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Divergent total syntheses of binding pocket and peripherally modified tetrachlorovancomycins, a non-native synthetic glycopeptide, and their evaluation are disclosed. Central to the approach is the synthesis of a single late-stage intermediate that bears a residue 4 thioamide ([Ψ[C(═S)NH]Tpg 4 ]tetrachlorovancomycin ( 3 ), LLS 15 steps, 14% overall) as a precursor to either of two key pocket modifications and their pairing with any combination of two peripheral modifications conducted without protecting groups. A stereochemical simplification achieved by the addition of two aryl chlorides removes two synthetically challenging atropisomer centers in native glycopeptides and streamlines the synthesis. Key features include in a convergent epimerization-free thioacylation of the AB ring system amine with an N -thioacylbenzotriazolyl DE tetrapeptide (85%) followed by simultaneous room-temperature S N Ar macrocyclizations of the CD and DE ring systems (96%). The approach provided 3 from which [Ψ[C(═N)NH]Tpg 4 ]tetrachlorovancomycin ( 4 ) and [Ψ(CH 2 NH)Tpg 4 ]tetrachlorovancomycin ( 5 ) were prepared in a single-step and bear binding pocket modifications that convey dual d-Ala-d-Ala/d-Lac ligand binding to overcome vancomycin resistance. The newest maxamycin members are disclosed, bearing two additional peripheral modifications that introduce two independent synergistic MOAs that do not rely on native ligand binding for activity. Ligand binding properties of pocket-modified tetrachlorovancomycins 3 - 5 , antibacterial activity of a key compound series, and PK assessments of two tetrachloromaxamycins are reported.

Purpose: The technical difficulties of laparoscopic liver resection (LLR) are greatly associated with the location of liver tumors. Since segment 8 (S8) contains a wide area, the difficulty of LLR for S8 tumors may vary depending on the location within the segment, such as the ventral (S8v) and dorsal (S8d) area, but the difference is unclear., Methods: We retrospectively investigated 30 patients who underwent primary laparoscopic partial liver resection for liver tumors in S8 at Kobe University Hospital between January 2018 and June 2023., Results: Thirteen and 17 patients underwent LLR for S8v and S8d, respectively. The operation time was significantly longer (S8v 203[135-259] vs. S8d 261[186-415] min, P = 0.002) and the amount of blood loss was significantly higher (10[10-150] vs. 10[10-200] mL, P = 0.034) in the S8d group than in the S8v group. No significant differences were observed in postoperative complications or postoperative length of hospital stay. Additionally, intraoperative findings revealed that the rate at which the case performed partial liver mobilization in the S8d group was higher (2[15.4%] vs. 8[47.1%], P = 0.060) and the median parenchymal transection time of the S8d group was longer (102[27-148] vs. 129[37-175] min, P = 0.097) than those in the S8v group, but there were no significant differences., Conclusion: The safety of LLR for the S8d was comparable to that of LLR for S8v, although LLR for S8d resulted in longer operative time and more blood loss., The Trial Registration Number: B230165 (approved at December 26, 2023)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The genome is constantly exposed to DNA damage from endogenous and exogenous sources. Fine modulation of DNA repair, chromatin remodeling, and transcription factors is necessary for protecting genome integrity, but the precise mechanisms are still largely unclear. We found that after ionizing radiation (IR), global trimethylation of histone H3 at lysine 4 (H3K4me3) was decreased at an early (5 min) post-IR phase but increased at an intermediate (180 min) post-IR phase in both human and mouse hematopoietic cells. We demonstrated that PTIP, a component of the MLL histone methyltransferase complex, is required for H3K4me3 upregulation in the intermediate post-IR phase and promotes cell cycle arrest by epigenetically inducing a cell cycle inhibitor, PRDM1. In addition, we found that PTIP expression is specifically downregulated in acute myeloid leukemia patients. These findings collectively suggest that the PTIP-PRDM1 axis plays an essential role in proper DNA damage response and its deregulation contributes to leukemogenesis., (© 2024. The Author(s).)

Aims: A fourth heart sound (S4) was reported to be almost never present in patients with amyloid light-chain cardiomyopathy. There have been no reports on S4 in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). This study aimed to clarify the clinical implications of S4 in patients with ATTRwt-CM., Methods and Results: Seventy-six patients with ATTRwt-CM (mean age: 80.4 ± 5.4 years, 68 males) who had undergone phonocardiography (PCG) were retrospectively assessed. We measured S4 amplitude on digitally recorded PCG. S4 was considered to be present when its amplitude was 1.0 mm or greater on the PCG. Distinct S4 was defined as S4 with an amplitude of 2.0 mm or greater, which is usually recognizable by auscultation. According to the rhythm and presence or absence of S4, the patients were divided into three groups, namely, sinus rhythm (SR) with S4, SR without S4, and non-SR. Non-SR consisted of atrial fibrillation, atrial flutter, and atrial tachycardia. Thirty-six patients were in SR and the remaining 40 patients were in non-SR. In the 36 patients in SR, S4 was shown by PCG to be present in 17 patients (47%), and distinct S4 was recognized in 7 patients (19%) by auscultation. In patients who were in SR, those with S4 had higher systolic blood pressure (124 ± 15 vs. 99 ± 8 mmHg, P < 0.001), lower level of plasma B-type natriuretic peptide (308 [interquartile range (IQR): 165, 354] vs. 508 [389, 765] pg/mL, P = 0.034) and lower level of high-sensitivity cardiac troponin T (0.068 [0.046, 0.089] vs. 0.109 [0.063, 0.148] ng/mL, P = 0.042) than those without S4. There was no significant difference in left atrium (LA) volume index or LA reservoir strain between patients with S4 and without S4. Patients with S4 had more preserved LA systolic function than those without S4 (peak atrial filling velocity: 53 ± 25 vs. 34 ± 9 cm/s, P = 0.033; LA contractile strain: 4.1 ± 2.1 vs. 1.6 ± 2.0%, P = 0.012). Patients in SR without S4 had worse short-term prognosis compared with the other two groups (generalized Wilcoxon test, P = 0.033)., Conclusions: S4 was present in 47% of the patients in SR with ATTRwt-CM. Patients in SR without S4 had more impaired LA systolic function than those in SR with S4. The absence of S4 portends a poor short-term prognosis in patients with ATTRwt-CM., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background/aim: Neskeep ® , an absorbable polyglycolic acid spacer, has been developed as the optimal material for spacer placement surgery. However, preventing its severe adhesion is a crucial concern. Therefore, we aimed to identify an effective anti-adhesion agent for Neskeep ® using rat models., Materials and Methods: Animal experiments were performed using 60 rats, which underwent Neskeep ® placement on the abdominal wall. Three types of anti-adhesion agents were employed, establishing four subgroups: Seprafilm ® , INTERCEED ® , AdSpray ® , and only Neskeep ® (control) groups. Rats were sacrificed on postoperative days 7, 14, and 28 to assess adhesion levels around the Neskeep ® Macroscopic visual assessment with the Lauder score and histopathological evaluation were performed to assess the degree of adhesion., Results: There were no significant differences in the proportion of Lauder scores on days 7 and 14 between the four groups. Histological evaluation revealed no significant differences between groups at any observation time. However, the mean Lauder scores at day 28 were 5.0, 1.6, 4.0, and 4.8 in the Neskeep ® , Seprafilm ® , INTERCEED ® , and AdSpray ® groups, respectively. The proportion of milder Lauder score was significantly higher in the Seprafilm ® group on day 28., Conclusion: Seprafilm ® may exhibit an anti-adhesive effect when used with Neskeep ® ., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The expression of nicotinic acetylcholine receptor (nAChR) subunits on various immune cells suggests their involvement in allergic rhinitis. However, how exactly they contribute to this pathogenesis is not yet confirmed. Our present study examined the therapeutic potential of GTS-21, an α7 nAChR agonist, for treating allergic rhinitis by employing its mouse models. GTS-21 treatment reduced allergen-induced immediate nasal response in ovalbumin (OVA)-sensitized model. However, nasal hyperresponsiveness or eosinophil infiltration elicited in either the OVA-sensitized or T helper 2 cell-transplanted model was not affected by GTS-21. GTS-21 did not alter allergen-induced passive cutaneous anaphylaxis response in anti-dinitrophenyl IgE-sensitized mice. This evidence implies GTS-21's potential to alleviate allergic rhinitis without perturbing T cells or mast cells.

