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Carotenoid-carrying lipoprotein (CCL) was rapidly isolated from the high density lipoprotein (HDL) fraction of the upstream migrating male chum salmon (Oncorhynchus keta) by a single-step density gradient ultracentrifugation. The two apolipoproteins (Mr = 24,000 and 12,000; designated apo-I and apo-II, respectively) were readily dissociated and separated in 0.1% SDS by gel filtration chromatography. Prominent features of the amino acid composition in the CCL included the relative high levels of glutamic acid, alanine, leucine, and lysine, and the low cysteine content. Apo-I, as well as the CCL, was rich in glutamic acid, alanine, leucine, and lysine. Compared to the amino acid composition of apo-I, apo-II included relatively high levels of glycine and tyrosine, and low threonine, serine, and arginine contents. When the intact CCL particle was treated with trypsin, apo-I was rapidly proteolyzed, while apo-II was resistant. However, both apo-I and apo-II isolated from the CCL particle were readily digested with trypsin. This suggested that a different structural arrangement rather than the amino acid compositions of the apolipoproteins was associated with the limited trypsin digestion of the CCL particle. Apo-II may be sheltered from the aqueous environment and lie partly within the CCL particle. The properties of both the HDL fraction and apolipoproteins from pink salmon (Oncorhynchus gorbuscha) were similar to those of the CCL from chum salmon.

Background: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has advanced significantly in recent years, thereby improving patient prognosis. However, the impact of cancer on the outcomes of patients with CTEPH under current treatment remains unclear. This study aimed to investigate the prevalence of cancer in patients with CTEPH and determine how comorbid cancer affects their prognosis and clinical course., Methods: Data from an ongoing Japanese prospective cohort study were analyzed. Prevalence and primary cancer sites were evaluated. The association of a history of cancer with a composite endpoint, including all-cause death, lung transplantation, and worsening of CTEPH, as well as venous thromboembolism and bleeding events, was assessed., Results: Of the 1,270 patients in the cohort, 134 (10.6%) had a history of cancer, with the most common primary sites being the breast in women and the prostate in men. The incidence of composite outcome and all-cause death was higher in those with a history of cancer (p<0.001, log-rank test). In the Cox proportional hazard model, age- and sex-adjusted hazard ratios for the composite outcome and all-cause death were 2.69 (95% confidence interval, 1.48-4.89, p=0.001) and 4.25 (95% confidence interval, 1.98-9.10, p<0.001), respectively, for patients with a history of cancer. No significant differences in venous thromboembolism and bleeding events were observed between patients with and those without a history of cancer., Conclusions: A history of cancer, with a prevalence of 10.6%, is an independent risk factor for mortality in patients with CTEPH undergoing the currently recommended treatment., Competing Interests: Disclosure of interest Tsujino I. reports personal fees from Janssen Pharmaceutical and Nippon Shinyaku and affiliation with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, Mochida Pharmaceutical, Kaneka, Takeyama, and the Medical System Network outside the submitted work. Hosokawa K. reports personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, and Pfizer outside the submitted work. Taniguchi Y. reported grants from Janssen Pharmaceutical and Nippon Shinyaku and personal fees from Janssen Pharmaceutical and Nippon Shinyaku outside the submitted work. Inami T. reports personal fees from Janssen Pharmaceutical and Bayer Yakuhin outside the submitted work. Yamashita J. reports a grant from Abbott Vascular Japan and personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin outside the submitted work. Ogino H. reports consulting fees from Terumo, Japan Lifeline, and Century Medical, outside the submitted work. Ikeda N. reports personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Bristol-Myers Squibb outside the submitted work. Yaoita N. reports personal fees from Bayer Yakuhin and Konica Minolta outside the submitted work. Shimokawahara H. reports a grant from Bayer Yakuhin and personal fees from Actelion Pharmaceuticals Japan, Bayer Yakuhin, and Nippon Shinyaku, outside the submitted work. Tanabe N. reports personal fees from Janssen Pharmaceutical, Bayer Yakuhin, and Nippon Shinyaku outside the submitted work. Kubota K. reports personal fees from Janssen Pharmaceutical and Nippon Shinyaku outside the submitted work. Ogihara Y. reports personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, and Daiichi Sankyo and grants from Bayer Yakuhin and Daiichi Sankyo outside the submitted work. Kawakami T. reports personal fees from Kaneka Medix, Abbott Medical Japan., and ACIST Japan outside the submitted work. Tamura Y. reports grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Pharmaceutical outside the submitted work. Abe K. reports a grant from Konica Minolta and Daiichi Sankyo outside the submitted work. Nakamura J., Masaki K., Funakoshi K., Adachi S., Hatano M, Shigeta A., Horimoto K., Dohi Y., and Tatsumi K. report no conflicts of interest., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient., Objectives: In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)-related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants., Methods: The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as "sarcomeric variants." In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as "other CVD-related variants.", Results: Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010)., Conclusions: Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from SENSHIN Medical Research Foundation (to Dr Ko and Dr Nomura), Japan Foundation for Applied Enzymology (to Dr Ko and Dr Nomura), Kanae Foundation for the Promotion of Medical Science (to Dr Nomura), Merck Sharp & Dohme Life Science Foundation (to Dr Ko and Dr Nomura), Sakakibara Heart Foundation Cardiovascular Research Program 2023 (to Dr Ko), Tokyo Biomedical Research Foundation (to Dr Nomura), Astellas Foundation for Research on Metabolic Disorders (to Dr Nomura), Novartis Foundation (Japan) for the Promotion of Science (to Dr Nomura), Japanese Circulation Society (to Dr Ko and Dr Nomura), Takeda Science Foundation (to Dr Ko and Dr Nomura), Cell Science Research Foundation (to Dr Nomura), Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Dr Nomura), Japan Heart Foundation (to Dr Ko), Daiichi Sankyo Foundation of Life Science (to Dr Nomura), a Grant-in-Aid for Scientific Research (A) (to Dr Nomura), a Grant-in-Aid for Scientific Research (S) (to Dr Komuro), UTEC-UTokyo FSI Research Grant Program (to Dr Nomura), JST FOREST Program (grant number JPMJFR210U) (to Dr Nomura), Japan Agency for Medical Research and Development (AMED) (JP18km0405209, JP21ek0109543, JP21ek0109569, JP22ama121016, JP22ek0210172, JP22ek0210167, JP22bm1123011, JP23tm0724607, JP23gm4010020, JP223fa627011, JP23tm0524009, JP23tm0524004, JP23jf0126003, JP24ek0109755, and JP24ek0210205) (to Dr Nomura and Dr Komuro), and JP23ek0109600h0002 (to Dr Ko). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A left ventricular assist device (LVAD) is an effective therapeutic option for advanced heart failure. Late right heart failure (LRHF) is a complication after LVAD implantation that is associated with increasing morbidity and mortality; however, the assessment of right heart function, including right heart reserve function after LVAD implantation, has not been established. We focused on a fluid-loading test with right heart catheterization to evaluate right heart preload reserve function and investigate its impact on LRHF., Methods: Patients aged > 18 years who received a continuous-flow LVAD between November 2007 and December 2022 at our institution, and underwent right heart catheterization with saline loading (10 mL/kg for 15 minutes) 1 month after LVAD implantation, were included., Results: Overall, 31 cases of LRHF or death (right heart failure [RHF] group) occurred in 149 patients. In the RHF vs the non-RHF groups, the pulmonary artery pulsatility index (PAPi) at rest (1.8 ± 0.89 vs 2.5 ± 1.4, P = 0.02) and the right ventricular stroke work index (RVSWi) change ratio with saline loading (0.96 ± 0.32 vs 1.1 ± 0.20, P = 0.03) were significantly different. The PAPi at rest and the RVSWi change ratio with saline loading were identified as postoperative risks for LRHF and death. The cohort was divided into 3 groups based on whether the PAPi at rest and the RVSWi change ratio were low. The event-free curve differed significantly among the 3 groups (P < 0.001)., Conclusions: Hemodynamic assessment with saline loading can evaluate the right ventricular preload reserve function of patients with an LVAD. A low RVSWi change with saline loading was a risk factor for LRHF following LVAD implantation., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Retroperitoneal leiomyosarcoma (RPLMS) is rare and usually presents as a large abdominal mass with poor clinical symptoms. Radiological findings of an RPLMS arising in the pelvis of a woman resemble those of adnexal tumors. Herein, we present a case of RPLMS mimicking an adnexal tumor which was differentiated from having an ovarian origin as the right ovarian vein was passing through the tumor but there was no direct vascular connection with the tumor. Therefore, it is important to identify the ovarian vein to distinguish between these tumors., (© 2024 The Authors.)

