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To evaluate the surgical results of patients with cervical spondylotic myelopathy (CSM) with inconsistency between deep tendon reflex findings and cervical magnetic resonance imaging (MRI) findings and to analyze the differences between patients with good and poor surgical outcomes.We evaluated 50 subjects with CSM (30 males, 20 females; mean age: 70.4 years) who underwent posterior surgery and were followed for at least 1 year postoperatively. Matched CSM was defined as a consistent preoperative neurological pattern determined by deep tendon reflex and cervical MRI T2-weighted high-signal intramedullary area or stenosis in the most cranial compression levels. A lack of consistency was classified as unmatched CSM. Recovery rate (RR) according to Japanese Orthopaedic Association (JOA) scoring preoperatively and at 1 year postoperatively were compared between the groups.The matched and unmatched CSM group included 27 subjects (13 males, 14 females; mean age: 68.2 years) and 23 subjects (17 males, 6 females; mean age: 72.8 years), respectively. RR was significantly higher in the matched CSM group (56.1 ± 3.7 % vs 36.8 ± 2.7 %; p = 0.002). Unmatched CSM was significantly associated with a lower RR independently of sex, patient age, surgical procedure, preoperative JOA score, diagnosis levels, and complication of diabetes.Postoperative JOA score RR was significantly diminished among unmatched CSM patients comprising of 46% of cases. Some patients with unmatched CSM had multiple levels of spinal canal stenosis, foraminal stenosis, and peripheral neuropathy, suggesting that surgical results were poorer than those of matched CSM.

Posterior spinal fusion with pedicle screws is commonly used for the treatment of adolescent idiopathic scoliosis (AIS). To reduce radiation exposure, methods other than computed tomography (CT) are desirable for preoperative determination of pedicle diameter.Investigate the differences between magnetic resonance imaging (MRI) and CT measurements of pedicle diameter.Cross-sectional research.Twenty-one AIS Lenke type 1 patients (19 female and 2 males, mean age at surgery: 15.4 years) who underwent posterior spinal fusion between April 2009 and October 2019.Gap between CT and MRI pedicle diameters.The inner and outer diameters of the right and left pedicles from T1 to L3 were measured separately by two spine surgeons for statistical comparisons.The respective minimum and maximum CT-MRI values were -3.7 mm and 4.7 mm for inner diameter and -4.6 mm and 5.3 mm for outer diameter. Regarding inter-examiner error, the probability of a 2 mm difference in measurement was less than 5% for both modalities. The probability of a 1 mm difference was also less than 5%, and that of a 3 mm or more difference was 2.1% for the inner diameter and 2.9% for the outer diameter. Whereas low body weight was significantly associated with measurement differences, pedicle laterality was not.MRI does not have the reliability to measure pedicle size in AIS patients at present. However, with advancements in image processing technology, the accuracy of pedicle size measurement by MRI may soon improve.

A first-morning urine test for screening urinary protein is important for distinguishing whether asymptomatic proteinuria, which is a common finding in school-aged children, is caused due to kidney disease or not. We report the case of a 12-year-old Japanese girl who was referred to our pediatric department for asymptomatic proteinuria detected during a school urinary screening. Proteinuria was found only on the first-morning urinalysis and not on the routine urinalysis. The patient had been diagnosed with adolescent idiopathic scoliosis and treated with a nighttime brace. As excess protein was not detected on urinalysis of the first-morning urine sample that was collected after a night without the brace, proteinuria due to the brace treatment for scoliosis was diagnosed. The present case revealed that brace treatment can cause proteinuria. Even if a first-morning urine is positive for protein, an unexpected cause can trigger asymptomatic proteinuria in a growing child.

BACKGROUND Acute myocardial infarction (AMI) patients with low body mass index (BMI) exhibit worse clinical outcomes than obese patients; however, to our knowledge, no prospective, nationwide study has assessed the effect of BMI on the clinical outcomes of AMI patients.Methods and Results:In this multi-center, prospective, nationwide Japanese trial, 2,373 AMI patients who underwent emergent percutaneous coronary intervention within 12 h of onset from the Japanese AMI Registry (JAMIR) were identified. Patients were divided into the following 4 groups based on their BMI at admission: Q1 group (BMI

Study DesignRetrospective studyPurposeThe upper end vertebra (UEV) is often selected as the upper instrumented vertebra (UIV) in patients with adolescent idiopathic scoliosis (AIS) with Lenke type 5C curves; however, the effect of adjusting UIV selection one level toward the cranial side (UEV+1) is unknown. Therefore, this study aimed to assess the effect of UIV extension on scoliosis correction and global alignment in patients with the UIV as the UEV and UEV+1.MethodsData of 52 patients with AIS with Lenke type 5C curves who underwent selective thoracolumbar/lumbar (TL/L) fusion with a minimum follow-up period of 2 years were retrospectively analyzed. The patients were divided according to the UIV in relation to the UEV: the UEV and UEV+1 groups. Radiographic parameters and clinical outcomes were compared between the two groups.ResultsAmong the 52 patients, 24 and 28 were included in the UEV and UEV+1 group. Baseline data showed no intergroup differences except for the UIV level. While the UEV+1 group showed a significantly greater TL/L curve correction (72.9% vs. 62.8%, p

To assess the points of consideration when performing surgical procedures for proximal femoral bone metastasis.Fourty patients who underwent surgery for proximal femoral bone metastasis from 2009 to 2019 were included. Prognostic assessments were performed based on the Katagiri scoring system. The low-risk group underwent endoprosthetic replacement (EPR) following resection, while the high-risk group underwent internal fixation (IF). For the intermediate-risk group, one of the surgical procedures was chosen depending on general and local condition. Survival period, walking ability, and treatment failure were evaluated.Sixteen and 24 patients underwent EPR and IF, respectively. Although walking reacquisition rate was 94% (15 of 16 patients) for EPR and 75% (18 of 24 patients) for IF (p = 0.210), the median time to walking was shorter in IF compared to EPR (EPR, 29 days, interquartile range [IQR] 23-40; IF, 14 days, IQR 9-24; p = 0.014). Neither EPR nor IF resulted in treatment failure for those with survival periods of1 year. The treatment failure rate for those with survival periods of ≥1 year was significantly different between EPR (9%, 1 of 11 patients) and IF (50%, 5 of 10 patients) (p = 0.038). All five patients of treatment failure for IF were renal cancer with no bone formation in the intermediate-risk group. Of the 13 patients who underwent IF for the intermediate-risk group, treatment failure did not occur in 5 patients with bone formation.Although EPR is a more reliable treatment than IF, patients with life expectancy of1 year are sufficiently manageable with IF. For the intermediate-risk group, EPR should be selected for cases without expected bone formation, and IF can be considered for cases with expected bone formation due to the risk of treatment failure for IF at ≥ 1 year after surgery.

Objective To predict the muscle strength and postoperative function for soft-tissue sarcoma arising from the adductor compartment of the thigh. Methods Between 2003 and 2019, 17 cases that underwent resection of the adductor muscle group (adductor longus, adductor magnus, adductor brevis, gracilis and pectineus) for soft-tissue sarcoma in the adductor compartment of the thigh were included. The muscle strength was measured with an isokinetic dynamometer for the knee joint and with a hand-held dynamometer for the hip joint (ratio of affected to unaffected side). The Musculoskeletal Tumor Society score, Toronto Extremity Salvage Score, European Quality of Life-5 Dimensions and maximum walking speed were used to assess postoperative function and examine correlations with muscle strength. Results In 13 cases that underwent an isolated resection of the adductor compartment, reduced adduction strength correlated with increased number of resected muscles in the adductor muscle group (P Conclusions Postoperative function can be preserved for isolated adductor compartment resection. Combined resections of multiple muscles in other compartments and most adductor muscles may result in decreased postoperative function.

