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Background: Understanding factors associated with improvements in subjective shoulder function after arthroscopic rotator cuff repair (ARCR) helps clinicians identify targets for postoperative rehabilitation. The aim of this study was to investigate the factors associated with subjective shoulder function after ARCR. Methods: Patients who underwent ARCR for rotator cuff tear with at least 12 months of follow-up were included. Subjective shoulder function was assessed preoperatively and at 6 and 12 months postoperatively, using the Shoulder36 (Sh36) 5 domain scores (pain, range of motion [ROM], strength, activities of daily living, and general health). Stepwise multivariable regression analysis was performed to extract the relevant factors for each Sh36 domain score using active shoulder ROM, isometric shoulder and elbow strength, pain score, demographic data, intraoperative findings, medical complications, and cuff integrity. Results: A total of 104 patients met the inclusion criteria for this study. Multivariable regression analysis identified active abduction ROM as the factor associated with 5 Sh36 domain scores at preoperatively. At 6 months postoperatively, isometric external rotation strength at the body side or 90° abduction position, but not the ROM factor, was identified as a significant associated factor with 5 Sh36 domain scores. At 12 months postoperatively, pain score was the most associated factor with pain, ROM, strength, and activities of daily living domain scores of Sh36. Conclusion: Factors associated with subjective shoulder function after ARCR differed between the preoperative and postoperative periods. Postoperative treatment, including rehabilitation, should be modified according to the postoperative period after ARCR.

Key Clinical Message Even in the absence of other symptoms or other pulmonary manifestations suggesting Sjögren's syndrome (SS), it is necessary to include SS in the differential diagnosis of diffuse cystic lung disease (CLD). Abstract A case of SS that presented initially with diffuse CLD is reported. This case is considered rare because diffuse pulmonary cysts were observed in the early stage with few symptoms, only cysts were observed without other lung lesions on imaging, cyst formation was histologically considered to be alveolar loss, and airway lesions not observed on imaging were suspected based on lung function testing. The details of this case provide extremely important information to consider for the diagnosis and management of CLD and SS.

Abstract Background Acute coronary syndrome (ACS) caused by mechanical obstruction of the coronary artery with a vegetation is extremely rare but associated with high mortality. The optimal management strategy of this condition remains controversial because of its scarcity. We experienced a case of sudden circulatory collapse due to mechanical occlusion of the left main coronary trunk with a vegetation. Case presentation A 68-year-old woman with aortic and mitral valve infective endocarditis suffered sudden dyspnea followed by heart arrest while awaiting surgery. Despite treatment with adequate antibiotic therapy, she had had multiple embolic infarctions and ruptured infectious cerebral aneurysms. We conducted transcatheter arterial embolization of the aneurysm and postponed the cardiac surgery due to residual aneurysmal blood flow. She suffered sudden cardiac arrest, and extracorporeal membrane oxygenation was applied after cardiopulmonary resuscitation. An echocardiogram revealed diffuse severe hypokinesis, and emergency coronary angiography was performed under suspicion of ACS. It revealed obstruction of the left main coronary trunk by a vegetation. Emergent cardiac surgery was performed. A vegetation had occluded the left coronary orifice. Aortic and mitral valve replacement with coronary artery bypass to the left antero-descending branch was performed. Regarding her cardiac function, she still required extracorporeal membrane oxygenation after surgery. She passed away 19 days after surgery due to multiple organ failure. Conclusions ACS caused by mechanical obstruction of the coronary artery with a vegetation is rare but associated with high mortality. When circulatory collapse acutely occurs in patients with aortic valve infective endocarditis, we should suspect acute coronary artery obstruction. Urgent coronary angiography is mandatory to rescue the patient while preparing for emergency surgery.

