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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Japan is one of the world's most aging societies and the number of elderly patients taking antithrombotic drugs is increasing. In recent years, dual antiplatelet therapy (DAPT), in which two antiplatelet drugs are administered, has become common in anticipation of its high therapeutic efficacy. However, there are concerns about increased bleeding complications in use of DAPT. Therefore, the goal of this study was to investigate the effects of DAPT in patients with traumatic brain injury (TBI). A prospective, multicenter, observational study was conducted from December 2019 to May 2021 to examine the effects of antithrombotic drugs and reversal drugs in 721 elderly patients with TBI. In the current study, the effect of DAPT on TBI was examined in a secondary analysis. Among the registered patients, 132 patients taking antiplatelet drugs only were divided into those treated with single antiplatelet therapy (SAPT) (n=106) and those treated with DAPT (n=26) prior to TBI. Glasgow Coma Scale (GCS) on admission, pupillary findings, course during hospitalization, and outcome were compared in the two groups. A similar analysis was performed in patients with a mild GCS of 13-15 (n=95) and a moderate to severe GCS of 3-12 (n=37) on admission. The DAPT group had significantly more males (67.0 % vs. 96.2 %), a higher severity of illness on admission, and a higher frequency of brain herniation findings on head CT (21.7 % vs. 46.2 %), resulting in significantly higher mortality (12.3 % vs. 30.8 %). The only significant factor for mortality was severity on admission. The rate of DAPT was significantly higher in patients with a moderate to severe GCS on admission, and DAPT was the only significant factor related to severity on admission. These findings suggest that the severity of injury on admission influences the outcome six months after injury, and that patients with more severe TBI on admission are more likely to have been treated with DAPT compared to SAPT., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Transplantation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) has emerged as a promising therapy to treat end-stage heart failure. However, the immunogenicity of hiPS-CMs in transplanted patients has not been fully elucidated. Thus, in vivo models are required to estimate immune responses against hiPS-CMs in transplant recipients., Methods: We transferred human peripheral blood mononuclear cells (hPBMCs) into NOD/Shi-scid IL-2rg null (NOG) MHC class I/II double knockout (NOG-ΔMHC) mice, which were reported to accept hPBMCs without xenogeneic-graft-versus-host disease (xeno-GVHD). Then, hiPS-CM sheets generated from the hiPS cell line 201B7 harboring a luciferase transgene were transplanted into the subcutaneous space of NOG-ΔMHC mice. Graft survival was monitored by bioluminescent images using a Xenogen In Vivo Imaging System., Results: The human immune cells were engrafted for more than 3 months in NOG-ΔMHC mice without lethal xeno-GVHD. The hiPS-CMs expressed a moderate level of human leukocyte antigen (HLA)-class I, but not HLA-class II, molecules even after interferon-gamma (IFN-γ) stimulation. Consistently, the allogenic IFN-γ-treated hiPS-CMs induced weak CD8 + but not CD4 + T cell responses in vitro. hiPS-CM sheets disappeared approximately 17 to 24 days after transplantation in hPBMC-transferred NOG-ΔMHC mice, and CD8 + T cell depletion significantly prolonged graft survival, similar to what was observed following tacrolimus treatment., Conclusions: hiPS-CMs are less immunogenic in vitro but induce sufficient CD8 + T cell-mediated immune responses for graft rejection in vivo., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Effective thrombectomies in the posterior circulation remain controversial. Previous reports have demonstrated the superiority of contact aspiration in anterior circulation. Aspiration catheters and stent retrievers are often used alone on a global scale, while combined techniques are commonly used in Japan. This study evaluated the effect of first-line contact aspiration with other strategies for the treatment of basilar artery occlusion., Methods: The primary outcome was the frequency of the first-pass effect, and the secondary outcome was the time from puncture to the first-pass effect. A multicenter observational registry including 16 Japanese stroke centers was used. Between December 2013 and February 2021, enrolled patients underwent endovascular thrombectomy for basilar artery occlusion. The efficacy of contact aspiration compared to other methods (including stent retrievers and combined techniques) was evaluated., Results: Eighty-four patients were included, all of whom had achieved effective recanalization. Twenty-six patients were treated with contact aspiration, 13 with combined technique, and 45 with stent retrievers. The two groups: contact aspiration and non-contact aspiration, had different backgrounds. Both had similar frequencies of effective recanalization and first-pass effects. The contact aspiration group experienced better functional outcomes without statistical significance, while this strategy was significantly associated with a shorter puncture-to-recanalization time (38 vs. 55 minutes, P=0.036). In particular, in the 55 patients with the first-pass effect, multivariate Cox proportional hazard analysis showed that contact aspiration was significantly associated with a shorter time from puncture to first-pass effect, independent of age and etiology of large-artery atherosclerosis (hazard ratio 2.02, 95% confidence intervals 1.10-3.69, P=0.023)., Conclusion: This study suggested that contact aspiration for basilar artery occlusion may shorten the puncture-to-first-pass effect, compared to stent retrievers and combined techniques., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The importance of temporary mechanical circulatory support for treating acute heart failure with cardiogenic shock is increasingly recognized, and Impella (Abiomed, Danvers, MA, USA) has received particular attention in this regard. Impella is an axial flow left ventricular assist device (LVAD) built into the tip of a catheter. It is inserted via a peripheral artery and implanted into the left ventricle. Although the morphology of Impella is different from a typical LVAD, it has similar actions and effects as an LVAD in terms of left ventricular drainage and aortic blood delivery. Impella increases mean arterial pressure (MAP) and systemic blood flow, thereby improving peripheral organ perfusion and promoting recovery from multiple organ failure. In addition, left ventricular unloading with increased MAP increases coronary perfusion and decreases myocardial oxygen demand, thereby promoting myocardial recovery. Impella is also useful as a mechanical vent of the left ventricle in patients supported with veno-arterial extracorporeal membrane oxygenation. Indications for Impella include emergency use for cardiogenic shock and non-emergent use during high-risk percutaneous coronary intervention and ventricular tachycardia ablation. Its intended uses for cardiogenic shock include bridge to recovery, durable device, heart transplantation, and heart surgery. Prophylactic use of Impella in high-risk patients undergoing open heart surgery to prevent postcardiotomy cardiogenic shock is also gaining attention. While there have been many case reports and retrospective studies on the benefits of Impella, there is little evidence based on sufficiently large randomized controlled trials (RCTs). Currently, several RCTs are now ongoing, which are critical to determine when, for whom, and how these devices should be used. In this review, we summarize the principles, physiology, indications, and complications of the Impella support and discuss current issues and future expectations for the device., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In a world increasingly confronted by cardiovascular diseases (CVDs) and an aging population, accurate risk assessment prior to cardiac surgery is critical. Although effective, traditional risk calculators such as the Japan SCORE, Society of Thoracic Surgeons score, and EuroSCORE II may not completely capture contemporary risks, particularly due to emerging factors such as frailty and sarcopenia. These calculators often focus on regional and ethnic specificity and rely heavily on evaluations based on age and underlying diseases. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that has been identified as a potential biomarker for sarcopenia and a tool for future cardiac risk assessment. Preoperative plasma GDF-15 levels have been associated with preoperative, intraoperative, and postoperative factors and short- and long-term mortality rates in patients undergoing cardiac surgery. Increased plasma GDF-15 levels have prognostic significance, having been correlated with the use of cardiopulmonary bypass during surgery, amount of bleeding, postoperative acute kidney injury, and intensive care unit stay duration. Notably, the inclusion of preoperative levels of GDF-15 in risk stratification models enhances their predictive value, especially when compared with those of the N-terminal prohormone of brain natriuretic peptide, which does not lead to reclassification. Thus, this review examines traditional risk assessments for cardiac surgery and the role of the novel biomarker GDF-15. This study acknowledges that the relationship between patient outcomes and elevated GDF-15 levels is not limited to CVDs or cardiac surgery but can be associated with variable diseases, including diabetes and cancer. Moreover, the normal range of GDF-15 is not well defined. Given its promise for improving patient care and outcomes in cardiovascular surgery, future research should explore the potential of GDF-15 as a biomarker for postoperative outcomes and target therapeutic intervention., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Recent advances in chemotherapy have resulted in successful conversion surgery (CS) for clinical stage (cStage) IVB gastric cancer (GC). This study aimed to evaluate the success rate of CS in clinical practice and determine optimal treatment strategies., Methods: Totally, 166 patients with cStage IVB gastric and gastroesophageal junction adenocarcinoma, who underwent chemotherapy at Hyogo Medical University Hospital between January 2017 and June 2022, were included. CS was performed after confirming tumor to be M0 based on imaging and/or staging laparoscopy, except for resectable liver metastases. Preoperative chemotherapy was continued for at least 6 months provided that adverse events were manageable., Results: Of 125 eligible patients, 23 were treated with CS, achieving a conversion rate of 18.4% and an R0 resection rate of 91.3%. The median duration of preoperative chemotherapy was 8.5 months; the median number of cycles was eight. The highest conversion rate was observed in patients receiving first-line treatment (14.4%), followed by those receiving second and third lines (5.8% and 2.3%, respectively). The median survival time in patients who received CS was significantly longer than that in patients who continued chemotherapy alone (56.7 versus 16 months, respectively, P < 0.0001). There was no significant difference in the 3-year overall survival between the patients who achieved CS after first-line treatment (63.2%, n = 18) and those who achieved CS after second- or third-line treatment (66.7%, n = 5)., Conclusion: Consistent chemotherapy strategies could lead to successful CS and improved prognosis in a greater number of patients with cStage IVB GC, regardless of line of treatment., Competing Interests: Declaration of competing interest None., (© 2023 Published by Elsevier Ltd.)

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). This study used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with that in WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Post-myocardial infarction ventricular septal rupture (PIVSR) is becoming increasingly rare in the percutaneous coronary intervention era; however, the mortality rates remain high. Surgical repair is the gold standard treatment for PIVSR but is associated with surgical difficulty and high mortality. Therefore, the timing of surgery is controversial (i.e. either undertake emergency surgery or wait for resolution of organ failure and scarring of the infarcted area). Although long-term medical management is usually ineffective, several mechanical circulatory support (MCS) devices have been used to postpone surgery to an optimal timing. Recently, in addition to venous arterial extracorporeal membrane oxygenation (VA-ECMO), new MCS devices, such as Impella (Abiomed Inc., Boston, MA, USA), have been developed. Impella is a pump catheter that pumps blood directly from the left ventricle, in a progressive fashion, into the ascending aorta. VA-ECMO is a temporary MCS system that provides complete and rapid cardiopulmonary support, with concurrent hemodynamic support and gas exchange. When left and right heart failure and/or respiratory failure occur in cardiogenic shock or PIVSR after acute myocardial infarction, ECpella (Impella and VA-ECMO) is often introduced, as it can provide circulatory and respiratory assistance in a shorter period. This review outlines the basic concepts of MCS in PIVSR treatment strategies and its role as a bridge device, and discusses the efficacy and complications of ECpella therapy and the timing of surgery., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Monoclonal antibody therapy has been reported to be highly effective for preventing hospitalisation and severe cases in patients with Coronavirus Disease 2019 (COVID-19). However, since the drug is not readily available, it is important to rapidly and appropriately identify high-risk patients who can benefit most from therapy. Therefore, we designed a risk scoring system to identify at-risk COVID-19 patients in our region during the largest surge of COVID-19, from July to September 2021., Methods: According to the risk scores, confirmed COVID-19 patients were introduced to receive REGN-CoV-2 to our hospital by regional health centre from 18th August (Term 3). The primary outcome was the comparison of the number of hospitalisation and severe condition with other periods, the 4th wave (Term 1) and the early part of the 5th wave (Term 2) in Japan., Results: During Term 3, 115 patients were stratified with the scoring system and administered REGN-COV-2. The number of hospitalisation vs severe cases were 60 (5.2%) vs 14 (1.2%), 8 (1.5%) vs 3 (0.6%) and 21 (1.2%) vs 2 (0.1%), in term 1, 2 and 3, respectively. Among those aged <60 years, compared with term 1, the relative risk of hospitalisation and severe condition were 0.25 (95% CI: 0.12-0.53) and 0.10 (95% CI: 0.01-0.80), respectively, in term 3. Drug adverse events were fever (3: 2.6%), headache (1: 0.9%) and neck rash (1: 0.9%), all events were resolved within 24 h wth no serious adverse event., Conclusions: The administration of monoclonal antibody therapy using a risk scoring system significantly reduced the number of hospitalisation and disease severity of COVID-19 without any serious adverse events and avoided regional medical collapse., (Copyright © 2021. Published by Elsevier Ltd.)

