Publishing type：Research paper (scientific journal)   Publisher：The American Association of Immunologists  

Abstract

The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3, also called cryopyrin) inflammasome is an intracellular innate immune complex, which consists of the pattern-recognition receptor NLRP3, the adaptor apoptosis-assciated speck-like protein containing a caspase recruitment domain, and procaspase-1. Aberrant activation of the NLRP3 inflammasome causes an autoinflammatory disease called cryopyrin-associated periodic syndrome (CAPS). CAPS is caused by gain-of-function mutations in the NLRP3-encoding gene CIAS1; however, the mechanism of CAPS pathogenesis has not been fully understood. Thus, unknown regulators of the NLRP3 inflammasome, which are associated with CAPS development, are being investigated. To identify novel components of the NLRP3 inflammasome, we performed a high-throughput screen using a human protein array, with NLRP3 as the bait. We identified a NLRP3-binding protein, which we called the cryopyrin-associated nano enhancer (CANE). We demonstrated that CANE increased IL-1β secretion after NLRP3 inflammasome reconstitution in human embryonic kidney 293T cells and formed a “speck” in the cytosol, a hallmark of NLRP3 inflammasome activity. Reduced expression of endogenous CANE decreased IL-1β secretion upon stimulation with the NLRP3 agonist nigericin. To investigate the role of CANE in vivo, we developed CANE-transgenic mice. The PBMCs and bone marrow–derived macrophages of CANE-transgenic mice exhibited increased IL-1β secretion. Moreover, increased autoinflammatory neutrophil infiltration was observed in the s.c. tissue of CANE-transgenic versus wild-type mice; these phenotypes were consistent with those of CAPS model mice. These findings suggest that CANE, a component of the NLRP3 inflammasome, is a potential modulator of the inflammasome and a contributor to CAPS pathogenesis.

DOI： 10.4049/jimmunol.2300175

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Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms25094818

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Language：Japanese   Publisher：愛媛医学会  

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Language：Japanese   Publisher：医学図書出版(株)  

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Language：English   Publishing type：Research paper (scientific journal)  

Histologic evaluations revealed excessive accumulations of macrophages and absence of fibroblastic interstitial cells in explanted bioprosthetic valves. Comprehensive gene and protein expression analysis and histology unveiled an accumulation of fibrinogen and plasminogen, an activator of infiltrated macrophages, from degenerated valve surfaces in the interstitial spaces. These pathologies were completely reproduced in a goat model replaced with an autologous pericardium-derived aortic valve. Further preclinical animal experiments using goats demonstrated that preventing infiltration of macrophages and circulating proteins by increasing collagen density and leaflet strength is an effective treatment option.

DOI： 10.1016/j.jacbts.2023.01.003

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：English   Publishing type：Research paper (scientific journal)  

Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.

DOI： 10.3390/ijms24108955

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The role of surgery in primary central nervous system lymphoma (PCNSL) is to allow pathological diagnosis from tumor biopsy. However, PCNSL is often difficult to distinguish from other tumors, particularly glioblastoma multiforme (GBM). Quantitative evaluations to facilitate differentiation between PCNSL and GBM would be useful. Here, we investigated the best examinations for exact differentiation of PCNSL from GBM among preoperative examinations, including imaging studies and tumor markers. METHODS: Various examinations were performed for 68 patients with PCNSL , including serum soluble interleukin 2 receptor, β2-microglobulin (MG) in cerebrospinal fluid (CSF), diffusion-weighted imaging, 11C-methionine-positron emission tomography (PET), and 18F-fluorodeoxyglucose (FDG)-PET. These results were compared with findings from 28 patients with consecutive GBM who underwent the same examinations to evaluate the utility and accuracy of different investigations. RESULTS: CSF β2-MG ≥2.0 mg/L was relatively specific for PCNSL, offering 95.0% sensitivity and 85.7% specificity. Tumor-to-contralateral normal brain tissue ratio ≥2.4 on 18F-FDG-PET was also quite specific for PCNSL, offering 83.8% sensitivity and 95.2% specificity. No other examinations displayed any significant differences in quantitative differential markers between PCNSL and GBM. CONCLUSIONS: Both β2-MG ≥2.0 mg/dL in CSF and tumor-to-contralateral normal brain tissue ratio ≥2.4 from 18F-FDG-PET allow quantitative differentiation of PCNSL from GBM, potentially representing clinically useful indicators. These findings could lead to innovative methods for differentiating PCNSL from GBM as well as new treatment strategies for other brain tumors.

DOI： 10.1016/j.wneu.2023.01.065

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Language：English   Publishing type：Research paper (scientific journal)  

The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/caspase-1/interleukin(IL)-1β axis, also known as the inflammasome pathway, is indispensable for IL-1β activation in response to various pathogens or own damages. Previously, we developed an NLRP3-inflammasome using a cell-free system and identified ASC targeting drugs; thus, examination of ASC-related histopathology in various diseases could help to provide indications for these drugs. Here, we generated mice deficient only in ASC-protein (ASC-deficient (AD) mice) using CRISPR/Cas9 technology, studied which tissues were most affected, and obtained histopathological images of lipopolysaccharide (LPS)-induced endotoxemia. C57BL/6 wild-type (WT) and (AD) mice were injected intraperitoneally with a lethal dose (50 μg/g) of LPS. Statistical analysis of the survival of C57BL/6 mice and AD mice was performed using the Kaplan-Meier method and the log-rank test. The histopathological findings of multiple tissues from these mice were compared. Acute inflammation (e.g., catarrhal inflammation), along with congestion was observed in the colon of WT mice but not in that of AD mice. Adhesion of neutrophils to capillaries, along with interstitial infiltration, were observed in multiple tissues from WT mice. In AD mice, neutrophil infiltration was less severe but remained evident in the stomach, small intestine, heart, liver, kidney, spleen, and brain. Notably, there was no difference between WT and AD mice with respect to alveolar neutrophil infiltration and interstitial edema. These findings suggest that even though ASC contributes to systemic inflammation, it is dependent on the tissue involved. Intestinal congestion and edema might be good candidates for anti-ASC-targeted therapy.

DOI： 10.1371/journal.pone.0281746

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Language：English   Publishing type：Research paper (scientific journal)  

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Conversely, LOX-1 deficiency has been shown to decrease inflammation and atherosclerosis, both of which have been proposed to contribute to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. Here, we investigated the effects of Olr1 (which encodes LOX-1) deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. To accomplish this, we used serial, non-invasive ultrasound assessment, which revealed that the incidence and expansion rate of AAA were similar regardless of Olr1 deletion. However, Olr1 deletion significantly increased severe AAAs, including ruptured AAAs resulting in death. Oil Red O staining of the harvested aortas showed that the extent of atheroma burden localized in aneurysmal lesions did not differ between LOX-1-deficient and control mice, suggesting that Olr1 deletion did not decrease atheroma burden in the aneurysmal wall. Further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. An in vitro study confirmed that the proliferation of adventitial fibroblasts collected from LOX-1-deficient mice was significantly attenuated despite Ang II stimulation. In conclusion, Olr1 deletion may not mitigate aneurysm development but rather increases the vulnerability of rupture by suppressing adventitial fibroblast proliferation and collagen synthesis.

DOI： 10.1038/s41440-022-01093-x

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Language：Japanese   Publisher：(一社)西日本泌尿器科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: To evaluate the usefulness of synthetic magnetic resonance imaging (MRI) performed before the initiation of neoadjuvant chemotherapy (NAC) in predicting whether breast cancers can achieve a pathological complete response (pCR) after the completion of NAC. MATERIALS AND METHODS: This retrospective study investigated 37 consecutive patients with 39 breast cancers (pCR: 14, and non-pCR: 25) who underwent dynamic contrast-enhanced (DCE)-MRI and synthetic MRI before the initiation of NAC. Using synthetic MRI images, quantitative values (T1 and T2 relaxation times, proton density [PD] and their standard deviations [SD]) were obtained in breast lesions, before (Pre-T1, Pre-T2, Pre-PD, SD of Pre-T1, SD of Pre-T2, SD of Pre-PD) and after (Gd-T1, Gd-T2, Gd-PD, SD of Gd-T1, SD of Gd-T2, SD of Gd-PD) contrast agent injection. The aforementioned quantitative values and several morphological features that were identified on DCE-MRI were compared between pCR and non-pCR. RESULTS: Multivariate analyses revealed that the SD of Pre-T2 (p=0.038) was significant and was an independent predictor of pCR, with an area under the receiver operating characteristics curve of 0.829. The sensitivity, specificity, and accuracy of the SD of Pre-T2 with an optimal cut-off value of 11.5 were 71.4%, 80%, and 76.3%, respectively. CONCLUSIONS: The SD of Pre-T2 obtained from synthetic MRI was used successfully to predict those breast cancers that would achieve a pCR after the completion of NAC; however, these results are preliminary and need to be verified by further studies.

DOI： 10.1016/j.crad.2022.06.019

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publishing type：Research paper (scientific journal)  

In the treatment of primary central nervous system lymphoma (PCNSL), intraoperative rapid pathological diagnosis can dramatically change the surgical strategy, and more accurate diagnostic methods are required. In April 2020, we adopted intraoperative rapid immunohistochemistry (IHC) in addition to conventional rapid intraoperative diagnosis based on morphological assessment, mainly for patients with PCNSL. Here, we investigate the usefulness and significance of intraoperative rapid IHC based on our initial experience. We performed intraoperative rapid IHC using antibodies for cluster of differentiation (CD)20, CD3, leukocyte common antigen (LCA) and glial fibrillary acidic protein (GFAP) using enzyme-labeled antibody methods in 25 patients, including PCNSL patients, from April 2020 to July 2022. We examined the utility of this approach in determining treatment strategies for brain tumors. Postoperative final pathological diagnoses from paraffin-embedded sections were as follows: diffuse large B-cell lymphoma, 16 cases; glioblastoma, six cases; pilocytic astrocytoma, one case; adenocarcinoma, one case; and inflammatory disorder, one case. The entire process took 32 min and staining for CD20, CD3, LCA, and GFAP was comparable to that using paraffin-embedded sections. In all cases, the results of intraoperative rapid IHC were consistent with final pathological diagnoses from paraffin-embedded sections. In addition, in two cases, the results of conventional intraoperative rapid pathological diagnosis based on morphological assessments using frozen sections were drastically changed by adding intraoperative rapid IHC. Intraoperative rapid IHC contributes to deciding appropriate treatment strategies and facilitating early initiation of chemotherapy for PCNSL. This may allow new therapeutic strategies not only for PCNSL but also for other brain tumors.

DOI： 10.1111/neup.12864

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Language：Japanese   Publisher：医学図書出版(株)  

神経内分泌前立腺癌(NEPC)は、アンドロゲン非依存性増殖を示し急速に進行する予後不良な疾患である。NEPCの遺伝学的発生機序に関しては不明な点が多く、今後さらなる解析によりNEPCの病態解明や診断・治療マーカーの導出が期待される。今回われわれは欧米人前立腺癌患者の約50%と最も多い染色体異常であるTMPRSS2-ERG融合遺伝子に注目した。当院での神経内分泌分化前立腺癌症例における病理学的ERG発現を検索し、診断マーカーとしての可能性を検討した。(著者抄録)

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Language：Japanese   Publisher：医学図書出版(株)  

神経内分泌前立腺癌(NEPC)は、アンドロゲン非依存性増殖を示し急速に進行する予後不良な疾患である。NEPCの遺伝学的発生機序に関しては不明な点が多く、今後さらなる解析によりNEPCの病態解明や診断・治療マーカーの導出が期待される。今回われわれは欧米人前立腺癌患者の約50%と最も多い染色体異常であるTMPRSS2-ERG融合遺伝子に注目した。当院での神経内分泌分化前立腺癌症例における病理学的ERG発現を検索し、診断マーカーとしての可能性を検討した。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The incidence of brain metastasis of pancreatic cancer has been reported to be approximately 0.3%. The blood-brain barrier of the central nervous system restricts the transfer of substances, including chemotherapeutic agents, from the bloodstream. It is hypothesized that brain metastasis may occur despite successful chemotherapy for the primary tumor. Herein, we report a case of brain metastases of pancreatic cancer that occurred after chemotherapy and discuss relevant literature. CASE PRESENTATION: A 64-year-old man underwent distal pancreatectomy with D2 lymph node dissection for resectable pancreatic tail cancer. Invasive ductal carcinoma of pancreas, pT3N2M0 pStageIII (TNM Classification of Malignant Tumors, UICC 8th edition) was diagnosed. S-1 adjuvant chemotherapy was initiated. Three months postoperatively, CA19-9 had increased to 619 U/mL. Additionally, contrast-enhanced computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT revealed local recurrence in the para-aortic lymph nodes. Chemotherapy was revised to a combined regimen of gemcitabine and nab-paclitaxel. After 4 cycles, tumor markers were normalized. After 5 cycles, recurrence could not be identified on contrast-enhanced CT; therefore, the patient was adjudged to be in complete remission. However, after 29 cycles of chemotherapy, the patient had symptoms of raised intracranial pressure. Magnetic resonance imaging showed two metastatic lesions of 20 mm and 32 mm in the left frontal lobe and cerebellum, respectively. Quasi-emergency resection of the metastatic brain tumors was performed. Pathological examination revealed that the resected specimens originated from primary pancreatic cancer. The patient was discharged on postoperative day 12, without any complications. Postoperatively, a total of 53 Gy of local brain radiation therapy was added. On postoperative day 30, blood carcinoembryonic antigen level had decreased to 5.4 ng/dl and all other tumor markers were negative. Additionally, tumor markers of the cerebrospinal fluid were markedly reduced and the cytology was negative for tumor cells. These results suggested complete resection of the metastatic brain tumors. CONCLUSIONS: Aggressive resection and salvage stereotactic radiotherapy for metastatic brain tumors may lead to complete cure and a good long-term prognosis.

