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Biomedical subjects

A G Sheil

Publications and source records attributed to A G Sheil.

At least 37 records · Page 2Linked to original sources
PubMed2000

A biodialysis system for liver support tested in a porcine hepatic failure model.

BACKGROUND: A practical liver support system for patients in fulminant hepatic failure (FHF) remains a needed therapeutic modality. A new method of bioartificial liver support, the liver biodialysis system (LBDS), is described. METHODS: Porcine hepatocytes, removed from direct contact with the treated subject's circulation, are in culture in a bioreactor which is combined in a dialysis circuit for patient treatment. The LBDS was tested in a porcine ischaemic hepatic failure model. RESULTS: The viable hepatocyte content of the bioreactor was 2.49 +/- 0.72 x 10(10). Cells remained viable in culture throughout the experiments (30 +/- 3 h) without evidence of immunological damage. A decrease in the degree of accumulation in the blood of ammonia (P < 0.02) and of 14 amino acids (P < 0.001) was achieved by the LBDS. Cerebral perfusion pressure was maintained at significantly higher levels in LBDS-treated animals (P < 0.05). CONCLUSIONS: In the LBDS, hepatocytes in large numbers and satisfactory culture conditions in a bioreactor have sustained viability and function. When combined in a dialysis circuit for the treatment of FHF pigs, immune reactions between the blood and hepatocytes were prevented and beneficial metabolic effects were observed.

Amino Acids↗
PubMed2000

Liver transplantation in patients with transjugular intrahepatic portosystemic shunts.

BACKGROUND: In patients with intractable oesophageal variceal bleeding, transjugular intrahepatic portosystemic shunts (TIPSS) are being used increasingly as a bridge to orthotopic liver transplantation (OLTx). There is little information in the literature concerning variations in the operative techniques of OLTx required because of the presence of TIPSS. METHODS: A retrospective review of patients treated by TIPSS prior to OLTx was undertaken. The aims were to assess the effectiveness of TIPSS in bridging patients to OLTx and to examine whether TIPSS influence the operative management of OLTx. RESULTS: Over a 4-year period eight adult patients underwent TIPSS insertion prior to OLTx in the Australian National Liver Transplant Unit (ANLTU). Transplantation was performed at a mean of 14.6 (0.3-53.8) months after TIPSS insertion. Prevention of major recurrent variceal haemorrhage prior to transplantation was achieved in six cases. In two patients the stents were predominantly intrahepatic and they did not interfere with OLTx. In five patients the stents extended into the portal vein, requiring removal during OLTx either by division of the stent with the recipient portal vein, followed by removal of the fractured stent wires from the portal veins (n = 3), or by 'endarterectomy' of the recipient portal vein, allowing removal of the intact stent (n = 2). In one case where the stent extended into the suprahepatic inferior vena cava, removal was achieved by traction without difficulty. All patients are alive at a mean of 24 (7-53) months post-transplant and none has portal vein abnormalities. When compared to 178 adult patients who had no TIPSS and underwent primary OLTx during the same study period, there was no difference in the length of operating time or the usage of blood products during OLTx. CONCLUSION: Transjugular intrahepatic portosystemic shunts offer a bridge to OLTx by providing effective control of variceal haemorrhage. In the present series TIPSS did not increase surgical morbidity or mortality, but emphasis is placed upon the need for optimal TIPSS placement within the liver to facilitate subsequent OLTx.

Adult↗
PubMed2000

Pancreatitis in adult orthotopic liver allograft recipients: risk factors and outcome.

Acute pancreatitis (AP) has been described after orthotopic liver transplantation but is uncommon in stable patients after the initial perioperative phase. The aim of this study is to review our experience with AP occurring more than 2 months after primary allografting and determine possible contributing factors plus patient outcome. A review of patient files and the unit database was performed. AP was diagnosed in 9 of 298 patients (3%) on 12 occasions. The incidence of AP was greater in men (8 of 163 men) than women (1 of 135 women; P <.04). Underlying factors to each episode of AP were biliary manipulation (4 of 12 episodes; 33%), history of recent alcohol ingestion (3 of 12 episodes; 25%), and malignancy in the region of the pancreas (2 of 12 episodes; 16%). AP was associated with a diagnosis of either hepatic artery thrombosis combined with biliary tract complications (P <.005) or malignancy (P <.004). In 7 of 12 episodes of AP (58%), conservative management alone was successful. In 3 of 9 patients (33%), subsequent surgery was required. One patient died of pancreatic malignancy. In conclusion, AP is uncommon in stable liver transplant recipients. Male sex, complications of hepatic artery thrombosis, and malignancy in the region of the pancreas are associated with AP in this study.

Acute Disease↗
PubMed2000

Factors affecting hepatocyte viability and CYPIA1 activity during encapsulation.