Abstract Background Peak oxygen uptake (peak VO2) is known not only as an index of aerobic fitness but also one of an index of life expectancy. Frailty, sarcopenia, and cachexia are associated with a poor prognosis and high mortality. The purpose of this study was to determine the relationships of peak VO2 with the features of sarcopenia, frailty, and cachexia, to provide insight into which might mediate the poor prognosis. Methods The first group of participants was 175 community‐dwelling older Japanese outpatients (58 men and 117 women; mean age 77.6 ± 6.4 years), in whom we assessed the features of sarcopenia, frailty, and cachexia, and measured peak VO2 during cardiopulmonary exercise. To confirm the relationships, we analysed another group of 162 participants (77.3 ± 5.5 years). Results There were significant correlations between peak VO2 and the features of sarcopenia, frailty, and cachexia, with the exception of high sensitivity C‐reactive protein. Multiple linear regression analysis for the prediction of peak VO2 (mL/min) identified following formula: predicted peak VO2 = −11.6 × age (years) + 25.5 × haemoglobin concentration (g/dL) + 114.2 × skeletal muscle mass index (kg/m2) + 8.9 × hand grip strength (kg) + 226.4 × usual walking speed (m/s) − 65.8 × fatiguability (absence 0, presence 1) − 177.4 × chronic heart failure (absence 0, presence 1) + 437.1 (R2 = 0.627, P

A 73-year-old man presented with multiple giant coronary artery aneurysms. Twelve years prior to the presentation, he had undergone coronary artery bypass grafting. At that time, he exhibited small aneurysms (16 mm diameter) in the right coronary artery and a single aneurysm (10 mm diameter) in the left circumflex artery. During follow-up, the aneurysms gradually increased in size (to 45 and 30 mm, respectively, at 12 years after surgery). We resected all of the aneurysms and performed coronary artery bypass grafting of the left circumflex artery through re-sternotomy.

Abstract To elucidate the disease-flare process in rheumatoid arthritis (RA) after discontinuing biological disease-modifying antirheumatic drugs (bDMARDs), we first focused on RA-flare prediction after achieving stringent remission criteria. Patients with RA who maintained a simplified disease activity index ≤ 3.3 for ≥ 3 months during November 2014–January 2018 in our medical centre in Tokyo, Japan, were eligible. The primary endpoint was flare (disease activity score 28—erythrocyte sedimentation rate ≥ 3.2 with increase from baseline > 0.6) within 2 years after bDMARD discontinuation. Comprehensive clinical assessments, ultrasonographic evaluation of 40 joints, and blood sampling for 12 biomarkers were performed every 2–3 months for 2 years unless patients experienced flare. Flare-positive and flare-negative patients were compared using univariate and Kaplan–Meier analyses. Thirty-six patients (80.6% female, median disease duration, 5.2 years; median treatment period with discontinued bDMARD, 2 years; median remission duration, 18 months) were enrolled. Twenty patients (55.6%) experienced RA flare 43–651 (median, 115) days after the first skipped date of bDMARDs. Two patients who withdrew without disease flare were excluded from the comparison. Clinical and ultrasonographic evaluations did not show significant between-group differences; Kaplan–Meier analysis showed that higher baseline soluble tumour necrosis factor receptor 1 (sTNFR1) concentration impacted subsequent disease flare (p = 0.0041); higher baseline interleukin (IL)-2 concentration was exclusively beneficial to patients with lower sTNFR1 (p = 0.0058), resulting in remission maintenance in 83.3% of patients with lower sTNFR1 and higher IL-2. We demonstrated the usefulness of combined biomarker evaluation for predicting sustained remission after bDMARD discontinuation in RA.

BackgroundCoronavirus disease 2019 (COVID-19) patients reportedly have high bicarbonate concentration. However, its relationship to the disease progression are obscure.MethodsIn this two-center retrospective study, we included COVID-19 patients with moderate severity between March 2020 and May 2021. We classified patients into three groups according to bicarbonate concentrations: high (>27 mEq/L), normal (21 to 27 mEq/L), and low (ResultsOf the 60 participants (median age 72 years), 60% were men. Participants were classified into high (13 patients), normal (30 patients), and low (17 patients) groups. Clinical worsening occurred in 54% of patients in the high group, 23% in the normal group, and 65% in the low group. Both high and low groups were associated with a higher clinical worsening rate: HR, 3.02 (95% CI, 1.05 to 8.63) in the high group; 3.49 (95% CI: 1.33 to 9.12) in the low group.ConclusionMonitoring of bicarbonate concentrations may be useful to predict the prognosis.

