The Journal of clinical endocrinology and metabolism, Jan 18, 2015
Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss ma... more Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses following their acute post-prandial suppression. Randomised placebo-controlled double-blind cross-over experimental medicine studies. Two groups, over 5 months after RYGB for obesity (n = 7-11), compared with non-obese controls (n =10), or patients after gastric banding (BAND) surgery (n = 9). Studies were performed after acute administration of the somatostatin analogue Octreotide or saline. In one study, patients after RYGB, and non-obese controls, performed a behavioral progressive ratio task (PRT) for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging (fMRI) food picture evaluation task. Octreotide increased both...
The management of pancreatic cysts poses challenges to both patients and their physicians. We inv... more The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid-pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53 and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers were compared with that of clinical markers, and a combination of molecular and clinical markers. We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery, and could therefore reduce the number of unnecessary operations by 91%. We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.
Laparoscopic adjustable gastric banding (LAGB) is a popular surgical procedure for the management... more Laparoscopic adjustable gastric banding (LAGB) is a popular surgical procedure for the management of morbid obesity. Gastric band slippage (GBS) is the most common long-term complication. In this study, the effect of GBS on body mass index (BMI) and quality of life (QOL) were assessed. This was a retrospective, case-controlled study. Patient demographics and BMI were prospectively recorded, and QOL was assessed via telephone questionnaire using the medical outcomes study short-form-36 (SF-36). The QOL of the GBS group were compared with an age, sex, and duration of follow-up matched control group who underwent uncomplicated LAGB (n = 10). Seventeen patients with GBS who underwent surgery were identified. Ten patients underwent band removal, and seven underwent revision surgery (six band repositioning and one Roux-en-Y gastric bypass); all were managed laparoscopically. Mean follow-up since re-operation was 17.2 ± 2.9 months. A significant increase in BMI occurred following GBS surgery (29.0 ± 1.5 vs. 33.8 ± 1.0, P = 0.035), which did not differ between the removal or revision groups. Overall, there was no difference in QOL between the GBS and control groups. On subgroup analysis, those who underwent revision surgery had a worse score in limitations in social activities because of physical or emotional problems than those who underwent band removal (92.0 ± 3.9 vs. 70.8 ± 10.0, P = 0.046). Following surgery for GBS, patients experience a rise in BMI. Overall, this does not affect patient QOL but may limit social activities because of physical or emotional problems in those who have band revision surgery.
Hepatobiliary & pancreatic diseases international: HBPD INT
The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma... more The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma of the ampulla of Vater with concurrent amiodarone hepatotoxicity. Painless jaundice associated with a palpable gallbladder was investigated clinically, radiologically, endoscopically and via liver biopsy. Liver biopsy showed amiodarone hepatotoxicity. Endoscopic biopsy identified an ampullary adenoma. However, the endoscopic ultrasound and intra-operative findings suggested a malignancy, which was confirmed postoperatively. While the classic findings of Courvoisier's Law are borne out in this case, the etiology of jaundice is twofold. Although dual pathology is uncommon it should always be considered.
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2015
Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate infla... more Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate inflammatory responses through the rapid production of cytokines. In this article, we show that circulating MAIT cells are depleted in obese adults, and depletion is associated with diabetic status. Circulating MAIT cells more frequently produced IL-17 upon stimulation ex vivo, a cytokine implicated in insulin resistance. MAIT cells were enriched in adipose tissue (AT) compared with blood. AT MAIT cells, but not circulating MAIT cells, were capable of producing IL-10. In AT from obese subjects, MAIT cells were depleted, were less likely to produce IL-10, and more frequently produced IL-17. Finally, we show that IL-17(+) MAIT cells are also increased in childhood obesity, and altered MAIT cell frequencies in obese children are positively associated with insulin resistance. These data indicate that MAIT cells are enriched in human AT and display an IL-17(+) phenotype in both obese adults and ch...
Journal of vascular and interventional radiology : JVIR, Jan 31, 2015
To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver met... more To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver metastases. A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included (N = 301). Twenty-six percent of RF ablation procedures were percutaneous (n = 156), with the remainder conducted at surgery. Forty-eight percent of patients had a concomitant liver resection. Fifty-four percent of patients presented with symptoms, with 92% reporting symptom improvement following RF ablation (alone or in combination with surgery). The median duration of symptom improvement was 14-27 months. However, recurrence was common (63%-87%). RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery.