Three families with multiple gastrointestinal stromal tumors (GISTs) caused by a germline Asp820Tyr mutation at exon 17 of the c-kit gene (KIT-Asp820Tyr) have been reported. We previously generated a knock-in mouse model of the family, and the mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal tumor equivalent to human GIST. In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. In this report, we examined whether a heat shock protein 90 inhibitor, pimitespib (TAS-116), has an inhibitory effect on phosphorylation of KIT-Asp818Tyr and can decrease the cecal tumor volume in the model mice. First, we showed that pimitespib inhibited KIT phosphorylation both dose- and time-dependently in KIT-Asp818Tyr transfected murine Ba/F3 cells. Then, four 1-week courses of pimitespib were orally administered to heterozygous (KIT-Asp818Tyr/+) model mice. Each course consisted of once-daily administration for consecutive 5 days followed by 2 days-off. Cecal tumors were dissected, and tumor volume was histologically analyzed, Ki-67 labeling index was immunohistochemically examined, and apoptotic figures were counted. Compared to the vehicle treated mice, pimitespib administered mice showed statistically significantly smaller cecal tumor volume, lower Ki-67 labeling index, and higher number of apoptotic figures in 10 high power fields (P = 0.0344, P = 0.0019 and P = 0.0269, respectively). Western blotting revealed that activation of KIT signaling molecules was strongly inhibited in the tumor tissues of pimitespib-administered mice compared to control mice. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We developed a deep learning (DL) model for automated atherosclerotic plaque categorization using optical frequency domain imaging (OFDI) and performed quantitative and visual evaluations., Methods: A total of 1103 histological cross-sections from 45 autopsy hearts were examined to compare the ex vivo OFDI scans. The images were segmented and annotated considering four histological categories: pathological intimal thickening (PIT), fibrous cap atheroma (FA), fibrocalcific plaque (FC), and healed erosion/rupture (HER). The DL model was developed based on pyramid scene parsing network (PSPNet). Given an input image, a convolutional neural network (ResNet50) was used as an encoder to generate feature maps of the last convolutional layer., Results: For the quantitative evaluation, the mean F-score and IoU values, which are used to evaluate how close the predicted results are to the ground truth, were used. The validation and test dataset had F-score and IoU values of 0.63, 0.49, and 0.66, 0.52, respectively. For the section-level diagnostic accuracy, the areas under the receiver-operating characteristic curve produced by the DL model for FC, PIT, FA, and HER were 0.91, 0.85, 0.86, and 0.86, respectively, and were comparable to those of an expert observer., Conclusions: DL semantic segmentation of coronary plaques in OFDI images was used as a tool to automatically categorize atherosclerotic plaques using histological findings as the gold standard. The proposed method can support interventional cardiologists in understanding histological properties of plaques., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: To date, there have been no data available regarding the diagnostic performance of optical frequency domain imaging (OFDI) for in vivo histological classification of atherosclerotic lesions. This study investigated whether OFDI can be used to diagnose and classify histological atherosclerotic lesions in the coronary artery by ex vivo histological examinations., Methods: Three-hundred-fifteen histological cross-sections from 21 autopsy hearts were matched with the OFDI images. Histological cross-sections were classified into six categories: adaptive intimal thickening (AIT), pathological intimal thickening (PIT), fibrous cap atheroma (FA), fibrocalcific plaque (FC), calcified nodule, and healed erosion/rupture. The five observers with different years of experience in the interpretation of OFDI provided a single diagnosis for the OFDI scans of each cross-section according to the aforementioned six histological categories. The diagnostic accuracy and interobserver variability of lesion types for each OFDI observer were determined using histology as the gold standard., Results: The overall agreement rates between OFDI and histopathologic diagnosis for OFDI observers 1-5 were 81%, 70%, 68%, 61%, and 50% (κ values of 0.75, 0.61, 0.58, 0.49, and 0.36), respectively. Although the diagnostic accuracy of OFDI for detecting AIT and FC was excellent for all five observers, the sensitivity, and positive predictive values of OFDI for detecting PIT and FA were low in proportion to years of experience., Conclusion: The diagnostic accuracy of atherosclerotic tissue properties from OFDI scans correlated with the observers' years of experience, especially when lesions contained lipid components., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

The metal active site is precisely designed in metalloproteins. Here we applied 3D domain swapping, a phenomenon in which a partial protein structure is exchanged between molecules, to introduce metal sites in proteins. We designed multiple metal-binding sites specific to domain-swapped myoglobin (Mb) with His mutation. Stable dimeric Mbs with metal-binding sites were obtained by shifting the His position and introducing two Ala residues in the hinge region (K78H/G80A/H82A and K79H/G80A/H81A Mbs). The absorption and circular dichroism spectra of the monomer and dimer of K78H/G80A/H82A and K79H/G80A/H81A Mbs were similar to the corresponding spectra, respectively, of wild-type Mb. No negative peak due to dimer-to-monomer dissociation was observed below the denaturation temperature in the differential scanning calorimetry thermograms of K78H/G80A/H82A and K79H/G80A/H81A Mbs, whereas the dimer dissociates into monomers at 68 °C for wild-type Mb. These results show that the two mutants were stable in the dimer state. Metal ions bound to the metal-binding sites containing the introduced His in the domain-swapped Mb dimers. Co 2+ -bound and Ni 2+ -bound K78H/G80A/H82A Mb exhibited octahedral metal-coordination structures, where His78, His81, Glu85, and three H 2 O/OH - molecules coordinated to the metal ion. On the other hand, Co 2+ -bound and Zn 2+ -bound K79H/G80A/H81A Mb exhibited