Background: The relationships between electrocardiography (ECG) findings and echocardiographic profiles in patients with hypertrophic cardiomyopathy (HCM) are not fully understood., Methods: One hundred forty patients (mean age: 62.9 ± 15.3 years, 96 men) with HCM were studied. We assessed the associations between ECG findings and echocardiographic findings including maximum left ventricular wall thickness, HCM subtypes and distribution of left ventricular hypertrophy (LVH): the LV was divided into basal, mid, and apical segments by dividing it into thirds along the long axis., Results: In ECG, LVH by voltage criteria, abnormal Q wave, negative T wave, and giant negative T wave (GNT) were observed in 74 (53 %), 30 (21 %), 132 (94 %), and 25 (18 %) of the patients, respectively. In two groups with and without an LVH pattern according to voltage criteria in ECG, there were no significant differences in maximum LV wall thickness, subtype of HCM, and distribution of LVH. Regarding an abnormal Q wave, the proportion of patients with LVH in the basal segment was significantly higher in patients with an abnormal Q wave than in patients without an abnormal Q wave (87 % vs 61 %, p = 0.008). An abnormal Q wave was not observed in patients with LVH confined to the apex. Patients with a GNT included patients with LVH located at only the apex (apical HCM), LVH from the mid segment to apex, and LVH from the base to apex. No GNT was found in patients with hypertrophy located in the upper region from the base to mid segment of the LV., Conclusions: In patients with HCM, there was no significant correlation between the presence of LVH by voltage criteria in ECG and echocardiographic findings. An abnormal Q wave was associated with disproportionate hypertrophy of the basal wall and a GNT reflected the presence of LVH in the apical segment., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pulsed cathodic arc-plasma deposition was employed to create a few nanometre-thick Pt overlayer on a 50 μm-thick Fe-Cr-Al metal (SUS) foil, resulting in an effective NH 3 oxidation catalyst fabrication. This catalyst exhibited a turnover frequency (TOF) exceeding 100 times that of Pt nanoparticles. In this study, Pt overlayer catalysts with varying degrees of surface roughness were fabricated using different metal foil substrates: mirror-polished (Pt/p-SUS), unpolished (Pt/SUS) and roughened by the formation of a surface oxide layer (Pt/Al 2 O 3 /SUS). The nanoscale roughness was comprehensively analysed using electron microscopy, laser scanning confocal microscopy and chemisorption techniques. NH 3 oxidation activity, measured at 200 °C, followed an increasing trend in the order of Pt/Al 2 O 3 /SUS < Pt/SUS < Pt/p-SUS, despite a decrease in the apparent Pt surface area in the same order. Consequently, the calculated TOF was markedly higher for Pt/p-SUS (267 min -1 ) compared to Pt/SUS (107 min -1 ) and Pt/Al 2 O 3 /SUS (≤22 min -1 ). The smooth Pt overlayer surface also favoured N 2 yield over N 2 O at this temperature. This discovery enhances our fundamental understanding of high-TOF NH 3 oxidation over Pt overlayer catalysts, which holds significance for the advancement and industrial implementation of selective NH 3 oxidation processes.

Background: Joint bleeding can lead to synovitis and arthropathy in people with hemophilia, reducing quality of life. Although early diagnosis is associated with improved therapeutic outcomes, diagnostic ultrasonography requires specialist experience. Artificial intelligence (AI) algorithms may support ultrasonography diagnoses., Objectives: This study will research, develop, and evaluate the diagnostic precision of an AI algorithm for detecting the presence or absence of hemarthrosis and synovitis in people with hemophilia., Methods: Elbow, knee, and ankle ultrasound images were obtained from people with hemophilia from January 2010 to March 2022. The images were used to train and test the AI models to estimate the presence/absence of hemarthrosis and synovitis. The primary endpoint was the area under the curve for the diagnostic precision to diagnose hemarthrosis and synovitis. Other endpoints were the rate of accuracy, precision, sensitivity, and specificity., Results: Out of 5649 images collected, 3435 were used for analysis. The area under the curve for hemarthrosis detection for the elbow, knee, and ankle joints was ≥0.87 and for synovitis, it was ≥0.90. The accuracy and precision for hemarthrosis detection were ≥0.74 and ≥0.67, respectively, and those for synovitis were ≥0.83 and ≥0.74, respectively. Analysis across people with hemophilia aged 10 to 60 years showed consistent results., Conclusion: AI models have the potential to aid diagnosis and enable earlier therapeutic interventions, helping people with hemophilia achieve healthy and active lives. Although AI models show potential in diagnosis, evidence is unclear on required control for abnormal findings. Long-term observation is crucial for assessing impact on joint health., (© 2024 The Authors.)

People living with HIV (PLWH) could be at risk of blunted immune responses to COVID-19 vaccination. We investigated factors associated with neutralizing antibody (NAb) responses against SARS-CoV-2 and variants of concern (VOCs), following two-dose and third booster monovalent COVID-19 mRNA vaccination in Japanese PLWH. NAb titers were assessed in polyclonal IgG fractions by lentiviral-based pseudovirus assays. Overall, NAb titers against Wuhan, following two-dose vaccination, were assessed in 82 PLWH on treatment, whereby 17/82 (20.73%) were classified as low-NAb participants. Within the low-NAb participants, the third booster vaccination enhanced NAb titers against Wuhan and VOCs, albeit to a significantly lower magnitude than the rest. In the multivariate analysis, NAb titers against Wuhan after two-dose vaccination correlated with age and days since vaccination, but not with CD4 + count, CD4 + /CD8 + ratio, and plasma high-sensitivity C-Reactive protein (hsCRP). Interestingly, an extended analysis within age subgroups revealed NAb titers to correlate positively with the CD4 + count and negatively with plasma hsCRP in younger, but not older, participants. In conclusion, a third booster vaccination substantially enhances NAb titers, but the benefit may be suboptimal in subpopulations of PLWH exhibiting low titers at baseline. Considering clinical and immune parameters could provide a nuanced understanding of factors associated with vaccine responses in PLWH.