The endothelium plays a pivotal role in the regulation of vascular tone by synthesizing and liberating endothelium-derived relaxing factors inclusive of vasodilator prostaglandins (eg, prostacyclin), nitric oxide (NO), and endothelium-dependent hyperpolarization factors in a distinct blood vessel size–dependent manner. Large conduit arteries are predominantly regulated by NO and small resistance arteries by endothelium-dependent hyperpolarization factors. Accumulating evidence over the past few decades has demonstrated that endothelial dysfunction and coronary vasomotion abnormalities play crucial roles in the pathogenesis of various cardiovascular diseases. Structural and functional alterations of the coronary microvasculature have been coined as coronary microvascular dysfunction (CMD), which is highly prevalent and associated with adverse clinical outcomes in many clinical settings. The major mechanisms of coronary vasomotion abnormalities include enhanced coronary vasoconstrictive reactivity at epicardial and microvascular levels, impaired endothelium-dependent and endothelium-independent coronary vasodilator capacities, and elevated coronary microvascular resistance caused by structural factors. Recent experimental and clinical research has highlighted CMD as the systemic small artery disease beyond the heart, emerging modulators of vascular functions, novel insights into the pathogenesis of cardiovascular diseases associated with CMD, and potential therapeutic interventions to CMD with major clinical implications. In this article, we will summarize the current knowledge on the endothelial modulation of vascular tone and the pathogenesis of coronary macrovascular and microvascular diseases from bench to bedside, with a special emphasis placed on the mechanisms and clinical implications of CMD.

Background A decrease in bone mineral density is common in patients with Williams syndrome. However, appropriate management for osteoporosis in Williams syndrome patients has not been established. We report the case of a 12-year-old female patient with Williams syndrome, who underwent denosumab treatment for osteoporosis. Case presentation A 12-year-old Japanese female patient with Williams syndrome was shown to have very low bone mineral density. Bone mineral density was evaluated before treatment and at 5, 9, 17, 23, and 29 months of treatment by dual-energy X-ray absorptiometry. After denosumab therapy for 29 months, lumbar and total hip bone mineral density values had increased by 51.6% and 37.6%, respectively. No new fractures occurred during the observation period. Conclusions To the best of our knowledge, this is the first experience with denosumab treatment in Williams syndrome patients with osteoporosis. Based on our findings, denosumab may be an effective treatment option for Williams syndrome patients with osteoporosis.

To improve cell production efficacy, it is important to evaluate cell conditions during culture. Extracellular vesicles (EVs) secreted from various cells are involved in stem cell differentiation. As EVs carry information about their source cells, we hypothesized that they may serve as a noninvasive index of cell conditions. We evaluated changes in EV morphology, concentration, and microRNA (miRNA) and protein expression in culture supernatants during the differentiation of induced pluripotent stem cells (iPSCs) into neural lineage cells, for application in regenerative medicine for Parkinson's disease. We observed EVs (50-150 nm) in culture supernatants of iPSCs and differentiated cells. The EVs expressed the exosome markers CD63, CD81, and CD9. Throughout differentiation, the EV concentration in the supernatants decreased, and EV miRNA and protein expression changed substantially. Especially, miR-106b, involved in neural stem cell differentiation and normal brain development, was considerably downregulated. CD63 expression correlated with the CORIN-positive cell rate, which is an index of differentiation. Thus, EV concentration and miRNA and protein expression may reflect the differentiation status of iPSCs. These findings pave the way for the development of novel and sensitive cell culture monitoring methods.

Musculocontractural Ehlers–Danlos syndrome (mcEDS) is a subtype of EDS caused by defective dermatan sulfate biosynthesis, characterized by multiple malformations (craniofacial features, ocular and visceral malformations) and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Repeated dislocations and deformities of the joints due to joint relaxation are observed, causing serious damage to the musculoskeletal system of the whole body; however, the motor function of the upper limbs and the morphology of the bone joints have not been systematically investigated. In this study, we present a detailed and comprehensive report on upper limb lesions of 13 patients with a mean age at the first visit of 21 years. Twelve patients (92.3%) had a history of dislocation. Eleven patients (84.6%) had shoulder dislocations, and two patients (15.4%) had elbow dislocations. Four patients (30.8%) had elbow osteoarthritis, and three patients (23.1%) had distal radioulnar joint (DRUJ) osteoarthritis. The phalanges and metacarpals are thin, and the ratio of medullary cavity of the metacarpal bone decreases with age. As bone and joint deformity progresses, patients with mcEDS should be recommended to receive regular follow-up, including radiology. The present findings suggest an important role for dermatan sulfate in the maintenance of the skeletal system.

Study design Retrospective observational study. Objective This study aimed to determine the effect of reducing the radiation dose of intraoperative cone beam computed tomography (CBCT) during posterior spinal fusion (PSF) for pediatric scoliosis on the rate of pedicle screw (PS) violation. Summary of background data Intraoperative CBCT for pediatric scoliosis improves the accuracy of PS insertion in PSF. However, few reports have addressed the PS perforation rate from reduced radiation doses in hybrid navigation. Methods We evaluated 855 PSs inserted into 58 pediatric scoliosis patients (11 male and 47 female, mean age: 16.6 years) who underwent PSF using CBCT. A radiation dose of 1/3 or 1/5 of the normal dose (ND) was defined as a low dose (LD). After PS insertion, intraoperative CBCT images were reviewed to assess the degree of PS perforation. G2-3 (i.e., perforations of 4 mm or more) was defined as a violation. The PS violation rate was compared between the groups, and factors associated with violations were examined. Results A total of 567 and 288 screws were inserted in the ND group and LD group, respectively. The PS violation rate was comparable at 1.8% in the ND group and 1.7% in the LD group. Multiple logistic regression analysis showed that distance from the upper instrumented vertebra (UIV) was an independently associated factor of PS violation (+1 vertebra, OR 0.73, P = 0.038). In addition, the mean height of patients with PS violations (148.8 ± 3.6 cm) was significantly shorter than that of patients without violations (157.9 ± 1.2 cm) (P = 0.034). Conclusion There was no increase in PS violation rate with lower doses of radiation for intraoperative navigation CBCT. Extra care is warranted for vertebrae close to the UIV and patients of shorter stature.Level of Evidence: 3.

Stem cell-based therapies for Parkinson’s disease are now being applied clinically. Notably, studies have shown that controlling the graft-induced immune response improves the results. In this mini-review, we concisely summarize current approaches used for this control. We focus on four modes of stem cell-based therapies: autologous transplantation, allogeneic transplantation with human leukocyte antigen-matching and allogeneic transplantation without, and finally the application of “universal” pluripotent stem cells. We also discuss immuno-suppressive treatments and the monitoring of immune reactions in the brain.

