Inducible deletion of microRNA activity in kidney mesenchymal cells exacerbates renal fibrosis.

MicroRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. However, the physiological functions of these non-coding RNAs in renal interstitial mesenchymal cells remain unclear. To conclusively evaluate the role of miRNAs, we generated conditional knockout (cKO) mice with platelet-derived growth factor receptor-ß (PDGFR-ß)-specific inactivation of the key miRNA pathway gene Dicer. The cKO mice were subjected to unilateral ureteral ligation, and renal interstitial fibrosis was quantitatively evaluated using real-time polymerase chain reaction and immunofluorescence staining. Compared with control mice, cKO mice had exacerbated interstitial fibrosis exhibited by immunofluorescence staining and mRNA expression of PDGFR-ß. A microarray analysis showed decreased expressions of miR-9-5p, miR-344g-3p, and miR-7074-3p in cKO mice compared with those in control mice, suggesting an association with the increased expression of PDGFR-ß. An analysis of the signaling pathways showed that the major transcriptional changes in cKO mice were related to smooth muscle cell differentiation, regulation of DNA metabolic processes and the actin cytoskeleton, positive regulation of fibroblast proliferation and Ras protein signal transduction, and focal adhesion-PI3K/Akt/mTOR signaling pathways. Depletion of Dicer in mesenchymal cells may downregulate the signaling pathway related to miR-9-5p, miR-344g-3p, and miR-7074-3p, which can lead to the progression of chronic kidney disease. These findings highlight the possibility for future diagnostic or therapeutic developments for renal fibrosis using miR-9-5p, miR-344g-3p, and miR-7074-3p.

Regional variation in pre-dialysis blood pressure and its association with cardiovascular mortality rates in Japanese patients undergoing dialysis.

Adequate blood pressure (BP) management poses a significant challenge in improving the prognosis of patients undergoing dialysis. We aimed to investigate the relationship between pre-dialysis systolic blood pressure (SBP) and underlying disease in Japanese patients undergoing dialysis, based on prefectural location, and assess the association between pre-dialysis SBP and cardiovascular disease (CVD) mortality rate. We extracted the basic information of 336,182 patients who were undergoing dialysis in 2021 from the Web-based Analysis of Dialysis Data Archives database. Data on average pre-dialysis SBP were analyzed according to sex, prefectural location, and diabetic status, and the CVD mortality rate for each prefecture was calculated. The mean pre-dialysis SBP of the patients (males, 66.3%; mean age, 69.7 ± 12.5 years) was 151.9 ± 24.7 mmHg. Overall, 133,037 patients had underlying diabetic kidney disease (DKD). The patients with DKD were younger, had a shorter dialysis duration, and a higher pre-dialysis SBP than those with non-DKD comorbidities. The prefecture-based mean pre-dialysis SBP values were all higher than 140 mmHg. At the prefectural level, CVD mortality rate was positively correlated with pre-dialysis SBP (r = 0.3127, p = 0.0324) and diastolic blood pressure (r = 0.3378, p = 0.0202) among female patients. At the prefectural level, pre-dialysis SBP is >140 mmHg in Japanese patients undergoing dialysis, especially in those with DKD. The positive association between pre-dialysis SBP and CVD mortality rate suggests that optimal BP management at the prefectural level may reduce CVD mortality rates. At the prefectural level, pre-dialysis SBP is higher than 140 mmHg in Japanese patients undergoing dialysis, especially higher in those with DKD.

Real-world trends in pre-dialysis blood pressure levels of patients undergoing dialysis in Japan using a web-based national database.

The prevalence of hypertension is high among patients undergoing dialysis. We extracted data of patients undergoing dialysis between 2012 and 2020 with recorded pre-dialysis systolic blood pressure (SBP) using a web-based national database in Japan. Following the 2019 Japanese Society of Hypertension guidelines, we classified SBP and assessed its trends over time based on sex, age, diabetes status, and the anti-hypertensive medication use. Using the 2020 database, we examined 336,759 Japanese patients undergoing dialysis (114,249 female; 222,510 male). The mean age was 69.4 ± 12.5 years, and the mean SBP was 152.3 ± 24.7 mm Hg. The prevalence rate of pre-dialysis hypertension was 70.2%, with 32.5%, 24.5%, and 13.2% of patients having grade I, grade II, and grade III hypertension, respectively. From 2014 to 2020, prevalence rate of pre-dialysis hypertension and absolute values of pre-dialysis SBP were higher in dialysis patients with diabetes than in those without diabetes across all age groups and sexes. Younger patients with diabetes or those on anti-hypertensive medication exhibited an SBP of approximately 160 mm Hg. Cerebrovascular death in patients with diabetes was associated with a higher rate of pre-dialysis hypertension than that in those without diabetes, and there was a significant difference in the prevalence of grade III hypertension between the two groups. In conclusion, the mean pre-dialysis SBP among patients undergoing dialysis remained high, and younger patients with diabetes or those receiving anti-hypertensive medications had poor blood pressure control. Optimal blood pressure management may be necessary to reduce the risk of cardiovascular mortality.