Background: Quadricuspid aortic valve (QAV) is a rare congenital disease. The clinical characteristics of this disease remain unclear except for those in relatively young patients reported from tertiary referral hospitals. The aim of this study was to determine the clinical features of QAV in a regional population., Methods and Results: We retrospectively investigated 25 340 consecutive patients over middle age (median age, 73 (IQR 65-80) years; range, 45-102 years) who underwent transthoracic echocardiography (TTE) at our institute during the period from April 2008 to December 2023. Eight (0.032%) of the patients (median age, 65 years; range, 47-91 years) were diagnosed with QAV. Six patients suffered from aortic regurgitation (AR), and one patient had mild aortic stenosis at the time of QAV diagnosis. Two patients who had severe AR at referral underwent aortic valve surgery. The severity of AR in the other patients was moderate or less. During a median follow-up period of 27 months (range, 1-171 months), none of the patients other than above two patients had cardiac events. One patient died from a non-cardiac cause at 94 years of age., Conclusions: Patients diagnosed with QAV after middle age, who do not exhibit severe valve insufficiency at the time of diagnosis, may not experience worse clinical outcomes. However, further research is required for a better understanding of the long-term outcomes., (© 2024 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Context: Older adults with sarcopenic obesity are at high risk for type 2 diabetes mellitus (T2DM). However, few East Asians have sarcopenic obesity. Since many East Asians have insulin resistance (IR) without obesity, it is possible that older East Asians with sarcopenia and IR might be at high risk for T2DM. However, this relationship has not been studied., Methods: This cross-sectional study included 1629 older adults aged 65 to 84 years registered in the Bunkyo Health Study. All underwent a 75-g oral glucose tolerance test and handgrip strength measurement. Participants were classified into 4 groups by possible sarcopenia (handgrip strength <28 kg in men and <18 kg in women) and IR status (triglyceride glucose [TyG] index ≥8.79 for men and ≥8.62 for women [third quartile]). Modified Poisson regression was used to estimate relative risk (RR) and 95% CIs for T2DM with adjustment for confounding factors., Results: The mean age was 73.1 ± 5.4 years. T2DM was diagnosed in 212 (13.0%) participants. After adjusting for age, sex, body mass index, use of lipid-lowering medications, hypertension, and cardiovascular disease, possible sarcopenia and IR were associated with T2DM, with their coexistence showing a notably stronger association (control: RR, 1.00 [Reference]; possible sarcopenia: RR, 1.55 [95% CI, 1.04-2.30]; IR: RR, 2.69 [95% CI, 1.99-3.65]; and IR possible sarcopenia: RR, 4.76 [95% CI, 3.34-6.79])., Conclusion: Possible sarcopenia based on low handgrip strength and IR based on the TyG index are independently associated with T2DM in older Japanese individuals. Their coexistence shows a particularly strong association with T2DM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, has been developed as a safe immunostimulator on the basis of a structure-activity relationship study with trehalose 6,6'-dicorynomycolate. Our recent study indicated that vizantin acts as an effective Toll-like receptor-4 (TLR4) partial agonist to reduce the lethality of an immune shock caused by lipopolysaccharide (LPS). However, because vizantin has low solubility in water, the aqueous solution used in in vivo assay systems settles out in tens of minutes. Here, vizantin was chemically modified in an attempt to facilitate the preparation of an aqueous solution of the drug. This paper describes the concise synthesis of a water-soluble vizantin analogue in which all the hydroxyl groups of the sugar unit were replaced by sulfates. The vizantin derivative displayed micelle-forming ability in water and potent TLR-4 partial agonist activity.

Context: Older adults have a high prevalence of new-onset diabetes, often attributed to age-related decreases in insulin sensitivity and secretion. It remains unclear whether both insulin sensitivity and secretion continue to deteriorate after age 65., Objective: To investigate the effects of aging on glucose metabolism after age 65 and to identify its determinants., Methods: This cross-sectional study involved 1438 Japanese older adults without diabetes. All participants underwent a 75-g oral glucose tolerance test (OGTT). Body composition and fat distribution were measured with dual-energy X-ray absorptiometry and magnetic resonance imaging. Participants were divided into 4 groups by age (65-69, 70-74, 75-79, and 80-84 years) to compare differences in metabolic parameters., Results: Mean age and body mass index were 73.0 ± 5.4 years and 22.7 ± 3.0 kg/m 2 . The prevalence of newly diagnosed diabetes increased with age. Fasting glucose, fasting insulin, the area under the curve (AUC)-insulin/AUC-glucose and insulinogenic index were comparable between groups. AUC-glucose and AUC-insulin during OGTT were significantly higher and Matsuda index and disposition index (Matsuda index · AUC-insulin/AUC-glucose) were significantly lower in the age 80-84 group than in the age 65-69 group. Age-related fat accumulation, particularly increased visceral fat area (VFA), and elevated free fatty acid (FFA) levels were observed. Multiple regression revealed strong correlations of both Matsuda index and disposition index with VFA and FFA., Conclusion: Glucose tolerance declined with age in Japanese older adults, possibly due to age-related insulin resistance and β-cell deterioration associated with fat accumulation and elevated FFA levels., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Nuclear factor of activated T cells (NFAT) is a transcription factor essential for immunological and other biological responses. To develop analyzing system for NFAT activity in vitro and in vivo, we generated reporter mouse lines introduced with NFAT-driven enhanced green fluorescent protein (EGFP) expressing gene construct. Six tandem repeats of -286 to -265 of the human IL2 gene to which NFAT binds in association with its co-transcription factor, activator protein (AP)-1, was conjunct with thymidine kinase minimum promoter and following EGFP coding sequence. Upon introduction of the resulting reporter cassette into C57BL/6 fertilized eggs, the transgenic mice were obtained. Among 7 transgene-positive mice in 110 mice bone, 2 mice showed the designated reporter mouse character. Thus, the EGFP fluorescence of CD4 + and CD8 + T cells in these mice was enhanced by stimulation through CD3 and CD28. Each of phorbol 12-myristate 13-acetate (PMA) and ionomycin (IOM) stimulation weakly but their combined stimulation strongly enhanced EGFP expression. The stimulation-induced EGFP upregulation was also observed following T cell subset differentiation in a different manner. The EGFP induction by PMA + IOM stimulation was more potent than that by CD3/CD28 stimulation in helper T (Th)1, Th2, Th9, and regulatory T cells, while both stimulation conditions displayed the equivalent EGFP induction in Th17 cells. Our NFAT reporter mouse lines are useful for analyzing stimulation-induced transcriptional activation mediated by NFAT in cooperation with AP-1 in T cells.

BACKGROUND Prostate cancer (PC) often metastasizes after primary resection, and long-term survival following surgical removal of multiple pulmonary metastases is rare. We present a case of a surgeon who demonstrated long-term survival after overcoming repeated surgical challenges for multiple pulmonary metastases from PC. CASE REPORT Twenty-six years ago, a 62-year-old man initially reported discomfort during urination. A prostate examination revealed mildly elevated prostate-specific antigen (PSA) levels. Six months later, PC was diagnosed, and a radical prostatectomy was performed, revealing moderately differentiated adenocarcinoma but no vessel infiltration. At 9 years after the operation, three 10-mm nodules were detected in the right lung. Then, surgical biopsy by wedge pulmonary resection revealed metastatic PC, and therefore, right lower lobectomy including all nodules was planned. Although postoperative maintenance with luteinizing hormone-releasing hormone agonists kept the low PSA levels for 3 years, other newly limited metastases were observed in the opposite left lung, necessitating more surgeries of partial left lung resection. Six years later, a third lung metastasis was detected, as well as mild increases in the tumor size and PSA level, and the patient died 26 years after the initial PC intervention because of malnutrition for 1 year after sustaining bone compression fractures due to a fall, and not due to PC progression. CONCLUSIONS Repeated surgical resections for slow-growing metastatic pulmonary PC was an alternative treatment that facilitated favorable survival and a good quality of life for 26 years in the present case.