The prevalence of Alzheimer's disease (AD) has been rapidly increasing worldwide. We have developed a novel angiogenic therapy with low-intensity pulsed ultrasound (LIPUS), which is effective and safe in animal models of AD and vascular dementia. We performed two trials of LIPUS therapy for AD (mild cognitive impairment due to AD and mild AD); a roll-in open trial for safety, and a randomized, double-blind, placebo-controlled (RCT) trial for efficacy and safety. The LIPUS therapy was performed for whole brain through the bilateral temporal bones for one hour 3 times a week as one session under the special conditions (1.3 MPa, 32 cycles, 5% duty cycle) we identified. The LIPUS therapy was performed for one session in the roll-in trial, and 6 sessions in the RCT trial with 3-month intervals for 1.5 years. The primary endpoint was ADAS-J cog scores. The RCT trial was terminated prematurely due to the COVID-19 pandemic. In the roll-in trial (N = 5), no adverse effects were noted. In the RCT trial (N = 22), the worsening of ADAS-J cog scores tended to be suppressed in the LIPUS group compared with the placebo group at week 72 (P = 0.257). When responders were defined as those with no worsening of ADAS-J cog scores at week 72, the prevalence was 50% (5/10) and 0% (0/5) in the LIPUS and placebo groups, respectively (P = 0.053). No adverse effects were noted. These results suggest that the LIPUS therapy is safe and tends to suppress cognitive impairment although a next pivotal trial with a large number of subjects is warranted.

Denosumab and romosozumab, a recently approved new drug, are effective and widely known molecular-targeted drugs for postmenopausal osteoporosis treatment. However, no studies have directly compared their therapeutic effects or safety in postmenopausal osteoporosis. This retrospective observational registry study compared the efficacy of 12-month denosumab or romosozumab treatment in postmenopausal osteoporosis patients. The primary outcome was the change in bone mineral density (BMD) at the lumbar spine. Secondary outcomes included BMD changes at the total hip and femoral neck, changes in bone turnover markers, and adverse events. Propensity score matching was employed to assemble patient groups with similar baseline characteristics. Sixty-nine patients each received either denosumab or romosozumab for 12 months. The mean 12-month percentage change from baseline in lumbar spine BMD was 7.2% in the denosumab group and 12.5% in the romosozumab group, indicating a significant difference between the groups. The percentage changes in BMD at both the total hip and femoral neck were also significantly higher at 12 months in the romosozumab group than in the denosumab group. In denosumab patients, bone formation and bone resorption markers were significantly decreased at 6 and 12 months from baseline. In the romosozumab group, the bone formation marker was significantly increased at 6 months and then returned to baseline, while the bone resorption marker was significantly decreased at both time points. Adverse events were few and predominantly minor in both groups, with no remarkable difference in the incidence of new vertebral fractures. Romosozumab showed a higher potential for improving BMD than denosumab in this clinical study of postmenopausal osteoporosis patient treatment.

BackgroundThe procoagulant state in cancer increases the thrombotic risk, and underlying cancer could affect treatment strategies and outcomes in patients with ischemic stroke. However, the histopathological characteristics of retrieved thrombi in patients with cancer have not been well studied. This study aimed to assess the histopathological difference between thrombi in patients with and without cancer.MethodsWe studied consecutive patients with acute major cerebral artery occlusion who were treated with endovascular therapy between October 2010 and December 2016 in our single-center registry. The retrieved thrombi were histopathologically investigated with hematoxylin and eosin and Masson’s trichrome staining. The organization and proportions of erythrocyte and fibrin/platelet components were studied using a lattice composed of 10×10 squares.ResultsOf the 180 patients studied, 17 (8 women, age 76.5±11.5 years) had cancer and 163 (69 women, age 74.1±11.2 years) did not. Those with cancer had a higher proportion of fibrin/platelets (56.6±27.4% vs 40.1±23.9%, p=0.008), a smaller proportion of erythrocytes (42.1±28.3% vs 57.5±25.1%, p=0.019), and higher serum D-dimer levels (5.9±8.2 vs 2.4±4.3 mg/dL, p=0.005) compared with the non-cancer cases. Receiver operating characteristic curve analysis showed the cut-off ratio of fibrin/platelet components related to cancer was 55.7% with a sensitivity of 74.8%, specificity 58.8% and area under the curve (AUC) value of 0.67 (95% CI 0.53 to 0.81), and the cut-off ratio of erythrocyte components was 44.7% with a sensitivity of 71.2%, specificity 58.9% and AUC value of 0.66 (95% CI 0.51 to 0.80).ConclusionsThromboemboli of major cerebral arteries in patients with cancer were mainly composed of fibrin/platelet-rich components.

Aims To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA). Methods and results The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365–744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05). Conclusions This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis., Graphical Abstract

Over the past couple of decades, accumulating evidence has shown that structural and functional abnormalities of coronary microvasculature are highly prevalent, associated with adverse clinical outcomes in patients with various cardiovascular diseases. The term coronary microvascular dysfunction (CMD) has been coined to refer to this clinical condition and is increasingly recognized as an important clinical entity in many clinical settings. The potential mechanisms of CMD appear to be heterogenous, including enhanced coronary vasoconstrictive reactivity at microvascular level, impaired endothelium-dependent and independent coronary vasodilator capacities, and increased coronary microvascular resistance secondary to structural factors. Recent experimental and clinical studies have highlighted emerging modulators of vascular functions, vital insight into the pathogenesis of cardiovascular diseases associated with CMD, and potential therapeutic interventions to CMD with major clinical implications. In this article, we will briefly review the current progress on pathophysiology, molecular mechanisms, and clinical management of CMD from bench to bedside.

In vasospastic angina (VSA), coronary vasomotion abnormalities could develop not only in epicardial coronary arteries but also in coronary microvessels, where calcium channel blockers (CCBs) have limited efficacy. However, efficacy of exercise training for VSA remains to be elucidated. We thus aimed to examine whether vasodilator capacity of coronary microvessels is impaired in VSA patients, and if so, whether exercise exerts beneficial effects on the top of CCBs.We performed 2 clinical protocols. In the protocol 1, we measured myocardial blood flow (MBF) using adenosine-stress dynamic computed tomography perfusion (CTP) in 38 consecutive VSA patients and 17 non-VSA controls. In the protocol 2, we conducted randomized controlled trial, where 20 VSA patients were randomly assigned to either 3-month exercise training group (Exercise group) or Non-Exercise group (n= 10 each).In the protocol 1, MBF on CTP was significantly decreased in the VSA group compared with the Non-VSA group (138 ± 6 vs 166 ± 10 ml/100 g/min, P = 0.02). In the protocol 2, exercise capacity was significantly increased in the Exercise group than in the Non-Exercise group (11.5 ± 0.5 to 15.4 ± 1.8 vs 12.6 ± 0.7 to 14.0 ± 0.8 ml/min/kg, P 0.01). MBF was also significantly improved after 3 months only in the Exercise group (Exercise group, 145 ± 12 to 172 ± 8 ml/100 g/min, P 0.04; Non-Exercise group, 143 ± 14 to 167 ± 8 ml/100 g/min, P = 0.11), although there were no significant between-group differences.These results provide the first evidence that, in VSA patients, exercise training on the top of CCBs treatment may be useful to improve physical performance, although its effect on MBF may be minimal.

Aims Acute myocardial infarction complicated by cardiogenic shock (AMICS) is associated with substantial mortality, although there are limited data available on bleeding in this critical condition. This study sought to investigate the incidence and impact of major in-hospital bleeding on all-cause mortality in patients with AMICS who undergo percutaneous coronary intervention (PCI). Methods and results Between 2015 and 2017, a total of 3411 patients hospitalized within 24 h after symptom onset were prospectively enrolled in the Japan Acute Myocardial Infarction Registry (JAMIR) and followed up for a median of 293 (interquartile range, 22–375) days. AMICS developed in 335 (9.8%) patients (mean age, 71.3 ± 13.6 years). Overall, the rate of major in-hospital bleeding (Bleeding Academic Research Consortium types 3 and 5) and in-hospital mortality was 14.6% and 28.7%, respectively. The majority of major in-hospital bleeding (73.5%) occurred within 48 h after PCI. Compared to patients without major in-hospital bleeding, those with it had higher rates of renal failure, left main coronary artery culprit lesion, and intra-aortic balloon pump or extracorporeal membrane oxygenation support, and had longer door-to-device time. The cumulative incidence of 1-year all-cause mortality was significantly higher in the major bleeding group compared to the non-major bleeding group (63.8% vs. 25.5%; log-rank P Conclusions These findings of JAMIR indicate that major in-hospital bleeding is associated with all-cause mortality in patients with AMICS who undergo PCI.