Herein we describe four cases of ruptured infected thoracic aortic aneurysm. All patients underwent emergent thoracic endovascular aortic repair to stabilize hemodynamics. After controlling infection, stent graft removal and in situ reconstruction with radical debridement were performed in all but one case. All patients survived during the median 31-month follow-up period, and only one exhibited infection reactivation, which occurred 294 days after initial endoaortic repair. That particular patient underwent open repair. The current cases suggest that emergent bridging endovascular repair for ruptured infected thoracic aortic aneurysm is feasible and, after controlling infection, open repair should be performed as soon as possible. Keywords: Aortic aneurysm, Aortic rupture, Endovascular procedure, Infection control

Abstract Introduction Understanding the association between cognitive impairment severity and potentially avoidable readmissions (PARs) in older patients may facilitate the identification of at‐risk individuals who would benefit from readmission prevention measures. Methods This retrospective cohort study was conducted using claims data linked with routinely collected cognitive impairment assessment results from a general acute care hospital in Tokyo, Japan. Patients were 65 years or age or older who were discharged from the subject hospital to home or a facility between July 2016 and September 2018. Results A multivariable logistic regression analysis adjusted for covariates showed that the odds of PARs within 90 days to the subject hospital for patients with moderate and severe cognitive impairment were 1.418 times (95% confidence interval: 1.005‐2.002) and 2.212 times (95% confidence interval: 1.206‐4.058) higher, respectively, that for patients with normal cognition. Discussion Older inpatients with later‐stage cognitive impairment may represent a suitable target population for transitional care programs aimed at reducing readmissions.

The Japanese government encourages older adults to participate in annual health checkups designed to detect lifestyle diseases such as hypertension, diabetes, and dyslipidemia. However, individuals who are already being treated for these diseases are unlikely to benefit from health checkup participation. This retrospective cohort study of older adults evaluated the associations of pharmacological treatments for these diseases with health checkup participation and identified the disease control factors among patients receiving treatments. Using medical claims data and health checkup data between September 2013 and August 2014 from 820,215 older adults aged ≥ 75 years residing in Tokyo, Japan, we examined the associations between pharmacological treatments and health checkup participation using binary logistic regression analysis. Next, patients receiving pharmacological treatments were categorized into intensive, moderate, or limited disease control based on their blood pressure, hemoglobin A1c levels, and lipid levels; multinomial logistic regression analyses were used to identify the disease control factors. The results showed that patients receiving pharmacological treatments were more likely (odds ratio: 1.374; P

Abstract Background Although frailty and cognitive impairment are critical risk factors for disability and mortality in the general population of older inhabitants, the prevalence and incidence of these factors in individuals treated in the specialty outpatient clinics are unknown. Methods We recently established a frailty clinic for comprehensive assessments of conditions such as frailty, sarcopenia, and cognition, and planned 3-year prospective observational study to identify the risk factors for progression of these aging-related statuses. To date, we recruited 323 patients who revealed symptoms suggestive of frailty mainly from a specialty outpatient clinic of cardiology and diabetes. Frailty status was diagnosed by the modified Cardiovascular Health Study (mCHS) criteria and some other scales. Cognitive function was assessed by Mini-Mental State Examination (MMSE), Japanese version of the Montreal Cognitive Assessment (MoCA-J), and some other modalities. Sarcopenia was defined by the criteria of the Asian Working Group for Sarcopenia (AWGS). In this report, we outlined our frailty clinic and analyzed the background characteristics of the subjects. Results Most patients reported hypertension (78%), diabetes mellitus (57%), or dyslipidemia (63%), and cardiovascular disease and probable heart failure also had a higher prevalence. The prevalence of frailty diagnosed according to the mCHS criteria, cognitive impairment defined by MMSE (≤27) and MoCA-J (≤25), and of AWGS-defined sarcopenia were 24, 41, and 84, and 31%, respectively. The prevalence of frailty and cognitive impairment increased with aging, whereas the increase in sarcopenia prevalence plateaued after the age of 80 years. No significant differences were observed in the prevalence of frailty, cognitive impairment, and sarcopenia between the groups with and without diabetes mellitus, hypertension, or dyslipidemia with a few exceptions, presumably due to the high-risk subjects who had multiple cardiovascular comorbidities. A majority of the frail and sarcopenic patients revealed cognitive impairment, whereas the frequency of suspected dementia among these patients were both approximately 20%. Conclusions We found a high prevalence of frailty, cognitive impairment, and sarcopenia in patients with cardiometabolic disease in our frailty clinic. Comprehensive assessment of the high-risk patients could be useful to identify the risk factors for progression of frailty and cognitive decline.