DOI： 10.1186/s40792-022-01461-2

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Language：Japanese   Publisher：愛媛医学会  

がんの発症や進展に関与する「がん関連遺伝子」を標的としたがんゲノム医療は、がん治療の大きな流れになろうとしている。本邦でも包括的がんゲノム遺伝子パネル(comprehensive cancer genomic profiling;comprehensive CGP)検査が、保険診療下で開始され2年余りが経過した。愛媛大学病院でも100例程度の症例を経験し、現在初期の総括が望まれる時期にある。本稿では、保険診療外で行われたCGP検査も含め、我々の経験を踏まえ今後の方向性を議論する。(著者抄録)

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：(NPO)日本医工学治療学会  

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Language：Japanese   Publisher：(NPO)日本医工学治療学会  

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Publishing type：Research paper (scientific journal)   Publisher：American Society of Clinical Oncology (ASCO)  

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Background: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. Methods: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected from patients with prostate cancer via robotic surgery in 2019 at Ehime University. In vitro, we prepared conditioned medium derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the conditioned medium. We assessed angiogenic activities by treating HUVECs with LNCaP-derived conditioned medium using a tube formation assay that mimics angiogenesis. Results: Immunohistochemical positivity of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in four of 33 prostate cancer patients (12.1%). We also found that the 10,000 ´ g pellet fraction of the LNCaP-derived conditioned medium containing PSMA-positive membranes, including microvesicles, transformed HUVECs from “PSMA-negative” to “PSMA-positive.” Mass spectrometry revealed that the fraction contained an important growth factor. Furthermore, treating HUVECs with the 10,000 ´ g pellet fraction of the LNCaP-derived conditioned medium significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. Conclusions: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which were found to enhance tumor angiogenesis in prostate cancer tissues. The endocytic process related to these PSMA-positive microvesicles in normal endothelial cells might be an attractive target to develop novel anti-angiogenic drugs, which could inhibit the transformation of normal endothelial cells into tumor endothelial cells (Watanabe et al., The Prostate. 2021. in press).

DOI： 10.1200/jco.2022.40.6_suppl.141

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Introduction

Dialysis-related amyloidosis (DRA) caused by β2-microgloblin (B2M) fibrils is a serious complication for patients with kidney failure on long-term dialysis. Deposition of B2M amyloid fibrils is thought to be due not only to serum extracellular B2M but also to infiltrating inflammatory cells, which may have an important role in B2M amyloid deposition in osteoarticular tissues in patients with DRA. Here, we asked whether B2M amyloid fibrils activate the inflammasome and contribute to formation and deposition of amyloid fibrils in cells.

Methods

Amyloid formation was confirmed by a thioflavin T (ThT) spectroscopic assay and scanning electron microscopy (SEM). Activation of inflammasomes was assessed by detecting interleukin (IL)-1β in culture supernatants from human embryonic kidney (HEK) 293T cells ectopically expressing inflammasome components. IL-1β secretion was measured by enzyme-linked immunosorbent assay. Expression and co-localization were analyzed by immunohistochemistry and dual immunofluorescence microscopy.

Results

B2M amyloid fibrils interacted directly with NLRP3/Pyrin and to activate the NLRP3/Pyrin inflammasomes, resulting in IL-1β secretion. When HEK293T cells were transfected with inflammasome components NLRP3 or Pyrin, along with ASC, pro-caspase-1, pro-IL-1β, and B2M, ThT fluorescence intensity increased. This was accompanied by IL-1β secretion, which increased in line with the amount of transfected B2M. In this case, morphological glowing of amyloid fibrils was observed by SEM. In the absence of ASC, there was no increase in ThT fluorescence intensity or IL-1β secretion, or any morphological glowing of amyloid fibrils. NLRP3 or Pyrin and B2M were co-localized in a “speck” in HEK293T cells, and co-expressed in infiltrated monocytes/macrophages in the osteoarticular synovial tissues in a patient with DRA.

Conclusion

Taken together, these data suggest that inflammasome assembly is required for the subsequent triggering of intracellular formation of B2M amyloid fibrils, which may contribute to osteoarticular deposition of B2M amyloid fibrils and inflammation in patients with DRA.

DOI： 10.1177/03946320221104554

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/03946320221104554

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>The long battle between humans and various physical, chemical, and biological insults that cause cell injury (e.g., products of tissue damage, metabolites, and/or infections) have led to the evolution of various adaptive responses. These responses are triggered by recognition of damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs), usually by cells of the innate immune system. DAMPs and PAMPs are recognized by pattern recognition receptors (PRRs) expressed by innate immune cells; this recognition triggers inflammation. Autoinflammatory diseases are strongly associated with dysregulation of PRR interactomes, which include inflammasomes, NF-κB-activating signalosomes, type I interferon-inducing signalosomes, and immuno-proteasome; disruptions of regulation of these interactomes leads to inflammasomopathies, relopathies, interferonopathies, and proteasome-associated autoinflammatory syndromes, respectively. In this review, we discuss the currently accepted molecular mechanisms underlying several autoinflammatory diseases.

DOI： 10.1186/s41232-021-00181-8

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Other Link： https://link.springer.com/article/10.1186/s41232-021-00181-8/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The characterization of aortic valve interstitial cells (VICs) cultured under optimal conditions is essential for understanding the molecular mechanisms underlying aortic valve stenosis. Here, we propose 2% hypoxia as an optimum VIC culture condition. Leaflets harvested from patients with aortic valve regurgitation were digested using collagenase and VICs were cultured under the 2% hypoxic condition. A significant increase in VIC growth was observed in 2% hypoxia (hypo-VICs), compared to normoxia (normo-VICs). RNA-sequencing revealed that downregulation of oxidative stress-marker genes (such as superoxide dismutase) and upregulation of cell cycle accelerators (such as cyclins) occurred in hypo-VICs. Accumulation of reactive oxygen species was observed in normo-VICs, indicating that low oxygen tension can avoid oxidative stress with cell-cycle arrest. Further mRNA quantifications revealed significant upregulation of several mesenchymal and hematopoietic progenitor markers, including CD34, in hypo-VICs. The stemness of hypo-VICs was confirmed using osteoblast differentiation assays, indicating that hypoxic culture is beneficial for maintaining growth and stemness, as well as for avoiding senescence via oxidative stress. The availability of hypoxic culture was also demonstrated in the molecular screening using proteomics. Therefore, hypoxic culture can be helpful for the identification of therapeutic targets and the evaluation of VIC molecular functions in vitro.

DOI： 10.3390/ijms221910534

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. METHODS: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium (CM) derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the CM. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived CM using a tube formation assay that mimics angiogenesis. RESULTS: Immunohistochemistry of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in 4 of 33 prostate cancer patients (12.1%). We also found that the 10,000g pellet fraction of the LNCaP-derived CM containing PSMA-positive membranes, such as microvesicles transformed HUVECs "PSMA-negative" into "PSMA-positive." Furthermore, treatment of HUVECs with the 10,000g pellet fraction of the LNCaP-derived CM significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. CONCLUSIONS: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues.

DOI： 10.1002/pros.24237

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

PURPOSE: This study aimed to compare the characteristics of triple-negative breast cancer (TNBC) with non-TNBC on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and synthetic MRI. METHOD: This retrospective study included 79 patients with histopathologically proven breast cancer (TNBC: 16, non-TNBC: 63) who underwent synthetic MRI. Using synthetic MR images, we obtained T1 and T2 relaxation times in breast lesions before (Pre-T1, Pre-T2, Pre-PD) and after (Gd-T1, Gd-T2, Gd-PD) contrast agent injection. Subsequently, we calculated the ΔT1 (Pre-T1 - Gd-T1), ΔT2 (Pre-T2 - Gd-T2), Pre-T1/T2, and Gd-T1/T2. We compared the aforementioned quantitative values, as well as several morphologic features between TNBCs and non-TNBCs that were identified on DCE-MRI. RESULTS: The multivariate analyses revealed that the Pre-T2 (P = 0.037) and the presence of rim enhancement (P-RIM) (P = 0.034) were significant and independent predictors of TNBC. The area under the receiver operating characteristics curve for all breast cancers was greater when a combination of Pre-T2 and P-RIM (Pre-T2＋P-RIM; Method 3, AUC (area under the curve) = 0.858) was used to distinguish between TNBCs and non-TNBCs versus the use of either Pre-T2 alone (Method 1, AUC = 0.786) or P-RIM alone (Method 2, AUC = 0.747). CONCLUSIONS: Pre-T2 obtained using synthetic MRI and P-RIM identified on DCE-MRI allowed the differentiation between TNBCs and non-TNBCs. However, these results are preliminary and need to be verified by further studies.

DOI： 10.1016/j.ejrad.2021.109838

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
We report a case of rupture of a synchronous metastatic liver tumor secondary to a thymoma. A 56-year-old woman was referred to our hospital with acute abdomen. Computed tomography (CT) revealed a 10 cm diameter tumor in the left lateral segment of the liver, together with ascites, which was suggestive of intra-abdominal bleeding. She was in stable condition and hemostasis was confirmed by angiography. CT also revealed a mass in the anterior mediastinum. Elective laparoscopic left lateral segmentectomy was performed to make a pathological diagnosis and for radical resection. No peritoneal dissemination was observed and the liver tumor was curatively resected. The patient subsequently underwent thymectomy. The pathological diagnoses were thymoma with the liver metastasis. Currently, at 30 months post-treatment, she has had no tumor recurrence. Rupture of a metastatic liver tumor secondary to a thymoma is a rare condition; careful preoperative management and aggressive treatment might improve the patient’s prognosis.

DOI： 10.1093/jscr/rjab341

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The progression of chronic kidney disease (CKD) depends on the extent of fibrosis in the kidneys; however, a renal biopsy is necessary to evaluate the severity of renal fibrosis. Real-time tissue elastography (RTE), which measures heartbeat-induced tissue displacement, can assess the elasticity of organs. Here, we aimed to investigate the correlation between renal elasticity and the extent of fibrosis in renal biopsy samples. METHODS: We investigated 29 consecutive patients who underwent a renal biopsy at Ehime University Hospital from February 2018 to August 2019. Renal fibrosis was categorized into three grades, mild (< 25%), moderate (25-50%), and severe (> 50%), based on the total affected area within the biopsy sample. The association between renal elasticity assessed by RTE and the grade of renal fibrosis was evaluated, and a receiver operating characteristic curve was used to distinguish the severity of renal fibrosis. RESULTS: The mean age and estimated glomerular filtration rate (eGFR) were 58.8 years and 55.2 mL/min/1.73 m2, respectively. The median urine protein-to-creatinine ratio was 1.24 g/gCr. The mean renal elasticity of mild, moderate, and severe renal fibrosis was 3.40, 3.98, and 4.77, respectively. Renal elasticity of native kidneys was significantly positively correlated with the grade of renal fibrosis (ρ = 0.529, P = 0.003). At the cutoff point of 3.81, the area under the curve, sensitivity, and specificity were 0.778, 68.4%, and 81.8%, respectively. CONCLUSION: Real-time tissue elastography is a promising, non-invasive method for assessing renal fibrosis in patients with CKD.

DOI： 10.1007/s10157-021-02063-2

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jccase.2020.11.005

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Language：English   Publishing type：Research paper (scientific journal)  

Cancer immunotherapy using T cells redirected with chimeric antigen receptor (CAR) has shown a lot of promise. We have established a single-chain antibody (scFv) generation system in which scFv library-expressing CAR-T cells can be screened appropriately based on their antitumor functions. A variable region library containing the variable and J regions of the human immunoglobulin light or heavy chain was fused with the variable region of a heavy or light chain encoded by an existing tumor-specific antibody to generate a new scFv library. Then, scFv library-expressing CAR-T cells were generated and stimulated with target cells to concentrate the antigen-specific population. Using this system, target-specific recognition of CAR-T cells appeared to be finely tuned by selecting a new variable region. Importantly, we have demonstrated that the newly optimized scFv-expressing CAR-T cells had better proliferation capacity and durable phenotypes, enabling superior reactivity against advanced tumors in vivo in comparison with the original CAR-T cells. Therefore, the optimization of an scFv is needed to maximize the in vivo antitumor functions of CAR-T cells. This system may allow us to adjust an immunological synapse formed by an scFv expressed by CAR-T cells and a target antigen, representing an ideal form of CAR-T-cell immunotherapy.

DOI： 10.1038/s42003-021-01791-1

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BACKGROUND: The addition of synthetic MRI might improve the diagnostic performance of dynamic contrast-enhanced MRI (DCE-MRI) in patients with breast cancer. PURPOSE: To evaluate the diagnostic value of a combination of DCE-MRI and quantitative evaluation using synthetic MRI for differentiation between benign and malignant breast masses. STUDY TYPE: Retrospective, observational. POPULATION: In all, 121 patients with 131 breast masses who underwent DCE-MRI with additional synthetic MRI were enrolled. FIELD STRENGTH/SEQUENCE: 3.0 Tesla, T1 -weighted DCE-MRI and synthetic MRI acquired by a multiple-dynamic, multiple-echo sequence. ASSESSMENT: All lesions were differentiated as benign or malignant using the following three diagnostic methods: DCE-MRI type based on the Breast Imaging-Reporting and Data System; synthetic MRI type using quantitative evaluation values calculated by synthetic MRI; and a combination of the DCE-MRI + Synthetic MRI types. The diagnostic performance of the three methods were compared. STATISTICAL TESTS: Univariate (Mann-Whitney U-test) and multivariate (binomial logistic regression) analyses were performed, followed by receiver-operating characteristic curve (AUC) analysis. RESULTS: Univariate and multivariate analyses showed that the mean T1 relaxation time in a breast mass obtained by synthetic MRI prior to injection of contrast agent (pre-T1 ) was the only significant quantitative value acquired by synthetic MRI that could independently differentiate between malignant and benign breast masses. The AUC for all enrolled breast masses assessed by DCE-MRI + Synthetic MRI type (0.83) was significantly greater than that for the DCE-MRI type (0.70, P < 0.05) or synthetic MRI type (0.73, P < 0.05). The AUC for category 4 masses assessed by the DCE-MRI + Synthetic MRI type was significantly greater than that for those assessed by the DCE-MRI type (0.74 vs. 0.50, P < 0.05). DATA CONCLUSION: A combination of synthetic MRI and DCE-MRI improves the accuracy of diagnosis of benign and malignant breast masses, especially category 4 masses. Level of Evidence 4 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:381-391.