The aim of this study was to provide definitive reference values for bone mineral density (BMD) and bone turnover markers in the general elderly population. Registered citizens of 50 to 89 years old were targeted for this survey. After random sampling from the resident registry of Obuse town, we established eight groups based on age (50 s, 60 s, 70 s, and 80 s) and gender. A total of 411 people were enrolled. We used a dual-energy x-ray absorptiometry device to measure and evaluate BMD. The bone formation marker bone alkaline phosphatase (BAP) was measured as a bone turnover marker. Bone quality marker pentosidine, and bone resorption markers including urinary total deoxypyridinoline (DPD), tartrate-resistant acid phosphatase 5b (TRACP-5b), 25-hydroxyvitamin D (25[OH]D), and whole parathyroid hormone (PTH) were also measured as bone turnover markers. Sixty-three people (15.3%) were diagnosed as osteoporosis. BMD decreased with age in the femoral neck and total hip. On the other hand, there was no characteristic change with age in the lumber spine. As for bone markers, pentosidine and DPD increased with aging, although 25(OH)D, whole PTH, and BAP showed no characteristic associations with gender and aging. In terms of the relationship between low BMD and bone markers, there was a significant independent association between low BMD and TRACP-5b in females. In conclusions, hip BMD decreased with aging in men and women. However, there was no characteristic decline with aging in the lumbar spine. All bone markers showed no significant independent characteristics associated with age or gender in a multivariate analysis model, except for a significant association between low BMD and TRACP-5b in females. TRACP-5b was a potentially useful marker for the detection of low BMD.

Objectives Whether there are prognostic links between coronary morphologies and coronary functional abnormalities was examined in ischemia and nonobstructive coronary artery disease (INOCA) patients. Background Although INOCA has attracted much attention, little is known about the prognostic impact of coronary morphologies in this disorder. Methods A total of 329 consecutive INOCA patients were enrolled and underwent spasm provocation testing combined with lactate sampling for diagnosis of epicardial and microvascular spasm (MVS). On the basis of the functional tests, the patients were classified into 4 groups: a control group without epicardial spasm or MVS (n = 32), MVS alone (n = 51), diffuse spasm in ≥2 coronary segments (n = 204), and focal spasm in 1 segment (n = 42). In this population, optical coherence tomography imaging of the left anterior descending coronary artery was performed for evaluation of adventitial vasa vasorum (AVV) and intraplaque neovessels (IPN). Index of microcirculatory resistance was also measured. Results MVS frequently coexisted with diffuse (70%) and focal spasm (68%) with a good correlation between AVV and index of microcirculatory resistance (R = 0.353; p = 0.022). For a median follow-up of 1,043 days, focal spasm showed the worst prognosis (log rank p = 0.005), for which IPN was a significant prognostic factor. By contrast, diffuse spasm showed the greatest AVV with an intermediate prognosis. The prognostic value of INOCA was significantly enhanced by adding AVV and IPN to the physiological indices (area under the curve = 0.88 vs. 0.76; p = 0.048). Conclusions These results provide the first evidence that there are important prognostic links between coronary morphologies (evaluated by optical coherence tomography) and coronary functional abnormalities in patients with INOCA, indicating the importance of both evaluations in this population.

Patients with intracranial hemorrhages (ICH) after mechanical thrombectomy (MT) may have a higher risk of early recurrent embolism (ERE) because of delayed initiation of anticoagulants. We assessed the rate of ischemic events in the early period after MT and the association with post-MT ICH. Patients who underwent MT in our institute were retrospectively reviewed. ERE was defined as recurrent ischemic stroke and systemic embolism within 14 days after MT. The association between ERE and parenchymal hematoma (PH) was assessed. Multivariable regression analysis and inverse probability of treatment weighting was used to adjust for differences in baseline characteristics between patients with and without PH. A total of 307 patients (median age, 78 years; female, 47%; median baseline National Institutes of Health Stroke Scale score, 19) were included. ERE was observed in 12 of 307 patients (8 strokes, 4 systemic embolisms; 3.9%). Median time from MT to ERE was 6.5 days (IQR, 3–8 days). PH occurred in 21 patients (6.8%). Median time from MT to initiating oral anticoagulants was longer in patients with PH (8 days) than in those without (3 days) (p

Objectives Delirium is an important prognostic factor in postoperative patients undergoing cardiovascular surgery and intervention, including transcatheter aortic valve implantation (TAVI). However, delirium after transcatheter aortic valve implantation (DAT) is difficult to predict and its pathophysiology is still unclear. We aimed to investigate whether preoperative cerebral blood flow (CBF) is associated with DAT and, if so, whether CBF measurement is useful for predicting DAT. Methods We evaluated CBF in 50 consecutive patients before TAVI (84.7±4.5 yrs., 36 females) using 99mTc ethyl cysteinate dimer single-photon emission computed tomography. Preoperative CBF of the DAT group (N = 12) was compared with that of the non-DAT group (N = 38) using whole brain voxel-wise analysis with SPM12 and region of interest-based analysis with the easy-Z score imaging system. Multivariable logistic regression analysis with the presence of DAT was used to create its prediction model. Results The whole brain analysis showed that preoperative CBF in the insula was lower in the DAT than in the non-DAT group (P Conclusions These results suggest that preoperative CBF in the insula is associated with DAT and may be useful for its prediction.

In this report, we, the Research Committee on Moyamoya Disease (Spontaneous Occlusion of the circle of Willis), describe in detail the changes in the new "Diagnostic Criteria 2021" for moyamoya disease and its scientific basis to make it widely known to the world. The revised criteria cover all aspects of the disease, including a definition of the disease concept, diagnostic imaging, and the concept of quasi-moyamoya disease (moyamoya syndrome).

The recent increase in the older adult population has led to a higher prevalence of cognitive impairment, which is often overlooked in routine health examinations. Citizens aged 50–89 years were targeted for this cohort survey by random sampling from the resident registry of a cooperating town in 2014. A total of 411 participants (202 male and 209 female) were enrolled. We analyzed the distribution of cognitive function test scores as determined by Montreal Cognitive Assessment and Mini-Mental State Examination tests in each age (50’s, 60’s, 70’s and 80’s) and sex group to examine whether cognitive decline could be detected by sagittal spinal balance measurement based on a radiological approach. Sagittal spinal balance was quantitatively measured as sagittal vertical axis (SVA). We observed significant associations for higher age and/or SVA anteriorization with lower cognitive function. In males, spinal balance anteriorization was associated with cognitive decline independently of age, with combinations of age and SVA also making valid cognitive decline determinations; male cases of SVA ≥ 100 mm at any age, SVA ≥ 90 mm at ≥ 70 years, and SVA ≥ 70 mm at ≥ 80 years were all more likely to have cognitive decline than cases below those values. For females, cognitive decline was more likely in cases of SVA ≥ 70 mm, regardless of age. Thus, spinal balance anteriorization can be regarded as an easily visible indicator of latent cognitive decline in community-dwelling older people.