tetrahedral metal-coordination structures, where His79, His82, Asp141, and a H 2 O/OH - molecule coordinated to the metal ion. The Co 2+ -bound site exists deep inside the protein in the K79H/G80A/H81A Mb dimer, which may allow the unique tetrahedral coordination for the Co 2+ ion. These results show that we can utilize domain swapping to construct artificial metalloproteins., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Many c-type cytochromes (cyts) can form domain-swapped oligomers. The positively charged Hydrogenobacter thermophilus (HT) cytochrome (cyt) c 552 forms domain-swapped oligomers during expression in the Escherichia coli (E. coli) expression system, but the factors influencing the oligomerization remain unrevealed. Here, we found that the dimer of the negatively charged Shewanella violacea (SV) cyt c 5 exhibits a domain-swapped structure, in which the N-terminal helix is exchanged between protomers, similar to the structures of the HT cyt c 552 and Pseudomonas aeruginosa (PA) cyt c 551 domain-swapped dimers. Positively charged horse cyt c and HT cyt c 552 domain swapped during expression in E. coli, whereas negatively charged PA cyt c 551 and SV cyt c 5 did not. Oligomers were formed during expression in E. coli for HT cyt c 552 attached to either a co- or post-translational signal peptide for transportation through the cytoplasm membrane, but not for PA cyt c 551 attached to either signal peptide. HT cyt c 552 formed oligomers in E. coli in the presence and absence of rare codons. More oligomers were obtained from the in vitro folding of horse cyt c and HT cyt c 552 by the addition of negatively charged liposomes during folding, whereas the amount of oligomers for the in vitro folding of PA cyt c 551 and SV cyt c 5 did not change significantly by the addition. These results indicate that the protein surface charge affects the oligomerization of c-type cyts in cells; positively charged c-type cyts assemble on a negatively charged membrane, inducing formation of domain-swapped oligomers during folding., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The objective of this study was to examine behavior and function of osteoblasts on saliva-contaminated titanium and its potential improvement after UV light treatment. Acid-etched titanium disks were contaminated with human saliva. Osteoblasts derived from rat femur were cultured on contaminated and clean titanium disks. Contaminated disks further treated with UV light were also tested. The number of attached cells, the degree of cell spreading, and the expression of adhesion protein were significantly decreased on saliva-contaminated surfaces compared with clean surfaces. The gene expression of osteocalcin was also downregulated on contaminated surfaces, whereas ALP activity and mineralization were not significantly influenced. The impaired functions on contaminated surfaces were significantly increased if the surfaces were further treated with UV and even outperformed the ones on clean titanium surfaces. XPS analysis revealed that the atomic percentage of carbon and nitrogen detected on contaminated surfaces were substantially decreased after UV treatment. These results suggest that osteoblastic behavior and function were compromised on titanium surfaces contaminated with saliva. The compromised functions no longer happened if the surfaces were further treated with UV light, providing the basis to understand the effect of biological contamination on osseointegration and to explore UV treatment as a decontaminating technology., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oligomerization of heme proteins is useful for construction of new materials with cooperative and systematic functions; thus, diverse methods have been applied for construction of artificial heme protein oligomers. Three-dimensional (3D) domain swapping is a protein oligomerization phenomenon that exchanges the same domain or secondary structural element between molecules. 3D domain swapping was first reported in 1994; since then many proteins have been reported to domain swap. Our research group has been showing that various heme proteins domain swap. We also found that domain swapping of heme proteins occurs at the early stage of protein folding, and utilized it to construct various heme protein assemblies, including nanorings, cages, hetero dimers with different active sites, and a ligand-binding reversible monomer-polymer system. In this review, the basics and applications of domain swapping of heme proteins are summarized., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Changes in brain tissue can be detected sensitively using PRESTO (principles of echo-shifting with a train of observations) magnetic resonance imaging (MRI). The aim of this study was to evaluate the correlation between the proliferative ability of astrocytoma and intratumoral spotty signal voids seen as hypo-intense dots on PRESTO MRI., Patients and Methods: Fifty-seven astrocytic tumors, comprising 14 astrocytomas, 12 anaplastic astrocytomas, and 31 glioblastomas, were included in this retrospective study. The tumors were classified independently by blinded radiologists according to the number of spotty signal voids detected on PRESTO-MRI as follows: spot-free (grade 0), less than 3 spots (grade 1), or more than 3 spots or a large spot (grade 2)., Results: Thirteen patients (92.9%) with astrocytoma were classified as PRESTO grade 0 and 1 patient (7.1%) was classified as grade 1. Seven patients (58.3%) with anaplastic astrocytoma were classified as PRESTO grade 0, 1 (8.3%) as grade 1, and 4 as grade 2 (33.3%). Three patients (9.7%) with glioblastoma were classified as grade 0, 6 (19.4%) as grade 1, and 22 (70.9%) as grade 2. There was a strong correlation between PRESTO tumor grade and the mean MIB-1 index., Conclusions: These results indicate that a grading system based on the number of spotty signal voids detected on PRESTO images would be useful for the diagnosis of astrocytic tumors and predicting their proliferative ability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Optical coherence tomography (OCT), a catheter-based imaging modality for the visualization of coronary arteries, is widely used during percutaneous coronary intervention to improve the understanding of the anatomy of coronary artery stenosis and to elucidate the mechanisms of atherosclerosis. In this review, we