Introduction: With the increasing life expectancy of people with haemophilia, the risk of cardiovascular disease (CVD) and thrombotic events has become a growing concern. Longitudinal studies on the incidence and risk factors of CVD in this population are limited, and optimal prevention and treatment strategies are yet to be established., Aim: This study aimed to present the baseline data of a prospective longitudinal study focusing on a subset of Japanese patients with haemophilia, specifically investigated the incidence, risk factors and treatment modalities for CVD and thrombotic diseases in people aged 40 years in Japan over 10 years through the ADVANCE Japan study., Methods: The ADVANCE Japan study is a prospective multicentre cohort study involving 600 adult individuals with haemophilia A/B aged 40 years in Japan. The primary endpoint was the incidence of CVD, with secondary endpoints encompassing anticoagulant use, mortality rates, and comparison with the general population., Results: Baseline data from the 600 participants revealed that thrombotic events occurred in 13 individuals (2.2%), mostly in those with haemophilia A. Atrial fibrillation was observed in 11 participants (1.8%). Hypertension and dyslipidaemia were identified as the prevalent risk factors. Various prophylactic treatments were employed, and no severe bleeding events were observed during the study period., Conclusion: This study provides vital baseline data for a 10-year prospective investigation of CVD and thrombotic disease risk in people with haemophilia. These findings will contribute to refining prevention and treatment approaches and improving patients' quality of life., (© 2023 John Wiley & Sons Ltd.)

Aim: To retrospectively investigate the relationship between the CD4+ T-cell counts at baseline and the efficacy of the initial periodontal treatment of patients undergoing treatment for human immunodeficiency virus (HIV) infection using the periodontal inflamed surface area (PISA)., Materials and Methods: Thirty-three patients with chronic periodontitis who had undergone periodontal examination at baseline and after the initial periodontal treatment were enrolled. PISA was calculated from the periodontal probing depth and bleeding on probing, and the ratio of PISA after treatment to that at baseline (PISA response ratio) was calculated. Groups with a response ratio of <1 and ≥1 were defined as the improvement and the non-improvement groups, respectively., Results: PISA after the initial periodontal treatment significantly decreased compared with that at baseline (p < .05). A weak negative correlation was found between the PISA response ratio and CD4+ T-cell counts at baseline (p < .05). The CD4+ T-cell counts at baseline were significantly higher in the improvement group than in the non-improvement group (p < .05). Multivariate analysis revealed that the CD4+ T-cell counts at baseline was an independent factor that affects the PISA (p < .05)., Conclusions: The higher the CD4+ T-cell counts at baseline in patients undergoing treatment for HIV infection, the more effective the initial periodontal treatment., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The safety and efficacy of laparoscopic liver resection (LLR) have been reported worldwide. However, those of LLR for tumors located in Couinaud's segment 8 are not sufficiently investigated., Methods: We retrospectively analyzed 108 patients who underwent liver resection for hepatocellular carcinoma (HCC) in segment 8 at Kobe University Hospital and Hyogo Cancer Center between January 2010 and December 2021. The patients were categorized in LLR and open liver resection (OLR) groups, and 1:1 propensity score matching (PSM) was performed to compare surgical outcomes between the groups., Results: Forty-seven and 61 patients underwent LLR and OLR, respectively. After PSM, each group contained 34 patients. There was no significant difference in operation time between the groups (331 min vs. 330 min, P = 0.844). Patients in the LLR group had significantly less blood loss (30 mL vs. 468 mL, P < 0.001) and shorter length of postoperative hospital stay (10 days vs. 12 days, P = 0.015) than those in the OLR group. There was no significant difference in the occurrence of postoperative complications between the groups (12% vs. 9%, P = 0.690). Further, the 1-year cumulative incidence of recurrence was not significantly different between the groups (16% vs. 19%, P = 0.734)., Conclusions: The surgical outcomes and short-term prognosis of LLR were similar or better than those of OLR. LLR could be an effective and safe procedure, even for lesions located in segment 8, which is considered a difficult anatomical location for LLR., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective Cardiac involvement defines the prognosis for patients with systemic sarcoidosis. Despite advancements in techniques for diagnosing cardiac lesions, there remains significant room for improvement in cardiac screening and prognostic prediction. The present study therefore assessed the prognostic factors associated with cardiovascular events in patients with sarcoidosis. Methods We retrospectively studied 132 patients with systemic sarcoidosis and evaluated the clinical data obtained between 2009 and 2022. A Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the associations between cardiovascular events and prognostic factors. Results The median age of the patients at the diagnosis was 64.0 (55.0-71.0) years old. During a mean follow-up period of 6.3±3.2 years, 28 patients suffered from cardiovascular events. Patients in the event group had more severe heart failure symptoms, more frequent ventricular tachycardia, higher serum high-sensitivity cardiac troponin T (hs-cTnT) values [0.025 (0.017-0.044) vs. 0.011 (0.007-0.019) ng/mL, p<0.001], and lower left ventricular ejection fraction values than those in the non-event group. These trends were observed even if the patients were not diagnosed with cardiac involvement at the time of enrollment. A multivariate analysis revealed that hs-cTnT was an independent biomarker for the prediction of cardiac events (hs-cTnT >0.014 ng/mL: HR: 7.31, 95% confidence interval: 2.20 to 24.28, p<0.001). Conclusion Hs-cTnT is a useful biomarker for predicting cardiovascular events in patients with sarcoidosis, even if cardiac involvement is not detected at the initial evaluation.

A technically straightforward total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed that provided tetrachlorovancomycin ( 1 , LLS = 15 steps, 15% overall yield) and its precursor aglycon 29 (nearly 20% overall yield). The class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the antimicrobial activity of vancomycin, and achieves the simplification by an unusual addition, not removal, of benign substituents to the core structure. The modification, accomplished by addition of two aryl chloride substituents to provide 1 , permitted a streamlined total synthesis of the new glycopeptide antibiotic class by removing the challenges associated with CD and DE ring system atropisomer stereochemical control. This also enabled their simultaneous and further-activated S N Ar macrocyclizations that establish the tricyclic skeleton of 1 . Key elements of the approach include catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an essentially instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), racemization free coupling of the E ring tetrapeptide, room temperature simultaneous CD and DE ring system cyclizations, a highly refined 4-step conversion of the cyclization product to the aglycon, and a protecting-group-free one-pot enzymatic glycosylation for disaccharide introduction. In addition to the antimicrobial evaluation of tetrachlorovancomycin ( 1 ), the preparation of key peripherally modified derivatives, which introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for future use of this new class of synthetic glycopeptide analogues.