OBJECTIVE Persistent coronal imbalance (PCI) can develop postoperatively. In this study, the authors aimed to clarify the risk factors and clinical impact of PCI after posterior spinal fusion (PSF) in idiopathic scoliosis (IS) patients with a major thoracolumbar/lumbar (TL/L) curve. METHODS Data on 108 patients with Lenke type 5C or 6C IS who underwent PSF with a minimum of 2 years of follow-up were retrospectively analyzed. PCI was defined as coronal imbalance persisting 2 years after surgery. Radiographic parameters and clinical outcomes were compared between the PCI (+) and PCI (−) groups. Multivariate regression analyses of associated factors were performed to determine the risk factors for PCI. RESULTS Of the 108 patients, 48 (44%) had immediate postoperative coronal imbalance, and 10 of these patients (9%) had coronal imbalance persisting 2 years after surgery. The PCI (+) group had significantly worse postoperative subtotal and satisfaction scores than the PCI (−) group. Preoperative apical vertebral translation (AVT) of the TL/L curve (AVT-TL/L) and postoperative coronal balance (CB) were identified as independent risk factors for PCI. The cutoff values of preoperative AVT-TL/L at 49.5 mm (area under the curve [AUC] 0.835, p = 0.001, 95% CI 0.728–0.941, sensitivity 70.0%, specificity 72.4%) and those of postoperative CB at −27.5 mm (AUC 0.837, p < 0.001, 95% CI 0.729–0.945, sensitivity 78.6%, specificity 70.0%) were used to predict PCI. In selective fusion cases, older age (OR 2.110, 95% CI 1.159–3.842, p = 0.015), greater preoperative AVT-TL/L (OR 1.199, 95% CI 1.029–1.398, p = 0.020), and less postoperative CB (OR 0.855, 95% CI 0.743–0.983, p = 0.027) were independent risk factors for PCI. CONCLUSIONS Preoperative AVT-TL/L and postoperative CB are important parameters for predicting PCI. PCI adversely affects postoperative clinical outcomes. In selective fusion surgery, PCI tends to occur in older patients due to reduced flexibility and compensatory abilities.

Aims Prognostic impacts of serum uric acid (UA) levels in patients with chronic heart failure (CHF) remain inconclusive, especially for the whole range of serum UA levels. Methods and results In the Chronic Heart Failure Registry and Analysis in the Tohoku District‐2 (CHART‐2) study, we enrolled 4652 consecutive patients with CHF and classified them into four groups based on baseline serum UA levels by the Classification and Regression Tree: G1 (9.2 mg/dL, N = 251). Mean age was 71 ± 12, 69 ± 12, 68 ± 13, and 69 ± 15 years in G1, G2, G3, and G4, respectively (P

BackgroundWe aimed to identify the large ischemic core (LIC) volume ranges in acute ischemic stroke patients that can benefit from mechanical thrombectomy (MT).MethodsConsecutive patients within 24 hours of onset of anterior circulation ischemic stroke with large vessel occlusion and ischemic core volumes of 70–300 mL were included from our single-center prospective database from March 2014 to December 2019. Subjects were divided into three groups by baseline ischemic core volume (A: 70–100 mL; B: 101–130 mL; C: >130 mL). We compared modified Rankin Scale (mRS) score 0–2 at 3 months and parenchymal hematoma between patients receiving MT and standard medical treatment (SMT), and determined clinically treatable core volume ranges for MT.ResultsOf 157 patients (86 women; median age, 81 years; median ischemic core volume, 123 mL), 49 patients underwent MT. In Group A (n=52), MT patients (n=31) showed a higher proportion of mRS 0–2 at 3 months (52% vs 5%, PConclusionsIschemic core volumes between 70 and 100 mL may benefit from MT. The treatable upper core limit is approximately 120 mL in selected patients with LIC of 70–300 mL.

Pentosidine (PEN) and carboxymethyl-lysine (CML) are well-recognized advanced glycation end products (AGEs). However, how these AGEs affect the pathophysiology of osteoporosis and osteoporotic fractures remains controversial. This cross-sectional study aimed to investigate the associations of PEN and CML with bone markers, bone mineral density (BMD), and osteoporotic fractures in postmenopausal women from the Nagano Cohort Study. A total of 444 Japanese postmenopausal outpatients (mean ± standard deviation age: 69.8 ± 10.2 years) were enrolled after the exclusion of patients with acute or severe illness or secondary osteoporosis. The relationships among urinary PEN and serum CML levels, various bone markers, lumbar and hip BMD, and prevalent vertebral and long-bone fractures were evaluated. PEN associated significantly with prevalent vertebral fracture after adjustment for other confounders (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.22–2.07; P r = − 0.180; P P

The number of elderly patients with subarachnoid hemorrhage is increasing. Elderly patients have been postulated to benefit more from endovascular coiling, compared with neurosurgical clipping. However, we based our therapeutic modality on the morphology and location of the aneurysms, rather than patients' age or their World Federation of Neurological Surgeons grade. The aim of this study was to investigate the validity of our therapeutic modality over earlier approaches by assessing their clinical outcomes.The study sample included 539 patients who underwent surgical procedures between January 2010 and May 2019. Baseline characteristics, aneurysmal morphology and location, surgical and clinical complications, and clinical outcomes were compared between elderly (defined as aged 75 years or older) and young patients.There were 124 elderly patients (23.0%) in the sample. Eighty-five elderly patients (68.5%) received neurosurgical clipping, whereas 67.0% of the young patients (P = 0.827) received neurosurgical clipping. Of the elderly patients who had a poor World Federation of Neurological Surgeons grade, 49.4% and 48.7% underwent neurosurgical clipping and endovascular coiling, respectively (P = 1.000). Elderly patients had fewer favorable outcomes (21.8%) relative to young patients (61.8%; P0.001). There were no significant differences in the rate of favorable outcomes between patients undergoing neurosurgical clipping relative to endovascular coiling (21.2% vs. 23.1%; P = 0.818).Neurosurgical clipping and endovascular coiling yield comparable clinical outcomes in elderly and young patients with subarachnoid hemorrhage. These findings indicate that using a therapeutic modality based on aneurysmal morphology and location may be an effective treatment approach.

Osteoporosis (OP) is a common disease in the elderly that causes bone fractures and increases mortality. Denosumab (DMAB) is one of several medications to treat OP. DMAB not only reduces the risk of fractures, but also improves the quality of life. However, an increase in the risk of multiple vertebral fractures has been reported after DMAB discontinuation. We described the rare case of a 71-year-old woman with severe OP who experienced same-side insufficiency fractures of the tibia and femur at 18 months after DMAB discontinuation. Careful monitoring for both vertebral and lower limb fragility fractures is advised after DMAB cessation.

Coronary spasm is an established cause for angina pectoris. Ethnic differences have been suggested among Asian compared to Caucasian patients regarding prevalence, gender distribution, and angiographic patterns of coronary spasm. The aim of this study was to compare contemporary German and Japanese patients with coronary spasm. Between 2011 and 2015, 149 patients with resting angina and unobstructed coronary arteries with acetylcholine-induced epicardial spasm were enrolled in Stuttgart, Germany (n = 69) and Sendai, Japan (n = 80). All patients underwent intracoronary acetylcholine testing according to a standardized protocol. Comprehensive analysis included type of spasm (focal/diffuse), dose of acetylcholine leading to spasm, and frequency of multivessel spasm. Patients in this study were 61 ± 11 years old, predominantly female (54%), and had normal left ventricular ejection fraction (73 ± 9%). Diffuse spasm was the most prevalent type of spasm (85%) whereas focal spasm was found in the remaining 15% of patients. 31% of patients had multivessel spasm. Comparing the German with the Japanese patients, distribution of spasm type (focal/diffuse, p = 0.19) and frequency of multivessel spasm (p = 0.22) were comparable. Moreover, when Japanese patients were compared with German patients and diffuse spasm with focal spasm patients, respectively, no significant differences were observed regarding the acetylcholine dose required to induce spasm (p = 0.078 and p = 0.46, respectively). In conclusion, diffuse epicardial coronary spasm is the most frequent finding among German and Japanese patients with resting angina, unobstructed coronary arteries, and epicardial spasm on acetylcholine testing. Japanese and German patients share several similarities including comparable types of spasm and frequency of multivessel spasm.