provide a short description of the histopathological validations of OCT for visualizing atherosclerotic plaques and vascular healing response after drug-eluting stent (DES) implantation. Because OCT measures the intensity of light returning from within a tissue, tissue having a higher heterogeneity of optical index of refraction, such as microcalcification deposition and foam cell accumulation on the luminal surface, may exhibit stronger optical scattering that appears as a thin-cap fibroatheroma image. Furthermore, even if OCT shows exposed uncovered stent struts, some of the struts could be re-endothelialized. In our ex vivo histopathological experience, re-endothelialization at the surface of stent struts was confirmed by histopathological analysis, although OCT images showed exposed uncovered struts after DES implantation. Therefore, careful interpretation is required to assess tissue morphology and stent strut coverage by OCT., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The Met80-heme iron bond of cytochrome c (cyt c) is cleaved by the interaction of cyt c with cardiolipin (CL) in membranes. The Met80 dissociation enhances the peroxidase activity of cyt c and triggers cyt c release from mitochondrion to the cytosol at the early stage of apoptosis. This paper demonstrates the selective oxidation of Met80 for the reaction of ferric cyt c with a peroxide, meta-chloroperbenzoic acid (mCPBA), in the presence of CL-containing liposomes by formation of a ferryl species (Compound I). After the reaction of cyt c with mCPBA in the presence of 1,2-dioloeyl-sn-glycero-3-phosphocholine (DOPC) liposomes containing CL, the electrospray ionization mass spectrum of the peptide fragments, obtained by digestion of cyt c with lysyl endopeptidase, exhibited a peak at m/z = 795.45; whereas, this peak was not observed for the peptide fragments obtained after the reaction in the presence of DOPC liposomes not containing CL. According to the tandem mass spectrum of the m/z = 795.45 peptide fragment, Met80 was modified with a 16 Da mass increase. The purified Met80-modified cyt c exhibited a peroxidase activity more than 5-fold higher than that of the unmodified protein. Transient absorption bands around 650 nm were generated by the reactions with mCPBA for ferric wild-type cyt c in the presence of CL-containing DOPC liposomes and ferric Y67F cyt c in the absence of liposomes. The formation and decomposition rates of the 650-nm absorption species increased and decreased, respectively, by increasing the mCPBA concentration in the reaction, indicating transient formation of Compound I., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The clinical benefit of second-generation drug-eluting stents (2nd DES) has been established, compared to first-generation drug-eluting stents (1st DES). However, pathological response after 2nd DES implantation remains unclear, particularly in the Japanese population., Methods: Using specimens obtained by autopsy, we compared the histology between 2nd DES (41 sections) and 1st DES (38 sections) lesions within 1 year after stent implantation to evaluate early tissue reaction in Japanese patients. Stent segments were fixed with 10% buffered formalin and embedded in plastic, followed by hematoxylin-eosin and Masson's trichrome staining. Ratio of covered stent struts was calculated, and the area of fibrin deposition was morphometrically evaluated. The degree of inflammation around struts was examined semi-quantitatively (score 0-3)., Results: The ratio of covered struts and mean fibrin area of 2nd DES were 0.69±0.05 and 658.0±173.4μm 2 . Those of 1st DES were 0.44±0.12 and 3107.5±1405.9μm 2 . In the 2nd DES, there was significantly less fibrin deposition and a higher covered struts ratio. The inflammation score was significantly lower in 2nd DESs compared to 1st DESs (1.02±0.16 vs. 1.19±0.54, p<0.05)., Conclusions: Histopathological analysis showed advanced healing process in 2nd DES compared with 1st DES lesions. These results are consistent with clinical beneficial outcome of 2nd DES implantation., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Although single-photon emission computerized tomography of the dopamine transporter (DAT-SPECT) is useful for diagnosing parkinsonian syndrome, its applicability toward the early phase of Parkinson's disease remains unknown., Methods: We enrolled 32 patients showing parkinsonism with normal cardiac 123 I-metaiodobenzylguanidine (MIBG) uptake and abnormal DAT-SPECT findings among 84 consecutive patients with parkinsonism. We divided these patients into two groups (group 1: Parkinson's disease, group 2: corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy), and compared their clinical characteristics, specific binding ratios, and striatal asymmetry indexes on DAT-SPECT examinations., Results: The striatal asymmetry indexes were significantly lower in group 1 than in group 2 (p<0.05), but there were no differences in the specific binding ratios between the two groups., Conclusion: The combined use of striatal asymmetry index on DAT-SPECT and cardiac MIBG scintigraphy might offer useful clues for the differential diagnosis of the early phase Parkinson's disease from other parkinsonian syndromes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Specific components of the intestinal microbiota are capable of influencing immune responses such that a mutualistic relationship is established. In mice, colonization with segmented filamentous bacteria (SFB) induces T-helper-17 (Th17) cell differentiation in the intestine, yet the effector functions of interleukin (IL)-17A in response to SFB remain incompletely understood. Here we report that colonization of mice with SFB-containing microbiota induced IL-17A- and CXCR2-dependent recruitment of neutrophils to the ileum. This response required adaptive immunity, as Rag-deficient mice colonized with SFB-containing microbiota failed to induce IL-17A, CXCL1 and CXCL2, and displayed defective neutrophil recruitment to the ileum. Interestingly, neutrophil depletion in wild-type mice resulted in significantly augmented Th17 responses and SFB expansion, which correlated with impaired expression of IL-22 and antimicrobial peptides. These data provide novel insight into a dynamic IL-17A-CXCR2-neutrophil axis during acute SFB colonization and demonstrate a central role for neutrophils in limiting SFB expansion.