Mbtd1 (mbt domain containing 1 ) encodes a nuclear protein containing a zinc finger domain and four malignant brain tumor (MBT) repeats. We previously generated Mbtd1 -deficient mice and found that MBTD1 is highly expressed in fetal hematopoietic stem cells (HSCs) and sustains the number and function of fetal HSCs. However, since Mbtd1 -deficient mice die soon after birth possibly due to skeletal abnormalities, its role in adult hematopoiesis remains unclear. To address this issue, we generated Mbtd1 conditional knockout mice and analyzed adult hematopoietic tissues deficient in Mbtd1 . We observed that the numbers of HSCs and progenitors increased and Mbtd1 -deficient HSCs exhibited hyperactive cell cycle, resulting in a defective response to exogenous stresses. Mechanistically, we found that MBTD1 directly binds to the promoter region of FoxO3a , encoding a forkhead protein essential for HSC quiescence, and interacts with components of TIP60 chromatin remodeling complex and other proteins involved in HSC and other stem cell functions. Restoration of FOXO3a activity in Mbtd1- deficient HSCs in vivo rescued cell cycle and pool size abnormalities. These findings indicate that MBTD1 is a critical regulator for HSC pool size and function, mainly through the maintenance of cell cycle quiescence by FOXO3a.

A short-term high-calorie high-fat diet (HCHFD) impairs insulin sensitivity in non-obese South Asian but not Caucasian men; however, the effect of short-term HCHFD on insulin sensitivity in East Asians is unknown. We recruited 21 healthy non-obese Japanese men to evaluate metabolic parameters and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus a 45% energy excess with dairy fat supplementation. We evaluated tissue-specific insulin sensitivity and metabolic clearance rate of insulin (MCRI) using a two-step hyperinsulinemic euglycemic clamp, glucose tolerance using the glucose tolerance test, and measured ectopic fat in muscle and the liver using ¹H-magnetic resonance spectroscopy. The primary outcome of this study was insulin sensitivity measured by the clamp study. The secondary/exploratory outcomes were other metabolic changes. After HCHFD, levels of circulating lipopolysaccharide binding protein (LBP), a marker of endotoxemia, increased by 14%. In addition, intramyocellular lipid levels in the tibialis anterior and soleus and intrahepatic lipid levels increased by 47%, 31%, and 200%, respectively. Insulin sensitivity decreased by 4% in muscle and 8% in liver. However, even with reduced insulin sensitivity, glucose metabolism was maintained by increased serum insulin concentrations due to lower MCRI and higher endogenous insulin secretion during the clamp. Glucose levels during the meal tolerance test were comparable before and after HCHFD. In conclusion, short-term HCHFD impaired insulin sensitivity in the muscle and livers of non-obese Japanese men with increased LBP and ectopic fat accumulation. Elevated insulin levels from modulated insulin secretion and clearance might contribute to the maintenance of normal glucose metabolism during the clamp and meal tolerance test.

Background: Curative treatment for hepatocellular carcinoma (HCC) is limited to hepatic resection (HR), radiofrequency ablation, and liver transplantation, but the value of particle therapy (PT) as an initial treatment remains unclear. This study aimed to compare the outcomes of HR and PT for single HCC., Study Design: A total of 554 patients with single HCC without vascular invasion were enrolled from January 2000 to December 2015. Patients underwent either HR (n = 279) or PT (n = 275) as initial treatments. A one-to-one propensity score-matching analysis was performed to evaluate the overall survival (OS) and progression-free survival after dividing patients according to liver function as assessed by the modified albumin-bilirubin grade., Results: The median OS (130 vs 85 months, p = 0.001) and progression-free survival (47 vs 30 months HR, p = 0.004) of HR were also significantly better than that of PT in the propensity score-matching cohort with modified albumin-bilirubin grade 1/2a (n = 145 per group). Meanwhile, in a propensity score-matching cohort with modified albumin-bilirubin grade 2b/3 (n = 53 per group), there were no significant differences in median OS and progression-free survival between HR and PT., Conclusions: HR may be preferable as an initial treatment for patients with single HCC without vascular invasion, especially those with preserved liver function. PT can be an acceptable alternative to HR for patients without surgical indication and/or impaired liver function., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To determine the relationship between the subjective age, higher-life function, and new certification for the need for long-term care among older adults in the community., Methods: A mail survey was conducted in 2016 among community-dwelling older adults, and the 2,323 participants who were available for follow-up in 2019 were included in the analysis. Subjective age was evaluated using the following three items in response to the question "Please answer how old you feel you are": "Same as actual age," "Feel younger," and "Feel older." Other assessments included an evaluation of the higher-life function, Geriatric Depression Scale scores, general self-efficacy, and exercise adherence. In addition, at follow-up, we investigated whether or not participants required new certification for the need for long-term care., Results: At baseline, participants who felt "older than their actual age" had a significantly lower life function and general self-efficacy and were less likely to exercise at least once a week than the other groups. Furthermore, those who felt "older than their actual age" was more likely than the other groups to be newly certified as needing long-term care, while those who felt "younger than their actual age" were less likely to receive new certification. A logistic regression analysis revealed that "feeling older" was a risk factor for being certified as needing long-term care, even after adjusting for other factors (odds ratio= 3.33, 95% confidence interval: 1.02-10.94, p=0.047)., Conclusions: Among community-dwelling older adults, those with a subjective age exceeding their chronological age were expected to show a decreased life function in the future and an increased risk of needing long-term care.