NG2-positive pericytes regulate homeostatic maintenance of slow-type skeletal muscle with rapid myonuclear turnover.

BACKGROUND: Skeletal muscle comprises almost 40% of the human body and is essential for movement, structural support and metabolic homeostasis. Size of multinuclear skeletal muscle is stably maintained under steady conditions with the sporadic fusion of newly produced myocytes to compensate for the muscular turnover caused by daily wear and tear. It is becoming clear that microvascular pericytes (PCs) exhibit myogenic activity. However, whether PCs act as myogenic stem cells for the homeostatic maintenance of skeletal muscles during adulthood remains uncertain. METHODS: We utilized PC-fused myofibers using PC-specific lineage tracing mouse (NG2-CreERT/Rosa-tdTomato) to observe whether muscle resident PCs have myogenic potential during daily life. Genetic PC deletion mouse model (NG2-CreERT/DTA) was used to test whether PC differentiates to myofibers for maintenance of muscle structure and function under homeostatic condition. RESULTS: Under steady breeding conditions, tdTomato-expressing PCs were infused into myofibers, and subsequently, PC-derived nuclei were incorporated into myofibers. Especially in type-I slow-type myofibers such as the soleus, tdTomato+ myofibers were already observed 3 days after PC labeling; their ratio reached a peak (approximately 80%) within 1 month and was maintained for more than 1 year. Consistently, the NG2+ PC-specific deletion induced muscular atrophy in a slow-type myofiber-specific manner under steady breeding conditions. The number of myonucleus per volume of each myofiber was constant during observation period. CONCLUSIONS: These findings demonstrate that the turnover of myonuclei in slow-type myofibers is relatively fast, with PCs acting as myogenic stem cells-the suppliers of new myonuclei under steady conditions-and play a vital role in the homeostatic maintenance of slow-type muscles.

Anticoagulant therapy and home blood pressure-associated risk for stroke/bleeding events in elderly patients with non-valvular atrial fibrillation: the sub-cohort study of ANAFIE registry.

The benefits of direct oral anticoagulants (DOACs) and warfarin in elderly Japanese patients with non-valvular atrial fibrillation (NVAF) and high home systolic blood pressure (H-SBP) are unclear. This sub-cohort study of the ANAFIE Registry estimated the incidence of clinical outcomes in patients receiving anticoagulant therapy (warfarin and DOACs) stratified by H-SBP levels (<125 mmHg, ≥125-<135 mmHg, ≥135-<145 mmHg and ≥145 mmHg). Of the overall ANAFIE population, 4933 patients who underwent home blood pressure (H-BP) measurements were analyzed; 93% received OACs (DOACs: 3494, 70.8%; warfarin: 1092, 22.1%). In the warfarin group, at <125 mmHg and ≥145 mmHg, the respective incidence rates (per 100 person-years) were 1.91 and 5.89 for net cardiovascular outcome (a composite of stroke/systemic embolic events (SEE) and major bleeding), 1.31 and 3.39 for stroke/SEE, 0.59 and 3.91 for major bleeding, 0.59 and 3.43 for intracranial hemorrhage (ICH), and 4.01 and 6.24 for all-cause death. Corresponding incidence rates in the DOACs group were 1.64 and 2.65, 1.00 and 1.88, 0.78 and 1.69, 0.55 and 1.31, and 3.43 and 3.51. In warfarin-treated patients, the incidence rates of net cardiovascular outcome, stroke/SEE, major bleeding, and ICH were significantly increased at H-SBP ≥ 145 mmHg versus <125 mmHg. In the DOAC group, although there was no significant difference between H-SBP < 125 mmHg and ≥145 mmHg, the incidence rates of these events tended to increase at ≥145 mmHg. These results suggest that strict BP control guided by H-BP is required in elderly NVAF patients receiving anticoagulant therapy.

NOTCH2NLC mutation-positive neuronal intranuclear inclusion disease with retinal dystrophy: A case report and literature review.

INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear. PATIENT CONCERNS: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed. CONCLUSION: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management.

Prostaglandin E2 mediates the late phase of ischemic preconditioning in the heart via its receptor subtype EP4.