Background: Optical coherence tomography (OCT) is one of the tools trying to distinguish neoatherosclerosis from other neointimal tissue but its role has to be still validated. This study evaluated the diagnostic accuracy of OCT for characterization of lipid-atherosclerotic neointima following drug-eluting stent (DES) implantation., Methods: Twelve stented coronary arteries from the 7 autopsy hearts were imaged by OCT. These OCT images were compared with histology. By OCT, the morphological appearances of neointima were classified into three patterns: homogeneous pattern, heterogeneous pattern with visible strut, or heterogeneous pattern with invisible strut., Results: Of 21 histological cross-sections, 6 were categorized as homogeneous patterns (29%), 11 as heterogeneous patterns with visible stent strut (52%), and 4 as heterogeneous patterns with invisible stent strut (19%). All homogeneous patterns were composed of smooth muscle cells with collagen fibers. The heterogeneous patterns with visible stent strut included proteoglycan-rich myxomatous matrix and calcium deposition. On the other hand, the heterogeneous patterns with invisible stent strut comprised atheromatous tissue, including a large amount of foam cell accumulation (25%) or large fibroatheroma/necrotic core (75%) inside the stent struts within neointima. The optical attenuation coefficient was highest in the heterogeneous pattern with invisible stent strut due to scattering of light by atheromatous tissue., Conclusion: The heterogeneous patterns with invisible stent strut on OCT imaging identify the presence of lipid-atherosclerotic tissue within neointima after DES. This may suggest the potential capability of OCT based on visualization of stent struts for discriminating atheromatous formation within neointima from other neointimal tissue., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

1'-Acetoxychavicol acetate (ACA) is naturally obtained from the rhizomes and seeds of Alpinia galangal. Here, we examined the effect of ACA on learning and memory in senescence-accelerated mice prone 8 (SAMP8). In mice that were fed a control diet containing 0.02% ACA for 25 weeks, the learning ability in the Morris water maze test was significantly enhanced in comparison with mice that were fed the control diet alone. In the Y-maze test, SAMP8 mice showed decreased spontaneous alterations in comparison with senescence-accelerated resistant/1 (SAMR1) mice, a homologous control, which was improved by ACA pretreatment. Serum metabolite profiles were obtained by GC-MS analysis, and each metabolic profile was plotted on a 3D score plot. Based upon the diagram, it can be seen that the distribution areas for the three groups were completely separate. Furthermore, the contents of β-hydroxybutyric acid and palmitic acid in the serum of SAMP8-ACA mice were higher than those of SAMP8-control mice and SAMR1-control mice. We also found that SAMR1 mice did not show histological abnormalities, whereas histological damage in the CA1 region of the hippocampus in SAMP8-control mice was observed. However, SAMP8-ACA mice were observed in a similar manner as SAMR1 mice. These findings confirm that ACA increases the serum concentrations of β-hydroxybutyric acid and palmitic acid levels and thus these fuels might contribute to the maintenance of the cognitive performance of SAMP8 mice., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Acute multifocal embolic infarction (AMEI) is conventionally caused by etiologies such as cardioembolism due to atrial fibrillation (Af), but can also be caused by serious underlying diseases such as cancer. We characterized cancer-related AMEI and identified useful indicators for cancer-associated strokes., Methods: A retrospective analysis was performed on 35 patients with Af-related AMEI and 35 patients with cancer-related AMEI selected from 1235 consecutive patients with acute infarcts. All patients received diffusion-weighted magnetic resonance (MR) imaging. Cerebral MR angiography, carotid and cardiac ultrasonography, electrocardiogram-monitoring and whole body computed tomography were also performed on these patients. D-dimer levels were evaluated on admission, and were measured during the sub-acute phase in 19 of the patients with Af and 27 of the patients with cancer., Results: Acute phase D-dimer levels were significantly higher in patients with cancer than in patients with Af alone. The cut-off D-dimer value to identify cancer-associated infarcts was 2.0μg/mL. D-dimer levels during the sub-acute phase remained elevated in the cancer patients., Conclusions: We may differentiate cancer-associated AMEI from Af using a D-dimer level≥2.0μg/mL, which does not decrease during the sub-acute phase., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Although most patients with Parkinson's disease (PD) show decreased cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake, some exhibit normal uptake. We evaluated the clinical characteristics of such patients., Methods: We enrolled 154 non-demented patients showing parkinsonism with normal cardiac MIBG uptake and had been clinically followed up during 29.9 ± 27.6 months. We defined the patients who did not fit the exclusion criteria for PD and demonstrated ≥ 30% reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score after anti-Parkinson agent administration as probable PD. We compared clinical characteristics and the cardiac MIBG heart-to-mediastinum (H/M) ratio between the probable PD group (N=37) and other groups (N=117)., Results: The probable PD group showed significantly higher UPDRS motor scores and greater incidence of tremor/rigidity than those of other groups. In addition, they showed a significantly lower cardiac MIBG H/M ratio in the delayed phase (delayed, p<0.0001). Washout-rate (WR) was significantly higher in probable PD cases (p<0.0001). Among 16 probable PD patients undergoing serial cardiac MIBG scintigraphy, the delayed phase cardiac MIBG H/M ratio showed a significant decrease and WR significantly increased during follow-up periods., Conclusions: An increase in WR and lower delayed phase cardiac MIBG uptake were found to be characteristics of such patients., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Lateral mesoderm-derived hemogenic endothelial cells are known to originate the definitive hematopoietic lineage in mouse embryogenesis. The developmental process of the definitive hematopoietic lineage can be recapitulated by inducing differentiation of mouse embryonic stem (ES) cells in a co-culture system with OP9 stromal cells. However, the signaling molecules that can modulate the development of the definitive hematopoietic lineage in