Evidence for the Immunosuppressive Potential of Calcineurin Inhibitor-Sparing Regimens in Liver Transplant Recipients with Impaired Renal Function

Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and mycophenolate mofetil, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the RI group had significantly improved, although it was still lower than that of the non-RI group. Serial mixed lymphocyte reaction assays revealed that antidonor T-cell responses were adequately suppressed in both groups. Thus, we provide evidence that CSR leads to improvement of eGFR after LT in patients with RI, while maintaining an appropriate immunosuppressive state

Research Report on Miyako Ryukyuan : General Study for Research and Conservation of Endangered Dialects in Japan

National Institute for Japanese Language and LinguisticsFrench National Centre for Scientific ResearchKyoto UniversityHiroshima UniversityUniversity of the RyukyusHokusei Gakuen UniversityHitotsubashi UniversityHitotsubashi UniversityHitotsubashi UniversityFirst Published: August 1, 2012 (in Japanese

Evidence for the Immunosuppressive Potential of Calcineurin Inhibitor-Sparing Regimens in Liver Transplant Recipients with Impaired Renal Function

Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and mycophenolate mofetil, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the RI group had significantly improved, although it was still lower than that of the non-RI group. Serial mixed lymphocyte reaction assays revealed that antidonor T-cell responses were adequately suppressed in both groups. Thus, we provide evidence that CSR leads to improvement of eGFR after LT in patients with RI, while maintaining an appropriate immunosuppressive state

Important parameters in the detection of left main trunk disease using stress myocardial perfusion imaging

SummaryObjectivesWe sought noninvasively to diagnose left main trunk (LMT) disease using myocardial perfusion imaging (MPI).MethodsFive hundred and eight patients with suspected coronary artery disease (CAD) underwent both stress MPI and coronary angiography. The extent and severity of perfusion abnormalities were assessed using a 20-segment model. In addition, perfusion defects in both left anterior descending and left circumflex arterial territories were defined as a left main (LM) pattern defect, and those in 3-coronary arterial territories as a 3-vessel pattern defect.ResultsIn 42 patients with LMT disease, a summed stress score (19.4±10.0 vs. 13.5±10.0; p<0.0001) and a summed rest score (12.1±9.7 vs. 7.0±7.8; p=0.002) were greater than in 466 patients without LMT disease, while a summed difference score was similar (7.3±7.7 vs. 6.5±6.1; p=NS). The prevalence of an LM-pattern defect was low in both groups (12% vs. 8%; p=NS). However, a 3-vessel pattern defect (33% vs. 7%; p<0.0001), lung uptake of radiotracers (38% vs. 11%; p<0.0001), and transient ischemic dilation (31% vs. 13%; p=0.003) were more frequently observed in patients with LMT disease than in those without. Logistic regression analysis showed that a 3-vessel pattern defect (OR=3.5, 95% CI=1.4–8.8; p=0.007), lung uptake of radiotracers (OR=2.5, 95% CI=1.1–5.7; p=0.03), and previous myocardial infarction (MI) (OR=2.4, 95% CI=1.0–5.7; p=0.05) were the most important parameters to detect LMT disease. After excluding 163 patients with previous MI, a repeat analysis revealed that lung uptake of radiotracers (OR=8.2, 95% CI=2.3–29.2; p=0.001) and an LM-pattern defect (OR=6.3, 95% CI=1.4–27.2; p<0.02) were independent predictors for LMT disease.ConclusionIn the identification of LMT disease, lung uptake of radiotracers was a single best parameter, which was independent of the presence or absence of previous MI

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

信州大学博士（医学）・学位論文・平成25年3月31日授与（甲第942号）・楊 磊Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene. Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule. We compared the effect of CGRP deficiency on neointimal formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointimal formation after vascular injury was markedly enhanced in CGRP-/- mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointimal formation in CGRP-/- mice. In vitro analysis showed that CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease. (C) 2013 Elsevier Ltd. All rights reserved.ArticleJOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY. 59(0):55-66 (2013)journal articl

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

信州大学博士（医学）・学位論文・平成25年3月31日授与（甲第935号）・小山 晃英Background-Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly. Methods and Results-We generated endothelial cell-specific RAMP2 and AM knockout mice (E-RAMP2(-/-) and E-AM(-/-)). Most E-RAMP2(-/-) mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2(-/-) mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2(-/-) mice (DI-E-RAMP2(-/-)) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion. Conclusions-Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage. (Circulation. 2013;127:842-853.)ArticleCIRCULATION. 127(7):842-853 (2013)journal articl