DOI： 10.1002/jmri.27362

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10143-020-01258-7

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Other Link： http://link.springer.com/article/10.1007/s10143-020-01258-7/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1161/CIRCHEARTFAILURE.120.007571

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Objectives: The molecular mechanisms underlying post-operative pericardial adhesions remain poorly understood. We aimed to unveil the temporal molecular and cellular mechanisms underlying tissue dynamics during adhesion formation, including inflammation, angiogenesis, and fibrosis. Methods and Results: We visualized cell-based tissue dynamics during pericardial adhesion using histological evaluations. To determine the molecular mechanism, RNA-seq was performed. Chemical inhibitors were administered to confirm the molecular mechanism underlying adhesion formation. A high degree of adhesion formation was observed during the stages in which collagen production was promoted. Histological analyses showed that arterioles excessively sprouted from pericardial tissues after the accumulation of neutrophils on the heart surface in mice as well as humans. The combination of RNA-seq and histological analyses revealed that hyperproliferative endothelial and smooth muscle cells with dedifferentiation appeared in cytokine-exposed sprouting vessels and adhesion tissue but not in quiescent vessels in the heart. SMAD2/3 and ERK activation was observed in sprouting vessels. The simultaneous abrogation of PI3K/ERK or TGF-β/MMP9 signaling significantly decreased angiogenic sprouting, followed by inhibition of adhesion formation. Depleting MMP9-positive neutrophils shortened mice survival and decreased angiogenic sprouting and fibrosis in the adhesion. Our data suggest that TGF-β/matrix metalloproteinase-dependent tissue remodeling and PI3K/ERK signaling activation might contribute to unique angiogenesis with dedifferentiation of vascular smooth muscle cells from the contractile to the synthetic phenotype for fibrosis in the pericardial cavity. Conclusions: Our findings provide new insights in developing prevention strategies for pericardial adhesions by targeting the recruitment of vascular cells from heart tissues.

DOI： 10.3389/fcvm.2021.761591

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The management of systemic artery aneurysms secondary to Kawasaki disease (KD) in adults remains a therapeutic challenge. KD guidelines recommend the use of anticoagulation therapy with warfarin in addition to antiplatelet therapy when a giant coronary aneurysm or a history of thrombosis is documented. However, long-term use of warfarin presents several concerns. This case reports acute thrombotic occlusion due to the giant arterial aneurysm in an adult KD. A surgical resection of the aneurysm was performed because of recurrent thrombotic events, despite anticoagulant therapy with warfarin. Pathological examinations revealed a layered thrombus with inflammation in the aneurysm and Factor Xa expression mainly in newly formed thrombus. This study provides an insight into the anticoagulation therapy for cardiovascular sequelae after KD. <<b>Learning objective:</b> This study, along with pathological evidence, illustrates that Factor Xa might contribute to thrombotic events after Kawasaki disease.>.

DOI： 10.1016/j.jccase.2020.11.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

NLRP3, an intracellular pattern recognition receptor, recognizes numerous pathogens and/or its own damage-associated molecules, and forms complexes with the adaptor protein ASC. These complexes constitute the NLRP3 inflammasome, a platform for processing interleukin (IL)-1β and/or IL-18. Several NLRP3 mutations result in constitutive activation of the NLRP3 inflammasome, causing cryopyrin-associated periodic syndrome (CAPS). To the best of our knowledge, small compounds that specifically inhibit inflammasome activation through the pyrin domain (PYD) have not yet been developed. This study describes an attempt to develop small compounds targeting the NLRP3 inflammasome. A core chemical library of 9,600 chemicals was screened against reconstituted NLRP3 inflammasome in a cell-free system with an amplified luminescence proximity homogeneous assay and a cell-based assay by human peripheral blood mononuclear cells (PBMCs). Inflammasome activation was evaluated by ASC-speck formation in human PBMCs, accompanied by IL-1β secretion and processing, and by using IL-1β-based dual operating luciferase (IDOL) mice. The activity of these compounds was evaluated clinically using PBMCs from a patient with Muckle-Wells syndrome (MWS), a type of CAPS, with an R260W mutation in NLRP3. Screening identified KN3014, a piperidine-containing compound targeting the interaction between NLRP3 and ASC through the PYD. KN3014 reduced ASC-speck formation in human PBMCs, luminescence from IDOL mice, and auto-secretion of IL-1β by PBMCs from the patient with MWS. These findings suggest that KN3014 may be an attractive candidate for treatment of MWS, as well as other NLRP3 inflammasomopathies.

DOI： 10.1038/s41598-020-70513-0

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Other Link： http://www.nature.com/articles/s41598-020-70513-0

Language：Japanese   Publisher：(公社)日本小児科学会  

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BACKGROUND: The molecular mechanisms underlying aortic valve calcification are poorly understood. Here, we aimed to identify the master regulators of calcification by comparison of genes in valve interstitial cells (VICs) with calcified and noncalcified aortic valves. METHODS: Calcified aortic valves were surgically excised from patients with aortic valve stenosis who required aortic valve replacements. Noncalcified and calcified sections were obtained from aortic valve leaflets. Collagenase-digested tissues were seeded into dishes, and VICs adhering to the dishes were cultured for 3 weeks, followed by comprehensive gene expression analysis. Functional analyses of identified proteins were performed by in vitro calcification assays. Tissue localization was determined by immunohistochemical staining for normal (n = 11) and stenotic valves (n = 30). RESULTS: We found 87 genes showing greater than a twofold change in calcified tissues. Among these genes, 68 were downregulated and 19 were upregulated. Cyclooxygenase-1 (COX1) messenger RNA and protein levels were upregulated in VICs from calcified tissues. The COX1 messenger RNA and protein levels in VICs were also strongly increased by stimulation with osteoblast differentiation medium. These were VIC-specific phenotypes and were not observed in other cell types. Immunohistochemical staining revealed that COX1-positive VICs were specifically localized in the calcified area of aortic valve tissues. CONCLUSIONS: The VIC-specific COX1 overexpression played a crucial role in calcification by promoting osteoblast differentiation in aortic valve tissues.

DOI： 10.1016/j.athoracsur.2019.09.085

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger {AG}  

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.

DOI： 10.1159/000506044

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Postoperative pericardial adhesions are considered a risk factor for redo cardiac surgery. Several large- and medium-size animal models of pericardial adhesions have been reported, but small animal models for investigating the development of anti-adhesion materials and molecular mechanisms of this condition are lacking. In this study, we aimed to establish a simple mouse model of pericardial adhesions to address this gap. METHODS: We administered blood, minocycline, picibanil, and talc into the murine pericardial cavity via one-shot injection. Micro-computed tomography analyses of contrast agent-injected mice were carried out for methodological evaluation. We investigated various dosages and treatment durations for molecules identified to be inducers of pericardial adhesion. The adhesive grade was quantified by scoring the strength and volume of adhesion tissues at sacrificed time points. Histological staining with hematoxylin and eosin and Masson's trichrome, and immunostaining for F4/80 or αSMA was performed to investigate the structural features of pericardial adhesions, and pathological features of the pericardial adhesion tissue were compared with human clinical specimens. RESULTS: Administration of talc resulted in the most extensive pericardial adhesions. Micro-computed tomography imaging data confirmed that accurate injection into the pericardial cavity was achieved. We found the optimal condition for the formation of strong pericardial adhesions to be injection of 2.5 mg/g talc for 2 weeks. Furthermore, histological analysis showed that talc administration led to an invasion of myofibroblasts and macrophages in the pericardial cavity and epicardium, consistent with pathological findings in patients with left ventricular assistive devices. CONCLUSIONS: We successfully established a simple mouse model of talc-induced pericardial adhesions, which mimics human pathology and could contribute to solving the clinical issues related to pericardial adhesions.

DOI： 10.1186/s13019-019-0940-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.ijcard.2018.10.106

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Interleukin-1, an inflammatory cytokine, is considered to have diverse physiological functions and pathological significances and play an important role in health and disease. In this decade, interleukin-1 family members have been expanding and evidence is accumulating that highlights the importance of interleukin-1 in linking innate immunity with a broad spectrum of diseases beyond inflammatory diseases. In this review, we look back on the definition of "inflammation" in traditional general pathology and discuss new insights into interleukin-1 in view of its history and the molecular bases of diseases, as well as current progress in therapeutics.

DOI： 10.1186/s41232-019-0101-5

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Primary central nervous system lymphoma (PCNSL) has been immunohistochemically classified into two subtypes, germinal center (GC) B-cell and non-GC B-cell, but the prognostic impact of these subtypes remains debated. We investigated clinical features and prognostic significance of immunohistochemical subtypes that were identified by expression patterns of three B-cell differentiation markers in PCNSL. We also analyzed a factor related to responsiveness to high-dose methotrexate (HD-MTX) chemotherapy. Tumors from 32 PCNSL patients were immunohistochemically evaluated for expression of cluster of differentiation (CD) 10, B-cell lymphoma-6 (BCL-6), and multiple myeloma oncogene-1 (MUM-1) and classified into subtypes according to the expression patterns of these markers. Clinical features and prognostic outcome of these subtypes were investigated. Twenty-three patients were treated with HD-MTX-based chemotherapy followed by whole-brain radiation therapy (WBRT), and nine were treated with WBRT alone. Three immunohistochemical subtypes were identified, including A-type expressing CD10, BCL-6, and MUM-1 (12 patients), B-type expressing BCL-6 and MUM-1 (12 patients) and C-type expressing MUM-1 only (8 patients). Response rate in the HD-MTX therapy group was 57.1% (4/7) in A-type, 87.5% (7/8) in B-type, and 75% (6/8) in C-type. C-type with the lowest metabolic activity showed significantly longer overall survival than A-type with the higher uptake of methionine (71.6 versus 39.6 months) (P<0.05). Immunohistochemical identification of PCNSL based on the B-cell differentiation stage revealed three types of tumors, showing different metabolic activity and survival time. Refined immunohistochemical classification of PCNSL subtypes may become a useful tool for predicting more accurate prognosis and accessing sensitivity to HD-MTX therapy.

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Calcification of bioprosthetic valves (BVs) implanted in aortic position can result in gradual deterioration and necessitate aortic valve replacement. The molecular mechanism of calcium deposition on BV leaflets has been investigated, but remains to be fully elucidated. The present study aimed to identify explanted bioprosthetic valve (eBV)-specific proteins using a proteomics approach and to unveil their biochemical and histological involvements in calcium deposition on BV leaflets. Calcification, fibrosis, and glycosylation of the valves were histologically assessed using Von Kossa, Masson's Trichrome and Alcian Blue staining, as well as immunostaining. Protein expression in the explanted biological valves was analysed using proteomics and western blotting. In a histological evaluation, αSMA-positive myofibroblasts were not observed in eBV, whereas severe fibrosis occurred around calcified areas. SDS-PAGE revealed three major bands with considerably increased intensity in BV leaflets that were identified as plasminogen and fibrinogen gamma chain (100 kDa), and fibrinogen beta chain (50 and 37 kDa) by mass analysis. Immunohistochemistry showed that fibrinogen β-chain was distributed throughout the valve tissue. On the contrary, plasminogen was strongly stained in CD68-positive macrophages, as evidenced by immunofluorescence. The results suggest that two important blood coagulation-related proteins, plasminogen and fibrinogen, might affect the progression of BV degeneration.

DOI： 10.1242/bio.034009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Medulloepithelioma is a rare and highly malignant primitive neuroectodermal tumor that usually occurs in childhood. The diagnosis of this entity required only morphological analysis until the World Health Organization classification of central nervous system (CNS) tumors was revised, and now genetic analysis is necessary. We report a case of medulloepithelioma in the posterior cranial fossa that was diagnosed by both morphological and genetic analyses based on this classification. A 10-month-old girl was admitted to our hospital with consciousness disturbance and vomiting. Neuroimaging revealed a partially calcified mass and cyst formation in the posterior cranial fossa. Partial resection of the tumor was performed and histological findings revealed multilayered rosettes with LIN28A staining, but genetic analysis showed no amplification of the C19MC microRNA cluster at 19q14.32. Therefore, we diagnosed the tumor as medulloepithelioma belonging to other CNS embryonal tumors. The patient was immediately treated with systemic high-dose chemotherapy. Follow-up neuroimaging 10 months later showed no signs of recurrence. Medulloepitheliomas are difficult to diagnose by routine HE staining and require combined morphological, immunohistochemical and genetic analyses to provide an accurate diagnosis.

DOI： 10.1111/neup.12431

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

DOI： 10.1177/2058738418788749

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/2058738418788749

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

Introduction: Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare and treatable variant of cerebral amyloid angiopathy, lacks specific imaging and clinical features, and requires invasive brain biopsy to confirm the diagnosis. We report the case of a patient with nonconvulsive status epilepticus (NCSE) caused by CAA-ri in the right occipital lobe. Presentation of case: A 78-year-old man with a history of hypertension and rheumatoid arthritis was admitted to our hospital following an episode of seizures. CT scan showed a low-attenuating subcortical lesion in the right occipital lobe. MRI revealed the lesion as hypointense on T1-weighted imaging (WI) and hyperintense on T2-WI, showing no enhancement on T1-WI contrast-enhanced with gadolinium. In addition, T2*-weighted gradient-recalled echo (T2*-GRE) and susceptibility-weighted imaging (SWI) revealed extensive cortical microbleeds. Biopsy to determine the exact diagnosis revealed histological findings of reactive changes and perivascular inflammatory infiltration associated with amyloid deposition in vessel walls. These findings were consistent with CAA-ri. Corticosteroid therapy with dexamethasone was initiated for a short period as a diagnostic and therapeutic maneuver, resulting in marked reductions in the lesion. Discussion: CAA is generally associated with intracerebral hemorrhage, dementia, and small cerebral infarctions in the elderly population, but in a small proportion of cases is related to inflammatory responses to vascular deposits of Aβ as so-called CAA-ri. Conclusion: CAA-ri should be considered among the differential diagnoses for causes of unprovoked seizure onset in elderly individuals, when associated with petechial hemorrhages on T2*-GRE and SWI sequences on MRI.