Hepatobiliary & pancreatic diseases international : HBPD INT, 2007
The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma... more The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma of the ampulla of Vater with concurrent amiodarone hepatotoxicity. Painless jaundice associated with a palpable gallbladder was investigated clinically, radiologically, endoscopically and via liver biopsy. Liver biopsy showed amiodarone hepatotoxicity. Endoscopic biopsy identified an ampullary adenoma. However, the endoscopic ultrasound and intra-operative findings suggested a malignancy, which was confirmed postoperatively. While the classic findings of Courvoisier's Law are borne out in this case, the etiology of jaundice is twofold. Although dual pathology is uncommon it should always be considered.
Involvement of the inferior vena cava (IVC) by neoplasm has traditionally been considered a contr... more Involvement of the inferior vena cava (IVC) by neoplasm has traditionally been considered a contra-indication to curative surgery because of high surgical risks and poor long-term prognosis. Advances in surgical and anaesthetic techniques however have made this feasible. The aim of this study is to evaluate the outcome of combined IVC and visceral resection in a single institution. A retrospective review of a prospectively maintained database was performed. Pre-operative clinicopathological data, operative details and post-operative outcomes including overall and disease-free survival were analysed. Clinicopathological data of patients over a seven-year period undergoing combined IVC and visceral resection was reviewed, including overall and disease-free survival. Between 2006 and 2012, 14 patients underwent IVC resection was accompanied by major hepatectomy (8), nephrectomy (6) and multivisceral resection (3). Post resection, the IVC was reconstructed primarily (3); with PTFE tube graft (9) or using a Gore-tex patch graft (2). All patients underwent a R0 resection. There were two postoperative deaths within 30 days. 6 patients had postoperative complications. There was 1 early and one late (after 6 months) IVC thrombosis. With a median follow up of 20 months (range 5-84 months), two patients died of tumour recurrence and ten are alive with (n = 5) or without (n = 5) disease. Combined IVC and visceral resection can be safely performed in selected patients. Surgery provides the possibility of negative margins, acceptable perioperative morbidity/mortality and prolonged survival. These factors combined with lack of alternative treatments justify this approach. However, specialist teams should perform the surgery preferably in centres with expertise in liver transplantation.
Pancreatic adenocarcinoma has been reported in kindreds with hereditary nonpolyposis colorectal c... more Pancreatic adenocarcinoma has been reported in kindreds with hereditary nonpolyposis colorectal cancer (HNPCC). Medullary carcinoma of the pancreas is a recently described rare variant of pancreatic adenocarcinoma. We describe a man with colorectal carcinoma who subsequently developed pancreatic medullary carcinoma. The tumor displayed microsatellite instability and loss of expression of the mismatch repair proteins MSH2 and MSH6. Mutational analysis of the mismatch repair genes MLH1 and MSH2 demonstrated a pathogenic nonsense mutation within the MSH2 gene, which is consistent with a diagnosis of HNPCC. This report adds support to an association between HNPCC and pancreatic adenocarcinoma displaying the medullary phenotype, suggesting that medullary features in a pancreatic carcinoma may point toward a genetic cancer predisposition. To our knowledge, this is the first reported case of medullary carcinoma of the pancreas in a patient with HNPCC due to a mutation of the MSH2 gene.
Spigelian hernias are a rare abdominal wall hernia. The aim of this study was to assess the effic... more Spigelian hernias are a rare abdominal wall hernia. The aim of this study was to assess the efficacy and outcomes of patients who underwent a laparoscopic spigelian hernia repair. A retrospective study was performed reviewing all patients who had a laparoscopic spigelian hernia repair. We assessed the success of the procedure including conversion rates, postoperative morbidities, and recurrence rates. Forty patents had a laparoscopic repair. Two thirds (n=25) had an intraperitoneal repair. There was no conversion to open repair. Four patients had postoperative morbidities. At 6-month follow-up all patients were pain free, with 1 recurrence. There is considerable evidence supporting the opinion that laparoscopic repair offers excellent outcomes. This report is the largest series to date, and we advocate that this approach should become the standard of care.