Hepatocytes encapsulated in alginate-poly-1-lysine-alginate (APA) are used in transplantation studies and in bioartificial liver support systems. Loss of cell viability in the process of APA encapsulation is usually 20-30% while the effect on cytochrome CYP450 activity is rarely reported. This work investigates the negative influences on hepatocyte viability and CYPIA1 activity during APA encapsulation, and reports methods to alleviate these influences by incorporating certain reagents into the encapsulation solution. The results show that loss of hepatocyte viability and CYPIA1 activity was caused almost entirely by extracellular calcium toxicity rather than by mechanical damage (p < 0.05). Use of 10 mM instead of 100 mM calcium chloride (CaCl2) in the encapsulation process improved CYPIA1 activity (p < 0.05), but did not improve hepatocyte viability (p > 0.05) or result in satisfactory microcapsules. Hepatocyte viability was 25% higher (p < 0.05) in CaCl2 than in calcium lactate (CaLa) when the cells were gelled by contact with these calcium solutions at room temperature (RT). Hepatocyte viability showed little improvement by processing at 4 degrees C than at RT in CaCl2 (p > 0.05) but was 23% higher at 4 degrees C than at RT in CaLa (p < 0.05). Calcium used in the process of encapsulation caused cell necrosis rather than apoptosis. Addition of Dulbecco's modified Eagle's medium (containing 10% foetal bovine serum) or 20 mM fructose to the calcium solution did not improve cell survival. However, nifedipine at a final concentration of 25 mM modestly improved hepatocyte survival in solution containing 100 mM CaCl2 (p = 0.003). Glutathione and taurine in certain concentrations showed protective effects against loss of CYPIA1 activity (p < 0.05 and <0.01 respectively). In conclusion, to optimise the use of calcium during the process of encapsulation, CaCl2 is preferred to CaLa and inclusion of nifedipine, glutathione or taurine in 100 mM CaCl2 solution is recommended.

Alginates↗
PubMed2000

Polycystic disease: a rare indication for combined liver and kidney transplantation.

We report on a 52-year-old woman who presented with polycystic disease. Both of her kidneys had been removed and she had undergone one failed kidney transplantation. She had severe symptoms from the polycystic liver. The diseased liver and kidney were both treated successfully by performing a combined liver and kidney transplantation.

Female↗
PubMed1999

Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance.

BACKGROUND: Fully allogeneic liver grafts from piebald virol glaxo to dark agouti rats are spontaneously tolerated, whereas kidney transplants between these strains are rejected. Liver tolerance is broken by donor irradiation or peritransplant corticosteroid treatment of recipient rats, both of which interfere with the activation of recipient cells. METHODS: In this study we used a combination of immunohistochemical staining, reverse transcription-polymerase chain reaction, and terminal deoxynucleotide transferase-mediated dUTP nick end labeling and Annexin-V apoptosis assays to compare donor cell migration, cytokine profiles, and leukocyte apoptosis in grafts and lymphoid organs from tolerant liver and rejecting kidney recipients. We then examined the effect on apoptosis of treatments which abrogate liver tolerance. RESULTS: Liver transplantation in this tolerant strain combination is accompanied by rapid migration of many passenger leukocytes to the recipient spleen and lymph node, concurrent with a marked but transient increase in the amount of mRNA for the cytokines interleukin-2 and interferon-gamma. Apoptotic cells appear promptly in the spleen, their numbers reaching a peak 2 days earlier than has been previously shown for the graft infiltrate. Both CD4+ and CD8+ T cells undergo apoptosis and apoptotic cells are most concentrated among CD25+ T cells. In contrast, renal transplant rejection is associated with limited donor cell migration to lymphoid tissues and significantly less up-regulation of interleukin-2 and interferon-gamma in the spleen. Few apoptotic cells are detected in spleen or graft infiltrate during rejection, whereas apoptotic renal tubular and glomerular cells are found from day 5. Either recipient steroid treatment or donor irradiation significantly reduced the number of apoptotic cells in liver graft infiltrates and recipient spleen. CONCLUSIONS: Taken together, these findings suggest that a mechanism akin to activation-induced cell death, with apoptosis of alloreactive recipient cells may be responsible for the induction of spontaneous liver transplant tolerance.

Animals↗
PubMed1999

Outcome of different models of multiorgan transplantation in rats.

In the PVG (RT1(c)) to DA(RT1(a)) rat combination, liver allografts are spontaneously accepted across a complete MHC barrier while cardiac and renal allografts are rejected. We postulated that this spontaneous liver acceptance was associated with the large quantity of antigen in the transplanted liver. In order to test this hypothesis, we have developed three different models of multiorgan transplantation: model I, triple heart transplantation; model II, triple kidney transplantation; and model III, double heart and double kidney transplantation. The results showed that prolongation of heart and kidney allografts was achieved with the increasing number of organs transplanted. The models proved reliable and useful in transplant immunological studies.

Abdomen↗
PubMed1999

A new vascularized skin transplant model in rats.