DOI： 10.1016/j.ijscr.2018.05.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：{SAGE} Publications  

<jats:p> Recent findings revealed that type 2 diabetes mellitus (T2D) is a chronic inflammatory disease and an islet amyloid polypeptide (IAPP)/amylin, is deposited within pancreatic islets. IAPP/amylin has been reported to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been shown to recognize pathogens and/or metabolites and complexes with the adopter protein apoptosis-associated speck-like protein containing a caspase-recruitment domain ASC to form a huge complex, called an inflammasome, an interleukin (IL)-1β-processing platform. Although reactive oxygen species (ROS) were reported to be involved in activation of NLRP3 inflammasome, we were hypothesized that IAPP could directly activate NLRP3 inflammasome, leading to islets β-cell death. We analyzed expression of the inflammasome components ASC, NLRP3, caspase-1, IL-1β, IAPP/amylin, and insulin immunohistochemically in Langerhans’ islets of autopsy cases. The initial event of NLRP3 inflammasome activation was assessed using a cell-free system consisting of NLRP3 and ASC with the amplified luminescent proximity homogeneous assay. IAPP/amylin deposition in Langerhans’ islets was detected and significantly correlated with expressions of IL-1β and ASC. IAPP/amylin directly interacted with NLRP3 and initiated an interaction between NLRP3 and ASC in a cell-free system. The deposition of IAPP/amylin in β-cells of Langerhans’ islets may act together with the expression level of an inflammasome component, ASC, to regulate IL-1β processing, and directly lead to the dysfunction of β-cells. The interaction between IAPP/amylin and NLRP3 could be an attractive drug target to avoid both inflammation and β-cell death for T2D therapy. </jats:p>

DOI： 10.1177/2058738418788749

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Background: Alzheimer's disease is a neurodegenerative disease characterized by the interstitial deposition of amyloid β (Aβ) plaque, which is thought to be related to chronic neuroinflammation. Aβ is known to make fibrils via oligomers from monomers. Aβ has been reported to activate the NLRP3 inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been reported to recognize numerous pathogens and/or metabolites and form complexes with adopter protein ASC to make the inflammasome, an interleukin (IL)-1β-processing platform. Although reactive oxygen species from mitochondria have been reported to be involved in the activation of the NLRP3 inflammasome in microglial cells upon the deposition of Aβ, whether Aβ directly or indirectly activates the NLRP3 inflammasome remains unclear. Methods: We prepared monomers, oligomers, and fibrils of Aβ, which promoted the interaction between NLRP3 and each form of Aβ and analyzed the interaction between NLRP3 and ASC induced by each form of Aβ in a cell-free system with the amplified luminescent proximity homogeneous assay. We also confirmed the physiological relevance in a cell-based assay using human embryonic kidney 293T cells and human peripheral mononuclear cells. Results: Monomers, oligomers, and fibrils of Aβ were successfully prepared. Aβ oligomers and fibrils interacted with NLRP3. Aβ oligomers and fibrils induced the interaction between NLRP3 and ASC. However, Aβ monomers did not interact with NLRP3 or induce interaction between NLRP3 and ASC in the cell-free system, and IL-1β was not secreted according to the cell-based assay. Conclusion: Oligomerized Aβ originating from non-toxic Aβ monomers directly interacted with NLRP3, leading to the activation of the NLRP3 inflammasome. This may be an attractive target for the treatment of Alzheimer's disease.

DOI： 10.1186/s41232-018-0085-6

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Language：Japanese   Publisher：生命科学系学会合同年次大会運営事務局  

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Language：Japanese   Publisher：生命科学系学会合同年次大会運営事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Perivascular adipose tissue exhibits characteristics of active local inflammation, which contributes to the development of atherosclerotic disease as a complication of obesity/metabolic syndrome. However, the precise role of perivascular adipose tissue in the progression of abdominal aortic aneurysm remains unclear. To test the hypothesis that genetic deletion of angiotensin II type 1a (AT(1a)) receptor in perivascular visceral adipose tissue (VAT) can attenuate aortic aneurysm formation in apolipoprotein E-deficient (ApoE(-/-)) mice, we performed adipose tissue transplantation experiments by using an angiotensin II-induced aneurysm murine model, in which we transplanted VAT from ApoE(-/-) or ApoE(-/-) AT(1a)(-/-) donor mice onto the abdominal aorta of ApoE(-/-) recipient mice. Compared with ApoE-/VAT transplantation, ApoE(-/-)AT(1a)(-/-) VAT transplantation markedly attenuated aortic aneurysm formation, macrophage infiltration, and gelatinolytic activity in the abdominal aorta. AT(1a) receptor activation led to the polarization of macrophages in perivascular VAT toward the proinflammatory phenotype. Moreover, osteopontin expression and gelatinolytic activity were considerably lower in ApoE(-/-)AT(1a)(-/-) perivascular VAT than in ApoE(-/-) perivascular VAT, and angiotensin II-induced osteopontin secretion from adipocytes was eliminated after deletion of AT(1a) receptor in adipocytes. Notably, induction of macrophage migration by conditioned medium from angiotensin II-stimulated wild-type adipocytes was suppressed by treatment with an osteopontin-neutralizing antibody, and ApoE(-/-) OPN-/- VAT transplantation more potently attenuated aortic aneurysm formation than ApoE(-/-) VAT transplantation. Our findings indicate a previously unrecognized effect of AT(1a) receptor in perivascular VAT on the pathogenesis of abdominal aortic aneurysm.

DOI： 10.1161/HYPERTENSIONAHA.117.09512

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background
DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS.
Aim
The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a 'fast-food' diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology.
Methods
Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed.
Results
Late lumen loss was high (similar to 60%) within the first 3M after BVS-implantation (P&lt;0.01 FF-DM vs. FF-NDM) and stabilized between 3M and 6M (&lt;5% change in FF-DM, similar to 10% in FF-NDM; P&gt;0.20). Neointimal coverage was highly heterogeneous in all swine ( DM vs. NDM P&gt;0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (similar to 2% at 3M, similar to 5% at 6M; P&gt;0.20) and not associated with DM or inflammation.
Conclusion
Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes.

DOI： 10.1371/journal.pone.0183419

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

In the NLR family, pyrin domain containing 3 (NLRP3) is an intracellular pattern recognition receptor that activates pro-caspase-1, leading to IL-1β and IL-18 processing and activation in a large complex called the NLRP3 inflammasome. Since various pathogens or endogenous metabolites have been reported to stimulate NLRP3 inflammasome, the interaction between NLRP3 and ASC induced by these stimulants may be an attractive drug target for NLRP3-related diseases, called inflammasomopathies. However, the endogenous ligand that directly interacts with NLRP3, leading to binding to ASC, remains unclear. Therefore, we developed a cell-free system consisting of NLRP3, ASC, and pro-caspase-1 or ASC and NLRP3 with an amplified luminescent proximity homogeneous assay (ALPHA). ALPHA signals of the interaction between NLRP3 and ASC were not enhanced following an incubation without any ligand, whereas strong ALPHA signals for the interaction between NLRP3 and ASC and between NLRP3 and pro-caspase-1 with the adaptor ASC were observed upon an incubation with poly (I:C) and hyaluronic acid (HA). Poly (I:C) and HA both directly interacted with NLRP3 within a specific concentration. These results suggest that NLRP3 directly interacts with intrinsic RNA and HA, which is followed by the activation of NLRP3 inflammasome, and the cell-free system consisting of NLRP3 and ASC, or NLRP3, ASC, and pro-caspase-1 may be a useful tool for elucidating the pathogenesis of inflammasomopathies and developing target therapeutics.

DOI： 10.1177/1721727X17711047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Background. Lung injury is a life-threatening complication in patients with liver dysfunction. We recently provided an experimental lung injury model in mouse with common bile duct ligation. In this study, we aimed to characterize the pathologic and biochemical features of lung tissues in common bile duct ligation mice using a proteomic approach.
Methods. Common bile ducts of BALB/c mice, 8 weeks of age, were ligated operatively. CD31-expressing pulmonary cells were sorted with immunomagnetic microbeads, and protein profiles were examined by 2 dimensional gel electrophoresis. Based on the results of protein identification, immunohistochemistry and quantitative reverse transcription polymerase chain reaction were carried out in pulmonary and hepatic tissues.
Results. Two-dimensional gel electrophoresis revealed 3 major inflammation-associated proteins exhibiting considerable increases in the number of CD31-positive pulmonary cells after common bile duct ligation. Mass spectrometry analysis identified these proteins as SerpinB 1 a (48 kDa), ANXA1 (46 kDa), and S100A9 (16 kDa). Furthermore, the 3 proteins were more highly expressed in dilated pulmonary blood vessels of common bile duct ligation mice, in which neutrophils and monocytes were prominent, as shown by immunohistochemistry. More importantly, SerpinB la mRNA and protein were significantly upregulated in the liver, whereas S100A9 and ANXA1 mRNA and protein were upregulated in the lungs, as shown by quantitative reverse transcription polymerase chain reaction and Western blotting.
Conclusion. We identified 3 proteins that were highly expressed in the lung after common bile duct ligation using a proteomics-based approach.

DOI： 10.1016/j.surg.2016.12.017

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Language：Japanese   Publisher：(NPO)日本呼吸器外科学会  

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A 58-year-old man was diagnosed with advanced hepatocellular carcinoma with portal vein tumor thrombosis (PVTT). The tumors were multiple and existed in both lobes. Drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) was performed for the tumors in the left lobe. Embosphere and Hepasphere were selected for embolization of the arterioportal shunt, followed by loaded epirubicin infusion into the left hepatic artery. Computed tomography showed reduction of PVTT. However, liver failure progressed, and the patient died 67 days after DEB-TACE. Autopsy showed that the beads reached the tumor thrombosis in the portal vein. The prognosis of hepatocellular carcinoma with PVTT is poor. Although there are no established treatments for unresectable PVTT, DEB-TACE might be a useful option for such cases.

DOI： 10.1016/j.radcr.2016.11.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We investigated whether thrombin-cleaved osteopontin N-terminal is useful as a blood biomarker of acute atherothrombotic ischemic stroke. Acute ischemic stroke patients were prospectively evaluated with brain magnetic resonance imaging and cardiac evaluations for etiological diagnosis according to the Trial of Org 10172 in Acute Stroke Treatment classification. They were divided into the atherothrombotic and non-atherothrombotic groups. Thrombin-cleaved osteopontin N-terminal, osteopontin, matrix metalloproteinase-9, S100B, C-reactive protein and D-dimer levels were measured from blood samples collected at admission. After excluding patients who met the exclusion criteria or had stroke of other/undetermined etiology, 60 of the 100 patients initially enrolled were included in the final analysis. The ischemic stroke subtypes were atherothrombotic (n=28, 46.7%), cardioembolic (n=19, 31.7%) and lacunar (n=13, 21.7%). Thrombin-cleaved osteopontin N-terminal and matrix metalloproteinase-9 levels were significantly higher in the atherothrombotic than in the non-atherothrombotic group (median (interquartile range): 5.83 (0.0-8.6) vs. 0.0 (0.0-3.3) pmol l(-1), P=0.03 and 544 (322-749) vs. 343 (254-485) ng ml(-)1, P=0.01, respectively). After adjustment for the prevalence of hypertension, diabetes and dyslipidemia, thrombin-cleaved osteopontin N-terminal levels of 45.47 p mol l(-1) (odds ratio, 16.81; 95% confidence interval, 3.53-80.10) and matrix metalloproteinase-9 levels of 4605.5 ng m l(-1) (6.59; 1.77-24.60) were identified as independent predictors of atherothrombosis. Within 3 h from stroke onset, only thrombin-cleaved osteopontin N-terminal independently predicted atherothrombosis and thus may add valuable, time-sensitive diagnostic information in the early evaluation of ischemic stroke, especially the atherothrombotic subtype.

DOI： 10.1038/hr.2016.110

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The inflammasome, typically consisting of a Nod-like receptor, apoptosis-associated speck-like protein, and pro-caspase-1, has recently been identified as a huge intracellular complex, which plays a crucial role in interleukin-1 maturation or specific physiological functions. Two Nod-like receptors, such as nucleotide-binding oligomerization domains-containing protein (Nod)1 and Nod2, interact with the receptor-interacting protein serine-threonine kinase (RIPK)2 accompanied by Iκ-B kinase (IKK) complexes to construct the nodosome, leading to nuclear factor (NF)-κB activation. The aberrant activation of inflammasomes or nodosomes causes autoinflammatory diseases. Therefore, inflammasomes may be attractive targets to treat autoinflammatory diseases. Our aim is to develop reconstituted inflammasomes in a cell-free system to discover specific molecular-target drugs and elucidate the molecular pathogenesis of autoinflammatory diseases. In this review, we describe reconstituted inflammasomes in a cell-free system.

DOI： 10.1186/s41232-017-0040-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE(-/-)) and ApoE/OPN knockout (ApoE(-/-)/OPN-/-) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE(-/-)HD mice, however, significantly suppressed in ApoE(-/-)/OPN-/-HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE(-/-)/OPN-/-HD mice than ApoE(-/-)HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia.