Abstract Background The aim of the present study was to evaluate clinical efficacy of constant rate infusions (CRIs) of medetomidine–propofol combined with sevoflurane anesthesia in Thoroughbred racehorses undergoing arthroscopic surgery. Thirty horses were sedated intravenously (IV) with medetomidine (6.0 μg/kg) and midazolam (0.02 mg/kg) and induced IV with ketamine (1.0 mg/kg) and propofol (1.0 mg/kg). These horses were randomly allocated to three groups and maintained with sevoflurane and CRI of either medetomidine (3.0 μg/kg/h) (Group M; n = 10); or medetomidine (3.0 μg/kg/h) and propofol (3.0 mg/kg/h) (Group MP3; n = 10); or medetomidine (3.0 μg/kg/h) and propofol (6.0 mg/kg/h) (Group MP6; n = 10). End-tidal sevoflurane concentration (ETSEVO), cardiovascular parameters, plasma propofol concentration, and recovery time and quality were compared among groups. Data were analyzed by using ANOVA with Tukey’s multiple comparison test, considering P

Abstract Background Alfaxalone has a number of pharmacological properties which are desirable for constant rate infusion (CRI). Previously, the co-administration of alfaxalone and medetomidine is shown to be suitable for short-term anesthesia in horses. However, the use of alfaxalone–medetomidine CRI with inhalational anesthesia under surgical procedures have not been investigated in clinical cases. The aim of the present study was to evaluate the clinical efficacy of alfaxalone–medetomidine CRI in sevoflurane-anesthetized Thoroughbred racehorses undergoing arthroscopic surgery. Sevoflurane requirement, cardiovascular function, and induction/recovery quality were compared between horses maintained with sevoflurane in combination with medetomidine CRI (3 µg/kg/h) (Group M; n = 25) and those maintained with sevoflurane in combination with alfaxalone–medetomidine CRI (0.5 mg/kg/h and 3 µg/kg/h, respectively) (Group AM; n = 25). Results The mean end-tidal sevoflurane concentrations were significantly lower in Group AM (1.8 ± 0.2%) than in Group M (2.4 ± 0.1%). The mean dobutamine infusion rate required for maintaining mean arterial blood pressure within the target values (60–80 mmHg) was significantly lower in Group AM (0.53 ± 0.20 µg/kg/min) than in Group M (0.85 ± 0.32 µg/kg/min). Induction and recovery scores were not significantly different between two groups. However, excitatory response during recovery were observed in five horses in Group AM. The mean plasma alfaxalone concentrations were stable throughout the maintenance period (0.77 ± 0.12 to 0.85 ± 0.13 µg/mL), and decreased significantly immediately after standing (0.32 ± 0.07 µg/mL). Conclusions Alfaxalone–medetomidine CRI reduced sevoflurane requirement by approximately 26% with good maintenance of cardiopulmonary function in Thoroughbred racehorses undergoing arthroscopic surgery. Sevoflurane in combination with alfaxalone–medetomidine CRI may be a clinically effective anesthetic technique for Thoroughbred racehorses. However, 20% of horses administered alfaxalone showed remarkable excitatory response during recovery. Greater attention to excitatory response may be advisable if alfaxalone is used for induction or maintenance of anesthesia. A larger study is needed to explore the clinical relevance of these findings.

GM3, a precursor for synthesis of a- and b-series gangliosides, is elevated in adipocytes of obese model animals and in sera of obese human patients with type 2 diabetes and/or dyslipidemia. GM3 synthase (GM3S)-KO C57BL/6 mice display enhanced insulin sensitivity and reduced development of high-fat diet-induced insulin resistance. However, the pathophysiological roles of GM3 and related gangliosides in the central control of feeding and metabolism remain unclear. We found that a mouse model (KKAy GM3S KO) generated by KO of the GM3S gene in the yellow obese strain, KKAy, displayed significant amelioration of obese phenotype. Whereas KKAy mice were hyperphagic and developed severe obesity, KKAy GM3S KO mice had significantly lower body weight and food intake, and greater glucose and insulin tolerance. The hypothalamic response to intraperitoneal administration of leptin was greatly reduced in KKAy mice, but was retained in KKAy GM3S KO mice. In studies of a cultured mouse hypothalamic neuronal cell line, enhanced leptin-dependent phosphorylation of ERK was observed in GM3S-deficient cells. Furthermore, KKAy GM3S KO mice did show altered coat color, suggesting that GM3S is also involved in melanocortin signaling. Our findings, taken together, indicate that GM3-related gangliosides play key roles in leptin and melanocortin signaling.