T cells play an essential role in the development of allergen-induced nasal hyperresponsiveness (NHR), a pathophysiological response in allergic rhinitis. The effects of histamine H1-receptor antagonists (antihistamines) on murine NHR models were investigated. Intragastric epinastine, fexofenadine, and loratadine administration suppressed allergen-induced immediate nasal response but not NHR in immunized mice. Regardless of the alleviation of stimulation-induced Th2 cytokine expression by loratadine and desloratadine in vitro, allergen-induced NHR and nasal eosinophil infiltration in Th2 cell-transferred mice were unaffected by loratadine in vivo. This influence on T cell-mediated NHR was excluded from the pharmacological effects of antihistamines., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Sarcopenia is a major cause of disability in the elderly. Although type 2 diabetes is a risk factor for increased sarcopenia, the relationship between prediabetes and sarcopenia has not been elucidated. We aimed to examine the relationship between sarcopenia and prediabetes., Methods: The design of this study is a cross-sectional study. We evaluated glucose metabolism using the 75-g oral glucose tolerance test and glycated haemoglobin, appendicular skeletal muscle mass, and hand grip strength in 1629 older adults living in an urban area of Tokyo, Japan. We investigated the frequency of sarcopenia in participants with normal glucose tolerance (NGT), prediabetes and diabetes. A multivariable logistic regression model was used to analyse the association between glucose tolerance and the prevalence of sarcopenia., Results: The mean age of participants was 73.1 ± 5.4 years. In men, 44.3% had NGT, 26.6% had prediabetes, and 29.1% had diabetes. In women, the distribution was 56.1%, 28.8% and 15.2%. The prevalence of sarcopenia was 12.7% in men and 11.9% in women. Logistic regression revealed that prediabetes and diabetes are independent risk factors for sarcopenia in men (prediabetes, odds ratio [OR] = 2.081 [95% confidence interval {CI}: 1.031-4.199]; diabetes, OR = 2.614 [95% CI: 1.362-5.018]) and diabetes, but not prediabetes, is an independent risk factor for sarcopenia in women (prediabetes, OR = 1.036 [95% CI: 0.611-1.757]; diabetes, OR = 2.099 [95% CI: 1.146-3.844]). In both sexes, higher age (men, OR = 1.086 [95% CI: 1.028-1.146]; women, OR = 1.195 [95% CI: 1.142-1.251]), higher body fat percentage (men, OR = 1.346 [95% CI: 1.240-1.461]; women, OR = 1.218 [95% CI: 1.138-1.303]) and lower body mass index (men, OR = 0.371 [95% CI: 0.299-0.461]; women, OR = 0.498 [95% CI: 0.419-0.593]) were independent risk factors for sarcopenia., Conclusions: Although we confirmed that diabetes mellitus is associated with sarcopenia in both sexes, prediabetes is associated with sarcopenia in men, but not in women., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: The clinical features of heart failure (HF) in patients with hypertrophic cardiomyopathy (HCM) in Japan have not been fully elucidated., Methods and results: In 293 patients with HCM (median age at registration, 65 (57-72) years) in a prospective cardiomyopathy registration network in Kochi Prefecture (Kochi RYOMA study), HF events (HF death or hospitalization for HF) occurred in 35 patients (11.9%) (median age, 76 (69-80) years), including 11 HF deaths during a median follow-up of 6.1 years. The 5-year HF events rate was 9.6%. Atrial fibrillation, low percentage of fractional shortening, and high B-type natriuretic peptide level at registration were predictors of HF events. The combination of these 3 factors had a relatively high positive predictive value (55%) for HF events and none of them had a high negative predictive value (99%). There were 4 types of HF profile: left ventricular (LV) systolic dysfunction (40%), severe LV diastolic dysfunction (34%), LV outflow tract obstruction (LVOTO) (20%), and primary mitral regurgitation (MR) (6%). HF deaths occurred in patients with LV systolic dysfunction or LV diastolic dysfunction, but none of patients with LVOTO or primary MR due to additional invasive therapies., Conclusions: In a Japanese HCM cohort, HF was an important complication, requiring careful follow-up and appropriate treatment.

Background: Cardiogenic unilateral pulmonary edema (UPE) has been reported as an unusual condition and to occur in association with severe mitral regurgitation (MR). However, the prevalence of UPE in patients with severe MR remains unknown. Methods and Results: Among 143 consecutive patients with chordal rupture and significant MR, 38 patients with acute severe MR were studied. The prevalence of UPE was 50% (19 patients); all these patients had right-sided UPE. Eight (21%) patients had bilateral pulmonary edema (BPE). All 8 patients with BPE and 18 of 19 patients with UPE had chordal rupture of the posterior leaflet. All patients with UPE and BPE had severe MR with similar left atrial size. Chest radiographs taken ≤48 h from symptom onset diagnosed UPE in 15 of 19 (79%) patients and BPE in 3 of 8 (38%) patients (P=0.037). Chest radiographs taken >48 h from symptom onset diagnosed UPE in 4 (21%) patients and BPE in 5 (62%) patients (P=0.037). Conclusions: The prevalence of UPE was estimated as 50%; it was most frequently right sided and almost always associated with chordal rupture of the posterior leaflet. UPE is not rare, but common, particularly shortly after the development of acute severe MR caused by chordal rupture., Competing Interests: All authors have no conflict of interest to disclose., (Copyright © 2022, THE JAPANESE CIRCULATION SOCIETY.)

Adeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic effect. Therefore, NAb prevalence in the target population is vital in designing clinical trials with AAV vectors. Hence, updating the seroprevalence of anti-AAV NAbs, herein we analyzed sera from 100 healthy individuals and 216 hemophiliacs in Japan. In both groups, the overall seroprevalence against various AAV serotypes was 20%-30%, and the ratio of the NAb-positive population increased with age. The seroprevalence did not differ between healthy participants and hemophiliacs and was not biased by the concomitant blood-borne viral infections. The high neutralizing activity, which strongly inhibits the transduction with all serotypes in vitro , was mostly found in people in their 60s or of older age. The multivariate analysis suggested that "60s or older age" was the only independent factor related to the high titer of NAbs. Conversely, a large proportion of younger hemophiliacs was seronegative, rendering them eligible for AAV-mediated gene therapy in Japan. Compared with our previous study, the peak of seroprevalences has shifted to older populations, indicating that natural AAV exposure in the elderly occurred in their youth but not during the last decade., Competing Interests: All authors have no competing financial interests to declare., (© 2022 The Author(s).)

Background: Histologic tumor necrosis (TN) is a well-established independent prognostic indicator in patients treated surgically for clear cell renal cell carcinoma (ccRCC). However, the precise mechanisms by which TN alters disease progression remain unknown. The DEAD-box protein DDX41, a member of a large family of helicases, has been characterized as a pattern recognition receptor against an array of double-stranded (ds)DNA produced from bacteria, dsDNA viruses, and nearby cells that have released dsDNA fragments through necrosis. We hypothesized that DDX41 expression may be upregulated in ccRCC with TN, leading to worse prognosis., Methods: Relationship between the presence of TN and DDX41 expression were examined using The Cancer Genome Atlas data sets or using ccRCC samples in our institution. Further, the molecular functions of DDX41 were investigated with human ccRCC cells., Results: The presence of TN was significantly associated with the upregulation of mRNA and protein expression of DDX41 in the 2different patient cohorts with ccRCC. In addition, the mRNA and protein expression levels of DDX41 revealed a worse prognosis. In vitro analyses with ccRCC cells revealed that DDX41 expression promotes tumor-promoting activity. Furthermore, VHL loss, 1of the most common features in ccRCC, was shown to play an extremely important role in increasing the expression of the CXCL family in DDX41-expressing ccRCC, leading to the acquisition of a worse malignant phenotype., Conclusions: DDX41 expression is associated with TN in ccRCC and leads to a worse prognosis in cooperation with VHL loss., Competing Interests: Conflict of interest All authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: The prevalence of Fabry disease (FD) in male patients with left ventricular hypertrophy (LVH) is about 1%. From the perspective of performing more efficient screening with measurement of α-galactosidase (α-Gal) activity, it is important to raise the pretest probability., Methods: We retrospectively investigated the prevalence of FD in 701 male patients with LVH who already had been screened by measurement of α-Gal activity in eight hospitals. From the viewpoint of enzymatic screening, we validated previously reported clinical features of FD including the electrocardiographic and echocardiographic characteristics with comparing each clinical determinant between patients with FD and non-FD patients. We finally aimed to establish a new screening approach for the detection of patients at high risk of FD., Results: There were five FD patients (0.7%) in the 701 male patients with LVH. Those five patients with FD all had the cardiac variant type and age at detection of LVH was ≥35 years in all patients. In LVH patients with LV ejection fraction (EF) ≥ 50%, Pend-Q interval < 40 msec, SV1 + RV5 > 4.0 mV, and diffuse LVH were important determinants of FD. In LVH patients with LVEF < 50%, asymmetric septal hypertrophy and posterior wall motion abnormality seemed to be associated with FD., Conclusions: In our retrospective study, the prevalence of FD in male patients with LVH was found to be 0.7%. We established the efficient combinations of clinical determinants using age at detection of LVH, Pend-Q interval, high voltage, and LVH pattern in an echocardiogram., Competing Interests: Declaration of competing interest Dr. Toru Kubo has received remuneration for lectures from Sumitomo Dainippon Pharma Co. The remaining authors have no conflicts of interest to declare. Dr. Yasuchika Takeishi is a chief editor of Journal of Cardiology., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute coronary syndrome (ACS) with occlusion of the left circumflex coronary artery (LCX) poses diagnostic problems that may lead to a delay in reperfusion. Methods and Results: From a group of 1,269 consecutive patients with ACS, 138 patients with ACS due to LCX occlusion were analyzed for clinical, electrocardiographic, and angiographic presentations, as well as door-to-balloon (DTB) time. Electrocardiographic changes were classified into 4 patterns: ST-segment elevation in inferior/lateral leads (ST-E); ST-segment depression in V1-V4 (ST-D); no significant ST changes (No-ST); and others. The No-ST group was associated with a longer DTB time (P<0.0001) compared with the ST-E and ST-D groups. Compared with the No-ST and ST-E groups, the ST-D group presented with a more advanced Killip class (P=0.003), greater peak creatine phosphokinase (P=0.007) and peak creatine kinase-MB (P=0.006), more frequent proximal LCX occlusion (P=0.007), and worse 1-year outcomes (P=0.0034). Conclusions: One-third of ACS patients with LCX occlusion showed no ST-segment changes, resulting in significantly longer DTB time. Improving diagnostic accuracy is challenging but critical to avoid delayed reperfusion in these patients without electrocardiographic changes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022, THE JAPANESE CIRCULATION SOCIETY.)