DOI： 10.1038/srep28882

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Nucleotide-binding oligomerization domain-containing protein (Nod) 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP), a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2). Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS)/early-onset sarcoidosis (EOS). For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system. FLAG-tagged RICK, biotinylated-Nod2, and BS/EOS-associated Nod2 mutants were synthesized, and proximity signals between FLAG-tagged and biotinylated proteins were detected by amplified luminescent proximity homogeneous assay (ALPHA). Upon incubation with MDP, the ALPHA signal of interaction between Nod2-WT and RICK was increased in a dose-dependent manner. The ALPHA signal of interaction between RICK and the BS/EOS-associated Nod2 mutants was more significantly increased than Nod2-WT. Notably, the ALPHA signal between Nod2-WT and RICK was increased upon incubation with MDP, but not when incubated with the same concentrations, L-alanine, D-isoglutamic acid, or the MDP-D-isoform. Thus, we successfully developed Nod2-nodosome in a cell-free system reflecting its function in vivo, and it can be useful for screening Nod2-nodosome-targeted therapeutic molecules for BS/EOS and granulomatous inflammatory diseases.

DOI： 10.1155/2016/2597376

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Absent in melanoma 2 (AIM2) is an intracellular pattern-recognition receptor, which is a member of the PYHIN protein family, consisting of a PYD domain and an IFN-inducible nuclear localization CHIN) domain. AIM2 is reported to oligomerize with adaptor protein ASC upon sensing bacterial and viral cytosolic DNA in order to form the AIM2 inflammasome, which activates caspase-1 leading to IL-1 beta secretion. Dysregulation of AIM2 inflammasome is supposed to result in autoinflammatory and autoimmune diseases. Thus, the development of new targeted drugs against AIM2 inflammasome would be important for the treatment of these diseases. However, since AIM2 inflammasome is an intracellular receptor, enforced internalization of both ligands and candidate molecules is necessary for the screening of AIM2-inflammasome-targeted molecules. We developed a reconstituted AIM2 inflammasome in a cell-free system with amplified luminescent proximity homogeneous assay (Alpha). Strong Alpha signal was detected upon incubation with poly-deoxyadenylic-deoxythymidylic acid, poly(dA:dT), whereas no Alpha signal was detected upon incubation with muramyl dipeptide, one of the NLR ligands of Nod2 ligand. The interaction between AIM2 and ASC was disrupted by an anti-human ASC monoclonal antibody, CRID3, a class of diarylsulfonylurea-containing compounds, and glycyrrhizin, a substance found in liquorice root. Thus, the reconstituted AIM2 inflammasome in a cell-free system is useful for screening AIM2-inflammasome-targeted therapeutic molecules. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jim.2015.08.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background-As bioresorbable vascular scaffolds (BVSs) are being increasingly used in complex real-world lesions and populations, BVS thrombosis cases have been reported. We present angiographic and optical coherence tomography (OCT) findings in a series of patients treated in our center for definite bioresorbable scaffold thrombosis.
Methods and Results-Up to June 2014, 14 patients presented with definite BVS thrombosis in our center. OCT was performed in 9 patients at the operator's discretion. Angiographic and OCT findings were compared with a control group comprising 15 patients with definite metallic stent thrombosis. In the BVS group, time interval from index procedure to scaffold thrombosis ranged from 0 to 675 days. Incomplete lesion coverage by angiography was identified in 4 of 14 cases, malapposition by OCT in 5 of 9 cases, strut discontinuity in 2 of 9 cases, and underexpansion in 2 of 9 cases. Five patients had discontinued dual antiplatelet therapy, and in 3 of them discontinued dual antiplatelet therapy discontinuation had occurred the week preceding the event. There were no significant differences in angiographic or OCT findings between BVS and metallic stent thrombosis.
Conclusions-Suboptimal implantation with incomplete lesion coverage, underexpansion, and malapposition comprises the main pathomechanism for both early and late BVS thrombosis, similar to metallic stent thrombosis. Dual antiplatelet therapy discontinuation seems to also be a secondary contributor in several late events. Our observations suggest that several potential triggers for BVS thrombosis could be avoided.

DOI： 10.1161/CIRCINTERVENTIONS.114.002369

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Background: Microvessels in atheromatous plaques are well known to play a role in plaque vulnerability associated with intraplaque hemorrhage, but their architecture remains unclear. The morphometry of the microvasculature and hemorrhage of human carotid atheromatous plaques (CAPs) were evaluated, and 3-dimensional (3D) reconstruction of the microvessels was performed. Methods: CAPs were obtained by endarterectomy in 42 patients. The specimens were analyzed using light microscopy. Plaque hemorrhage was defined as an area-containing red blood cells (&gt;1 mm(2)). To determine the histopathologic features of plaque hemorrhage, the plaque area was divided into 4 regions: cap, shoulder, lipid/ necrotic core, and media. Then, the density of microvessels and macrophages in each region was quantified. Two representative lesions with either hemorrhagic or nonhemorrhagic plaque were cut into 90 serial sections. The sections were double stained with anti-CD34 and anti-alpha smooth muscle actin antibodies, scanned using a digital microscope, and reconstructed using TRI-SRF2 software. Results: The hemorrhagic plaques showed a higher density of microvessels than nonhemorrhagic plaques in the shoulder, cap, and lipid/ necrotic core (P = .03,.009, and .001, respectively), and there was positive correlations between its density and macrophages in each regions (P &lt;.001,.001, and .019, respectively). 3D imaging also revealed dense microvessels with a network structure in the cap and shoulder regions of hemorrhagic plaques, and some of the vessels were fenestrated to the arterial lumen. Conclusions: The microvasculature of plaques with intraplaque hemorrhage was dense, some of which fenestrated to the arterial lumen. The pathologic 3D imaging revealed precise architecture of microvasculature of plaques. (C) 2014 by National Stroke Association

DOI： 10.1016/j.jstrokecerebrovasdis.2013.12.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background: Liver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. Establishment of a mouse model of hepatopulmonary syndrome (HPS) would provide greater insights into the genetic basis of the disease. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches.
Methods: Eight-week-old Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers was detected by western blot and microarray analyses.
Results: We observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells at 2 weeks after CBDL and identified 10 upregulated and 9 down-regulated proteins that were associated with angiogenesis. TNF-a and MMP-9 were highly expressed at 3 weeks after CBDL and were less expressed in the lungs of the control group.
Conclusions: We constructed a mouse lung injury model by using CBDL. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase. Thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome.

DOI： 10.1371/journal.pone.0094550

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

In this study, a highly sensitive capillary-based enzyme-linked immunosorbent assay (ELISA) has been developed for the analysis of picomolar levels of thrombin-cleaved osteopontin (trOPN), a potential biomarker for ischemic stroke, in human plasma. Using a square capillary coated with 8.5 mu g/ml anti-human trOPN capture antibody for ELISA, the linear range obtained was 2 to 16 pM trOPN antigen. This concentration range was in the detection window of trOPN antigen in plasma samples. Compared with the conventional microplate-based ELISA, the current capillary technique significantly reduced the amounts of reagent from milliliter to microliter, reduced the analysis time from 8 to 3 h, and had a better sensitivity and detection limit performance from approximately 50 pM down to 2 pM of trOPN antigen. These results indicate that this capillary-based immunoassay is a potential tool for biomarker detection and may be useful in clinical trials and medical diagnostic applications. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ab.2013.05.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Diabetes induces advanced glycation end products (AGEs) that per se are not only a major cause of oxidative stress but also reduce the plasticity of connective tissue by pathological collagen cross-linking. We describe a case of severe pulmonary hypertension manifesting as a major diabetic complication. Impaired pulmonary arteriolar plasticity attributed to pentosidine, together with increased circulation volume by hyperosmotic pressure and reduction in myocardial compliance by multiple patchy fibrosis, may contribute to the clinical manifestation of severe pulmonary hypertension. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2013.01.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Background-Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are a promising source of cells for regenerating myocardium. However, several issues, especially the large-scale preparation of hiPS-CMs and elimination of undifferentiated iPS cells, must be resolved before hiPS cells can be used clinically. The cell-sheet technique is one of the useful methods for transplanting large numbers of cells. We hypothesized that hiPS-CM-sheet transplantation would be feasible, safe, and therapeutically effective for the treatment of ischemic cardiomyopathy. Methods and Results-Human iPS cells were established by infecting human dermal fibroblasts with a retrovirus carrying Oct3/4, Sox2, Klf4, and c-Myc. Cardiomyogenic differentiation was induced by WNT signaling molecules, yielding hiPS-CMs that were almost 90% positive for α-actinin, Nkx2.5, and cardiac troponin T. hiPS-CM sheets were created using thermoresponsive dishes and transplanted over the myocardial infarcts in a porcine model of ischemic cardiomyopathy induced by ameroid constriction of the left anterior descending coronary artery (n=6 for the iPS group receiving sheet transplantation and the sham-operated group
both groups received tacrolimus daily). Transplantation significantly improved cardiac performance and attenuated left ventricular remodeling. hiPS-CMs were detectable 8 weeks after transplantation, but very few survived long term. No teratoma formation was observed in animals that received hiPS-CM sheets. Conclusions-The culture system used yields a large number of highly pure hiPS-CMs, and hiPS-CM sheets could improve cardiac function after ischemic cardiomyopathy. This newly developed culture system and the hiPS-CM sheets may provide a basis for the clinical use of hiPS cells in cardiac regeneration therapy. © 2012 American Heart Association, Inc.

DOI： 10.1161/circulationaha.111.084343

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger {AG}  

DOI： 10.1159/000337330

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Atherothrombosis is the primary pathophysiology that underlies ischemic cerebral infarction. Osteopontin (OPN) is produced in atherosclerotic lesions and is cleaved by activated thrombin. We hypothesized that the rupture or damage of an unstable atherosclerotic plaque increases plasma levels of thrombin-cleaved OPN (trOPN). This study included 90 patients who received carotid angioplasty with stenting (CAS), 23 patients with essential hypertension (EHT) and 10 patients who were treated with carotid endarterectomy (CEA). The CAS patient group included 36 patients that had pre- and post-operative blood tests, diffusion-weighted imaging (DWI) using cerebral MRIs and estimated thrombus debris within the protection device. Immunohistochemistry of CEA specimens revealed that trOPN was detected around intra-plaque vessels. The highest tertile of plasma trOPN levels in CAS patients was higher than trOPN levels in EHT patients. Post-operative trOPN levels were significantly higher in symptomatic compared with asymptomatic patients (P=0.003). New ipsilateral DWI-positive patients revealed higher post-operative trOPN levels (P-0.003) and a higher grade of thrombi (P&lt;0.001) than DWI-negative patients. TrOPN may be a novel biomarker that reflects the atherothrombotic status in ischemic stroke. Hypertension Research (2012) 35, 207-212; doi:10.1038/hr.2011.177; published online 24 November 2011

DOI： 10.1038/hr.2011.177

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

Atherothrombosis is the primary pathophysiology that underlies ischemic cerebral infarction. Osteopontin (OPN) is produced in atherosclerotic lesions and is cleaved by activated thrombin. We hypothesized that the rupture or damage of an unstable atherosclerotic plaque increases plasma levels of thrombin-cleaved OPN (trOPN). Thisstudy included 90 patients who received carotid angioplasty with stenting (CAS), 23 patients with essential hypertension (EHT) and 10 patients who were treated with carotid endarterectomy (CEA). The CAS patient group included 36 patients that had pre- and post-operative blood tests, diffusion-weighted imaging (DWI) using cerebral MRIs and estimated thrombus debris within the protection device. Immunohistochemistry of CEA specimens revealed that trOPN was detected around intra-plaque vessels. The highest tertile of plasma trOPN levels in CAS patients was higher than trOPN levels in EHT patients. Post-operative trOPN levels were significantly higher in symptomatic compared with asymptomatic patients (P=0.003). New ipsilateral DWI-positive patients revealed higher post-operative trOPN levels (P=0.003) and a higher grade of thrombi (P&lt;0.001) than DWI-negative pa

DOI： 10.1038/hr.2011.177

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Irita J, Okura T, Jotoku M, Nagao T, Enomoto D, Kurata M, Desilva VR, Miyoshi K, Matsui Y, Uede T, Denhardt DT, Rittiling SR, Higaki J. Osteopontin deficiency protects against aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney. Am J Physiol Renal Physiol 301: F833-F844, 2011. First published July 6, 2011; doi:10.1152/ajprenal.00557.2010.-Osteopontin (OPN) has been implicated in the pathology of several renal conditions. Recently, we demonstrated in vitro that aldosterone has important roles in collagen synthesis by inducing OPN (Irita J, Okura T, Kurata M, Miyoshi K, Fukuoka T, Higaki J. Hypertension 51: 507-513, 2008). The aim of the present study was to clarify the roles of OPN in aldosterone-mediated renal fibrosis by infusing aldosterone into either wild-type (WT) or OPN knockout mice (OPN(-/-)). We used uninephrectomized mice treated with aldosterone and high salt to exacerbate renal fibrosis. After 4 wk of treatment with aldosterone, we showed similar increases in systolic blood pressure in both strains of mice. Urine albumin excretion was greater in aldosterone-infused WT mice than in aldosterone-infused OPN(-/-) mice. Immunohistochemical analysis showed high levels of OPN expression in aldosterone-infused WT mice. Interstitial fibrosis and inflammatory infiltrations were increased in aldosterone-infused WT mice compared with either vehicle-infused WT or aldosterone-infused OPN(-/-) mice. These changes were ameliorated markedly by eplerenone treatment in aldosterone-infused WT mice. Aldosterone-infused WT mice also had increased expression of NADPH oxidase subunits compared with aldosterone-infused OPN(-/-) mice. We observed a marked increase in oxidative stress markers in aldosterone-infused WT mice compared with aldosterone-infused OPN(-/-) mice. These results indicate that OPN is a promoter of aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney and suggest that inhibition of OPN may be a potential therapeutic target for prevention of renal injury.