Background: Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure., Objectives: The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure., Methods: The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation., Results: Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01]; P < 0.001; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72]; P < 0.001)., Conclusions: DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies., Competing Interests: Funding Support and Author Disclosures This work was supported by a Japan Society for the Promotion Science (JSPS) Grant-in-Aid for Scientific Research (A) (to Dr Nomura), a JSPS Grant-in-Aid for Scientific Research (S) (to Dr Komuro), a JSPS Grant-in-Aid for JSPS fellows (grant number 23KJ0434 to Dr Dai), the UTEC-UTokyo FSI Research Grant Program (to Dr Nomura), JST FOREST Program (grant number JPMJFR210U to Dr Nomura), Japan Foundation for Applied Enzymology (to Drs Ko and Dai), SENSHIN Medical Research Foundation (to Dr Ko), Merck Sharp & Dohme Life Science Foundation (to Dr Ko), Takeda Science Foundation (to Dr Ko), Japanese Circulation Society (to Dr Ko), Japan Heart Foundation (to Dr Ko), Sakakibara Heart Foundation Cardiovascular Research Program 2023 (to Dr Ko), and Japan Agency for Medical Research and Development (AMED) (grant nos. 22ek0109600h0002 to Dr Ko and JP20ek0210141, JP20ek0109487, JP17gm0810013, JP18km0405209, JP19ek0210118, JP21ek0109543, and JP21ek0109569 to Drs Nomura and Komuro). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Periprosthetic bone loss following total hip arthroplasty (THA) threatens prosthesis stability. This systematic review and network meta-analysis aimed to compare the efficacy of anti-osteoporotic drugs for measures of hip function according to functional outcomes, periprosthetic femoral bone mineral density loss in each Gruen zone, and revision surgery after THA., Methods: The systematic search of six literature databases was conducted in December 2021 in accordance with PRISMA guidelines. Adult participants who underwent primary THA were included. A random-effects network meta-analysis was performed within a frequentist framework, and the confidence in the evidence for each outcome was evaluated using the CINeMA tool, which assessed the credibility of results from the network meta-analysis. We included 22 randomized controlled trials (1243 participants) comparing the efficacy and safety of bisphosphonates (including etidronate, clodronate, alendronate, risedronate, pamidronate, and zoledronate), denosumab, selective estrogen receptor modulator, teriparatide, calcium + vitamin D, calcium, and vitamin D. We defined the period for revision surgery as the final follow-up period., Results: Raloxifene, bisphosphonate, calcium + vitamin D, and denosumab for prosthetic hip function might have minimal differences when compared with placebos. The magnitude of the anti-osteoporotic drug effect on periprosthetic femoral bone loss varied across different Gruen zones. Bisphosphonate, denosumab, teriparatide might be more effective than placebo in Gruen zone 1 at 12 months after THA. Additionally, bisphosphonate might be more effective than placebo in Gruen zones 2, 5, 6, and 7 at 12 months after THA. Denosumab was efficacious in preventing bone loss in Gruen zones 6 and 7 at 12 months after THA. Teriparatide was likely to be efficacious in preventing bone loss in Gruen zone 7 at 12 months after THA. Raloxifene was slightly efficacious in preventing bone loss in Gruen zones 2 and 3 at 12 months after THA. Calcium was slightly efficacious in preventing bone loss in Gruen zone 5 at 12 months after THA. None of the studies reported revision surgery., Conclusions: Bisphosphonate and denosumab may be effective anti-osteoporotic drugs for preventing periprosthetic proximal femoral bone loss due to stress shielding after THA, particularly in cementless proximal fixation stems, which are the most commonly used prostheses worldwide., Competing Interests: Declaration of competing interest The first author would like to declare that they received financial support in the form of J&J Medical Research Grant. However, this financial assistance has not directly or indirectly influenced the work submitted for publication in Journal of Orthopaedic Science. The funding was utilized solely for the purpose of data collection and analysis of the manuscript. There are no other financial or non-financial competing interests that the author needs to disclose., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) requires lifelong anticoagulation. Long-term outcomes of CTEPH under current anticoagulants are unclear., Objectives: The CTEPH AC registry is a prospective, nationwide cohort study comparing the safety and effectiveness of direct oral anticoagulants (DOACs) and warfarin for CTEPH., Patients/methods: Patients with CTEPH, both tre atment-naïve and on treatment, were eligible for the registry. Inclusion criteria were patients aged ≥20 years and those who were diagnosed with CTEPH according to standard guidelines. Exclusion criteria were not specified. The primary efficacy outcome was a composite morbidity, and mortality outcome comprised all-cause death, rescue reperfusion therapy, initiation of parenteral pulmonary vasodilators, and worsened 6-minute walk distance and WHO functional class. The safety outcome was clinically relevant bleeding, including major bleeding., Results: Nine hundred twenty-seven patients on oral anticoagulants at baseline were analyzed: 481 (52%) used DOACs and 446 (48%) used warfarin. The 1-, 2-, and 3-year rates of composite morbidity and mortality outcome were comparable between the DOAC and warfarin groups (2.6%, 3.1%, and 4.2% vs 3.0%, 4.8%, and 5.9%, respectively; P = .52). The 1-, 2-, and 3-year rates of clinically relevant bleeding were significantly lower in DOACs than in the warfarin group (0.8%, 2.4%, and 2.4% vs 2.5%, 4.8%, and 6.4%, respectively; P = 0.036). Multivariable Cox proportional-hazards regression models revealed lower risk of clinically relevant bleeding in the DOAC group than the warfarin group (hazard ratio: 0.35; 95% CI: 0.13-0.91; P = .032)., Conclusion: This registry demonstrated that under current standard of care, morbidity and mortality events were effectively prevented regardless of anticoagulants, while the clinically relevant bleeding rate was lower when using DOACs compared with warfarin., Competing Interests: Declaration of competing interests K.H. received personal fees from Janssen Pharmaceuticals, Bayer Yakuhin, Nippon Shinyaku, and Pfizer, outside of the submitted work. K.A. received a grant from Konica Minolta and Daiichi Sankyo, outside of the submitted work. Y. Tamura received grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Pharmaceutical, outside of the submitted work. N.N. is member of the board of directors of the Japan Association for Medical Informatics. K. Todaka reports receiving a grant from Mochida Pharmaceutical and received a personal fee from Bayer Yakuhin, outside of the submitted work. Y. Taniguchi received grants from Janssen Pharmaceutical and Nippon Shinyak and received personal fees from Janssen Pharmaceutical and Nippon Shinyaku, outside of the submitted work. T.I. received personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside of the submitted work. I.T. received personal fees from Janssen Pharmaceutical and Nippon Shinyak and is affiliated with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida Pharmaceutical, outside of the submitted work. J.Y. received a grant from Abbott Vascular Japan and received personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin, outside of the submitted work. N.I. received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Bristol-Myers Squibb, outside of the submitted work. H.S. received a grant from Bayer Yakuhin and received personal fees from Actelion Pharmaceuticals Japan, Bayer Yakuhin, and Nippon Shinyaku, outside of the submitted work. T.K. reports receiving personal fees from Kaneka Medix, Abbott Medical Japan, and ACIST Japan, outside of the submitted work. M.H. received personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside of the submitted work. H.O. received grants from Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer Japan, Eisai, GlaxoSmithKline, Mochida Pharmaceutical, Janssen Pharmaceutical, and Nippon Shinyaku, and received consulting fees from Terumo, Japan Lifeline, and Century Medical and personal fees from Bayer Yakuhin, Daiichi Sankyo, Pfizer Japan, and Nippon Shinyaku, outside of the submitted work. Y.F. received grants from Actelion Pharmaceuticals Japan, Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, Pfizer Japa, and personal fees from Actelion Pharmaceuticals Japan, Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, Pfizer Japan, and Bristol-Myers Squibb, outside of the submitted work. N.T. received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, and Nippon Shinyaku, outside of the submitted work. H.M. received grants from Bayer and Nippon Shinyaku; received personal fees from Bayer Yakuhin, Nippon Shinyaku, Mochida Pharmaceutical, Kaneka Medix, and Janssen Pharmaceutical, , outside of the submitted work; is a member of the board of directors or advisory committees for the International CTEPH Association and Japanese Pulmonary Circulation and Pulmonary Hypertension Society; and is a member of the data safety monitoring boards for Janssen Pharmaceutical, United Therapeutics, and Bayer. K. Fukuda received grants from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, and received personal fees from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, outside of the submitted work. H.T. received grants from Mitsubishi Tanabe Pharma, IQVIA Services Japan, Medinet, Medical Innovation Kyushu, Kowa, Daiichi Sankyo, Johnson & Johnson, NEC, and Nippon Boehringer Ingelheim; received personal fees from Novartis Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Bayer Yakuhin, Kowa, Teijin Pharma, Mitsubishi Tanabe Pharma, Pfizer Japan, Daiichi Sankyo, Novartis Pharma, Janssen Pharmaceutical, Pfizer Japan, Bayer Yakuhin, Otsuka Pharmaceutical, AstraZeneca, and Nippon Rinsho, outside the submitted work; and is the chairman of the Japan Heart Failure Society. Soiken Corp accessed and verified the data. The remaining authors K. Funakoshi, S.A., S.M., K. Tatsumi, and T.O. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Systemic sclerosis (SSc) is divided into diffuse and limited cutaneous SSc (dcSSc and lcSSc). The dcSSc subtype has more severe internal organ damage. This study aimed to assess whether cardiovascular magnetic resonance (CMR) parametric mapping could detect early cardiac involvement and evaluate differences between these two subtypes., Methods: Eighty SSc patients (37 dcSSc and 43 lcSSc) underwent CMR at 3.0 T (Philips Healthcare, Best, The Netherlands) in our hospital between July 2018 and July 2021. We analyzed myocardial damage by CMR parametric mapping and compared it with clinical data., Results: The median duration of the disease was 10.2 months. The left ventricular ejection fraction was preserved in both groups. DcSSc had significantly higher native T1 (1333.4 ± 71.2 ms vs. 1295.0 ± 42.7 ms, p = 0.006) and extracellular volume fraction (32.6 ± 4.1 % vs. 30.3 ± 4.0 %, p = 0.018) in the mid-ventricular septum as compared to lcSSc, although there were no differences in T2 values. Native T1 values were positively correlated with the E/e' ratio and left atrial volume indices evaluated by transthoracic echocardiography in overall SSc and dcSSc, but not in lcSSc. Logistic regression analysis revealed that native T1 was an independent predictor of left ventricular diastolic dysfunction in SSc patients (odds ratio, 1.194; 95 % confidence interval, 1.021-1.396; p = 0.026). Native T1 was higher in SSc patients with progressive skin lesions. Additionally, there were positive correlations between brain natriuretic peptide, New York Heart Association functional classification, and native T1., Conclusions: CMR parametric mapping is a useful tool for detecting myocardial changes. Native T1 was the most sensitive parameter for identifying diffuse myocardial changes in the early stages of SSc and was associated with left ventricular diastolic function. DcSSc had more severe myocardial involvement than lcSSc; therefore, the use of CMR parametric mapping may aid in its prediction., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute vasoreactivity test with inhaled nitric oxide (NO) is performed during diagnostic right heart catheterization (RHC) to identify patients with pulmonary arterial hypertension (PAH) who respond to calcium channel blockers. Our purpose was to investigate the prognostic importance of follow-up vasoreactivity test after treatment., Methods: We retrospectively analyzed 36 PAH patients (mean age, 47 years; 61 % treatment-naïve), who underwent diagnostic and follow-up RHC and vasoreactivity tests at our center. The primary outcome was all-cause mortality., Results: The median time between baseline and follow-up RHC was 9.7 months. Absolute change in mean pulmonary arterial pressure (ΔmPAP) during NO challenge was less pronounced after treatment, but there was great variability among patients. Overall cohort was dichotomized into two groups: preserved vasoreactivity (ΔmPAP ≤ -1 mmHg) and less vasoreactivity (ΔmPAP ≥0 mmHg) at follow-up RHC. Less vasoreactivity group had higher usage rate of endothelin receptor antagonists and parenteral prostacyclin analogues. During a median observation period of 6.3 years after follow-up RHC, 7 patients died, of which 6 showed less vasoreactivity at follow-up. Absolute ΔmPAP ≥0 at follow-up RHC was associated with all-cause mortality in univariable Cox regression analysis (hazard ratio, 8.728; 95 % confidence interval, 1.045-72.887; p = 0.045), whereas other hemodynamic parameters were not. Absolute ΔmPAP ≥0 at follow-up RHC was associated with all-cause mortality in multivariable Cox analysis adjusted for age and known PAH prognostic factors (HR, 12.814; 95 % CI, 1.088-150.891; p = 0.043). Kaplan-Meier survival analysis revealed a significantly worse survival of less vasoreactivity group compared to preserved vasoreactivity group (log-rank test, p = 0.016)., Conclusions: Follow-up vasoreactivity test after treatment could contribute to the detection of high-risk subgroups who might need careful monitoring and referral for lung transplantation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With the widespread use of implantable left ventricular assist device (LVAD), right ventricular failure (RVF) has become a serious problem that becomes apparent several weeks or later after LVAD implantation. However, there are no marked preoperative signs of RVF. This is called late-onset RVF and is currently a major problem leading to long-term complications following implantable LVAD use. Pathogenically, this could be the result of left ventricular suction by LVAD that causes the septum shift to the left ventricular side. This causes a change in morphology of the right ventricle, resulting in impaired right ventricular function. Aortic insufficiency and ventricular arrhythmia, which are also important as long-term complications after LVAD implantation, are considered to be closely involved in the onset and progression of RVF. Once late-onset RVF develops, exercise capacity declines and inotrope administration may be required. Late-onset RVF was also reported to be significantly associated with increased mortality. Several predictors of RVF have been proposed such as preoperative left ventricular diastolic dimension <64 mm, tricuspid valve annulus diameter ≥41 mm, and so on. However, some reports identified no predictors. The basic treatment strategy for late-onset RVF is to optimize volume status by administering diuretics and ensuring inotrope as needed. β-blockers and antiarrhythmic agents often need to be reduced in terms of dosage or even discontinued because these might reduce right ventricular function. Although their efficacy is unclear, pulmonary vasodilators may be used to reduce right ventricular afterload. It is better to decrease the rotation speed of LVAD to minimize the displacement of the septum; however, this is often difficult because the required flow rate cannot be secured. Progress in the prevention and management of late-onset RVF is required because the number of patients who require longer-term LVAD support will increase with the spread of LVAD use as destination therapy., (Copyright © 2021. Published by Elsevier Ltd.)