The cellular mechanisms involved in mediating cytoprotection against ischemia-reperfusion (IR) in... more The cellular mechanisms involved in mediating cytoprotection against ischemia-reperfusion (IR) injury are not well understood. In animal models, NF-E2-related factor-2 (Nrf2) protects against IR injury by transcriptional activation of phase II antioxidants. Here, we investigate how the expression of Nrf2 mRNA in human donor livers in the setting of liver transplantation (LT) correlates with the histological damage associated with IR injury and whether or not this influences the outcome of LT. Pairs of biopsies were acquired from 14 donor livers; the first biopsy of each pair was taken at the start of the retrieval operation, prior to the IR phase of LT and the second at the end of transplantation. RNA was extracted from snap frozen tissue and cDNA was prepared. Nrf2 mRNA expression was determined using real-time polymerase chain reaction (PCR). The modified Suzuki scoring system was used for histological grading of IR injury and relevant donor, recipient, and after LT clinical data were compiled. Nrf2 expression was observed in all biopsies, both before and after IR. Some donor organs had greater expression of Nrf2 mRNA before IR injury, and these organs had lower Suzuki scores and better liver functions (ALT) after LT. Donors of livers with greater Nrf2 levels were significantly younger (40.5 yrs, range 28-53 yrs) than those with low Nrf2 levels (55.5 yrs, range 48-61 yrs), P<0.05. Livers from older donors have lower levels of Nrf2 perhaps exposing these organs to more IR-related damage.
1 Department of Endocrinology & Diabetes Mellitus, St Vincent's Universi... more 1 Department of Endocrinology & Diabetes Mellitus, St Vincent's University Hospital, Dublin 4, Ireland, 2 Department of Pathology & Laboratory Medicine, St Vincent's University Hospital, Dublin 4, Ireland, 3 Department of Radiology, St Vincent's University Hospital, ...
Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused... more Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease. During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion. Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs. Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity.
The Journal of clinical endocrinology and metabolism, Jan 18, 2015
Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss ma... more Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses following their acute post-prandial suppression. Randomised placebo-controlled double-blind cross-over experimental medicine studies. Two groups, over 5 months after RYGB for obesity (n = 7-11), compared with non-obese controls (n =10), or patients after gastric banding (BAND) surgery (n = 9). Studies were performed after acute administration of the somatostatin analogue Octreotide or saline. In one study, patients after RYGB, and non-obese controls, performed a behavioral progressive ratio task (PRT) for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging (fMRI) food picture evaluation task. Octreotide increased both...
The management of pancreatic cysts poses challenges to both patients and their physicians. We inv... more The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid-pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53 and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers were compared with that of clinical markers, and a combination of molecular and clinical markers. We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery, and could therefore reduce the number of unnecessary operations by 91%. We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.
Laparoscopic adjustable gastric banding (LAGB) is a popular surgical procedure for the management... more Laparoscopic adjustable gastric banding (LAGB) is a popular surgical procedure for the management of morbid obesity. Gastric band slippage (GBS) is the most common long-term complication. In this study, the effect of GBS on body mass index (BMI) and quality of life (QOL) were assessed. This was a retrospective, case-controlled study. Patient demographics and BMI were prospectively recorded, and QOL was assessed via telephone questionnaire using the medical outcomes study short-form-36 (SF-36). The QOL of the GBS group were compared with an age, sex, and duration of follow-up matched control group who underwent uncomplicated LAGB (n = 10). Seventeen patients with GBS who underwent surgery were identified. Ten patients underwent band removal, and seven underwent revision surgery (six band repositioning and one Roux-en-Y gastric bypass); all were managed laparoscopically. Mean follow-up since re-operation was 17.2 ± 2.9 months. A significant increase in BMI occurred following GBS surgery (29.0 ± 1.5 vs. 33.8 ± 1.0, P = 0.035), which did not differ between the removal or revision groups. Overall, there was no difference in QOL between the GBS and control groups. On subgroup analysis, those who underwent revision surgery had a worse score in limitations in social activities because of physical or emotional problems than those who underwent band removal (92.0 ± 3.9 vs. 70.8 ± 10.0, P = 0.046). Following surgery for GBS, patients experience a rise in BMI. Overall, this does not affect patient QOL but may limit social activities because of physical or emotional problems in those who have band revision surgery.