DOI： 10.1152/ajprenal.00557.2010

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Osteopontin (OPN) has been implicated in the pathology of several renal conditions. Recently, we demonstrated in vitro that aldosterone has important roles in collagen synthesis by inducing OPN (Irita J, Okura T, Kurata M, Miyoshi K, Fukuoka T, Higaki J. Hypertension 51: 507-513, 2008). The aim of the present study was to clarify the roles of OPN in aldosterone-mediated renal fibrosis by infusing aldosterone into either wild-type (WT) or OPN knockout mice (OPN-/-). We used uninephrectomized mice treated with aldosterone and high salt to exacerbate renal fibrosis. After 4 wk of treatment with aldosterone, we showed similar increases in systolic blood pressure in both strains of mice. Urine albumin excretion was greater in aldosterone-infused WT mice than in aldosterone-infused OPN-/- mice. Immunohistochemical analysis showed high levels of OPN expression in aldosteroneinfused WT mice. Interstitial fibrosis and inflammatory infiltrations were increased in aldosterone-infused WT mice compared with either vehicle-infused WT or aldosterone-infused OPN-/- mice. These changes were ameliorated markedly by eplerenone treatment in aldosterone- infused WT mice. Aldosterone-infused WT mice also had increased expression of NADPH oxidase subunits compared with aldosterone-infused OPN-/- mice. We observed a marked increase in oxidative stress markers in aldosterone-infused WT mice compared with aldosterone-infused OPN-/- mice. These results indicate that OPN is a promoter of aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney and suggest that inhibition of OPN may be a potential therapeutic target for prevention of renal injury. © 2011 the American Physiological Society.

DOI： 10.1152/ajprenal.00557.2010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Osteopontin (OPN) has recently emerged as a key factor in both vascular remodelling and development of atherosclerosis. It has been reported that OPN is regulated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to clarify the effect of angiotensin II receptor blockade with valsartan on plasma OPN levels in patients with essential hypertension (EHT). Forty-six patients (mean age, 64 +/- 11 years) with EHT were randomly assigned to treatment with amlodipine or valsartan. There were no significant differences in baseline clinical characteristics between the two groups. Blood sampling and blood pressure evaluation were performed before and after 24 weeks of treatment. After 24 weeks, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were decreased significantly and by the same degree in each treatment group. However, valsartan but not amlodipine decreased plasma OPN levels (baseline and 24-week data-valsartan: 614 +/- 224 ng ml(-1), 472 +/- 268 ng ml(-1), P = 0.006; amlodipine: 680 +/- 151 ng ml(-1), 687 +/- 234 ng ml(-1), P &gt; 0.999). A positive correlation between the reduction in OPN and the log natural (ln) C-reactive protein (CRP) was seen in the valsartan-treated group. Stepwise regression analysis showed that treatment with valsartan and the reduction of ln CRP were associated with the reduction in OPN levels, and this association was independent of the reduction in SBP or aldosterone levels (valsartan: beta = 0.332, P = 026; ln CRP reduction: beta = 0.366, P = 0.015). These results suggest that suppression of the RAAS and inflammation may decrease plasma OPN levels. Journal of Human Hypertension (2011) 25, 334-339; doi:10.1038/jhh.2010.73; published online 22 July 2010

DOI： 10.1038/jhh.2010.73

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Serum cystatin C is not only a marker of renal function but also acts as an independent risk factor for cardiovascular damage, heart failure, and death. It is known that the initiation and progression of these cardiovascular events contributes to renal dysfunction and chronic inflammation. In this study, we investigated the relationship between cystatin C and proinflammatory cytokines.
Eighty-eight patients with essential hypertension participated in the study, which involved measuring proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and C reactive protein (CRP).
Positive correlations were detected between cystatin C and estimated glomerular filtration rate (eGFR) (r = -0.503, p &lt; 0.001), systolic blood pressure (r = -0.246, p = 0.034), and pulse pressure (r = -0.295, p = 0.010). In contrast, serum creatinine correlated only with eGFR (r = -0.755, p &lt; 0.001) and eGFR correlated only with age (r = -0.339, p = 0.001) and not with the other clinical parameters, whereas cystatin C also correlated with log natural (ln) IL-6 (r = -0.247, p = 0.033) and ln TNF-alpha (r = -0.405, p &lt; 0.001) but not with CRP (r = -0.188, p = 0.108). In contrast, plasma creatinine and eGFR did not correlate with any of these proinflammatory cytokines. Stepwise regression analysis showed that ln TNF-alpha, eGFR and pulse pressure were independent determinants of serum cystatin C concentration.
This study showed that cystatin C is a marker of inflammation as well as renal function.

DOI： 10.1007/s10157-010-0334-8

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Language：Japanese   Publisher：愛媛医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WICHTIG EDITORE  

Aim: In patients with essential hypertension (EHT), the intrarenal resistance index (RI) has been shown to be related to the severity of target organ damage (TOD). Cystatin C is has been reported to be related to TOD in EHT. The aim of the present study was to clarify whether the RI predicts future renal function assessed by cystatin C levels in EHT.
Methods: One-hundred and twelve patients participated. RI and cystatin C were measured at baseline, and 12 months later, cystatin C was measured again.
Results: The patients were divided into 2 groups according to RI value: the low RI group (RI&lt;0.7) and the high RI group (RI=0.7). After 12 months, cystatin C levels were significantly elevated in the high RI group, whereas the levels remained unchanged in the low RI group. Stepwise regression analysis using the baseline values of RI, age, pulse pressure, HbA1c, cystatin C, log-transformed (ln) C-reactive protein and ln urinary albumin/creatinine as covariates, showed baseline RI was the only independent determinant of the time-related changes in cystatin C levels.
Conclusion: This finding suggests that the renal RI may be a marker of future renal dysfunction in EHT.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

The renin angiotensin aldosterone system (RAAS) induces inflammation and accelerates atherosclerosis, contributes to both pro-and anti-inflammatory cytokines. Osteopontin (OPN) is known as a pro-inflammatory cytokine and adiponectin is known as an anti-inflammatory cytokine. C-reactive protein (CRP) not only reflects an inflammatory state but also leads to inflammation. Previous studies clarified that OPN and adiponectin were regulated by RAAS. In this study, we hypothesized that plasma OPN level relates to serum adiponectin level in patients with essential hypertension (EHT). Sixty-two patients (32 females) with EHT were enrolled in this study. They were evaluated for conventional risk factors for atherosclerosis, further plasma aldosterone, plasma OPN, serum adiponectin, and CRP levels were assayed. There were significant gender differences in creatinine, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-denisty lipoprotein(LDL) cholesterol, log transformed (ln) adiponectin and ln CRP. Osteopontin was correlated positively with aldosterone and ln CRP (r = 0.277, p = 0.029, r = 0.278, p = 0.029, respectively), negatively with adiponectin (r = -0.346, p = 0.006). Ln adiponectin was correlated positively with HDL cholesterol (r = 0.373, p = 0.003) and negatively with gender (male as 1), creatinine, triglyceride, aldosterone, and ln CRP (r = -0.55, p &lt; 0.001, r = -0.279, p = 0.028, r = -0.406, p = 0.001, r = -0.307, p &lt; 0.015, r = -0.289, p = 0.023, respectively). Stepwise regression analysis showed that adiponectin was an independent predictor of OPN beta= -0.0339, p = 0.004). Our results suggest that OPN and adiponectin are related to each other underlying the mechanisms of RAAS and inflammation.

DOI： 10.3109/10641961003628494

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

The development of vascular calcification is an active, highly regulated process with similarities to bone formation. Osteocalcin (OC), a vitamin K-dependent protein expressed by osteoblasts, contains 3 gamma-carboxyglutamic acid residues derived from the vitamin K-dependent posttranslational modification of glutamic acid residues. Circulating undercarboxylated OC (ucOC) is increased in vitamin K deficiency and serum ucOC is reported to be a clinical marker of vitamin K status. Vitamin K deficiency is associated with vascular calcification as well as osteoporosis. We evaluated the relationship between ucOC and carotid artery calcification in 92 patients with essential hypertension. Ultrasound of the common carotid artery was performed to identify vascular calcification and subjects were divided into 2 groups: a calcification (+) group and a calcification (-) group. Serum creatinine and ucOC levels were higher in the calcification (+) group than in the calcification (-) group and serum ucOC correlated with serum creatinine. To identify the independent determinant factor for carotid artery calcification, we applied both ucOC and estimated glomerular filtration rate as independent factors in logistic regression analysis. Serum ucOC was an independent determinant of carotid calcification, suggesting that circulating ucOC may be an important biomarker of carotid artery calcification. Copyright (C) 2010 S. Karger AG, Basel

DOI： 10.1159/000289575

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/s1875-4570(09)60564-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: The association of elevated serum Uric acid (UA) with cardiovascular events in patients with severe coronary artery stenosis was examined.
Methods and Results: Patients with stenosis &gt;= 75% (n=8,832) were followed for "all events" (cardiovascular events and all-cause mortality) for 3 years. The group was divided into quartiles based on baseline UA level. The incidence rate of all events was significantly different among quartiles (58.3. 56.5, 61.2, 76.3/1,000 patients-year, P&lt;0.601). Cox&apos;s proportional hazard regression analysis showed that the hazard ratio (HR) for all events was 1.25 195% confidence interval (Cl): 1.07-1.45, P&lt;0.0 I in the highest quartile (UA !6.8 rng/dl). The group in which UA increased &gt;= 1.0mg/dl after 6 months had significantly higher cardiovasular events rate than the group in which UA did not change (70.6 vs 58.8/1,000 patients-year, P=0.042). Propensity score matching was performed and 4,206 patients were divided into the highest quartile and the rest. High UA remained an independent predictor of all events (HR 1.25, 95%Cl 1.06-1.43). However, no significant difference was observed between the group with increased UA &gt;= 1.0mg/dl and tile group With unchanged UA level.
Conclusions: Elevated UA is an independent predictor of cardiovascular events and all-cause mortality combined in patients with coronary artery stenosis. (Circ J 2009; 73: 885-891)

DOI： 10.1253/circj.CJ-08-0828

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

An 81-year-old man was admitted to our hospital because of leg edema. Serological studies for anti-neutrophil cytoplasmic antibody (ANCA), anti-double stranded DNA antibodies, and antibodies to hepatitis C and B were negative. Severe hypocomplementemia was present and a cryoglobulin was detected with serum immunoelectrophoresis being positive for the immunoglobulin (Ig)M kappa type. The cryoglobulin was characterized by immunoelectrophoresis which showed that the protein was composed of polyclonal IgG and kappa-type monoclonal IgM. A diagnosis of essential type II cryoglobulinemia was made and the patient underwent a renal biopsy. The renal biopsy revealed endocapillary and mesangial cell proliferation with increased matrix. The resultant lobular appearance of the glomerulus and double contours of the basement membrane were indicative of membranoproliferative glomerulonephritis (MPGN). Immunofluorescence studies demonstrated granular staining in the capillary wall for IgG, IgA, IgM and C4 with little C3 deposition but no C1q. He was finally diagnosed with MPGN due to mixed cryoglobulinemia type II. MPGN with essential cryoglobulinemia type II without evidence of hepatitis C virus infection, like that found in the present case, is very rare.

DOI： 10.1111/j.1447-0594.2008.00493.x

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 53-year-old man was admitted to Ehime University Hospital because of a left adrenal tumor, which was detected by a routine medical examination. Blood pressure was 124/74 mmHg and the pulse rate was 80/min and regular. Computed tomography showed the tumor consisting mainly of low-density areas and partly of heterogeneous density areas. Magnetic resonance imaging demonstrated that the tumor consisted mainly of low intensity areas, partly of heterogeneous intensity areas determined by T1-weighted images
T2-weighted images showed that the tumor consisted mainly of high intensity areas and partly of heterogeneous intensity areas. These images suggested that the left adrenal tumor was a pheochromocytoma. The concentrations of serum adrenaline and noradrenaline were slightly elevated (adrenaline 0.11 ng/mL (normal : &lt
0.1) and noradrenaline 1.11 ng/mL (normal 0.1-0.5)). Although 131I-meta-iodobenzylguanidine (MIBG) scintigraphy did not show an accumulation of the tracer, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) showed an increased accumulation of the tracer in the left adrenal tumor. These results were suggestive of the diagnosis of pheochromocytoma, and left adrenalectomy was performed by endoscopy. He was finally diagnosed with pheochromocytoma. The detection rate of pheochromocytoma by FDG-PET is not very high and has been reported to be about 70 %. However, FDG-PET may be useful for detecting local recurrence or distant metastasis, in patients with MIBG-negative pheochromocytoma.

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A 64-year-old woman was admitted because of leg edema. Fifteen years previously she had been diagnosed with monoclonal gammopathy of undetermined significance (MGUS). Urinary immunoelectrophoresis demonstrated positivity for IgA kappa light chains. Bone marrow aspiration revealed a mild plasmacytosis. Her renal biopsy specimen revealed thickened basement membrane, mesangial cell proliferation and an increase in the mesangial matrix. Immunofluorescence studies showed the deposition of kappa light chains in the capillary wall and nodular lesions. These findings confirmed a diagnosis of light chain deposit disease (LCDD) with MGUS. The development of LCDD in patients with MGUS for fifteen years is very rare.