Peripheral pulmonary arterial stenosis (PPAS) is known to cause pulmonary hypertension (PH). Although adult patients at advanced stage have been increasingly reported, there are few reports on clinical characteristics and pulmonary angiography (PAG) findings of early stage PPAS. We present two Japanese siblings with PPAS with homozygosity of RNF213 p.Arg4810Lys-one with advanced stage and the other with early stage. The latter case was an asymptomatic 37-year-old woman with mild PH. Notably, her PAG demonstrated nonthrombotic stenosis in the subsegmental branches of the pulmonary arteries with varying degrees of stenosis among lung segments. Taken together with a family history, genetic analysis, and cerebral angiography, the obtained images were considered as showing PPAS with early stage. This result is clinically informative to diagnose PPAS at an early stage and is also important to understand the pathogenesis of PPAS., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The association of simultaneous bilateral total hip arthroplasty (THA) with postoperative deep venous thrombosis (DVT) remains controversial. The aim of the study is to determine whether simultaneous bilateral THA without chemoprophylaxis has a higher risk than unilateral THA without chemoprophylaxis., Methods: This is a population-based retrospective cohort study of all adults who underwent primary THA without any anticoagulant or antiplatelet therapy between July 2012 and March 2021 at the Department of Orthopedic Surgery, Toranomon Hospital, Tokyo, Japan. The association of simultaneous bilateral THA with postoperative DVT was examined by unadjusted analysis and overlap propensity score weighting. The primary outcome was the incidence of DVT (confirmed by ultrasonography of the lower limb veins) within 7 days postoperatively., Results: Of the 557 consecutive patients who underwent primary THA in the study period, 458 met the inclusion criteria. The mean (standard deviation) age of these patients was 67 (11.7) years, and 364 (79.5%) were women; 75 (16.4%) of the 458 patients underwent simultaneous bilateral THA, and 383 (83.6%), unilateral THA. A total of 64 patients (14.0%) developed a postoperative venous thromboembolism, all of which were a distal DVT. The overlap weighting analysis found no significant difference in the incidence of postoperative DVT complications among patients who underwent simultaneous bilateral THA and those who underwent unilateral THA (31.1 [13.6%] vs 22.9 [10.0%], respectively; risk ratio, 1.36; 95% confidence interval, 0.67 to 2.77; P  = .40)., Conclusions: Our findings indicate that the occurrence of DVT within 7 days after surgery is not significantly different between patients undergoing simultaneous bilateral THA or unilateral THA without any anticoagulant or antiplatelet therapy ., Level of Evidence: Level II-III., (© 2021 The Authors.)