the OP9 co-culture system have yet to be identified. Here we report that activin A enhanced the hematopoietic potential of endothelial cells derived from ES cells in the OP9 co-culture system. Activin A in combination with OP9 cells augmented development of Flk-1(+) PDGFRα(+) early mesodermal cells and Flk-1(+) PDGFRα(-) lateral mesodermal cells from ES cells. These Flk-1(+) mesodermal cells further differentiated into CD41(+) endothelial cells, which preferentially possessed high hematopoietic potential. Furthermore, Flk-1(+) PDGFRα(+) cells but not Flk-1(+) PDGFRα(-) cells produced hematopoietic progenitors with a bimodal pattern when cultured as an aggregate with OP9 cells. Our results suggest that activin A in combination with OP9 cells facilitates differentiation of ES cells to Flk-1(+) mesodermal cells, which encompass various precursors that separately contribute to the development of hematopoietic lineages., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Accumulating evidence suggests that inflammation plays a role in the pathophysiology of depression and that anti-inflammatory substances have antidepressant effects. Amycenone is obtained from extracts of the Yamabushitake (Hericium erinaceum). The purpose of this study is to examine whether amycenone shows anti-inflammatory and antidepressant effects in an inflammation-induced mouse model of depression. First, we examined the effects of amycenone on the serum levels of the pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), and the anti-inflammatory cytokine, interleukin-10 (IL-10), after intraperitoneal administration of the bacterial endotoxin lipopolysaccharide (LPS). Oral administration of amycenone (50, 100, or 200mg/kg) markedly blocked an increase in the serum TNF-α levels after a single administration of LPS (0.5mg/kg). Furthermore, amycenone (200mg/kg) markedly increased the serum IL-10 levels by a single administration of LPS (0.5mg/kg). Next, we examined the effects of amycenone on depression-like behaviors in the tail-suspension test (TST) and forced swimming test (FST). Pretreatment with amycenone (200mg/kg) significantly attenuated LPS (0.5mg/kg)-induced increase of the immobility time by the TST and FST, indicating antidepressant effects of amycenone. In addition, oral administration of paroxetine (30mg/kg) showed anti-inflammatory and antidepressant effects in the same model. These findings suggest that amycenone has antidepressant effects in LPS-induced inflammation model of depression. Therefore, amycenone could represent a potential supplement to prevent inflammation-related depression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: We determined the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways in 108 cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with high and low Ki-67 expression. The expression levels of Ki-67, p53, phosphorylated MAPK (pMAPK), and protein S6 (pS6; downstream molecule of PI3K/Akt/mammalian target of rapamycin/S6 kinase pathway) were determined immunohistochemically. pS6 positivity, but not pMAPK positivity, was significantly associated with the high Ki-67 expression subset., Background: Evaluation of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered important. Although the phosphoinositide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are thought to be involved in the luminal B subtype, the details of their contribution to breast cancer remain unclear., Materials and Methods: We determined the activation of these pathways (phosphorylated MAPK [pMAPK] and protein S6 [pS6; a downstream molecule of PI3K/Akt/mammalian target of rapamycin (mTOR)/S6 kinase (S6K)]) in 108 ER(+), HER2(-) breast cancer cases with high and low Ki-67 expression. The ER, progesterone receptor (PgR), Ki-67, p53 expression levels were also determined immunohistochemically. The cutoff value for Ki-67 was set at 15%., Results: A significantly greater percentage of cancer cases with high Ki-67 expression showed pS6 positivity than did those with low Ki-67 expression (53.2% vs. 19.7%; P = .0003). No significant differences were found between the cases with high and low expression levels were detected for p53 (23.4% vs. 11.5%; P = .12) or pMAPK (36.2% vs. 34.4%; P = .85) positivity. Multivariate analysis showed that pS6 positivity (odds ratio 5.16, 95% confidence interval 1.95-13.63; P = .0009), nuclear grade 2 and 3, and low PgR expression (≤ 20%) were independently associated with the high Ki-67 subset., Conclusion: From our findings, we have concluded that the pS6 expression level is associated with the characteristics of breast cancer with high Ki-67 expression. Because these associations were observed, irrespective of menopausal status, the biologic difference seems to be less affected by estrogen signaling than by activation of S6 protein, especially in terms of proliferation. Our findings have also indicated that targeting the mTOR/S6K pathway might be a useful strategy for the treatment of ER(+)/HER2(-) breast cancer with high Ki-67 expression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. We have previously shown that clioquinol inhibits nerve growth factor (NGF)-induced Trk autophosphorylation in PC12 cells transformed with human Trk cDNA. To explore the further mechanism of neuronal damage by clioquinol, we evaluated the acetylation status of histones in PC12 cells. Clioquinol reduced the level of histone acetylation, and the histone deacetylase (HDAC) inhibitor Trichostatin A upregulated acetylated histones and prevented the neuronal cell damage caused by clioquinol. In addition, treatment with HDAC inhibitor decreased neurite retraction and restored the inhibition of NGF-induced Trk autophosphorylation by clioquinol. Thus, clioquinol induced neuronal cell death via deacetylation of histones, and HDAC inhibitor alleviates the neurotoxicity of clioquinol. Clioquinol is now used as a potential medicine for malignancies and neurodegenerative diseases. Therefore, HDAC inhibitors can be used as a candidate medicine for the prevention of its side effects on neuronal cells., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study sought to assess the accuracy of optical coherence tomography (OCT), gray-scale intravascular ultrasound (IVUS), and their combination for detecting thin-cap fibroatheromas (TCFA)., Background: The extent to which the imaging characteristics of OCT and IVUS correlate with histologically defined TCFA is unknown., Methods: IVUS and OCT examinations identified focal plaques in 165 coronary arteries from 60 autopsy hearts. A total of 685 pairs of images of OCT and IVUS were compared with histology. By OCT, a TCFA was defined as a signal-poor region