Phosphonic acid (phosphonate) that possesses a carbon-phosphours bond is a chemically stable form of organic phosphorus. Various phosphonic acids are widely distributed in oceanic waters; in particular, methylphosphonic acid (namely methylphosphonate) is believed to be responsible for global methane production. To discuss the microbial degradation of phosphonic acids, we investigated the utilization of phosphonic acid compounds by cultures of marine bacteria, Phaeobacter sp., Ruegeria sp. (Rhodobacterales), and Thalassospira sp. (Rhodospirillales). These bacterial cultures were able to grow on methylphosphonic acid as well as on the tested alkyl-, carboxy-, aminoalkyl-, and hydroxyalkyl-phosphonic acid compounds. Cell yields and growth rates of Ruegeria and Thalassospira cultures grown on methyl-, ethyl-, propyl-, and butyl-phosphonic acid compounds tended to decrease with increasing alkyl chain length. In contrast, Phaeobacter sp. grew well on such alkyl-phosphonic acids. Our results suggest that these marine bacteria, which exhibit varied utilization, are involved in microbial degradation of various phosphonic acid compounds., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

Aims: We aim to clarify the prognosis on patients with hypertrophic cardiomyopathy (HCM) for a follow-up period of more than 10 years., Methods and Results: We retrospectively analysed 102 consecutive patients with HCM diagnosed by 31 December 2000. Complete and detailed clinical records were obtained for 93 (91%) of the 102 patients. Sixty-three (68%) of the 93 patients were men, and the mean age of the patients at the initial evaluation was 51.5 ± 13.0 years. During the mean follow-up period of 19.6 ± 8.1 years (median 20.1 years), HCM-related deaths occurred in 20 patients (21% [1.1%/year]). HCM-related adverse events (including HCM-related deaths and nonfatal HCM-related events: hospitalization for heart failure, embolic stroke admission, and sustained ventricular tachycardia with haemodynamic instability or appropriate implantable cardioverter-defibrillator discharge) occurred in 45 patients (48%). The first HCM-related adverse events occurred in approximately 20% of the patients in every decade, the first decade to the third decade, from the initial evaluation. Forty-seven patients (51%) had documentation of atrial fibrillation at the last follow-up. There were seven patients in the end-stage HCM group at the initial evaluation, and 22 patients (24%) had progression to end-stage HCM during the follow-up period., Conclusions: In our cohort of patients, HCM-related mortality was relatively favourable. However, approximately half of the patients suffered from HCM-related adverse events during the follow-up period of 20 years. It is important for HCM patients to be carefully followed up over the long-term because HCM is a lifelong disease., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Tafamidis has emerged as an effective treatment for patients with wild-type transthyretin cardiac amyloidosis (ATTRwt CA). The early experience of tafamidis treatment for Japanese patients with ATTRwt CA is reported here., Methods and results: Over the past 2 years, in 82 patients with ATTRwt CA (mean age of 81.7±6.0 years), tafamidis treatment was initiated for 38 patients. The remaining 44 patients were not administered tafamidis. The most frequent reason for non-administration of tafamidis was advanced heart failure and the second most reason was the patient's frailty. In patients who received tafamidis treatment, there was no discontinuation of tafamidis due to adverse events, the rate of cardiovascular-related hospitalizations per year was 0.19, and the 1-year survival rate was 92%. In the patients who continued tafamidis for 12-18 months, there was no significant deterioration from baseline for high-sensitivity cardiac troponin T level, plasma B-type natriuretic peptide level, left ventricular ejection fraction, inter-ventricular septum wall thickness, or value of left ventricular longitudinal strain., Conclusions: Tafamidis treatment was introduced for approximately half of the study patients with ATTRwt CA in real-world practice. Tafamidis is likely to be safe and may maintain the status of disease severity in the short-term in selected Japanese patients with ATTRwt CA. Further research is needed to determine appropriate patient selection for tafamidis treatment and efficacy of tafamidis in the long term.

Although takotsubo syndrome (TTS) has been reported in patients with subarachnoid hemorrhage (SAH), its incidence and relation to the severity of SAH are unknown.Of 319 consecutive patients with aneurysmal SAH, 245 patients who underwent both the ECG and echocardiography were analyzed.The incidence of TTS was 6.9% (22 patients (21 women), median age 68 years (range, 60-83) ). Regional wall motion abnormalities were present as apical (64%), mid-ventricular (9%), basal (4%) and focal (23%) forms. Heart failure was found in 10 patients (45%) but there was no cardiac death. Regarding SAH severity, 10 patients (45%) with TTS were in World Federation of Neurosurgical Societies classification grade V, as compared to 40 patients (18%) without TTS (P = 0.005). Seven patients (32%) with TTS died during hospitalization, as compared to 26 patients (12%) without TTS (P = 0.018). Four patients (18%) with TTS were estimated as independent at discharge, as compared to 100 patients (45%) without TTS (P = 0.013).The incidence of TTS in patients with SAH was estimated as 6.9% with significant predominance of women. The severity of SAH was significantly greater in patients with TTS than in those without TTS.

Th17 cells are implicated in allergic inflammatory diseases, including allergic rhinitis (AR), though the effect of steroids on Th17 cell-dependent nasal responses is unclear. Herein, we investigated a nasal inflammation model elicited by allergen provocation in mice infused with Th17 cells and its responsiveness against steroid treatment. We transferred BALB/c mice with Th17 cells, which were differentiated in vitro and showed a specific reaction to ovalbumin (OVA). We challenged the transferred mice by intranasal injection of OVA and to some of them, administered dexamethasone (Dex) subcutaneously in advance. Then, we assessed immediate nasal response (INR), nasal hyperresponsiveness (NHR), and inflammatory cell infiltration into the nasal mucosa. The significant nasal inflammatory responses with massive neutrophil accumulation, INR, and NHR were induced upon allergen challenge. Allergen-induced INR and NHR were significantly suppressed by Dex treatment. This study suggested the effectiveness of steroids on Th17 cell-mediated nasal responses in AR.