Background: The conventional treatment goal for chronic thromboembolic pulmonary hypertension (CTEPH) is improving hemodynamic status, particularly mean pulmonary artery pressure (mPAP); however, some patients complain of impaired quality of life (QOL) caused by dyspnea on effort, even after hemodynamic status has fully improved. It remains unclear whether treatment for CTEPH can improve patients' QOL or whether quantitative measures of QOL correlate with hemodynamic status. This study quantified QOL among Japanese CTEPH patients and investigated whether balloon pulmonary angioplasty (BPA) improved QOL., Methods and Results: We calculated the QOL scores of 45 CTEPH patients using the European Quality of Life Five Dimension scale (EQ-5D). The mean QOL score among 12 of those 45 not involved in any therapy except supplemental oxygen at the time of initial measurement was 0.673 ± 0.251. QOL was measured before and after BPA for 17 patients, and the mean significantly improved (QOL from 0.741 ± 0.195 to 0.802 ± 0.160, p < 0.05; mPAP from 33.0 ± 8.4 to 23.4 ± 4.2 mmHg, p < 0.05; pulmonary vascular resistance from 441.4 ±  214.2 to 268.4 ± 85.6 dyne/s/cm 5 , p < 0.05). Moreover, the index significantly correlated with mPAP (r = -0.37, p < 0.05), pulmonary vascular resistance (r = -0.40, p < 0.05), 6-min walking distance (r = 0.45, p < 0.05), and percutaneous oxygen saturation at rest (r = 0.32, p < 0.05). Regarding individual items, median values improved only regarding "usual activities." Our findings prove that BPA improved QOL measured by the EQ-5D in Japanese CTEPH patients by improving "usual activities" scores., Conclusion: BPA improved QOL in patients with CTEPH mainly by improving "usual activities," besides the improvement in mPAP., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Fractional exhaled nitric oxide levels are related to various clinical diseases. This study investigated the associations between the clinical characteristics and the level of fractional exhaled nitric oxide in patients with adult congenital heart disease., Methods and Results: Fractional exhaled nitric oxide values were measured in 30 adult patients with stable congenital heart disease who had undergone right heart catheterization and 17 healthy individuals (controls). There was no significant difference in fractional exhaled nitric oxide values between patients with congenital heart disease and healthy controls. Depending on whether their fractional exhaled nitric oxide values were above or below the median value, patients with congenital heart disease were divided into two groups (low vs. high fractional exhaled nitric oxide groups). The relationship between fractional exhaled nitric oxide values and clinical characteristics was investigated. There was a higher percentage of patients with cyanosis in the low fractional exhaled nitric oxide group (50%) than in the high fractional exhaled nitric oxide group (7.1%). There was no significant difference in right heart catheterization data between the low and high fractional exhaled nitric oxide groups. The fractional exhaled nitric oxide value was correlated to the number of neutrophils in patients with cyanosis (r = 0.84 (N = 8), p = 0.005)., Conclusions: In this cohort of patients with adult congenital heart disease, lower levels of fractional exhaled nitric oxide corresponded to the presence of cyanosis., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Balloon pulmonary angioplasty (BPA) has been performed in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, some patients have inoperable CTEPH despite having lesions suitable for surgical treatment. The effectiveness of BPA in such cases is unclear. The aim of this study was to clarify the effectiveness of BPA in these cases., Methods: We retrospectively investigated patients with inoperable CTEPH and divided them into two groups: BPA-suitable and BPA-unsuitable groups based on the findings of pulmonary angiography, computed tomography, and perfusion scintigraphy. The BPA-unsuitable group included patients whose lesions are suitable for surgical treatment but who did not undergo the procedure for any specified reason. We analyzed the hemodynamic, respiratory, and functional status of the patients before and after BPA., Results: Forty-three consecutive patients with inoperable CTEPH (age, 62.6 ± 13.5 years; 31 women) were included; all of them underwent BPA. There were 10 patients in the BPA-unsuitable group. In all patients, the mean pulmonary artery pressure, pulmonary vascular resistance, arterial oxygen saturation level, and 6-min walking distance significantly improved after BPA (mean pulmonary artery pressure, from 43.3 ± 7.8 mmHg to 23.9 ± 4.7 mmHg; pulmonary vascular resistance, from 924.1 ± 462.2 dynes/s/cm -5 to 319.7 ± 163.8 dynes/s/cm -5 ; arterial oxygen saturation level, from 89.3 ± 4.3% to 93.4 ± 3.3%; 6-min walking distance, from 370.0 ± 107.4 m to 443.8 ± 101.4 m). Notably, none of the parameters significantly differed between the groups after BPA. Importantly, the amount of lung bleeding did not differ between them. However, several sessions were required in the BPA-unsuitable group (BPA-unsuitable group: six sessions vs. BPA-suitable group: four sessions)., Conclusions: BPA safely improved the hemodynamic and functional statuses of the patients with CTEPH who are judged as inoperable for any reason despite lesion being suitable for surgical treatment. However, numerous BPA sessions were required in these patients., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