Hepatobiliary & pancreatic diseases international: HBPD INT
The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma... more The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma of the ampulla of Vater with concurrent amiodarone hepatotoxicity. Painless jaundice associated with a palpable gallbladder was investigated clinically, radiologically, endoscopically and via liver biopsy. Liver biopsy showed amiodarone hepatotoxicity. Endoscopic biopsy identified an ampullary adenoma. However, the endoscopic ultrasound and intra-operative findings suggested a malignancy, which was confirmed postoperatively. While the classic findings of Courvoisier's Law are borne out in this case, the etiology of jaundice is twofold. Although dual pathology is uncommon it should always be considered.
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2015
Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate infla... more Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate inflammatory responses through the rapid production of cytokines. In this article, we show that circulating MAIT cells are depleted in obese adults, and depletion is associated with diabetic status. Circulating MAIT cells more frequently produced IL-17 upon stimulation ex vivo, a cytokine implicated in insulin resistance. MAIT cells were enriched in adipose tissue (AT) compared with blood. AT MAIT cells, but not circulating MAIT cells, were capable of producing IL-10. In AT from obese subjects, MAIT cells were depleted, were less likely to produce IL-10, and more frequently produced IL-17. Finally, we show that IL-17(+) MAIT cells are also increased in childhood obesity, and altered MAIT cell frequencies in obese children are positively associated with insulin resistance. These data indicate that MAIT cells are enriched in human AT and display an IL-17(+) phenotype in both obese adults and ch...
Journal of vascular and interventional radiology : JVIR, Jan 31, 2015
To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver met... more To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver metastases. A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included (N = 301). Twenty-six percent of RF ablation procedures were percutaneous (n = 156), with the remainder conducted at surgery. Forty-eight percent of patients had a concomitant liver resection. Fifty-four percent of patients presented with symptoms, with 92% reporting symptom improvement following RF ablation (alone or in combination with surgery). The median duration of symptom improvement was 14-27 months. However, recurrence was common (63%-87%). RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery.
Hepatobiliary & pancreatic diseases international : HBPD INT, 2007
The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma... more The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma of the ampulla of Vater with concurrent amiodarone hepatotoxicity. Painless jaundice associated with a palpable gallbladder was investigated clinically, radiologically, endoscopically and via liver biopsy. Liver biopsy showed amiodarone hepatotoxicity. Endoscopic biopsy identified an ampullary adenoma. However, the endoscopic ultrasound and intra-operative findings suggested a malignancy, which was confirmed postoperatively. While the classic findings of Courvoisier's Law are borne out in this case, the etiology of jaundice is twofold. Although dual pathology is uncommon it should always be considered.
Involvement of the inferior vena cava (IVC) by neoplasm has traditionally been considered a contr... more Involvement of the inferior vena cava (IVC) by neoplasm has traditionally been considered a contra-indication to curative surgery because of high surgical risks and poor long-term prognosis. Advances in surgical and anaesthetic techniques however have made this feasible. The aim of this study is to evaluate the outcome of combined IVC and visceral resection in a single institution. A retrospective review of a prospectively maintained database was performed. Pre-operative clinicopathological data, operative details and post-operative outcomes including overall and disease-free survival were analysed. Clinicopathological data of patients over a seven-year period undergoing combined IVC and visceral resection was reviewed, including overall and disease-free survival. Between 2006 and 2012, 14 patients underwent IVC resection was accompanied by major hepatectomy (8), nephrectomy (6) and multivisceral resection (3). Post resection, the IVC was reconstructed primarily (3); with PTFE tube graft (9) or using a Gore-tex patch graft (2). All patients underwent a R0 resection. There were two postoperative deaths within 30 days. 6 patients had postoperative complications. There was 1 early and one late (after 6 months) IVC thrombosis. With a median follow up of 20 months (range 5-84 months), two patients died of tumour recurrence and ten are alive with (n = 5) or without (n = 5) disease. Combined IVC and visceral resection can be safely performed in selected patients. Surgery provides the possibility of negative margins, acceptable perioperative morbidity/mortality and prolonged survival. These factors combined with lack of alternative treatments justify this approach. However, specialist teams should perform the surgery preferably in centres with expertise in liver transplantation.