Study design Japanese resident cohort study based on a municipal registry. Objective This study of a community-dwelling elderly Japanese population employed random sampling from the basic resident registry of a rural town for subject selection to investigate the differences in bone mineral density (BMD) and bone turnover markers between subjects with and without diffuse idiopathic skeletal hyperostosis (DISH). Summary of background data DISH is a condition characterized by the calcification and ossification of soft tissues. Although some reports have addressed BMD in DISH, the precise status of BMD and bone metabolism in individuals with DISH remains unclear. Methods Eight groups based on age (50s, 60s, 70s, and 80s) and sex after random sampling from the resident registry of Obuse town were established. A total of 411 participants (202 males and 209 females) were enrolled for the evaluation of BMD and bone turnover markers. All subjects underwent a single whole-spine lateral radiographic examination for the existence of DISH. The BMD and bone turnover markers of subjects with and without DISH were analyzed for associations with the disorder using multivariate analysis. Results DISH was detected in 66 (16.1%) participants in our population cohort. According to multivariate analysis, increased lumbar and hip BMD were significantly related to DISH (odds ratio: 7.47 and 22.8, respectively). Conclusion This study clarified the differences in BMD and bone turnover markers between subjects with and without DISH on a general population basis. Multivariate analysis revealed increased lumbar and hip BMD to be significantly associated with DISH, with no remarkable findings for bone turnover markers. Level of evidence 4.

Background Hashimoto’s disease has reportedly been associated with stroke; however, cerebrovascular morphology and clinical course remain poorly documented. The present study aimed to determine the angiographic features and clinical outcomes of intracranial arterial stenosis (IAS) associated with Hashimoto’s disease in a retrospective cohort. Methods Overall, 107 adult patients with IAS were screened for anti-thyroid antibodies; of these, 26 patients tested positive. The 42 affected hemispheres were classified into subgroups according to the steno-occlusion site and the development of abnormal collateral (moyamoya) vessels. These subgroups were dichotomized into moyamoya vessels positive (MM type) and negative (non-MM type). The initial presentation, IAS progression, and vascular events during the follow-up period were compared. Results The following sites of stenosis were identified: the bifurcation of the internal carotid artery in 11 (26.2%), M1 or A1 in 29 (69.0%), and more distal (M2-M4/A2-A4) in 2 (4.8%) hemispheres. Further, 17 hemispheres were categorized into the MM type and 25 were classified into the non-MM type. During the follow-up period (mean 2.5 years), IAS progression was identified in 8 (32%) hemispheres of the non-MM type and 0 (0%) hemispheres of the MM type (p = 0.041). Ischemic attacks occurred in 5 (20.0%) hemispheres of the non-MM type (4.6%/year) and 0 hemispheres of the MM type (p = 0.08). Further, 4 (23.5%) hemispheres of the MM type experienced intracerebral hemorrhage, whereas none of the non-MM type hemorrhaged (p = 0.012). Conclusions Hashimoto’s disease-associated IAS exhibits various angiographic morphologies, resulting in different clinical presentations. Screening for anti-thyroid antibodies and careful management based on vascular morphology appears important in adults with IAS.

STUDY DESIGN Retrospective observational study from the Nagano Cohort Study. OBJECTIVE Clarify the association between spinal osteoarthritis and loss of stature in postmenopausal women. SUMMARY OF BACKGROUND DATA Loss of stature with aging is known to deteriorate health-related quality of life and has been implicated with increased mortality. Although the association of vertebral fracture with height loss has been well documented, the relationship between stature loss and spinal osteoarthritis remains unclear. METHODS We retrospectively investigated Japanese postmenopausal women recruited from the Nagano Cohort Study. The participants were outpatients at a primary care institute in Nagano prefecture, Japan. A total of 977 postmenopausal patients (mean age: 65.8 yr) completed a minimum of 1 year of follow-up, with an average observation period of 7.6 years. Quartile analysis on the prevalence of spinal osteoarthritis and occurrence of incident fracture was performed based on the rate of stature change per year (Δ cm/yr). Multiple regression analysis was also conducted to identify the determinants of stature change. RESULTS The lower quartiles of stature change rate (i.e., more rapid stature loss) displayed a significantly higher prevalence of spinal osteoarthritis (P

AIMS We aimed to examine temporal changes in left ventricular (LV) structures and their prognostic impacts in patients with heart failure (HF) and preserved ejection fraction (HFpEF). METHODS AND RESULTS In the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) study (n = 10 219), we divided 2698 consecutive HFpEF patients (68.9 ± 12.2 years, 32.1% female) into three groups by LV hypertrophy (LVH) and enlargement (LVE) at baseline: (-)LVH/(-)LVE (n = 989), (+)LVH/(-)LVE (n = 1448), and (+)LVH/(+)LVE (n = 261). We examined temporal changes in LV structures and their prognostic impacts during a median 8.7-year follow-up. From (-)LVH/(-)LVE, (+)LVH/(-)LVE to (+)LVH/(+)LVE at baseline, the incidence of the primary outcome, a composite of cardiovascular death or HF admission, significantly increased. Among 1808 patients who underwent echocardiography at both baseline and 1 year, we noted substantial group transitions from baseline to 1 year; the transition rates from (-)LVH/(-)LVE to (+)LVH/(-)LVE, from (+)LVH/(-)LVE to (-)LVH/(-)LVE, from (+)LVH/(-)LVE to (+)LVH/(+)LVE, and from (+)LVH/(+)LVE to (+)LVH/(-)LVE were 27% (182/671), 22% (213/967), 6% (59/967), and 26% (44/170), respectively. In the univariable Cox proportional hazard model, patients who transitioned from (+)LVH/(-)LVE to (+)LVH/(+)LVE or remained in (+)LVH/(+)LVE had the worst subsequent prognosis [hazard ratio (HR) 4.65, 95% confidence interval (CI) 3.09-6.99, P

Summary The reconstruction of lost neural circuits by cell replacement is a possible treatment for neurological deficits after cerebral cortex injury. Cerebral organoids can be a novel source for cell transplantation, but because the cellular composition of the organoids changes along the time course of the development, it remains unclear which developmental stage of the organoids is most suitable for reconstructing the corticospinal tract. Here, we transplanted human embryonic stem cell-derived cerebral organoids at 6 or 10 weeks after differentiation (6w- or 10w-organoids) into mouse cerebral cortices. 6w-organoids extended more axons along the corticospinal tract but caused graft overgrowth with a higher percentage of proliferative cells. Axonal extensions from 10w-organoids were smaller in number but were enhanced when the organoids were grafted 1 week after brain injury. Finally, 10w-organoids extended axons in cynomolgus monkey brains. These results contribute to the development of a cell-replacement therapy for brain injury and stroke., Graphical Abstract, Highlights • Human cerebral organoids extended axons along the corticospinal tract in mice • Early-stage organoids extended more axons but caused graft overgrowth • Axonal extensions from the organoids were enhanced in injured brains • Human cerebral organoids extended axons in the brains of nonhuman primates, Kitahara et al. show that cerebral organoids at early stage (SCPN-generating stage) extend more axons along the host corticospinal tract compared with those at late stage (CPN-generating stage) but cause graft overgrowth. Axonal extensions from the organoids are enhanced in an injured brain. Optimization of donor cells and host environment will enable successful transplantation to reconstruct the corticospinal tract.