We describe a case of anti-mitochondrial antibody-positive myositis associated with cardiovascular involvement. An electrophysiological study (EPS) showed binodal dysfunction, and cardiac magnetic resonance (CMR) imaging revealed left ventricular dysfunction with diffuse, patchy T2 high-intensity areas and late gadolinium enhancement indicative of inflammation and fibrosis. The left ventricular dysfunction was successfully treated with immunosuppressive therapy as documented by CMR. Persistence of conduction system dysfunction was confirmed by EPS, and a pacemaker was implanted. CMR and EPS concisely documented the variable cardiac response to treatment in anti-mitochondrial antibody-positive myositis. We demonstrate the utility of cardiac investigations in this rare disorder., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Mucormycosis generally develops under immunocompromised conditions, including hematological malignancies and solid organ or hematopoietic stem cell transplantation. Although mucormycosis usually affects the lungs and paranasal sinuses, sporadic cases of invasive mucormycosis of the liver have been reported. We hereby report a patient with myelofibrosis who developed hepatic mucormycosis diagnosed by post-mortem examination. An extensive literature review identified 13 reported cases of hepatic mucormycosis, including ours, without lung involvement. Most of the underlying diseases or conditions were hematological malignancies and solid organ transplantation. Three cases had splenic lesions and four had gastrointestinal lesions, suggesting the possibility of translocation to the liver and/or spleen from the gastrointestinal tracts. Hepatic mucormycosis should be recognized as one of the presentations of invasive mucormycosis, especially when hepatic nodules are found in immunocompromised patients such as those with hematological malignancy or recipients of solid organ transplantation., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Methylmercury (MeHg) is the causative substance of Minamata disease, which is associated with various neurological disorders such as sensory disturbance and ataxia. It has been suggested low-level dietary intake of MeHg from MeHg-containing fish during gestation adversely affects the fetus. In our study, we investigated the toxicological effects of MeHg exposure on neuronal differentiation focusing on epigenetics. We used human fetal brain-derived immortalized cells (LUHMES cells) as a human neuronal differentiation model. Cell viability, neuronal, and catecholamine markers in LUHMES cells were assessed after exposure to MeHg (0-1000 nM) for 6 days (from day 2 to day 8 of neuronal differentiation). Cell viability on day 8 was not affected by exposure to 1 nM MeHg for 6 days. mRNA levels of AADC, DBH, TUJ1, and SYN1 also were unaffected by MeHg exposure. In contrast, levels of TH, the rate-limiting enzyme for dopamine synthesis, were significantly decreased after MeHg exposure. Acetylated histone H3, acetylated histone H3 lysine 9, and tri-methyl histone H3 lysine 9 levels at the TH gene promoter were not altered by MeHg exposure. However, tri-methylation of histone H3 lysine 27 levels, related to transcriptional repression, were significantly increased at the TH gene promotor after MeHg exposure. In summary, MeHg exposure during neuronal differentiation led to epigenetic changes that repressed TH gene expression. This study provides useful insights into the toxicological mechanisms underlying the effects of developmental MeHg exposure during neuronal differentiation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The role of caregivers is important for the successful support of left ventricular assist device (LVAD) patients. We aimed to (1) evaluate quality of life (QoL) of caregivers pre-and post-LVAD implant and (2) identify factors associated with caregivers' QoL., Methods: The caregivers' QoL was assessed with the Short Form-8 before implant, at 3 and 6 months after LVAD implantation. The physical and mental component summary (PCS and MCS) scores were calculated. Caregiver burden was evaluated using the 8-item Zarit Caregiver Burden Interview., Results: Data were collected from LVAD patients as bridge-to-transplant and their family caregivers in Japan. No significant changes were found in caregivers' PCS scores during the follow-up (before 52.7±7.1; at 3 months 49.7±6.5, and at 6 months 50.7±6.4, n=20). Compared with the scores before implant (38.9±9.3), the caregivers' MCS scores improved after LVAD implantation at 3 months (44.2±7.7; p=0.03) and at 6 months (46.2±7.4, p=0.003), but they were still lower than those of the Japanese general population (p<0.01). In multiple regression analysis at 3 months (n=40), caregivers' lower PCS scores were associated with older patient age [standard partial regression coefficients (sβ)=-0.36, p=0.02] and caregiver unemployment (sβ=0.30, p=0.04), whereas being female (sβ=-0.26, p=0.03), being the patient's spouse (sβ=-0.23, p=0.03), and having a mild to moderate caregiving burden (sβ=-0.63, p<0.001) were associated with lower MCS scores among caregivers., Conclusions: LVAD implantation improves caregivers' mental QoL. Since caregivers' MCS scores are lower than the general population, it is important to identify family caregivers at risk for low QoL and reduce their caregiving burden., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Using hearts from marginal donors could be related to increased risk of primary graft dysfunction and poor long-term survival. However, factors associated with delayed myocardial recovery after heart transplantation (HTx) remain unknown. We sought to clarify risk factors that predict early low output after HTx, and investigated whether early low output affects mid-term graft dysfunction., Methods: We retrospectively analyzed patients who had undergone HTx at The University of Tokyo Hospital. We defined early low output patients as those whose cardiac index (CI) was <2.2 L/min/m(2) despite the use of intravenous inotrope at 1 week after HTx., Results: We included 45 consecutive HTx recipients, and classified 11 patients into early low output group, and the others into early preserved output group. We performed univariable logistic analysis and found that donor age was the only significant factor that predicted early low output (odds ratio 1.107, 95% confidence interval 1.034-1.210, p=0.002). CI of early low output patients gradually increased and it caught up with that of early preserved output patients at 2 weeks after HTx (2.4±0.6 L/min/m(2) in early low output group vs 2.5±0.5 L/min/m(2) in early preserved output group, p=0.684). Plasma B-type natriuretic peptide concentration of early low output patients was higher (1118.5±1250.2 pg/ml vs 526.4±399.5 pg/ml; p=0.033) at 1 week, 703.6±518.4 pg/ml vs 464.6±509.0 pg/ml (p=0.033) at 2 weeks, and 387.7±231.9 pg/ml vs 249.4±209.5 pg/ml (p=0.010) at 4 weeks after HTx, and it came down to that of early preserved output patients at 12 weeks after HTx., Conclusions: Donor age was a predictor of early low output after HTx. We should be careful after HTx from old donors. However, hemodynamic parameters of early low output patients gradually caught up with those of early preserved output patients., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Two implantable continuous-flow left ventricular assist devices (LVADs), DuraHeart (Terumo Heart, Ann Arbor, MI, USA) and EVAHEART (Sun Medical, Nagano, Japan), were approved in Japan in April 2011. We analyzed the midterm outcome of patients implanted with these implantable LVADs at the University of Tokyo Hospital., Methods and Results: A total of 31 patients who underwent implantation of LVADs (10 DuraHeart, 21 EVAHEART) as a bridge to transplantation at our institution between April 2011 and August 2013 were retrospectively reviewed. All patients were followed up through December 2013. Seven patients underwent conversions from NIPRO paracorporeal LVAD (Nipro, Osaka, Japan) to an implantable LVAD. The mean observation period was 483±239 days (41.0 patient years). Eight patients were transplanted and one patient showed functional recovery with subsequent LVAD explantation. Four patients died due to cerebrovascular accident, empyema, or device malfunction due to pump thrombosis after cerebral bleeding. Kaplan-Meier analysis revealed 6-, 12-, and 24-month survival rates of 93%, 86%, and 86%, respectively. The rates of freedom from cerebrovascular accidents and device-related infections at 1 year after LVAD implantation were 65% and 36%, respectively. Twenty-nine patients were discharged home after LVAD implantation. During the period of this study, there were 59 readmissions (53 urgent, 6 elective) among 22 patients (76%). The overall and urgent readmission rates were 1.66 and 1.49 per patient year, respectively. The common reason for readmission was device-related infection (31%), followed by cerebrovascular accidents (17%). The total out-of-hospital time after the primary discharge was 90%., Conclusions: Our midterm survival rate after LVAD implantation is satisfactory. However, patients undergoing LVAD support were often readmitted with adverse events., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Aims: We investigated the pathophysiological changes in mice lacking α2-antiplasmin (α2-AP) and plasminogen activator inhibitor type-1 (PAI-1) genes, and elucidated the involvement of these inhibitors for fibrinolysis in immune response., Main Methods: The pathophysiological changes induced by a lack of both α2-AP and PAI-1 were investigated using double knockout (KO) mice. The lung, liver, kidney and spleen tissues from α2-AP/PAI-1-double KO mice were compared with those from wild-type (WT) mice. Furthermore, the bone marrow cells from α2-AP/PAI-1-double KO mice were transplanted into 10-Gy X ray irradiated WT mice, and then the effects of the transplantation were studied., Key Findings: Plasma IgE levels in the α2-AP/PAI-1-double KO mice increased with age and exceeded 1000 ng/mL after 6 months of age. The plasma cells that produced IgE were detected in perivascular assembled lymphocytes. In the α2-AP/PAI-1-double KO mice, perivascular lymphocyte infiltration was observed in the lung, liver, and kidneys and peribronchial lymphocyte infiltration was present in the lung. When the bone marrow cells from α2-AP/PAI-1-double KO mice were transplanted into 10-Gy X ray irradiated WT mice, the phenotypes of the recipients were similar to those of α2-AP/PAI-1-double KO mice., Significance: The simultaneous expression of both the α2-AP and PAI-1 genes contributes to the maintenance of immunological functions that are related to IgE. Moreover, it is suggested that both α2-AP and PAI-1 are involved in the recruitment of lymphocytes in the peripheral tissues., (Copyright © 2013 Elsevier Inc. All rights reserved.)

