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Rea I.M.,Queen's University of Belfast | McNerlan S.E.,Queen's University of Belfast | Archbold G.P.,Belfast City Hospital | Middleton D.,Belfast City Hospital | And 4 more authors.
Age | Year: 2013

Mitochondria produce cellular energy but also free-radicals, which damage cells despite an array of endogenous anti-oxidants. In Northern Europe, the mitochondrial haplogroup J has been related to longevity in nonagenarians and centenarians but also with age-related disease. Hypertension is an important contributor to atherosclerotic-related diseases and its pathogenesis is associated with increased oxidative stress. In this study, we questioned whether J haplogroup octononagenarians from the Belfast Elderly Longitudinal Free-living Elderly STudy (BELFAST) study showed evidence of protective blood pressure or anti-oxidant profile which might explain their longevity advantage. Briefly, in a cross-sectional study, community-living, mentally alert (Folstein >2530), octononagenarian subjects, recruited for good health, were enlisted and consented as part of the BELFAST study, for blood pressure, anthropometricmeasurements and blood sampling. DNA typing for mitochondrial haplotypes was carried out with measurements for enzymatic and non-enzymatic antioxidants. J haplogroup carriers showed lower systolic blood pressure and glutathione peroxidase activity (Gpx) with higher folate measurements. There was no change in urate, bilirubin, albumin or nutrition-related antioxidants-selenium or vitamins A, C and α and ? carotene. BELFAST study mtDNA J haplogroup octononagenarians showed lower blood pressure and reduced glutathione peroxidase activity and higher folate, but no change for other antioxidants. These findings are of interest in view of mtDNA J haplogroup's association with increased age in some previous studies. © 2012 The Author(s).


PubMed | Tokyo Women's Medical University, Transplantation Center, Kumamoto University, Osaka University and 10 more.
Type: Journal Article | Journal: Transplantation direct | Year: 2016

Because simultaneous liver and kidney transplantation has been limited as a standard practice because of a severe shortage of deceased donors in Japan, living donor (LD) liver transplantation alone (LTA) is indicated in most recipients with maintenance renal replacement therapy (MRRT).A retrospective nationwide survey of LD LTA was performed for liver transplant patients on MRRT. The characteristics of donors and recipients, postoperative complications, survival rate, and causes of death were analyzed.In the adult cases (n = 28), the overall survival rate at 1 year and 5 years were 66.1% and 57.3%, respectively. When compared with those adults without MRRT (n = 237), it was significantly worse. In the 7 pediatric cases, the overall survival rate at 1 and 5 years were both 83.3%. Three adult recipients died of nonaneurysm cerebral hemorrhage after 1 year and 1 adult recipient died of acute heart failure after 7 months. In adult recipients with MRRT, graft weight versus standard liver volume, and duration and blood loss in LTA surgery were associated with poor outcomes after LD LTA. Multivariate analysis revealed that MRRT was highest hazard ratio on patient survival after LD LTA.Early post-LD LTA mortality was higher in patients with MRRT than in those without MRRT with characteristic causes. Smaller grafts for size and a complicated surgery were associated with poor outcome after LD LTA. Thus, LD LTA in adult patients on MRRT should be carefully treated with meticulous postoperative management and follow-up.


Rea I.M.,Queen's University of Belfast | Maxwell L.D.,Immunology and Microbiology Laboratory | McNerlan S.E.,Cytogenetics Laboratory | Alexander H.D.,University of Ulster | And 3 more authors.
Immunity and Ageing | Year: 2013

Background: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well.Results: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 (high or low) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99-1.09; p=0.027) and 14% higher levels for TGF-β (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99-1.09; p=0.002).Conclusion: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood. © 2013 Rea et al.; licensee BioMed Central Ltd.