Ischemic preconditioning (IPC) describes a phenomenon wherein brief ischemia of the heart induces a potent cardioprotective mechanism against succeeding ischemic insult. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostanoid biosynthesis, is upregulated in the ischemic heart and contributes to IPC. Prostaglandin E2 (PGE2) protects the heart from ischemia-reperfusion (I/R) injury via its receptor subtype EP4. We sought to clarify the role of the PGE2/EP4 system in the late phase of IPC. Mice were subjected to four IPC treatment cycles, consisting of 5 min of occlusion of the left anterior descending coronary artery (LAD). We found that COX-2 mRNA was significantly upregulated in wild-type hearts at 6 h after IPC treatment. Cardiac PGE2 levels at 24 h after IPC treatment were significantly increased in both wild-type mice and mice lacking EP4 (EP4-/-). At 24 h after IPC treatment, I/R injury was induced by 30 min of LAD occlusion followed by 2 h of reperfusion and the cardiac infarct size was determined. The infarct size was significantly reduced by IPC treatment in wild-type mice; a reduction was not observed in EP4-/- mice. AE1-329, an EP4 agonist, significantly reduced infarct size and significantly ameliorated deterioration of cardiac function in wild-type mice subjected to I/R without IPC treatment. Furthermore, AE1-329 significantly enhanced the I/R-induced activation of Akt, a pro-survival kinase. We demonstrated that the PGE2/EP4 system in the heart plays a critical role in the late phase of IPC, partly by augmenting Akt-mediated signaling. These findings clarify the mechanism of IPC and may contribute to the development of therapeutic strategies for ischemic heart disease.

Home Blood Pressure Can Predict the Risk for Stroke/Bleeding Events in Elderly Patients With Nonvalvular Atrial Fibrillation From the ANAFIE Registry.

BACKGROUND: Blood pressure (BP) fluctuates significantly in patients with atrial fibrillation (AF); office BP measurements seem insufficient to assess AF patient risk accurately. We hypothesized that home BP could better predict the risk of stroke/systemic embolic events (SEE) and major bleeding in patients with AF than office BP. METHODS: In this prespecified subcohort study of the ANAFIE (All Nippon AF in the Elderly) Registry, we evaluated the impact of home BP on the risk of stroke/SEE, major bleeding, intracranial hemorrhage, all-cause death, and net cardiovascular outcome (a composite of stroke/SEE and major bleeding). At enrollment, home BP was measured twice in the morning and evening for 7 days. RESULTS: In total, 4933 elderly patients (aged ≥75 years) with nonvalvular AF participated. Incidences of net cardiovascular outcome, stroke/SEE, major bleeding, and intracranial hemorrhage increased significantly with increasing home systolic BP (H-SBP). Compared with H-SBP <125 mm Hg, ≥145 mm Hg was associated with increased risk of these events. The association between H-SBP and the events was observed only in patients with ≥20 H-SBP measurements. CONCLUSIONS: In elderly patients with nonvalvular AF, high H-SBP (≥145 mm Hg) was a significant predictor of stroke/SEE, major bleeding, and intracranial hemorrhage risk. Strict BP control guided by the increasing number of home BP measurements may provide an accurate clinical outcome risk assessment. REGISTRATION: URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000024006.

Ninjurin1 Deletion in NG2-Positive Pericytes Prevents Microvessel Maturation and Delays Wound Healing.

The formation of mature vasculature through angiogenesis is essential for adequate wound healing, such that blood-borne cells, nutrients, and oxygen can be delivered to the remodeling skin area. Neovessel maturation is highly dependent on the coordinated functions of vascular endothelial cells and perivascular cells, namely pericytes (PCs). However, the underlying mechanism for vascular maturation has not been completely elucidated, and its role in wound healing remains unclear. In this study, we investigated the role of Ninjurin-1 (Ninj1), a new molecule mediating vascular maturation, in wound healing using an inducible PC-specific Ninj1 deletion mouse model. Ninj1 expression increased temporarily in NG2-positive PCs in response to skin injury. When tamoxifen treatment induced a decreased Ninj1 expression in PCs, the neovessels in the regenerating wound margins were structurally and functionally immature, but the total number of microvessels was unaltered. This phenotypic change is associated with a reduction in PC-associated microvessels. Wound healing was significantly delayed in the NG2-specific Ninj1 deletion mouse model. Finally, we showed that Ninj1 is a crucial molecule that mediates vascular maturation in injured skin tissue through the interaction of vascular endothelial cells and PCs, thereby inducing adequate and prompt wound healing.

Impact of risk factors related to metabolic syndrome on acute myocardial infarction in younger patients.