CD8(+) T cells are critical for the control of various intracellular infections and cancers. To date, however, effective T cell-based vaccines remain elusive, due, in part, to the lack of in vivo models that facilitate the dissection of antigen-specific CD8(+) T-cell responses primed by different antigen-presenting cells (APCs). In this study, we generated four lines of H-2K(d) transgenic (K(d) Tg) mice that differed in their expression of H-2K(d): dendritic cells (DCs) only (CD11c-K(d)), macrophages only (huCD68-K(d)), hepatocytes only (Alb-K(d)), or all nucleated cells (major histocompatibility complex-I-K(d)). Immunization of each of these K(d) Tg mouse strains with a synthetic peptide or a recombinant adenovirus expressing a well-known immunodominant, H-2K(d)-restricted CD8(+) T-cell epitope, SYVPSAEQI, which was derived from the circumsporozoite protein of Plasmodium yoelii, promoted distinct SYVPSAEQI-specific CD8(+) T-cell responses. The route of immunization also greatly influenced the magnitude of the epitope-specific CD8(+) T-cell response. These tissue-specific K(d) Tg mice may be valuable tools for determining the mode of induction of CD8(+) T-cell responses by different APCs in vivo and for characterizing the CD8(+) T-cell responses promoted in response to various microbial infections and/or different types of vaccines., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Several groups have reported that an elevated ratio of early (E) to late (A) diastolic filling velocities is observed in patients after heart transplantation. However, the mechanism has not been fully analyzed., Methods: Serial echocardiography and hemodynamic study were performed in 16 patients who had received heart transplantation and had no evidence of rejection during 1 month after the operation., Results: On Day 1 after the surgery, E/A ratio was higher and peak velocity of A wave was lower than normal range among the patients after heart transplantation. E/A ratio and peak velocity of A wave gradually normalized during 1 moth after the surgery. Meanwhile, early mitral annular velocity and pulmonary capillary wedge pressure remained within normal range during the study period., Conclusions: Longer ischemic time during heart transplantation procedure may cause atrial stunning, but it appears to recover within 1 month. We have to be alert to misinterpretation of this "psuedo-psuedonormal" mitral inflow pattern early after transplantation., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Little is known about depressive symptoms in heart failure with preserved ejection fraction (HFpEF, EF ≥50%). We aimed to assess the prevalence of depression, to clarify the impact of depressive symptoms upon clinical outcomes, and to identify factors associated with these symptoms in HF with reduced EF (HFrEF, EF <50%) and HFpEF., Methods and Results: A total of 106 HF outpatients were enrolled. Of them, 61 (58%) had HFpEF. Most patients were male (HFrEF 80%, HFpEF 70%) and the mean of plasma B-type natriuretic peptide (BNP) level in the HFrEF group was similar to that in the HFpEF group (164.8 ± 232.8 vs. 98.7 ± 94.8 pg/mL). HFrEF patients were treated more frequently with beta-blockers compared with HFpEF patients (71% vs. 43%, p=0.004). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The prevalence of depression (CES-D score ≥16), and CES-D score did not significantly differ between HFrEF and HFpEF (24% vs. 25%, 14.1 ± 8.3 vs. 12.1 ± 8.3, respectively). During the 2-year follow-up, depressed patients had more cardiac death or HF hospitalization in HFrEF (55% vs. 12%, p=0.002) and HFpEF (35% vs. 11%, p=0.031). Cox proportional hazard analysis revealed that a higher CES-D score, indicating increased depressive symptoms, predicted cardiac events independent of BNP in HFrEF [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.01-1.13] and HFpEF (HR 1.09, 95% CI 1.04-1.15). Multiple regression analyses adjusted for BNP showed that independent predictors of depressive symptoms were non-usage of beta-blockers and being widowed or divorced in HFrEF. On the other hand, usage of warfarin was the only independent risk factor for depressive symptoms in HFpEF (all, p<0.05)., Conclusions: Depressive symptoms are common and independently predict adverse events in HFrEF/HFpEF patients. This study suggests that beta-blockers reduce depressive symptoms in HFrEF. In contrast, treatment for depression remains to be elucidated in HFpEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signaling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signaling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signaling factor C-promoter binding factor 1 (CBF1), and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, overlapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF(-/-) mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signaling.

Background: Although the importance of monocyte trans-endothelial migration in early atherogenesis is well recognized, it is unclear whether and how one transmigration event affects endothelium to facilitate subsequent ones. In this study, we tested the hypothesis that monocyte transmigration alters endothelial junctional organization to facilitate subsequent transmigration., Methods and Results: When human monocytes were added twice at intervals of ≈30 min to IL-1beta-prestimulated human umbilical vein endothelial cells in vitro, significant augmentation of transmigration was observed at the second addition (≈1.5-fold, analyzed from a total of 231 monocytes in 3 experiments). Endothelial surface expressions of two major junctional molecules, PECAM-1 and VE-cadherin, increased and decreased respectively, in response to monocyte addition, which could facilitate subsequent transmigration. To further investigate spatiotemporal dynamics of the increasing molecule, PECAM-1, we constructed a PECAM-1-GFP expression system and found that monocyte transmigration induced local accumulation of endothelial PECAM-1 around the transmigration spot, which was followed by transmigration of subsequent monocyte around the same location. Detailed analysis revealed that within the defined region around one transmigration event, 50% of later transmigrating monocytes used the same or similar location as the previous one (10 out of 20 transmigrating monocytes in 11 experiments)., Conclusions: These findings show that monocyte trans-endothelial migration alters endothelial junctional organization to a more monocyte-permeable state (increased PECAM-1 and decreased VE-cadherin), resulting in the augmented transmigratory activity at a later stage. This positive feedback mechanism is partially associated with monocyte transmigration-induced local accumulation of endothelial PECAM-1, which promotes transmigration of following monocytes at the same location., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The aim of this study was to evaluate the validity and reliability of the Seattle Angina Questionnaire, Japanese version (SAQ-J) as a disease-specific health outcome scale in patients with coronary artery disease., Methods: Patients with coronary artery disease were recruited from a university hospital in Tokyo. The patients completed self-administered questionnaires, and medical information was obtained from the subjects' medical records. Face validity, concurrent validity evaluated using Short Form 36 (SF-36), known group differences, internal consistency, and test-retest reliability were statistically analyzed., Results: A total of 354 patients gave informed consent, and 331 of them responded (93.5%). The concurrent validity was mostly supported by the pattern of association between SAQ-J and SF-36. The patients without chest symptoms showed significantly higher SAQ-J scores than did the patients with chest symptoms in 4 domains. Cronbach's alpha ranged from .51 to .96, meaning that internal consistency was confirmed to a certain extent. The intraclass correlation coefficient of most domains was higher than the recommended value of 0.70. The weighted kappa ranged from .24 to .57, and it was greater than .4 for 14 of the 19 items., Conclusions: The SAQ-J could be a valid and reliable disease-specific scale in some part for measuring health outcomes in patients with coronary artery disease, and requires cautious use., (Copyright © 2010 Korean Society of Nursing Science. Published by . All rights reserved.)