Levesque V.,Transplantation Biology Research Center | Bardwell P.D.,Transplantation Biology Research Center | Shimizu I.,Transplantation Biology Research Center | Haspot F.,Transplantation Biology Research Center | And 3 more authors.
American Journal of Transplantation | Year: 2011

Presensitization to HLA antigens limits the success of organ transplantation. The achievement of donorspecific tolerance via mixed chimerism could improve outcomes of transplantation in presensitized patients. In presensitized B-cell-deficient lMT B6 mice, we developed nonmyeloablative bone marrow transplantation (BMT) regimens that successfully tolerized presensitized T cells, achieving long-term(LT) multilineage chimerism and tolerance to donor-type skin. To apply these regimens in wild-type (WT) animals while avoiding antibody-mediated destruction of donor bone marrow cells, presensitized WT B6 mice were rested >2 years to allow alloantibody clearance. However, chimerism and tolerance were not reliably achieved in LT presensitized WT B6 mice in which alloantibody had declined to minimal or undetectable levels before BMT. Strong antidonor memory T-cell responses were detected in LT presensitizedWT B6mice after rejection of donor bone marrow (BM) occurred, whereas levels of alloantibody remained consistently low. In contrast, presensitized lMT B6 mice had diminished memory Tcell responses compared to WT B6 mice. These data implicate T-cell memory, but not alloantibody, in rejection of donor BM in LT presensitized WT mice. © Copyright 2011 The American Society of Transplantation.


Corey R.,Transplantation Center | Werner K.T.,Transplantation Center | Singer A.,Mayo Medical School | Moss A.,Mayo Medical School | And 3 more authors.
Annals of Hepatology | Year: 2016

Millions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed. © 2016, Fundacion Clinica Medica Sur. All rights reserved.


Kasahara M.,Transplantation Center | Umeshita K.,Osaka University | Inomata Y.,Kumamoto University | Uemoto S.,Kyoto University
American Journal of Transplantation | Year: 2013

The Japanese Liver Transplantation Society (JLTS) was established in 1980 in order to characterize and follow trends in patient characteristics and graft survival among all liver transplant patients in Japan. This study analyzed the comprehensive factors that may influence the outcomes of pediatric patients who undergo living donor liver transplantation (LDLT) by evaluating the largest cohort in the world. Between November 1989 and December 2010, 2224 pediatric patients underwent LDLT in Japan. There were 998 male (44.9%) and 1226 female donors (55.1%) without donor mortalities related to transplant surgery. There were 946 male (42.5%) and 1278 female (57.5%) recipients with a median age of 4.0 years (range: 13 days to 17.9 years). Cholestatic liver disease was the leading indication for LDLT (n = 1649; 76.2%), followed by metabolic disorders (n = 194; 8.7%), acute liver failure (n = 192; 8.6%) and neoplastic liver disease (n = 66; 3.0%). The 1-, 5-, 10- and 20-year patient survival rates were 88.3%, 85.4%, 82.8% and 79.6%, respectively. Blood-type incompatibility, recipient age, etiology of liver disease and transplant era were found to be significant predictors of overall survival. We are able to achieve satisfactory long-term pediatric patient survival outcomes in the JLTS series without compromising the living donors. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.


PubMed | National Center for Child Health and Development and Transplantation Center
Type: | Journal: Hepatology research : the official journal of the Japan Society of Hepatology | Year: 2016

Our aim was to analyze serial changes in the predictive variables and a scoring system retrospectively adapted to evaluate outcomes in pediatric patients with acute liver failure (ALF).We retrospectively collected data on 65 patients with ALF. The 65 patients were divided into 2 groups according to the need for liver transplantation (LT) as follows: LT group (n=54) and non-LT group (n=11). The early determination scoring system of the indications for LT proposed by the Intractable Hepato-Biliary Diseases Study Group of Japan (JIHBDSG) was used in our study. The area under the receiver operating characteristic (AUROC) was calculated for the JIHBDSG score between the LT group and non-LT group at the time of diagnosis (Day 0) and Day 3, and 5 after the diagnosis.A JIHBDSG score of>3 at Day 5 was found to identify the patients requiring LT with 83.7% sensitivity, 81.8% specificity and 83.3% diagnostic accuracy. Based on a comparison of AUROC values, the JIHBDSG score on Day 5 (AUROC 0.91) was higher than that on Day 0 (AUROC 0.75) and Day 3 (AUROC 0.84).We demonstrated that a serial analysis of the JIHBDSG score might be useful for predicting outcomes of ALF in pediatric patients who fulfilled the criteria of LT indication in our center. However, further studies are needed to validate our results.