Background: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy worldwide, but there are few reports investigating its prevalence using subjects diagnosed by both clinical symptoms and nerve conduction studies (NCSs) in a population-based cohort. This study aimed to determine the epidemiology of CTS diagnosed by sensory disturbance findings and NCSs using a randomly sampled resident population. Methods: Subjects aged between 50 and 89 years were randomly sampled from the basic resident registry of a rural Japanese town. Subjects indicating a history of CTS surgery in a written questionnaire were classified as having past CTS. Subjects with both sensory disturbance of the median nerve area and delays in NCSs were diagnosed as having present CTS. Subjects with past or present CTS were judged as affected with CTS. We calculated the prevalence of CTS and investigated for possible risk factors. Results: Seventeen subjects (14 female and 3 male) were affected with CTS among 379 enrolled subjects. Adjusting these results to Japanese population values, the weighted prevalence of CTS was 4.7% (female: 7.2%, male: 1.8%) in the Japanese population aged 50 to 89 years. Statistically significant positive correlations were found between CTS and female, higher BMI, rheumatoid arthritis, and trigger digit. In females affected with CTS, third metacarpal length was significantly shorter than in those without CTS. Conclusions: This epidemiological study clarified the prevalence of CTS among Japanese seniors as 4.7%. Female, higher BMI, rheumatoid arthritis, trigger digit, and shorter third metacarpal length in females were risk factors for CTS.

The goal of this study is to find clues to improve perinatal outcomes in the case of cerebrovascular acute disorders during pregnancy.We analyzed 35 cases of cerebrovascular diseases related to maternal deaths in Japan those that occurred during pregnancy and reported to the Committee of the Ministry of Health, Labor, and Welfare from 2010 to 2018.Cerebrovascular acute disorders occurred at 34.6 ± 6.6 gestational weeks. There were seven intrauterine fetal deaths (IUFD), and eight cases showed neonatal asphyxia with umbilical arterial pH between 6.7 and 7.0 (asphyxia cases,More than 40% of cases experienced fetal asphyxia, and 20% ended in IUFD in maternal deaths related to cerebrovascular acute disorders. Maternal respiratory support and rapid delivery would be the keys to improve perinatal outcomes in case of cerebrovascular acute disorders during pregnancy.

Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons are an expected source for cell-based therapies for Parkinson’s disease (PD). The regulatory criteria for the clinical application of these therapies, however, have not been established. Here we show the results of our pre-clinical study, in which we evaluate the safety and efficacy of dopaminergic progenitors (DAPs) derived from a clinical-grade human iPSC line. We confirm the characteristics of DAPs by in vitro analyses. We also verify that the DAP population include no residual undifferentiated iPSCs or early neural stem cells and have no genetic aberration in cancer-related genes. Furthermore, in vivo studies using immunodeficient mice reveal no tumorigenicity or toxicity of the cells. When the DAPs are transplanted into the striatum of 6-OHDA-lesioned rats, the animals show behavioral improvement. Based on these results, we started a clinical trial to treat PD patients in 2018., Induced pluripotent stem cell (iPSC) derived dopaminergic neurons are a promising source for cell-based Parkinson’s disease (PD) therapy. Here the authors report a comprehensive pre-clinical evaluation of the safety and efficacy of dopaminergic progenitors derived from a clinical-grade human iPSC line.

Although depressive symptoms increased mortality and hospitalization in chronic heart failure (CHF) patients, the underlying mechanism remains unclear. The aim of this study was to investigate whether an alteration in hippocampal perfusion, which is the neural substrate of depressive symptoms, is associated with changes in cardiac structures and/or functions in CHF patients.We used baseline data of 70 CHF patients (66.8 ± 8.9 yrs, 32.5% women), including cerebral blood flow (CBF) in the hippocampus, geriatric depression scale (GDS) scores and echocardiographic parameters, in the Brain Assessment and Investigation in Heart Failure Trial (B-HeFT) (UMIN000008584). Echocardiography was repeated at 3.1 ± 0.5 years after the baseline evaluation. We first tested voxel-wise regression model with hippocampal CBF as dependent variable and each of echocardiographic parameter change as independent variable, adjusted for age and sex. Structural equation modeling was used to test a mediation effect of cognitive test scores on associations between hippocampal perfusion and changes in cardiac structures and/or functions.Baseline anterior hippocampal CBF was negatively correlated with changes in left ventricular posterior wall thickness (PWT) (P 0.05 with family-wise error corrections). An existence of depressive symptoms was positively correlated with the baseline anterior CBF and negatively with the PWT changes (P 0.05, both). There were both direct effects of the baseline anterior hippocampal CBF on PWT thinning and effects mediated through the depressive symptoms (P 0.05, both).This study provides the first evidence that the alteration in hippocampal perfusion may lead to changes in cardiac structures via increase in depressive symptoms in CHF patients.

The transplantation of dopaminergic (DA) progenitors derived from pluripotent stem cells improves the behavior of Parkinson's disease model animals. However, the survival of DA progenitors is low, and the final yield of DA neurons is only approximately 0.3%–2% the number of transplanted cells. Zonisamide (ZNS) increases the number of survived DA neurons upon the transplantation of mouse‐induced pluripotent stem (iPS) cell‐derived DA progenitors in the rat striatum. In this study, we induced DA progenitors from human iPS cells and transplanted them into the striatum of female rats with daily administration of ZNS. The number of survived DA neurons was evaluated 1 and 4 months after transplantation by immunohistochemistry, which revealed that the number of survived DA neurons was significantly increased with the administration of ZNS. To assess the mechanism of action of ZNS, we performed a gene expression analysis to compare the gene expression profiles in striatum treated with or without ZNS. The analysis revealed that the expression of SLIT‐and NTRK‐like protein 6 (SLITRK6) was upregulated in rat striatum treated with ZNS. In conclusion, ZNS promotes the survival of DA neurons after the transplantation of human‐iPS cell‐derived DA progenitors in the rat striatum. SLITRK6 is suggested to be involved in this supportive effect of ZNS by modulating the environment of the host brain., We examined the effects of zonisamide on transplanted human dopaminergic neurons in the rat striatum and found that zonisamide facilitates the survival of dopamine neurons, an effect that may be related to an increase in the expression of SLIT‐and NTRK‐like protein 6 in rat striatum.

Aims Asymptomatic patients with structural heart diseases are classified as a population at high risk for heart failure (HF) in Stage B. However, limited data are available regarding incidence and related factors of de-novo HF (DNHF) considering competing risk in this population. Methods and results In 3362 Stage B patients (mean age 68 yrs, male 76%) from the CHART-2 Study (N = 10,219), we examined incidence of death and DNHF, defined as the first episode of either HF hospitalization or HF death, and factors related to DNHF. Results During the median 6.0-year follow-up, 627 deaths (31/1000 person-years) and 293 DNHF (15/1000 person-years) occurred. Among the 627 deaths, 212 (34%) and 325 (52%) were specified as cardiovascular and non-cardiovascular deaths, respectively. During the follow-up of 271 DNHF hospitalizations, we observed 124 deaths, including 65 (52%) cardiovascular and 47 (40%) non-cardiovascular deaths. The competing risk model showed that age, diabetes mellitus, stroke, atrial fibrillation, diastolic blood pressure, hemoglobin levels, estimated glomerular filtration ratio and left ventricular ejection fraction was significantly associated with DNHF. Bayesian structural equation modeling showed that many of these cardiac and non-cardiac variables contribute to DNHF by affecting each other, while diabetes mellitus was independently associated with DNHF. Conclusions Stage B patients had a high incidence of DNHF as well as that of death due to both cardiovascular and non-cardiovascular causes. Thus, management of Stage B patients should include multidisciplinary approaches considering both cardiac and non-cardiac factors, in order to prevent DNHF as well as non-HF death as a competing risk. Trial registration: clinicaltrials.gov identifier: NCT00418041 .