DOI： 10.2169/internalmedicine.48.1679

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER  

BACKGROUND: Aortic stiffness assessed by brachio-ankle pulse wave velocity (baPWV) can be used to predict cardiovascular events. However, baPWV is dependent on blood pressure. Antihypertensive drugs have been reported to reduce baPWV; but it is difficult to determine if this effect is associated with lowered blood pressure or reduced arterial stiffness.
OBJECTIVES: The primary end point of this study was to assess, whether antihypertensive drugs reduce arterial stiffness as estimated by cardio-ankle vascular index (CAVI). The secondary end point was to compare the effects of 2 widely used drugs, the calcium-channel blocker amlodipine and the angiotensin II receptor blocker candesartan, on arterial stiffness.
METHODS: Between October 2005 and September 2006, consecutive Japanese outpatients with essential hypertension (EHT) (defined as Using antihypertensive drugs at screening, systolic blood pressure [SBP] &gt; 140 mm Hg, or diastolic BP [DBP] &gt; 90 mm Hg) were assigned to treatment for 24 weeks with either amlodipine (5-10 mg/d) or candesartan (8-12 mg/d). Arterial stiffness was evaluated with CAVI before and after 24 weeks of treatment. Relative change in arterial stiffness from baseline was also compared. The evaluator was blinded to treatment.
RESULTS: Twenty patients (11 men, 9 women; mean [SD] age, 62 [10] years) were included in the study. There were no significant differences in clinical characteristics between the 2 groups. At baseline, mean (SD) CAVI was nor significantly different in the amlodipine group compared with the candesartan group (8.93 [0.93] vs 8.46 [1.34], respectively). During the 24-week treatment period, mean SBP and DBP decreased significantly in both the amlodipine (1.4/10 mm Hg; P = 0.006 and P = 0.005) and the candesartan groups (13/11 mm Hg; P = 0.033 and P = 0.005). Amlodipine was associated with a significant change in CAVI from baseline (8.93 [0.931 vs 8.60 [1.50]; P = 0.017), whereas candesartan was nor (8.46 [1.34] vs 8.81 [1.20]). The percentage change in CAVI was significantly different in the amlodipine group compared with the candesartan group (-7.14 [8.83] vs 5.85 [16.0], respectively; P = 0.038). After 24 weeks of treatment, the CAVI of the amlodipine group was still numerically larger than baseline CAVI of the candesartan group, although the difference was not statistically significant. Furthermore, there was no significant difference in absolute CAVI between the 2 groups after 24 weeks, but the relative change from baseline was significant in favor of amlodipine. Logistic regression analysis revealed that amlodipine improved CAVI independent of its antihypertensive effect.
CONCLUSION: These data suggest that amlodipine and candesartan had different effects on aortic stiffness estimated by CAVI, despite similar effects on brachial blood pressure after 24 weeks of treatment in these Japanese patients with EHT. (Curr Ther Res Clin Exp. 2008;69:412-422) (C) 2008 Excerpta Medica Inc.

DOI： 10.1016/j.curtheres.2008.10.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

A 34-year-old woman was admitted to our hospital because of hypertension with hypokalemia. Her past medical history revealed that at age 24 she had been diagnosed with left renal lithiasis and had undergone extracorporeal shock-wave lithotripsy (ESWL). Physical examination showed that her peripheral pulses were intact and no peripheral edema or audible bruits were detected. Her serum potassium concentration was 2.7 mEq/mL, her plasma aldosterone concentration (PAC) was 96.7 ng/dL, and her plasma renin activity (PRA) was 28.1 ng/mL/h. Intrarenal lobar artery flow pattern assessed by Doppler ultrasound showed no abnormality. A renogram demonstrated a normal symmetrical tracing pattern. However, administration of 50 mg captopril induced delayed transit of tracer in both kidneys. Selective angiographic studies showed no stenotic lesions in the proximal to distal renal arteries. Blood sampling from each renal vein showed no laterality of PRA. While the possibility of the Page kidney phenomenon resulting from ESWL could not be excluded completely, the patient was diagnosed as a very rare case of hyperreninemic essential hypertension with positive captopril renography in both kidneys.

DOI： 10.1291/hypres.31.383

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Osteopontin (OPN), a proinflammatory cytokine, plays an important role in renal fibrosis. We reported that plasma OPN levels were higher in patients with primary aldosteronism than with essential hypertension. However, the regulatory mechanism of OPN by aldosterone remains unclear. Here, we report the transcriptional regulation of OPN expression by aldosterone and the functional effects of aldosterone-mediated OPN transcription in renal fibroblasts. Aldosterone induced OPN expression in a dose-dependent manner with significant responses at 10 nmol/L (1.6 +/- 0.2-fold of controls, P &lt; 0.05, n = 5) and elicited maximal effects at 10 mu mol/L (3.5 +/- 0.4-fold of controls, P &lt; 0.01, n = 5). Aldosterone increased OPN expression in a time-dependent manner with a maximal effect after 48 hours (2.7 +/- 0.3-fold of controls, P &lt; 0.01, n = 5). This effect was abolished by the mineralocorticoid receptor (MR) antagonist spironolactone. Luciferase promoter deletion assays identified a novel cis regulatory element (-2153 to-1758) in the OPN promoter that is responsive to aldosterone. This element contains an activator protein-1 (AP-1) and nuclear factor kappa B (NF kappa B) site. Electrophoretic mobility shift assays, supershift assays, and chromatin immunoprecipitation assays identified both AP-1 and NF kappa B as the DNA binding proteins induced by aldosterone with spironolactone inhibiting aldosterone-induced AP-1 or NF kappa B activity. OPN-siRNA inhibited completely the induction of cell proliferation, type I, III, and IV collagen synthesis by aldosterone. These results indicate that aldosterone induced MR-mediated OPN expression through AP-1 and NF kappa B activation and suggest that aldosterone plays an important role in renal fibrosis through the induction of OPN.

DOI： 10.1161/HYPERTENSIONAHA.107.102640

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Numerous studies have demonstrated that high blood pressure substantially increases the risk of microvascular and macrovascular complications in patients with type 2 diabetes mellitus (T2DM). Currently, we found that serum resistin, an adipocyte-and monocyte-derived cytokine, was positively correlated with several components of the metabolic syndrome, including hypertension in T2DM. To investigate the association of resistin with an etiologic difference among subjects with hypertension with T2DM, hypertension without T2DM, and normotensive T2DM, we analyzed 210 subjects, including 91 with hypertension with T2DM, 55 with hypertension without T2DM, and 64 with normotensive T2DM. Serum resistin level was higher in subjects with hypertension with T2DM, followed by subjects with normotensive T2DM and hypertension without T2DM, irrespective of antihypertensive treatment status (20.9 +/- 17.6 and 14.0 +/- 8.9 versus 11.2 +/- 7.6 ng/mL, respectively; P &lt; 0.01). Simple regression analysis revealed that resistin positively correlated with blood pressure (systolic blood pressure: r = 0.29, P &lt; 0.01; diastolic blood pressure: r = 0.21, P &lt; 0.05) and intima-media thickness (r = 0.27; P &lt; 0.05) in patients with T2DM but not in subjects with hypertension without T2DM. Multiple regression analysis, adjusted for age, gender, body mass index, fasting glucose, high-density lipoprotein cholesterol, white blood cell counts, and glomerular filtration rate, further revealed that resistin was an independent factor for high blood pressure in patients with T2DM (P &lt; 0.05). In vitro gene expression analysis in human coronary endothelial cells revealed that resistin induced fatty acid binding protein, a key molecule of insulin resistance, diabetes, and atherosclerosis. These results suggest that hyperresistinemia would contribute to the pathogenesis of hypertension in patients with T2DM, significantly linked to vascular complications and cardiovascular events.

DOI： 10.1161/HYPERTENSIONAHA.107.103077

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Increased arterial stiffness and intima media thickness (IMT) in the common carotid artery (CCA) are related to cardiovascular risk in essential hypertension. Angiotensin II plays an important role in structural and functional changes in the vasculature. In this study, we evaluated the long-term effect of the angiotensin II receptor blocker, valsartan, on IMT, arterial stiffness, and hemodynamics in the CCA in patients with essential hypertension. A prospective 24 month study of treatment with valsartan (80-160mg/day) was performed in 24 hypertensive patients. An ultrasound of the CCA was carried out to determine IMT, the cross-sectional distensibility coefficient (CSDC), the carotid arterial stiffness index , and diastolic flow velocity to systolic flow velocity ratio (Vd/Vs). Treatment with valsartan for 24 months reduced systolic and diastolic blood pressure significantly. Compared to baseline, the decrease in pulse pressure was greater after 24 months treatment than after 12 months treatment. Valsartan did not influence IMT; however, after 24 months, it caused a significant increase in CSDC and a decrease in stiffness index compared to baseline. These changes were not observed after 12 months of treatment. In addition, Vd/Vs, a sensitive marker of relative diastolic blood flow, increased after 24 months&apos; treatment with valsartan. These results suggest that long-term treatment with valsartan improves vascular wall function and hemodynamics in patients with essential hypertension.

DOI： 10.1080/10641960802279108

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

Aortic stiffness measured by aorta-iliac or carotid-femoral pulse wave velocity (PWV) predicts all-cause and cardiovascular mortality. Elrachial-ankle PWV (baPWV) has been developed as a more convenient assessment of arterial stiffness. However, the problem with clinical use of baPWV is that the index itself is closely dependent on blood pressure. Recently, a new method, termed the cardio-ankle vascular index (CAVI), has been proposed in Japan to overcome the disadvantages associated with measuring PWV. However, its clinical usefulness has not yet been fully clarified. In the present study, we compared the usefulness of CAVI with that of ultrasound for evaluating atherosclerosis in patients with essential hypertension. CAVI was measured in 70 hypertensive patients. The intima-media thickness (IMT), cross-sectional distensibility coefficient (CSDC), stiffness parameter beta, and mean diastolic (V-d) and systolic (V-s) flow velocities were evaluated by carotid ultrasound. The V-d/V-s ratio, an index of peripheral arterial resistance, was also calculated. CAVI was positively correlated with IMT (r=0.360, p=0.0022) and stiffness beta (r=0.270, p=0.0239) and negatively correlated with V-d/V-s (r=-0.471, p &lt; 0.0001) and CSDC (r=-0.315, p=0.0079). Stepwise regression analysis revealed that age (r=0.475, p &lt; 0.0001) and pulse pressure (r=0.492, r &lt; 0.0001) were independent determinants of CAVI. These results suggest that CAVI is a useful clinical marker for evaluating atherosclerosis and arteriolosclerosis in patients with essential hypertension.

DOI： 10.1291/hypres.30.335

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Background: Angiotensin II (A II) plays an important role in the regulation of blood pressure (BP). In addition, A II has significant pro-inflammatory actions in the vascular wall, inducing the production of reactive oxygen species and inflammatory cytokines. Recent randomized clinical trials showed that BP lowering to normal or optimal levels is essential for the prevention of cardiovascular complications. To achieve the recommend levels of BP control, 2 or 3 different antihypertensive medications are often required. In the present study, we evaluated the anti-inflammatory effects as well as BP lowering effects of combination therapy with an A II receptor blocker (ARB) and a low dose diuretic or Ca channel blocker in patients with essential hypertension (EHT). Methods and Results: EHT patients were recruited who were already receiving 8 mg of candesartan for at least one month, but still had a systolic BP (SBP) &gt
140 mmHg and/or diastolic BP (DBP) &gt
90 mmHg. Fifty-eight patients were assigned to three treatment groups : the addition of 4 mg candesartan (12 mg total), the addition of a Ca channel blocker (CCB), and the addition of a diuretic (DT). BP and a blood test for pro-inflammatory cytokines (C-reactive protein (CRP), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8 and tumor necrosis factor (TNF)-α were evaluated before randomization and 3 and 6 months after randomization. SBP and DBP were reduced to the same level in all 3 groups after 3 and 6 months of treatment. Serum potassium, blood glucose total cholesterol, uric acid, CRP MCP-1 and IL-8 were not altered by the 3 different treatments. The addition of either 4 mg candesartan or a CCB reduced TNF-α concentration, but the addition of a DT did not. Conclusion: Combination therapy with an ARB and a CCB or a low dose DT is useful for the reduction of BP without metabolic and inflammatory aggravation in patients with EHT.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PORTLAND PRESS LTD  

OPN (osteopontin), a pro-inflammatory cytokine, has recently emerged as a key factor in both vascular remodelling and the development of atherosclerosis. However, the relationship between OPN and atherosclerosis in patients without symptomatic cardiovascular. disease is not clear. Therefore we measured plasma OPN levels and evaluated the correlation between plasma OPN levels and atherosclerosis as target organ damage in patients with EHT (essential hypertension). Plasma OPN levels were measured in 76 patients with EHT using a solid-phase sandwich ELISA. IMT (intima-media thickness), and V-d and V-s (mean diastolic and systolic flow velocities respectively) were evaluated by carotid ultrasound. The V-d/V-s ratio, an index of peripheral arterial resistance, was also calculated. The patients were divided on the basis of median OPN levels into a high-OPN group and a low-OPN group. The mean IMT and aldosterone levels were higher (P = 0.024 and 0.031 respectively) and V-d/V-s was lower (P = 0.007) in the high-OPN group than in the low-OPN group. Plasma OPN levels were positively correlated with mean IMT (r = 0.308, P = 0.0068) and negatively with V-d/V-s (r = -0.293, P = 0.010). Stepwise regression analysis revealed that OPN was an independent determinant of mean IMT (P = 0.007) and V-d/V-s (P = 0.009), and aldosterone was an independent determinant of OPN. These results suggest that OPN plays a role in the development of atherosclerosis and may be a potential clinical marker for the prediction of atherosclerosis in patients with EHT.