PubMed | Transplantation Center, Aichi University and Health Science University
Type: Case Reports | Journal: Pediatric transplantation | Year: 2016

MSUD is an autosomal recessive condition characterized by a deficiency in the enzyme, BCKDH, which catalyzes the breakdown of BCAAs. If left untreated, MSUD can result in mental retardation, central nervous system disorders, and even death. Most patients with MSUD are treated with a restricted protein diet and milk from which BCAAs have been removed. LT has been shown effective in patients with MSUD. This report describes the case of a 15-month-old boy who received a liver graft from his mother. Transplantation was successful, and the patient was then able to ingest a normal diet. Despite episodes of acute rejection, chylous ascites, and high fever (40 C), he has shown no evidence of MSUD recurrence. These findings indicate that patients with MSUD can be successfully treated by LDLT, even when the donor is a heterozygous carrier of a mutated BCKDH gene.


PubMed | Kumamoto University, Transplantation Center, Kyoto University and Nagoya University
Type: Journal Article | Journal: Journal of hepato-biliary-pancreatic sciences | Year: 2016

The aim of this study was to analyze the outcomes of deceased donor split liver transplantation (LT) in Japan.Among 257 deceased donor LTs, 36 recipients underwent split LT until the end of 2014. The clinical data of donors and recipients were collected from the national organ transplant network and 11 liver transplant institutions, and the outcomes of split LT were evaluated.Most of the whole livers were divided using the ex-situ splitting technique. Twelve livers were divided to left lateral segment/extended right lobe grafts and six livers to left lobe/right lobe grafts. The common underlying liver diseases consisted of graft failure in 11 patients, followed by acute liver failure in nine. Seventeen cases (48.6%) suffered from surgical complications, including biliary complications in six, all of which occurred in the cases receiving right-sided lobe grafts; intra-abdominal hemorrhage in five; and vascular complications in four. The overall graft 1-year and 3-year survival rates were 91.0% and 87.1%, respectively.An initial experience of deceased donor split LT in Japan shows acceptable outcomes despite the high incidence of surgical complications. Further advances in the development of the splitting technique are necessary to expand the application of split LT.


PubMed | Fukuoka University, Transplantation Center, Juntendo University, Kumamoto University and 7 more.
Type: Journal Article | Journal: Hepatology research : the official journal of the Japan Society of Hepatology | Year: 2016

As of December 31, 2013, a total of 7474 liver transplants have been carried out at 66 institutions in Japan. This total included 7255 living-donor transplants and 219 deceased-donor transplants (216 from heart-beating donors and 3 from non-heart-beating donors). The annual total of liver transplants in 2013 decreased to 408, from 422 in 2012. The number of liver transplants from living donors decreased to 369, from 381, whereas the number of liver transplants from heart-beating deceased donors did not change significantly. The most frequent indication was cholestatic disease, followed by neoplastic disease. In terms of graft liver in living-donor cases, right-lobe graft was the most popular (36%). Patient survival following transplantations from heart-beating donors (1year, 85.9%; 3years, 82.6%; 5years, 81.3%; 10years, 73.8%) was similar to those from living donors (1year, 83.8%; 3years, 79.6%; 5years, 77.1%; 10years, 71.9%; 15years, 67.8%; 20years, 66.1%). Graft survival was very much the same as patient survival. As for ABO-incompatible transplantation, transplant period affected the outcome significantly, probably due to local infusion therapy and rituximab prophylaxis, which were introduced in many transplant centers after 2000 and 2004, respectively.

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