Despite diagnostic and therapeutic advancements in cardiovascular medicine, myocardial infarction (MI) remains a major cause of adverse outcomes in younger MI patients, i.e., those who are aged 55 years or younger. Traditional cardiovascular risk factors have not often been emphasized in the management of younger MI patients. However, plaque rupture or erosion, which is deeply related to cardiovascular risk factors, remains the most common etiology of MI even in younger patients. The global increase in the prevalence of obesity underscores the clinical importance of metabolic syndrome (MetS), i.e., obesity-associated cardiovascular risk factors, dyslipidemia, diabetes mellitus and particularly hypertension, in younger people. The concept of "lifetime risk" of cardiovascular disease reinforces the need for prevention or treatment of MetS. This review focuses on the risk factors related to MetS and an overall understanding of recent profiles of younger MI patients. We hope that this review will aid in the primary prevention of MetS-related risk factors and the prevention of cardiovascular disease, particularly MI, in younger patients.

Utility of Geriatric Nutritional Risk Index in Patients with Chronic Kidney Disease: A Mini-Review.

Chronic kidney disease (CKD) is one of the most significant risk factors for cardiovasculardisese. Malnutrition has been recognized as a significant risk factor for cardiovascular disease in patients with CKD, including those on chronic dialysis. Current studies showed higher all-cause and cardiovascular mortality rates in patients with CKD and malnutrition. Geriatric nutritional risk index (GNRI), a simple and validated nutritional screening measure for both elderly people and patients on dialysis, is based only on three objective parameters: body weight, height, and serum albumin level. Recently, we demonstrated that the cutoff GNRI for predicting all-cause and cardiovascular mortality was 96 in patients on hemodialysis. Moreover, together with left ventricular hypertrophy and low estimated glomerular filtration rate, the utility of GNRI as a significant determinant of cardiovascular events was demonstrated in non-dialysis-dependent patients with CKD. In the present review, we summarize available evidence regarding the relationship of GNRI with all-cause and cardiovascular mortality in patients with CKD including those on dialysis.

Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.

BACKGROUND: This study examined the usefulness of cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels as a candidate biomarker of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). METHODS: We performed a systematic search of PubMed, the Cochrane Library, Scopus, and Google Scholar to find studies that measured CSF NSE levels in AD, PD, DLB, and/or MSA. For each disease, we pooled all available data and performed a meta-analysis, and meta-regression analyses of age and sex were conducted if the main analysis found a significant association. RESULTS: Twenty studies were included (13 for AD, 8 for PD/PDD/DLB, and 4 for MSA). Significantly elevated CSF NSE levels were detected in AD (Hedges' g = 0.822, 95% confidence interval [95% CI] 0.332 to 1.311, p = 0.0010), but the data exhibited high heterogeneity (I2 = 88.43%, p < 0.001). The meta-regression analysis of AD showed that age (p < 0.001), but not sex, had a significant effect on CSF NSE levels. A meta-analysis of the pooled data for PD/PDD/DLB did not show any significant changes in the CSF NSE level, but a sub-group analysis of PDD/DLB revealed significantly elevated CSF NSE levels (Hedges' g = 0.507, 95% CI 0.020 to 0.993, p = 0.0412). No significant changes in CSF NSE levels were detected in MSA. CONCLUSIONS: The CSF NSE level may be a useful biomarker of neurodegeneration in AD and PDD/DLB. Age was found to affect the CSF NSE levels of AD patients.

Sarcopenia-derived exosomal micro-RNA 16-5p disturbs cardio-repair via a pro-apoptotic mechanism in myocardial infarction in mice.

Sarcopenia is a pathophysiological malfunction induced by skeletal muscle atrophy. Several studies reported an association between sarcopenia-induced cardiac cachexia and poor prognosis in heart disease. However, due to lack of an established animal models, the underlying mechanism of disturbed cardiac repair accompanied with sarcopenia remains poorly understood. Here, we developed a novel sarcopenia-induced cardiac repair disturbance mouse model induced by tail suspension (TS) after cardiac ischemia and reperfusion (I/R). Importantly, we identified a specific exosomal-microRNA marker, miR-16-5p, in the circulating exosomes of I/R-TS mice. Of note, sarcopenia after I/R disturbed cardiac repair and raised the level of circulating-exosomal-miR-16-5p secreting from both the atrophic limbs and heart of TS mice. Likewise, miR-16-5p mimic plasmid disturbed cardiac repair in I/R mice directly. Additionally, in neonatal rat ventricular myocytes (NRVMs) cultured in vitro under hypoxic conditions in the presence of a miR-16-5p mimic, we observed increased apoptosis through p53 and Caspase3 upregulation, and also clarified that autophagosomes were decreased in NRVMs via SESN1 transcript interference-mediated mTOR activation. In conclusion, we show the pro-apoptotic effect of sarcopenia-derived miR-16-5p, which may be behind the exacerbation of myocardial infarction. Therefore, miR-16-5p can be a novel therapeutic target in the context of cardiac repair disturbances in sarcopenia-cachexia.