Although IL-4 and IL-21 synergistically promote proliferation and differentiation of activated B cells, the mutual role in their collaboration is not known. When splenic B cells were sequentially stimulated with anti-IgM Ab and anti-CD40 Ab plus IL-4 and then with IL-21 at a 2-day interval, proliferation, frequency of class switching to IgG1 and plasma cell differentiation were continuously enhanced until day 5 of culture. Amounts of AID and Blimp1 mRNA in sequentially activated B cells with IL-4 and IL-21 increased more than those in activated B cells without IL-21. However, sequential stimulation of B cells with anti-IgM Ab and anti-CD40 Ab plus IL-21 and then with IL-4 at more than 1-day interval did not display the synergistic effect. Furthermore, sequential stimulation of activated B cells with a low dose of IL-4, which did not induce Ig class switching, at the beginning of culture and with IL-21 or IL-4 on day 2 of culture induced proliferation and differentiation of CXCR4(-) or CXCR4(+) B cells, respectively. Thus, IL-21 effectively promotes proliferation and differentiation of CXCR4(-) B cells pre-activated with anti-IgM Ab and anti-CD40 Ab plus IL-4.

TNF-alpha, IFN-gamma, IL-4, and MIP-2 are known to be involved in Con A-induced hepatitis. Although Kupffer cells are reportedly involved in TNF-alpha production, it is largely unknown whether or not Kupffer cells also play a role in the production of other cytokines, such as IFN-gamma, IL-4, and MIP-2. In this study we examined the liver injury and the levels of plasma cytokines, including above four cytokines, KC, and IL-10 in Kupffer cell-depleted mice obtained through administration of liposome-encapsulated dichloromethylene bisphosphonate. The liver injury was significantly suppressed in Kupffer cell-depleted mice, as assessed as to the plasma ALT level and histochemistry. The cytokine levels were also significantly suppressed in such mice except for those of IFN-gamma, which was slightly suppressed at 12h, and IL-10, which was not significantly suppressed at any time. Apoptosis was also significantly suppressed in such mice, as found immunohistochemically with anti-ssDNA Ab. Taken together, these results suggest that Kupffer cells are involved in the production of MIP-2, KC, IL-4, and TNF-alpha in Con A-induced hepatitis, thereby contributing to the liver injury either directly or indirectly.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TYRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X, L668P, 532insC, 1691delA). An IVS5+5G --> A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melan-ep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.

EphA2 is a receptor tyrosine kinase and is frequently overexpressed in a wide array of advanced cancers. We demonstrate in the current study that the EphA2 protein is restrictedly expressed in primary glioblastoma multiforme and anaplastic astrocytoma tissues in comparison to normal brain tissues. To evaluate the possibility of targeting EphA2 in glioma vaccine strategies, we stimulated human leukocyte antigen (HLA) A2+ peripheral blood mononuclear cells (PBMCs) obtained from healthy donors and glioma patients with autologous dendritic cells (DCs) loaded with synthetic EphA2883-891 peptide (TLADFDPRV), which has previously been reported to induce interferon-gamma in HLA-A2+ PBMCs. Stimulated PBMCs demonstrated antigen-specific cytotoxic T lymphocyte (CTL) responses as detected by specific lysis of T2 cells loaded with the EphA2883 peptide as well as HLA-A2+ glioma cells, SNB19 and U251, that express EphA2. Furthermore, in vivo immunization of HLA-A2 transgenic HHD mice with the EphA2883-891 peptide resulted in the development of an epitope-specific CTL response in splenocytes, despite the fact that EphA2883-891 is an autoantigen in these mice. Taken together, these data suggest that EphA2883-891 may be an attractive antigen epitope for molecularly targeted glioma vaccines.

Concanavalin A (Con A)-induced hepatitis has been investigated as a model of T cell-mediated liver injury, in which IFN-gamma plays an essential role by inducing apoptosis of liver cells. Since a large number of neutrophils infiltrate into the liver in the model, the role of neutrophils was investigated in this study. Con A hardly caused liver injury in neutrophil-depleted mice, as assessed as to the plasma alanine aminotransferase level as well as histochemistry. Neutrophil-depleted mice also failed to produce IFN-gamma. Intracellular IFN-gamma staining revealed that, among liver leukocytes, T and NK cells but not neutrophils are the main producers of IFN-gamma. Nylon wool-purified "T cells", however, failed to produce IFN-gamma in response to Con A in vitro, while the production was restored by the addition of neutrophils. Overall, this study suggests that neutrophils play a novel accessory role in IFN-gamma production in Con A-induced hepatitis.

Pancreatic exocrine secretion is known to be facilitated by gastric antral distension via long- and short-route reflexes. In this study, we studied the effects of gastric distension on intra-pancreatic nerve discharges and blood insulin level as well as pancreatic exocrine secretion. Mongrel dogs were anesthetized with ketamine and thiopental, and immediately decerebrated. This study consisted of two series of experiments. In the first series, efferent discharges in an intra-pancreatic nerve branch were recorded, and its responses to antral distension were analyzed. In the second series, effects of antral distension on pancreatic exocrine secretion and blood insulin level were observed before and after vagotomy in splanchnicectomized dogs. Efferent discharges in a pancreatic nerve branch were increased by antral distension. Neither vagotomy nor splanchnicectomy produced obvious changes in the neural response. In splanchnicectomized dogs, antral distension elevated blood insulin level and increased pancreatic exocrine secretion. After subsequent vagotomy, these effects were reduced, but the increases were still greater than 50%. These results indicate that the antro-pancreatic short-route reflex plays a significant role in exocrine secretion, and also suggest that insulin release is increased by antral distension independent of blood glucose level.

BAZF, a member of Bcl6 gene family, acts as a sequence-specific transcriptional repressor in various cells including NIH3T3 cells. The DNA-binding sequence for BAZF is the same as that for Bcl6 and the repressor activity of BAZF was also inhibited by Tricostatin A, an inhibitor of histone deacetylase, suggesting the functional homology between them. However, BAZF unlike Bcl6 cannot function as a transcriptional repressor in embryonal fibroblasts of Bcl6-deficient mice and in Bcl6-null cell lines such as K562 and WIL2-NS. The BTB/POZ domain and the middle portion of BAZF bound to the BTB/POZ domain and the middle portion of Bcl6, respectively. There is an identical 17 amino acid sequence in their middle portions and the sequence was important for the binding. Since BAZF did not directly bind to mSin3A and histone deacetylase 1 and the repressor activity of BAZF was detected in K562 cells replenished with the BTB/POZ domain or the middle portion of Bcl6, BAZF may display its transrepressor activity by recruiting an mSin3A/histone deacetylase 1 complex through association with Bcl6.