with diffuse borders and cap thickness <65 μm. By IVUS, a TCFA was defined by the presence of echolucent zones and/or ultrasound attenuation in areas of positive remodeling. By histology, 12 of 685 focal plaques were classified as TCFAs., Results: With histology as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy for OCT-derived TCFA were 100%, 97%, 41%, 100%, and 98%, respectively. The corresponding numbers for IVUS-derived TCFA were 92%, 93%, 19%, 99%, and 93%, respectively. The histological findings underlying the false positive diagnoses of OCT for TCFA included large amounts of foam cell accumulation on the luminal surface, large amounts of microcalcifications at the surface, large amounts of hemosiderin accumulation, or organized thrombus. In contrast, histological causes of mischaracterization of TCFA by IVUS were mostly TCFA. When both OCT and IVUS criteria for TCFA were required to be met, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy were 92%, 99%, 69%, 99%, and 99%, respectively., Conclusions: In the present study, neither OCT nor IVUS were optimal to detect TCFA. The combined use of OCT and IVUS may improve TCFA detection accuracy., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Leptin is thought to be not only a satiety factor but also a stimulator of angiogenesis. We examined leptin, PPARγ2, and vascular endothelial growth factor (VEGF) expression in bovine intramuscular preadipocyte (BIP) cells during proliferation. The cells were seeded at 0.85 × 10(4) cells/cm(2) and collected every day until the fifth day after passage. Leptin mRNA was present in the cells between days 2 and 4, as indicated by RT-PCR analysis. Western blot analysis showed a band for leptin at approximately 16 kDa on all of the days during growth, and the cytoplasmic concentration of leptin was highest on day 2 and decreased gradually thereafter. A PPARγ2 band at approximately 54 kDa was also observed on all days. The concentration was highest on day 2 and decreased thereafter, which is similar to the expression pattern of leptin. In constant, the expression level of VEGF protein did not change while in culture. We have demonstrated that BIP cells can synthesize both leptin and PPARγ2, with maximal synthesis occurring during maximal proliferation. Given the role of leptin in angiogenesis, we speculate that leptin is involved in the neovascularization of adipose tissue, because new organization of adipose tissue requires the growth of new blood vessels., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) failure. Recently, iron deficiency is reported to be prevalent in patients with PH. However, the mechanism by which iron deficiency occurs in patients with PH remains unknown. Here, we investigated the effects of dietary iron restriction on the development of monocrotaline-induced pulmonary vascular remodeling and the involved mechanisms. Male Sprague-Dawley rats were subcutaneously injected with monocrotaline (60mg/kg). Afterwards, monocrotaline-injected rats were randomly divided into two groups and were given a normal diet (n=6) or an iron-restricted diet (n=6) for 4weeks. Saline-injected rats given a normal diet were served as controls (n=6). Monocrotaline-injected rats showed pulmonary vascular remodeling, increased RV pressure, RV hypertrophy, and decreased RV ejection fraction, followed by RV failure after 4weeks. In contrast, iron restriction attenuated the development of pulmonary vascular remodeling and RV failure. Of interest, expression of cellular iron transport protein, transferrin receptor 1 was increased in the pulmonary remodeled artery and the failing right ventricle of monocrotaline-injected rats, as compared with the controls. Moreover, a key regulator of iron homeostasis, hepcidin gene expression was increased in the failing right ventricle of monocrotaline-injected rats. Iron restriction attenuated the development of monocrotaline-induced pulmonary vascular remodeling and RV failure. Cellular iron transport might be involved in the pathophysiology of PH and PH induced RV failure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

[NiFe] hydrogenase catalyzes reversible oxidation of molecular hydrogen. Its active site is constructed of a hetero dinuclear Ni-Fe complex, and the oxidation state of the Ni ion changes according to the redox state of the enzyme. We found that the Ni-A state (an inactive unready, oxidized state) of [NiFe] hydrogenase from Desulfovibrio vulgaris Miyazaki F (DvMF) is light sensitive and forms a new state (Ni-AL) with irradiation of visible light. The Fourier transform infrared (FT-IR) bands at 1956, 2084 and 2094 cm(-1) of the Ni-A state shifted to 1971, 2086 and 2098 cm(-1) in the Ni-AL state. The g-values of g(x)=2.30, g(y)=2.23 and g(z)=2.01 for the signals in the electron paramagnetic resonance (EPR) spectrum of the Ni-A state at room temperature varied for -0.009, +0.012 and +0.010, respectively, upon light irradiation. The light-induced Ni-AL state converted back immediately to the Ni-A state under dark condition at room temperature. These results show that the coordination structure of the Fe site of the Ni-A state of [NiFe] hydrogenase is perturbed significantly by light irradiation with relatively small coordination change at the Ni site., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The subthalamic nucleus (STN) is a frequent target of deep brain stimulation (DBS), which is used to treat patients with advanced Parkinson's disease (PD). However, few studies have assessed the relationship between the STN and the clinical characteristics of PD patients. We identified the STN of 17 PD patients and 7 control subjects using coronal Short TI Inversion Recovery (STIR) magnetic resonance imaging (MRI) and estimated the T2 relaxation time (T2) of the STN on the subsequent coronal images that were acquired from T2-weighted MRI. The relationships between the STN T2 measurements and the PD patients' age, disease duration, laterality, and clinical scores were examined. STN T2 measurements tended to be lower in PD patients than in controls, although the difference was not significant. STN T2 measurements were significantly and inversely correlated (p=0.03) with scores on the Unified Parkinson's Disease Rating Scale (UPDRS) part 1, which was applied to evaluate the mentation, behavior, and mood of PD patients. However, no significant correlations were found between the STN T2 measurements and the patients' age, disease duration, laterality, or motor clinical scores. These results suggest that degeneration of the STN in PD patients may contribute to their neuropsychological symptoms., (Copyright © 2011 Elsevier B.V. All rights reserved.)