Pancreatic adenocarcinoma has been reported in kindreds with hereditary nonpolyposis colorectal c... more Pancreatic adenocarcinoma has been reported in kindreds with hereditary nonpolyposis colorectal cancer (HNPCC). Medullary carcinoma of the pancreas is a recently described rare variant of pancreatic adenocarcinoma. We describe a man with colorectal carcinoma who subsequently developed pancreatic medullary carcinoma. The tumor displayed microsatellite instability and loss of expression of the mismatch repair proteins MSH2 and MSH6. Mutational analysis of the mismatch repair genes MLH1 and MSH2 demonstrated a pathogenic nonsense mutation within the MSH2 gene, which is consistent with a diagnosis of HNPCC. This report adds support to an association between HNPCC and pancreatic adenocarcinoma displaying the medullary phenotype, suggesting that medullary features in a pancreatic carcinoma may point toward a genetic cancer predisposition. To our knowledge, this is the first reported case of medullary carcinoma of the pancreas in a patient with HNPCC due to a mutation of the MSH2 gene.
Spigelian hernias are a rare abdominal wall hernia. The aim of this study was to assess the effic... more Spigelian hernias are a rare abdominal wall hernia. The aim of this study was to assess the efficacy and outcomes of patients who underwent a laparoscopic spigelian hernia repair. A retrospective study was performed reviewing all patients who had a laparoscopic spigelian hernia repair. We assessed the success of the procedure including conversion rates, postoperative morbidities, and recurrence rates. Forty patents had a laparoscopic repair. Two thirds (n=25) had an intraperitoneal repair. There was no conversion to open repair. Four patients had postoperative morbidities. At 6-month follow-up all patients were pain free, with 1 recurrence. There is considerable evidence supporting the opinion that laparoscopic repair offers excellent outcomes. This report is the largest series to date, and we advocate that this approach should become the standard of care.
The cellular mechanisms involved in mediating cytoprotection against ischemia-reperfusion (IR) in... more The cellular mechanisms involved in mediating cytoprotection against ischemia-reperfusion (IR) injury are not well understood. In animal models, NF-E2-related factor-2 (Nrf2) protects against IR injury by transcriptional activation of phase II antioxidants. Here, we investigate how the expression of Nrf2 mRNA in human donor livers in the setting of liver transplantation (LT) correlates with the histological damage associated with IR injury and whether or not this influences the outcome of LT. Pairs of biopsies were acquired from 14 donor livers; the first biopsy of each pair was taken at the start of the retrieval operation, prior to the IR phase of LT and the second at the end of transplantation. RNA was extracted from snap frozen tissue and cDNA was prepared. Nrf2 mRNA expression was determined using real-time polymerase chain reaction (PCR). The modified Suzuki scoring system was used for histological grading of IR injury and relevant donor, recipient, and after LT clinical data were compiled. Nrf2 expression was observed in all biopsies, both before and after IR. Some donor organs had greater expression of Nrf2 mRNA before IR injury, and these organs had lower Suzuki scores and better liver functions (ALT) after LT. Donors of livers with greater Nrf2 levels were significantly younger (40.5 yrs, range 28-53 yrs) than those with low Nrf2 levels (55.5 yrs, range 48-61 yrs), P<0.05. Livers from older donors have lower levels of Nrf2 perhaps exposing these organs to more IR-related damage.
1 Department of Endocrinology & Diabetes Mellitus, St Vincent's Universi... more 1 Department of Endocrinology & Diabetes Mellitus, St Vincent's University Hospital, Dublin 4, Ireland, 2 Department of Pathology & Laboratory Medicine, St Vincent's University Hospital, Dublin 4, Ireland, 3 Department of Radiology, St Vincent's University Hospital, ...
Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused... more Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease. During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion. Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs. Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity.
Uploads