DOI： 10.1042/CS20060074

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Background: Adiponectin, an adipocyte-derived protein, is reduced in patients with hypertension and insulin resistance (IR). Angiotensin II receptor blockers (ARBs) have been reported to improve IR and reduce albuminuria. The purpose of this study was to evaluate the influence of an ARB and a calcium channel blocker on serum adiponectin levels in Japanese patients with hypertension who were treated with losartan or amlodipine for 3 months.
Methods: Patients with essential hypertension (EHT) were randomized to treatment prospectively with losartan (50-100 mg/d) or amlodipine (5-10 mg/d) for 3 months. Patients with renal damage and/or macroproteinuria were excluded. The urine albumin/creatinine ratio, homeostasis model assessment (HOMA) index, adiponectin concentration, and tumor necrosis factor-alpha (TNF-alpha) concentration of each patient were evaluated before and after 3 months of treatment. When the HOMA index exceeded 1.73, a patient was considered to have IR.
Results: All 40 participants completed both 3-month treatment periods. Study patients were primarily male (52.5%) with a mean (SD) age of 63.8 (10.6) years and a mean body weight of 60.7 (10.8) kg. Patients with EHT and diabetes mellitus (n = 9) and IR (n = 12) had significantly lower adiponectin concentrations than patients who had EHT without diabetes or IR (n = 19; mean [SD], 7.84 [5.54] vs 12.81 [7.36] mu g/mL, P = 0.034; and 6.12 [3.04] vs 12.81 [7.36] mu g/mL, P = 0.004, respectively). Adiponectin concentrations correlated negatively with body mass index (r = -0.393; P = 0.012) and HOMA index (r = -0.440; P = 0.005) and positively with high-density lipoprotein cholesterol (r = 0.441; P = 0.004) before treatment. Systolic blood pressure was significantly decreased in patients treated with losartan (n = 20; mean [SD], 166 [19] to 140 [15] mm Hg; P &lt; 0.001) or amlodipine (n = 20; 164 [15] to 136 [15] mm Hg; P &lt; 0.001), and diastolic blood pressure also was significantly decreased with losartan (93 [14] to 83 [10] mm Hg; P = 0.031) or amlodipine (96 [12] to 82 [10] mm Hg; P &lt; 0.001). Losartan increased adiponectin concentrations (9.56 [6.75] to 10.36 [6.94] mu g/mL; P = 0.038), whereas amlodipine had no significant effect (9.67 [6.62] to 10.01 [6.79] mu g/mL). The difference in TNF-alpha concentration before and after treatment with losartan and amlodipine did not reach statistical significance (mean [SD], 15.2 [1.4] to 14.8 [1.5] pg/mL; and 14.3 [1.4] to 14.5 [1.7] pg/mL, respectively).
Conclusion: In this study, Japanese adults with EHT had significant increases in adiponectin after 3 months of treatment with 50 to 100 mg/d of losartan, but not with 5 to 10 mg/d of amlodipine. (Clin Ther. 2006;28: 1677-1685) Copyright (c) 2006 Excerpta Medica, Inc.

DOI： 10.1016/j.clinthera.2006.10.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

A high level of albuminuria and increased renal vascular resistance are associated with hypertensive renal damage. In this study, the authors investigated the effect of the angiotensin II receptor blocker, valsartan, on renal function and intrarenal hemodynamics in non-diabetic patients with essential hypertension. A prospective three-month study of the effects of valsartan, 40-80 mg/day, was performed in 30 hypertensive patients. As an assessment of renal function, serum creatinine, urine albumin/creatinine (Alb/Cr) ratio, and serum cystatin C levels were evaluated. Doppler ultrasonography of the kidney was performed for the evaluation of renal hemodynamics. Peak-systolic, end-diastolic, and mean velocities of interlobar arteries were evaluated, and the pulsatility index (PI) and resistive index (RI) were calculated. It was determined that patients with microalbuminuria had higher levels of serum cystatin C, PI, and RI compared to patients without microalbuminuria. Valsartan treatment significantly reduced systolic and diastolic blood pressure and decreased the Alb/Cr ratio. Serum creatinine was not changed, whereas serum cystatin C levels were significantly reduced. Valsartan treatment significantly decreased the PI in all patients and both PI and RI in patients with microalbuminuria. These results suggest that the angiotensin II receptor blocker, valsartan, is able to improve renal function by reducing renal vascular resistance in hypertensive patients, especially in patients with microalbuminuria, and may prevent future renal failure in patients with essential hypertension.

DOI： 10.1080/10641960600798671

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A 62-year-old woman was admitted to our hospital because of hypokalemia. Physical examination revealed no signs of excessive adrenocortical steroid production, as are found in Cushing's syndrome. Her plasma renin activity (PRA) was suppressed (0.10ng/ml per h), and her serum aldosterone level was high (30.0ng/dl). PRA was not increased after a renin-releasing test. Her plasma adrenocorticotropic hormone (ACTH) level was low (&lt
5pg/ml), but her serum cortisol level was normal (21.0μg/dl). Administration of 8mg dexamethasone did not suppress her plasma cortisol level. Finally, she was diagnosed with clinical primary aldosteronism associated with preclinical Cushing's syndrome. Magnetic resonance image revealed three sequential nodular masses (each 15mm × 15mm) in the right adrenal gland. A right adrenalectomy was performed by endoscopy. The three removed tumors appeared to have different characteristics. Microscopic examination revealed that the upper and lower tumors were adrenocortical adenomas, and the middle tumor was a black adenoma. Immunohistochemical staining for the enzymes involved in cortisol biosynthesis suggested that the upper tumor secreted aldosterone, whereas either or both of the two other tumors secreted cortisol. Surprisingly, at 33 years of age, she had been diagnosed with Cushing's syndrome, due to a cortisol-producing adrenocortical adenoma, and she had received a left adrenalectomy. Clinically and pathophysiologically, this was a very rare case. © Japanese Society of Nephrology 2006.

DOI： 10.1007/s10157-006-0413-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background: The incidence of cardiovascular events is higher in patients with primary aldosteronism (PA) than in patients with essential hypertension (EHT). Aldosterone has been shown to play an important role in the development of vascular inflammation and myocardial fibrosis in animal models. Elevated serum inflammatory cytokine is an independent cardiovascular risk factor in patients with EHT. In the present study, we compared levels of inflammatory cytokines between patients with PA and EHT.
Methods: The study subjects were 15 patients with PA and 15 age-matched patients with EHT. Serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), high sensitive C-reactive protein (hsCRP), and plasma osteopontin (OPN) levels were measured by enzyme-linked immunosorbent assays.
Results: Systolic and diastolic blood pressure (BP) did not differ between the PA and EHT patient groups. Levels of serum IL-6 (P =.563), TNF-alpha (P =.480), and hsCRP (P =.870) did not differ between the two groups. In contrast, plasma OPN levels in patients with PA were significantly higher than those in patients with EHT (P &lt;.0001). There was no relationship between BP and plasma OPN levels in patients with PA.
Conclusions: The present study showed that plasma OPN levels were higher in patients with PA than in patients with EHT.

DOI： 10.1016/j.amjhyper.2005.08.019

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Objectives: Blood pressure measured at home is superior to office-measured blood pressure in predicting the risk of cerebro-cardiovascular mortality and morbidity. A high morning blood pressure surge is an independent risk factor of cardiovascular events. For these reasons, control of blood pressure in the morning is essential. Methods: We surveyed self-measured morning home blood pressure levels in essential hypertensive patients who were taking angiotensin II receptor blockers, candesartan, losartan, and valsartan. Results: The mean blood pressure in candesartan, losartan, and valsartan groups was 141.7 ± 8.4/74.7 ± 4.6mmHg, 148.2 ± 18.2/ 78.4 ± 5.1mmHg, and 147.2 ± 19.0/77.7 ± 9.1mmHg, respectively. Systolic pressure was significantly lower in the candesartan treatment group than in the losartan treatment group (p = 0.044). Diastolic pressure was reduced by candesartan more effectively than by losartan and valsartan (p = 0.019 and 0.0359). Conclusion: We conclude that candesartan is useful to control high morning blood pressure in patients with essential hypertension.

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The aim of this study was to clarify the magnitude of common carotid artery (CCA) structural and hemodynamic parameters on brain white and gray matter lesions in patients with essential hypertension (EHT). The study subjects were 49 EHT patients without a history of previous myocardial infarction, atrial fibrillation, diabetes mellitus, impaired glucose tolerance, chronic renal failure, symptomatic cerebrovascular events, or asymptomatic carotid artery stenosis. All patients underwent brain MRI and ultrasound imaging of the CCA. MRI findings were evaluated by periventricular hyperintensity (PVH), deep and subcortical white matter hyperintensity (DSWMH), and etat crible according to the Japanese Brain dock Guidelines of 2003. Intima media thickness (IMT), and mean diastolic (V-d) and systolic (V-s) velocities were evaluated by carotid ultrasound. The V-d/V-s ratio was further calculated as a relative diastolic flow velocity. The mean IMT and max IMT were positively associated with PVH, DSWMH, and etat crible (mean IMT: rho=0.473, 0.465, 0.494, p=0.0007, 0.0014, 0.0008, respectively; max IMT: rho=0.558, 0.443, 0.514, p=0.0001, 0.0024, 0.0004, respectively). V-d/V-s was negatively associated with etat crible (rho=-0.418, p=0.0038). Carotid structure and hemodynamics are potentially related to asymptomatic lesions in the cerebrum, and might be predictors of future cerebral vascular events in patients with EHT.

DOI： 10.1291/hypres.28.797

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A 79-year-old woman was admitted to our hospital because of leg edema due to a nephrotic syndrome. Urinary and serum immunoelectrophoresis showed positive for the lambda type of Bence Jones protein. A bone marrow aspiration test revealed mild plasmacytosis (6.4% of the total cells). These findings confirmed her diagnosis of monoclonal gammopathy of undetermined significance (MGUS). Her renal biopsy specimen revealed mild mesangial cell proliferation and an increase in the mesangial matrix. Immunofluorescence studies showed positive staining for IgG, IgA, C3, and kappa and lambda light chains in the capillary wall and mesangium area. Electron microscopy showed that the electron deposits in the thickened basement membrane were formed by randomly arranged 16- to 18-nm nonbranching fibrils. A Congo red stain for amyloid was negative. These findings corresponded with the diagnosis of fibrillary glomerulonephritis. Therefore, this case showed a rare combination of fibrillary glomerulonephritis and MGUS. © Japanese Society of Nephrology 2005.

DOI： 10.1007/s10157-005-0361-z

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BACKGROUND: It was recently suggested that insulin resistance is significantly correlated with activation of the cardiac sympathetic nervous system in patients with essential hypertension. OBJECTIVES: To examine the effects of troglitazone, an agent used to treat insulin resistance, on cardiac sympathetic nervous dysfunction and insulin resistance in patients with essential hypertension. METHODS: The study participants included 34 patients (14 men, 20 women) with mild essential hypertension and 17 normal controls (group C, seven men). The patients were randomly divided into two groups, one treated with 400 mg troglitazone and antihypertensive drugs (group T, n = 17) and the other treated with antihypertensive drugs only (group N, n = 17). We evaluated insulin resistance and cardiac sympathetic nervous function before and after 6 months of treatment. Insulin resistance was evaluated using steady-state plasma glucose (SSPG; mg/dl) concentrations and cardiac sympathetic nervous function was evaluated using the heart-to-mediastinum ratio (H : M) and mean washout rate measured by 123I-meta-iodobenzylguanidine (MIBG) cardiac imaging. RESULTS: There were significant differences in SSPG (P < 0.01), early (P < 0.05) and delayed (P < 0.05) phases of H : M and washout rate (P < 0.05) between the hypertensive patients and group C. The SSPG concentration was significantly improved after treatment only in group T, from 153.3 to 123.7 mg/dl (P < 0.01). The early and delayed phases of H : M and washout rate also were significantly improved (P < 0.05) (from 2.59 to 2.63, from 2.12 to 2.27 and from 18.1 to 13.7%, respectively) in only group T.The change in SSPG was significantly correlated with the changes in H : M and washout rate (r = -0.639 and 0.577, respectively). CONCLUSION: Troglitazone had a beneficial effect on cardiac sympathetic nervous function through a decrease in insulin resistance in patients with essential hypertension.

PubMed

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Publishing type：Research paper (scientific journal)  

B lymphopoiesis in the mouse and in man can be divided into two phases, one in which the compartments of the B lineage are filled with cells, and a second in which these compartments are maintained by regeneration, turnover and selection. Once the immune system has been built it contains around 5 x 10(8) and 10(12) cells of the B-lymphocyte lineage in the mouse and in man, respectively, of which nearly 10 per cent are precursors that are active in regeneration, whereas over 90 per cent are resting, mature B cells.

DOI： 10.1016/0952-7915(93)90006-e

PubMed

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Language：English  

PURPOSE: To evaluate the image quality and lesion visibility of virtual monoenergetic images (VMIs) reconstructed using a new monoenergetic reconstruction algorithm (nMERA) for evaluation of breast cancer. MATERIALS AND METHODS: Forty-two patients with 46 breast cancers who underwent 4-phasic breast contrast-enhanced computed tomography (CT) using dual-energy CT (DECT) were enrolled. We selected the peak enhancement phase of the lesion in each patient. The selected phase images were generated by 120-kVp-equivalent linear blended (M120) and monoenergetic reconstructions from 40 to 80 keV using the standard reconstruction algorithm (sMERA: 40, 50, 60, 70, 80) and nMERA (40 +, 50 +, 60 +, 70 +, 80 +). The contrast-to-noise ratio (CNR) was calculated and objectively analyzed. Two independent readers subjectively scored tumor visibility and image quality each on a 5-point scale. RESULTS: The CNR at 40 + and tumor visibility scores at 40 + and 50 + were significantly higher than those on M120. The CNR at 50 + was not significantly different from that on M120. However, the overall image quality score at 40 + was significantly lower than that at 50 + and on M120 (40 + vs M120, P < 0.0001 and 40 + vs 50 +, P = 0.0001). CONCLUSIONS: VMI reconstructed with nMERA at 50 keV is preferable for evaluation of patients with breast cancer.

DOI： 10.1007/s11604-019-00897-1

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Language：Japanese   Publisher：日本心脈管作動物質学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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CiNii Books

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Language：Japanese   Publisher：愛媛医学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：愛媛医学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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J-GLOBAL

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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J-GLOBAL

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Language：English   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

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Other Link： http://search.jamas.or.jp/link/ui/2010038584

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.ijcard.2009.09.515

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.ijcard.2009.09.517

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.ijcard.2009.09.516

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Language：English   Publisher：Japanese Circulation Society  

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Language：Japanese   Publisher：羊土社  

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Other Link： http://search.jamas.or.jp/link/ui/2009127347

Language：Japanese   Publisher：社団法人日本循環器学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：社団法人日本循環器学会  

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Language：English   Publisher：Japanese Circulation Society  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：Japanese   Publisher：社団法人日本循環器学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：社団法人日本循環器学会  

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Language：Japanese   Publisher：社団法人日本循環器学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publisher：Japanese Circulation Society  

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