Aim: This study investigated neighborhood walkability using Walk Score® and social participation in districts within a city among older Japanese adults., Methods: This study was a cross-sectional study using baseline data of older adults from the Keeping Active across Generations Uniting the Youth and the Aged study. In total, 2750 participants (1361 men and 1389 women, mean age 72.8 ± 6.4 years) were included in the analysis. The questionnaire included socioeconomic status, self-rated health, medical history, depressive symptoms, instrumental activities of daily living and social participation. We used the Walk Score® as neighborhood walkability and a walk score <50 was categorized as a "car-dependent" area and a score ≥50 as a "walkable" area. A Poisson regression analysis stratified by sex was performed to investigate the association of neighborhood walkability with social participation. Prevalence ratios were calculated and their 95% confidence intervals., Results: We found that dwelling in car-dependent areas (prevalence ratio 0.78, 95% confidence interval 0.64-0.94) had a significant negative effect on women's social participation, unlike men., Conclusions: Our study showed that neighborhood walkability and social participation were associated with older Japanese women after adjusting for the covariates. These findings might provide helpful information for public health interventions targeted to promote social participation among older adults. Geriatr Gerontol Int 2022; 22: 350-359., (© 2022 Japan Geriatrics Society.)

A contribution of the cholinergic system to immune cell function has been suggested, though the role of nicotine and its receptors in T cells, especially regulatory T (Treg) cells, is unclear. We herein investigated the expression and function of nicotinic acetylcholine receptors (nAChRs) in murine-induced Treg (iTreg) cells. Upon differentiation of naive BALB/c T cells into iTreg cells and other T-cell subsets, the effect of nicotine on cytokine production and proliferation of iTreg cells was examined. The expression of nAChRs and its regulatory mechanisms were comparatively analyzed among T-cell subsets. Stimulation-induced transforming growth factor-β1 (TGF-β1) production of iTreg cells was suppressed by nicotine, whereas interleukin (IL)-10 production and proliferation was not affected. α2-, α5-, α9-, and β2-nAChRs were differentially expressed in naive, Th1, Th2, Th9, Th17, and iTreg cells. Among these cell types, the α9-nAChR was particularly upregulated in iTreg cells via its gene promoter, but not through tri-methylation at the 4th lysine residue of the histone H3-dependent mechanisms. We conclude that the immunoregulatory role of Treg cells is modified by the cholinergic system, probably through the characteristic expression of nAChRs.

An on-site electrochemical antioxidant capacity measurement system was developed using a screen print electrode (SPE) and circuit tester. The antioxidant capacities of eight antioxidants were evaluated with the handheld electrochemical antioxidant capacity measurement system to compare with those measured with spectroscopic methods, namely, oxygen radical absorbance capacity (ORAC) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assays, as well as the reported electrochemical method with three conventional electrodes (a glassy carbon electrode, Ag/AgCl electrode and platinum wire electrode) and a potentiostat. Additionally, the potential shifts were proportional to the logarithm of the antioxidant concentration, which obeyed the Nernstian equation. Moreover, the antioxidant capacities of extracts from vegetables (green pepper, ginger and eggplant) were measured with a handheld electrochemical system. Each measurement was finished in only ca. 3 min. The electrochemically obtained antioxidant data were comparable to those from DPPH free-radical scavenging assays and superoxide anion scavenging activity (SOSA) assays, as well as the total phenolic compound content., (© 2022. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Aims: There is limited information about the clinical significance of atrial fibrillation (AF), particularly new-onset AF, in patients with hypertrophic cardiomyopathy (HCM) in a community-based patient cohort. This study was carried out to clarify the prevalence and prognostic impact of AF in Japanese HCM patients., Methods and Results: In 2004, we established a cardiomyopathy registration network in Kochi Prefecture as a prospective study, and finally, 293 patients with HCM were followed. In the patients' cohort, we recently reported the clinical outcomes including mortality and HCM-related morbid events. HCM-related adverse cardiovascular events were defined in the following: (i) sudden cardiac death (SCD)-relevant events including SCD, spontaneous sustained ventricular tachycardia, and appropriate implantable cardioverter defibrillator discharge; (ii) heart failure (HF) events with the composite of HF death and hospitalization for HF; and (iii) embolic events included embolic stroke-related death and admission for embolic events. In the present study, we focused on AF and conducted a detailed investigation. At registration, the mean age of the patients was 63 ± 14 years, and 86 patients (29%) had documented AF including paroxysmal AF. Patients with AF at registration were characterized by worse clinical profiles including more advanced age, more symptomatic, more advanced left ventricular, and left atrial remodelling at registration. During a mean follow-up period of 6.1 ± 3.2 years, a total of 77 HCM-related adverse events occurred, and the presence of AF at registration was associated with an increased risk of HCM-related adverse events, particularly heart failure events. During the follow-up period, an additional 31 patients (11%) had documentation of AF for the first time, defined as new-onset AF, with an annual incidence of approximately 1.8%, and finally, a total of 117 patients (40%) showed AF. The presence of palpitation and enlarged left atrial diameter, particularly left atrial diameter ≥50 mm, at registration were significant predictors of new-onset AF. Importantly, the incidence of overall HCM-related adverse events was further higher in patients with new-onset AF observed from AF onset than in patients with AF at registration., Conclusions: In our HCM registry in an aged Japanese community, a significant proportion developed AF. The presence of AF, particularly new-onset AF, was associated with increased incidence of HCM-related events. AF may not be just a marker of disease stage but an important trigger of adverse events., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Competing Interests: T.K. and H.K. have received consulting fees or honoraria and remuneration for lectures from Pfizer Japan Inc. H.K. is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to declare.

Background: Takotsubo syndrome (TTS) in the very elderly is poorly understood. We sought to clarify the characteristics of octogenarians and nonagenarians with TTS. Methods and Results: From 148 patients with TTS who underwent coronary angiography, 68 very elderly patients aged ≥80 years (octogenarians/nonagenarians) were compared with 80 younger patients aged ≤79 years. Emotional triggers of TTS were less frequent (7% vs. 19%; P=0.043), whereas physical triggers were more frequent (69% vs. 46%; P=0.005), in octogenarians/nonagenarians than in patients aged ≤79 years. As initial clues to the diagnosis, electrocardiogram changes were more frequent (71% vs. 46%; P=0.003) and chest pain and/or dyspnea were less common (25% vs. 51%; P=0.001) in octogenarians/nonagenarians than in patients aged ≤79 years. Twenty-nine patients had acute heart failure (AHF) as a complication. AHF was more frequently found in octogenarians/nonagenarians than in patients aged ≤79 years (29% vs. 11%, respectively; P=0.006). Cardiac death occurred in 2 octogenarians/nonagenarians; non-cardiac death occurred in 3 octogenarians/nonagenarians and in 2 patients aged ≤79 years. Conclusions: Emotional triggers of TTS were infrequent in octogenarians/nonagenarians with TTS. AHF was common and there was significant in-hospital all-cause mortality among octogenarians/nonagenarians., Competing Interests: H.K. is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021, THE JAPANESE CIRCULATION SOCIETY.)