Objective: It remains to be elucidated whether and how endothelial functions are impaired in peripheral circulation of patients with coronary functional disorders, such as vasospastic angina (VSA) and microvascular angina (MVA). We simultaneously examined endothelial functions of peripheral conduit and resistance arteries in patients with coronary functional disorders, with a special reference to NO and endothelium-dependent hyperpolarization factors. Approach and Results: Based on the results of invasive coronary acetylcholine testing and coronary physiological measurements, we divided 43 patients into 3 groups; VSA, MVA, and VSA+MVA. Endothelium-dependent vasodilatations of the brachial artery and fingertip arterioles to intra-arterial infusion of bradykinin were simultaneously evaluated by ultrasonography and peripheral arterial tonometry, respectively. To assess NO and endothelium-dependent hyperpolarization factors, measurements were repeated after oral aspirin and intra-arterial infusion of N G -monomethyl-L-arginine. Additionally, endothelium-independent vasodilatations to sublingual nitroglycerin and plasma levels of biomarkers for endothelial functions were measured. Surprisingly, digital vasodilatations to bradykinin were almost absent in patients with MVA alone and those with VSA+MVA compared with those with VSA alone. Mechanistically, both NO- and endothelium-dependent hyperpolarization–mediated digital vasodilatations were markedly impaired in patients with MVA alone. In contrast, endothelium-independent vasodilatations to nitroglycerin were comparable among the 3 groups. Plasma levels of soluble VCAM (vascular cell adhesion molecule)-1 were significantly higher in patients with MVA alone compared with those with VSA alone. Conclusions: These results provide the first evidence that both NO- and endothelium-dependent hyperpolarization–mediated digital vasodilatations are markedly impaired in MVA patients, suggesting that MVA is a cardiac manifestation of the systemic small artery disease.

Background We have recently demonstrated that left ventricular ejection fraction (LVEF) dynamically changes over time with prognostic impacts in Stage C/D patients, namely, those who have a current or past history of heart failure (HF). However, it is unknown whether this is also the case in asymptomatic Stage B patients, namely, those who have a risk of HF, but do not have a history of HF. Methods In our CHART-2 Study (N = 10,219), we enrolled 4005 Stage B patients and divided them into 3 groups by LVEF; preserved EF (pEF, LVEF ≥50%, N = 3526), mid-range EF (mrEF, LVEF 41–49%, N = 302), and reduced EF (rEF, LVEF ≤40%, N = 177). We examined the prognostic impacts of LVEF transitions among the 3 groups in comparison with 4477 patients with Stage C/D HF. Results Stage B were characterized by less severe clinical status and better prognosis compared with Stage C/D. Stage B in mrEF and rEF at baseline dynamically transitioned to other groups at 1-year, whereas those in pEF unchanged; at 1-year, mrEF transitioned to pEF/rEF by 50/16%, and rEF transitioned to pEF/mrEF by 25/31%, respectively, whereas pEF transitioned to mrEF/rEF by only 3.6/0.7%, respectively, which were consistent with findings in findings with Stage C/D. Although LVEF decrease was directly associated with all-cause mortality in both the Stage B and Stage C/D with pEF, factors related to LVEF changes were different between the 2 groups. Conclusions In Stage B, LVEF dynamically changes with prognostic impacts as in Stage C/D, whereas different determination factors may be involved in the 2 stages. Clinical trial registration: Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 (NCT00418041).

Periventricular anastomosis (PA), which is a novel term for extended collateral vessels in moyamoya disease (MMD), is reportedly associated with a high risk of intracranial hemorrhage in adult patients. The present study aimed to clarify the similarities and the differences in the development of PA between three MMD groups, classified by age at the time of diagnosis and clinical phenotype. This study included 232 hemispheres of 132 patients with MMD who underwent surgical revascularization. The subjects were classified into child ischemic (CI) group, adult ischemic (AI) group, and adult hemorrhagic (AH) group. We evaluated the lenticulostriate (LSA), thalamic (THA), choroidal (ChA), anterior choroidal (AChA), and posterior choroidal (PChA) anastomosis as well as the posterior cerebral artery (PCA) involvement. The PA scores and the sums of each grade of LSA, THA, and ChA anastomosis were also calculated in all of the cases. In a multiple comparison test, the PA scores (P

Study design Retrospective multicenter cohort study. Objective We evaluated a new upper instrumented vertebra (UIV) selection method that used the modified Shinshu line (MSL) to establish the selected UIV as the MSL vertebra (MSLV). Summary of background data No reports have addressed optimal UIV selection according to the lower instrumented vertebra (LIV) for good trunk balance in Lenke 1A curves. Methods Forty-five consecutive patients (44 female, 14.4 ± 2.4 yrs) receiving posterior spinal fusion (PSF) for a Lenke 1A adolescent idiopathic scoliosis (AIS) curve were analyzed. We defined the novel MSL as the line between the center of the spinous process of C7 and that of the spinous process of the LIV. The vertebral body with which the MSL first contacted proximally was defined as the MSLV. The groups in which the UIV was at, proximal to, or distal to the MSLV were defined as the matched group (M-group; 15 cases [15 female], 14.7 ± 2.1 yrs), proximal group (P-group; 20 cases, [19 female], 15.0 ± 2.2 yrs), and distal group (D-group; 10 case [10 female], 14.8 ± 2.5 yrs), respectively. We measured Cobb angle, main thoracic (MT) curve correction rate, and C7 plumb line absolute value (C7PL) at pre- and 2 years postoperatively for comparisons using Dunnett test, with the M-group as the control. Results In the M-group, P-group, and D-group, the Cobb angle correction rate between pre- and postoperative time points were 65.3 ± 1.3%, 62.4 ± 1.6%, and 52.8 ± 6.8%, respectively, and comparable apart from a smaller correction tendency in the D-group versus the M-group (P = 0.08). At 2 years postoperatively, C7PL was 0.5 ± 0.4, 1.0 ± 0.6, and 1.3 ± 0.9 cm, respectively, and significantly smaller for the M-group (both P Conclusion Better trunk balance were obtained without reducing correction rate by setting the novel MSLV as the UIV in PSF for Lenke type 1A curves. Level of evidence 3.

AIMS The aim of this study was to examine the mechanisms of cognitive impairment and reversibility in elderly patients with severe aortic stenosis (AS) after transcatheter aortic valve implantation (TAVI) with special reference to cerebral blood flow (CBF). METHODS AND RESULTS We examined 15 elderly patients with severe AS (mean age 83.2±4.5 years, 12 female) who underwent TAVI. Before and three months after TAVI, we evaluated cognitive function with the Logical Memory II test (LM II), cardiac output (CO) with echocardiography, and CBF with 99mTc single-photon emission computed tomography (SPECT). LM II score and CO were significantly increased after TAVI compared with baseline (p