Back somersault-induced atrioventricular nodal reentrant tachycardia - A case of a 15-year-old promising gymnast.

A male 15-year-old promising gymnast suffered palpitations, which emerged only after landing a round-off back somersault. The performance induced an attack of regular narrow QRS complex tachycardia that was highly reproducible. Not a single element of the performance, but a whole sequence of round-off back somersault was required to induce the attack. An electrophysiologic study revealed an intra-nodal dual pathway causing atrioventricular nodal reentrant tachycardia (AVNRT). A complication of a tiny atrial septal defect (ASD) was incidentally detected, thus we initially suspected a causal relation of ASD as the platypnea-orthodeoxia syndrome. However, it was denied as the major mechanism of attack because of a very faint shunt flow and no-induction of hypoxemia during a round-off back somersault. The major triggering mechanisms of a whole sequence of round-off back somersaults were speculated to be related to transient atrial overload and autonomic imbalance induced by a swift postural-axial change together with an intense Valsalva maneuver with the maximal level of breath holding. The AVNRT attack was successfully treated by radiofrequency catheter ablation and has never recurred even by a whole sequence of round-off back somersaults. Currently he is a healthy and active gymnast with no symptoms. .

Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly: A Meta-Analysis.

[Figure: see text].

Pericyte-specific deletion of ninjurin-1 induces fragile vasa vasorum formation and enhances intimal hyperplasia of injured vasculature.

Adventitial abnormalities including enhanced vasa vasorum malformation are associated with development and vulnerability of atherosclerotic plaque. However, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. We recently reported that ninjurin-1 (Ninj1) is a crucial adhesion molecule for pericytes to form matured neovessels. The purpose is to examine if Ninj1 regulates adventitial angiogenesis and affects the vascular remodeling of injured vessels using pericyte-specific Ninj1 deletion mouse model. Mouse femoral arteries were injured by insertion of coiled wire. Four weeks after vascular injury, fixed arteries were decolorized. Vascular remodeling, including intimal hyperplasia and adventitial microvessel formation were estimated in a three-dimensional view. Vascular fragility, including blood leakiness was estimated by extravasation of fluorescein isothiocyanate (FITC)-lectin or FITC-dextran from microvessels. Ninj1 expression was increased in pericytes in response to vascular injury. NG2-CreER/Ninj1loxp mice were treated with tamoxifen (Tam) to induce deletion of Ninj1 in pericyte (Ninj1 KO). Tam-treated NG2-CreER or Tam-nontreated NG2-CreER/Ninj1loxp mice were used as controls. Intimal hyperplasia was significantly enhanced in Ninj1 KO compared with controls. Vascular leakiness was significantly enhanced in Ninj1 KO. In Ninj1 KO, the number of infiltrated macrophages in adventitia was increased, along with the expression of inflammatory cytokines. In conclusion, deletion of Ninj1 in pericytes induces the immature vasa vasorum formation of injured vasculature and exacerbates adventitial inflammation and intimal hyperplasia. Thus, Ninj1 contributes to the vasa vasorum maturation in response to vascular injury and to reduction of vascular remodeling.NEW & NOTEWORTHY Although abnormalities of adventitial vasa vasorum are associated with vascular remodeling such as atherosclerosis, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. The present study provides a line of novel evidence that ninjurin-1 contributes to adventitial microvascular maturation during vascular injury and regulates vascular remodeling.

[A case of anti-Th/To antibody-positive systemic sclerosis with muscle symptoms and interstitial pneumonia].

A 62-year-old Japanese man with swollen fingers and walking difficulty due to myalgia and muscle weakness in proximal limb muscles was admitted to our hospital. Serum creatine kinase was remarkably increased (7,380 U/l) and rapidly progressing interstitial pneumonia developed. Muscle biopsy showed necrotic and regenerating fibers without mononuclear infiltration and fibrosis. Anti-Th/To antibodies were detected in the serum, and anti-Th/To antibody-positive systemic sclerosis was diagnosed. Anti-Th/To antibody-positive sclerosis-associated myopathy has not yet been reported in the literature. The present case suggests that anti-Th/To antibody-positive systemic sclerosis can be accompanied by immune-mediated necrotizing myopathy and be effectively treated with immunotherapy comprising corticosteroids, tacrolimus and immunoglobulin.