aquaporin 7 (AQP7), a glycerol channel in cardiomyocytes, increased the myocardial infarct size and apoptosis in response to ischemia. Ischemic conditions activated glycerol-3-phosphate dehydrogenase 2 (GPD2), which converts glycerol-3-phosphate into dihydroxyacetone phosphate to facilitate adenosine triphosphate (ATP) synthesis from glycerol. Conversely, GPD2 deficiency exacerbated cardiac dysfunction after acute MI. Moreover, cardiomyocyte-specific LPL deficiency suppressed the effectiveness of peroxisome proliferator-activated receptor alpha (PPARα) agonist treatment for MI-induced cardiac dysfunction. These results suggest that LPL/AQP7/GPD2-mediated glycerol metabolism plays an important role in preventing myocardial ischemia-related damage.

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia.

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

Prognostic impact of immune-related adverse events on patients with and without cardiovascular disease: a retrospective review.

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history. METHODS: We performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019. RESULTS: Median patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs ( +) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality. CONCLUSIONS: Although cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.

Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.

[Figure: see text].

High-output Heart Failure Caused by a Tumor-related Arteriovenous Fistula: A Case Report and Literature Review.

High-output heart failure caused by a tumor-related arteriovenous fistula in adults is a rare clinical condition. We herein report a case of high-output heart failure caused by an arteriovenous fistula associated with renal cell carcinoma and a literature review of 29 published cases to date. Renal cell carcinoma seems to be the most common underlying tumor. For the diagnosis, right heart catheterization and enhanced computed tomography (CT) are considered useful. The removal of the underlying tumor and arteriovenous fistula is the best treatment for heart failure.

A case of reexpansion pulmonary edema and acute pulmonary thromboembolism associated with diffuse large B-cell lymphoma treated with venovenous extracorporeal membrane oxygenation.

A 37-year-old man diagnosed with diffuse large B-cell lymphoma two weeks previously, visited our emergency department with sudden dyspnea. He had a severe respiratory failure with saturated percutaneous oxygen at 80% (room air). Chest radiography showed a large amount of left pleural effusion. After 1000 mL of the effusion was urgently drained, reexpansion pulmonary edema (RPE) occurred. Despite ventilator management, oxygenation did not improve and venovenous extracorporeal membrane oxygenation (VV-ECMO) was initiated in the intensive care unit. The next day, contrast-enhanced computed tomography showed a massive thrombus in the right pulmonary artery, at this point the presence of pulmonary thromboembolism (PTE) was revealed. Fortunately, the patient's condition gradually improved with anticoagulant therapy and VV-ECMO support. VV-ECMO was successfully discontinued on day 4, and chemotherapy was initiated on day 8. We speculated the following mechanism in this case: blood flow to the right lung significantly reduced due to acute massive PTE, and blood flow to the left lung correspondingly increased, which could have caused RPE in the left lung. Therefore, our observations suggest that drainage of pleural effusion when contralateral blood flow is impaired due to acute PTE may increase the risk of RPE. .

Myocardial Vasculitis Associated With the Immune Checkpoint Inhibitor Pembrolizumab.

Recent developments in immune checkpoint inhibitors (ICIs) have provided new treatment strategies for advanced cancer. However, ICIs lead to an imbalance between T cell-mediated inflammatory responses and immune tolerance in the myocardium. Here we report the first case that implicates the contribution of ICI-induced vasculitis to myocardial injury. (Level of Difficulty: Intermediate.).

Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin.

BACKGROUND: Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear. METHODS: To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line with Pkn1flox/flox and Pkn2flox/flox mice and applied a mouse model of transverse aortic constriction- and angiotensin II-induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA. RESULTS: We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 (cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload- and angiotensin II-induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload- and angiotensin II-induced cardiac dysfunction in wild-type mice, whereas cmc-PKN1/2 DKO mice suppressed transverse aortic constriction- and angiotensin II-induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with globular actin by phosphorylating MRTFA, causing increased serum response factor-mediated expression of cardiac hypertrophy- and fibrosis-associated genes. CONCLUSIONS: Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.