Abstract Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

Abstract Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer’s disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-β proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-β and amyloid-β1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n = 5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n = 10–17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n = 4–6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n = 4–5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-β oligomer formation. In conclusion, taxifolin prevents amyloid-β oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.

A genetic risk score (GRS) was developed for predicting fracture risk based on the prevalence of vertebral fractures in 441 Japanese females with osteoporosis. A total of 979 (858 nonsynonymous and 121 silent) single-nucleotide polymorphisms (SNPs) located in 74 osteoporosis-susceptibility genes were genotyped and evaluated for their association with fracture prevalence. Four SNPs (protein kinase domain containing, cytoplasmic [PKDCC; rs4952590], CDK5-regulatory subunit-associated protein 1-like 1 [CDKAL1; rs4712556], wingless-type MMTV-integration site family member 16 [WNT16; rs2707466], and G-patch domain-containing gene 1 [GPATCH1; rs10416265]) showed a significant association (p

Drug repositioning (DR) is the process of identifying new indications for existing drugs. DR usually focuses on drugs that have cleared phase-I safety trials but has yet to show efficacy for the intended indication. Therefore, DR can probably skip the preclinical and phase-I study, which can reduce the cost throughout drug development. However, the expensive phase-II/III trials are required to establish efficacy. The obstacles to DR include identification of new indications with a high success rate in clinical studies, obtaining funding for clinical studies, patent protection, and approval systems. To tackle these obstacles, various approaches have been applied to DR worldwide. In this perspective, we provide representative examples of DR and discuss the ongoing efforts to overcome obstacles to DR in Japan.

Aims: Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus (DM) is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients.Methods: This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research.Results: We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001).Conclusion: GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with DM.

The purpose of this study was to use black blood magnetic resonance imaging (BB-MRI) to assess delayed cerebral vasospasm (DCV) after subarachnoid hemorrhage (SAH) in rats, and evaluate whether delayed treatment with the anti-platelet agent cilostazol was effective on DCV. BA vasospasm was sequentially assessed at 1, 2, and 3 h, and 1–6 days after SAH by BB-MRI. BB-MRI clearly visualized biphasic vasospasm; early vasospasm at 1 h later and the maximal DCV at day 2. Cilostazol was perorally administered twice at day 1 after having confirmed significant DCV using BB-MRI. The effect of cilostazol on DCV was evaluated at day 2. Cilostazol significantly attenuated DCV and suppressed the levels of malondialdehide and 8-isoprostane in CSF after SAH. This study shows that BB-MRI is a useful and less invasive method for the evaluation of DCV, and cilostazol may be effective on DCV.

Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is known as an anti-platelet drug and acts directly on platelets. Cilostazol has been shown to exhibit vascular protection in ischemic diseases. Although vascular endothelium-derived prostaglandin I2 (PGI2) plays an important role in vascular protection, it is unknown whether cilostazol directly stimulates PGI2 synthesis in endothelial cells. Here, we elucidate the mechanism of cilostazol-induced PGI2 stimulation in endothelial cells.Human aortic endothelial cells (HAECs) were stimulated with cilostazol and PGI2 accumulation in the culture media was measured. Cilostazol increased PGI2 synthesis via the arachidonic acid pathway. Cilostazol-induced intracellular calcium also promoted PGI2 synthesis via the inositol 1,4,5-trisphosphate receptor. Using RNAi, silencing of PDE3B abolished the induction effect of cilostazol on PGI2 synthesis and intracellular cAMP accumulation. Inhibition of the exchange protein, which was directly activated by cyclic AMP 1 (Epac-1) and its downstream signal the Ras-like small GTPase (Rap-1), abolished cilostazol-induced PGI2 synthesis, but this did not take place via protein kinase A (PKA). Inhibition of downstream signaling, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) γ, and phospholipase C (PLC) ε, suppressed cilostazol-induced PGI2 synthesis.The PDE3/Epac-1/Rap-1 signaling pathway plays an important role in cilostazol-induced PGI2 synthesis. Namely, stimulation of HAECs with cilostazol induces intracellular calcium elevation via the Rap-1/PLCε/IP3 pathway, along with MAPK activation via direct activation by Epac-1/Rap-1 and indirect activation by Epac-1/Rap-1/PI3Kγ, resulting in synergistically induced PGI2 synthesis.