CD40 is a member of the tumor necrosis factor receptor family and mediates a variety of functions of B cells, including B cell survival, proliferation, immunoglobulin gene class switching, memory B cell formation, and regulation of Fas-mediated apoptosis. To begin to elucidate the molecular mechanism governing such diverse functions of CD40, we have isolated a gene from mouse splenic B cells, termed Clast5, whose expression is strongly repressed during B cell activation. Clast5 is identical with Stra13, a recently identified member of the basic helix-loop-helix family of transcription factors. Clast5/Stra13 is highly expressed in unstimulated, resting B cells and is rapidly downregulated by a variety of stimuli that activate B cells, including CD40 ligand, anti-IgM antibodies, lipopolysaccharides and interleukin-4. Forced expression of Clast5/Stra13 in B cells delayed the cell cycle progression into S phase and strongly suppressed Fas-mediated apoptosis. Moreover, Clast5/Stra13 inhibited the colony formation in fibroblasts. Our results suggest that Clast5/Stra13 functions as a negative regulator of B cell activation by inhibiting cell cycle progression and cell growth., ((C)2002 Elsevier Science (USA).)

Tec is the prototype of an emerging family of protein-tyrosine kinases. Tec and Btk, another member of this family, together participate in the development of B-cell immune system. We previously identified one of the downstream messengers for human Tec kinase, BRDG1. BRDG1 is associated with Tec and becomes tyrosine-phosphorylated in B-cells by the engagement of B-cell antigen receptor (BCR). Here we show that overexpression of BRDG1 strongly augments BCR-mediated activation of cAMP-response element binding protein (CREB) but not that of c-Jun and the promoters of c-MYC and BCL-xL genes. Furthermore, we isolated the murine orthologue of BRDG1. Three isoforms of BRDG1 are generated by alternative splicing of the message. Two of them have a deletion of 33 amino acids in a Pleckstrin homology (PH) domain of BRDG1. Both the tyrosine-phosphorylation and CREB-activating ability of BRDG1 were isoform-dependent, suggesting a role of the PH domain of BRDG1. These data have identified a novel regulatory mechanism of CREB family of transcriptional factors.

We previously reported that intra-4th-ventricular (i.4th.v.) administration of a non-NMDA receptor antagonist, NBQX, abolished vagally induced retching. This study was undertaken to ascertain whether or not the neuronal response in the solitary tract nucleus (NTS) to vagal stimulation and the vago-vagal gastric reflexes induced by non-emetic stimulation are also abolished by NBQX with a similar latency as in the case of retching. Ketamine and thiopental- or chloralose-anesthetized dogs were decerebrated, and the dorsal surface of the medulla was exposed. This study consisted of two series of experiments. In the first series, extracellular neuronal responses in the NTS to pulse-train vagal stimulation were recorded. Effects of NBQX on the neural response and vagally induced fictive retching were observed. In the second series, effects of glutamate receptor antagonists on gastric corpus responses to esophageal or gastric antral distension were observed. Retching was abolished 5-15 min after an i.4th.v. application of NBQX. and the neuronal responses disappeared within 14 min after application in nine of 10 NTS neurons. On the other hand, corpus contractility was inhibited by esophageal distension, and inhibited and/or enhanced by antral distension. While the inhibitory responses disappeared within 17 min after NBQX, the enhanced response remained even after NBQX and vagotomy, but was abolished by i.v. administration of hexamethonium. These results suggest that adaptive relaxation in the corpus, as well as retching, may be mediated by glutaminergic vagal afferents and non-NMDA receptors in the NTS.

BAZF, a family member of Bcl6, can function as a sequence-specific transcriptional repressor. We determined BAZF-binding DNA sequence. The consensus binding sequence (CBS) of BAZF is almost the same as those of Bcl6 previously described. Three nucleotides of T, G and A at position 6, 8, and 9 in the CBS (5'-ATTCCTAGAAAG-3') are important nucleotides for binding of both BAZF and Bcl6. Since a part (5'-TTC-CTA-GAA-3') of the CBS resembled the sequence motif (5'-TTC-(N3-4)-GAA-3') bound by STAT factors, BAZF and Bcl6 can bind to the CD23b-STAT6-binding sequence (5'-TTTC-TTA-GAAAT-3'), the immunoglobulin germline epsilon-STAT6-binding sequence (5'-CTTC-CCAA-GAAC-3'), and the IL4-STAT6-binding sequence (5'-TTTC-CCA-GAAAA-3') with weak affinity. However, a mutation of C nucleotide to T nucleotide in the IL4-STAT6-binding sequence (5'-TTTC-CTA-GAAAA-3') strongly increased the binding activity of BAZF and Bcl6. These results suggest that BAZF and Bcl6 can repress some of STAT-induced transcription by binding to DNA sequences recognized by STAT factors., (Copyright 2001 Academic Press.)

The inhibitor of apoptosis (IAP) proteins comprise a highly conserved gene family that prevents cell death in response to a variety of stimuli. TIAP/m-survivin, a murine homologue of human Survivin, is a member of the IAP family. TIAP/m-survivin has one baculovirus IAP repeat (BIR) and lacks a C-terminal RING finger motif. Here we identified the genomic DNA region (TIAP-2) that is homologous to the TIAP/m-survivin gene by a low stringency genomic DNA hybridization. The region is on the chromomsome 9 which is distinct from that (chromosome 11) of the TIAP/m-survivin gene, and contains DNA sequence similar to a part of the BIR and the 3' side of the TIAP/m-survivin gene and the sequence homology between them is 92%. Expression of TIAP-2 mRNA was detected in various murine tissues by RT-PCR. Although expression of TIAP/m-survivin mRNA is upregulated in synchronized cells at S to G2/M phase of the cell cycle, expression of TIAP-2 mRNA was constant in the cell cycle, suggesting the different role of TIAP-2 from that of TIAP/m-survivin., (Copyright 2001 Academic Press.)

Background/aims: Hepatitis C virus (HCV) is a major etiologic agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The aim of this study was to elucidate pathological effects of HCV-core protein on liver cells., Methods: We have generated transgenic mice carrying HCV-core cDNA (Px-core) and pathologically examined livers of Px-core mice., Results: HCV-core protein was detectable in livers from lines 5 (C5) and 8 (C8) of Px-core transgenic mice. Since chronic hepatitis and cirrhosis precede hepatocellular carcinoma in patients with HCV infection, we tried to examine the effect of repetitive injection of a small dose of anti-Fas antibody in the transgenic mice. Surprisingly, an initial injection of anti-Fas antibody induced resistance of liver cells to the second injection of anti-Fas antibody in both Px-core and littermate control mice. The insensitivity of liver cells induced in the control mice continued for more than 24 weeks after the first injection but was broken within 1 week after partial hepatectomy. However, the sensitivity was restored in the Px-core mice within 12 weeks after the injection., Conclusion: HCV-core protein in liver cells may affect persistence of Fas-mediated liver cell injury.

We analyzed the expression of the BCL6 gene in mouse tissues by in situ hybridization. The expression was strong in the upper layer but undetectable in the basal layer of epidermis from adult mice. When human keratinocytes were cultured with a high concentration of calcium ion, these cells stopped their proliferation and differentiated to their terminal stage. In these keratinocytes, BCL6 expression was induced after stimulation and progressively up-regulated. The kinetics was very similar to that of a cyclin dependent kinase inhibitor p21sdil/cip1/WAF1 in these cells. These results suggest that BCL6 plays a role in keratinocytes at terminal differentiation stage.