Cilostazol is clinically used for the treatment of ischemic symptoms in patients with chronic peripheral arterial obstruction and for the secondary prevention of brain infarction. Recently, it has been reported that cilostazol has preventive effects on atherogenesis and decreased serum triglyceride in rodent models. There are, however, few reports on the evaluation of cilostazol using atherosclerotic rabbits, which have similar lipid metabolism to humans, and are used for investigating the lipid content in aorta and platelet aggregation under conditions of hyperlipidemia. Therefore, we evaluated the effect of cilostazol on the atherosclerosis and platelet aggregation in rabbits fed a normal diet or a cholesterol-containing diet supplemented with or without cilostazol. We evaluated the effects of cilostazol on the atherogenesis by measuring serum and aortic lipid content, and the lesion area after a 10-week treatment and the effect on platelet aggregation after 1- and 10-week treatment. From the lipid analyses, cilostazol significantly reduced the total cholesterol, triglyceride and phospholipids in serum, and moreover, the triglyceride content in the atherosclerotic aorta. Cilostazol significantly reduced the intimal atherosclerotic area. Platelet aggregation was enhanced in cholesterol-fed rabbits. Cilostazol significantly inhibited the platelet aggregation in rabbits fed both a normal diet and a high cholesterol diet. Cilostazol showed anti-atherosclerotic and anti-platelet effects in cholesterol-fed rabbits possibly due to the improvement of lipid metabolism and the attenuation of platelet activation. The results suggest that cilostazol is useful for prevention and treatment of atherothrombotic diseases with the lipid abnormalities.

Osteoporosis is a common disease characterized by low bone mass, decreased bone quality and increased predisposition to fracture. Genetic factors have been implicated in its etiology; however, the specific genes related to susceptibility to osteoporosis are not entirely known. To detect susceptibility genes for osteoporosis, we conducted a genome-wide association study in Japanese using ∼270,000 SNPs in 1,747 subjects (190 cases and 1,557 controls) followed by multiple levels of replication of the association using a total of ∼5,000 subjects (2,092 cases and 3,114 controls). Through these staged association studies followed by resequencing and linkage disequilibrium mapping, we identified a single nucleotide polymorphism (SNP), rs7605378 associated with osteoporosis. (combined P = 1.51×10(-8), odds ratio = 1.25). This SNP is in a previously unknown gene on chromosome 2q33.1, FONG. FONG is predicted to encode a 147 amino-acid protein with a formiminotransferase domain in its N-terminal (FTCD_N domain) and is ubiquitously expressed in various tissues including bone. Our findings would give a new insight into osteoporosis etiology and pathogenesis.

At our hospital, we are conducting the "Clinical Study of a Patient-Specific Cardiac Support Net for Dilated Cardiomyopathy (jRCTs042180025)", a multi-facility clinical study of a customized cardiac support net (CSN). Here, we describe the cardiac rehabilitation (CR) of a heart failure (HF) patient after CSN treatment. The patient was a 65-year-old man who exhibited dilated cardiomyopathy (DCM) because of left ventricular non-compaction; his New York Heart Association status was class III. In November 2019, he received CSN treatment. The early CR program was adapted for this patient, and his postoperative course was uneventful. Functional measurements showed improved leg-muscle strength (before treatment: 61.4% BW; at discharge: 77.3% BW). During long-term follow-up, the patient's exercise tolerance increased, as shown by 6-minute walk distance (before treatment: 576 m; long-term follow-up: 600 m) and peak oxygen uptake (before treatment: 12.5 mL/kg/min; long-term follow-up: 13.3 mL/kg/min). In the 2 years since discharge, the patient has not been hospitalized for HF. This report is the first to show that the CSN can be used to perform a CR program in a DCM patient without significant functional decline. [ABSTRACT FROM AUTHOR]