The aim of this work was to develop a vascularized skin transplantation model in the rat to allow comparison of the immunological events with those of classic free skin grafts and vascularized organ grafts. Seventy-nine syngeneic transplants were performed using inbred Wistar and PVG rats to develop the model. Epigastric skin flaps were taken with a vascular pedicle of common femoral artery and vein and implanted on the back of the neck. The graft vessels were anastomosed end-to-end and end-to-side to the recipient common carotid artery and external jugular vein with interrupted 10-0 nylon sutures under an operating microscope. A high success rate (11 of 11) was achieved in the final method developed, with light microscopy confirming normal skin structure in the flaps following transplantation. The advantages of the model include comparable skin size to that commonly used for nonvascularized skin grafts, while the physiology in terms of blood supply is similar to that of vascularized organ grafts; the grafts are visible with free access for biopsy; and the size of the graft can easily be varied to allow studies concerning antigen load.

Animals↗
PubMed1999

Lamivudine therapy in patients undergoing liver transplantation for hepatitis B virus precore mutant-associated infection: high resistance rates in treatment of recurrence but universal prevention if used as prophylaxis with very low dose hepatitis B immune globulin.

Recurrent hepatitis B virus (HBV) infection remains a major cause of morbidity and mortality after liver transplantation. Recently, antiviral therapy, such as lamivudine, has become available for prophylaxis against HBV reactivation posttransplantation and for the treatment of HBV recurrent disease. We report our initial experience with lamivudine therapy in patients with precore mutant-associated HBV infection undergoing liver transplantation (n = 29). Outcomes were compared in three patient groups: group 1, precore mutant HBV infection not receiving lamivudine (n = 10); group 2, recurrent precore mutant HBV infection posttransplantation subsequently treated with lamivudine (n = 10); and group 3, HBV precore mutant patients undergoing liver transplantation and receiving lamivudine and low-dose hepatitis B immune globulin (HBIG) from the time of transplantation (n = 9). In group 1, HBV recurred in 9 of 10 patients, with subsequent graft loss in all 9 patients. In group 2, all patients developed HBV recurrence at a mean of 7.3 months posttransplantation and started lamivudine therapy at a median of 16 months posttransplantation. Follow-up on lamivudine therapy was for a median of 11 months. Six of these 10 patients developed mutations in the HBV polymerase gene associated with lamivudine resistance. There were two liver failure-related deaths in this group. In group 3 patients, there was one death from graft-versus-host disease. The remaining 8 patients have been followed up for a mean of 15.6 months posttransplantation, and all remain hepatitis B surface antigen negative and HBV DNA negative. In conclusion, lamivudine therapy in association with low-dose HBIG is effective in preventing HBV reactivation posttransplantation. Rescue therapy with lamivudine in patients with HBV recurrence is only moderately effective, with a 60% lamivudine resistance rate in patients treated for longer than 6 months.

Adult↗
PubMed1999

An active liver transplant programme for hepatocellular carcinoma in cirrhotic patients: is it justified?

Even at an early stage, hepatocellular carcinoma (HCC) in patients with cirrhosis is often deemed unresectable because of limited liver reserve. In these circumstances, liver transplantation (LTx) offers some hope for palliation or cure. The results of LTx for selected cirrhotic patients with HCC were analysed. The outcomes were compared with those of patients who underwent LTx for other forms of hepatic malignancy and those who underwent LTx for non-malignant conditions. Four hundred and eighty LTx were performed in 441 patients between January 1986 and December 1998. Twenty-eight LTx recipients (25 males, 3 females) of mean age 51 (14 63) yr had cirrhosis and HCC. Twenty-seven patients had underlying predisposing conditions (11 had hepatitis B, 10 had hepatitis C, 2 had hepatitis B and C, 1 had haemochromatosis, 1 had autoimmune hepatitis, 1 had alcoholic cirrhosis and 1 had alpha-1 antitrypsin deficiency). In 22 patients, HCC was diagnosed pre-LTx, and in 6 patients, the cancers were discovered incidentally. The average tumour size and number were 2.8 (0.4-11.5) cm and 1.3 (1-4), respectively. Two patients with known HCC died during and shortly after the LTx operation. Of the other patients, 3 died; 1 died of HCC recurrence 18 months post-LTx, 1 died of graft failure from recurrent hepatitis C and 1 died of fungal sepsis. Twenty-three (82%) patients survived to 22.5 (0.5-96) months post-LTx without HCC recurrence and with 1- and 3-yr actuarial patient survival rates of 87 and 76%, respectively. Equivalent survival rates of patients who underwent LTx for other malignancies (n = 11) were 82 and 46% (p = NS), and for those who underwent LTx for benign causes (n = 402), they were 77 and 73% (p = NS). All 15 patients with known HCC, who met the selection criteria now in use, survived. LTx can result in prolonged. cancer-free survival in a good proportion of patients with cirrhosis and HCC, particularly when the cancers are incidental, or when diagnosed pre-LTx, conforming to established selection criteria. An active LTx programme for this group of patients is justified.

Adult↗
PubMed1999

Liver transplantation for hepatocellular carcinoma in cirrhotic patients.

BACKGROUND: Hepatocellular carcinoma (HCC) in patients with cirrhosis, due to a limited liver reserve, is often deemed unresectable, even at an early stage. METHODS: In order to evaluate the ongoing transplant programme for cirrhotic patients with HCC at Royal Prince Alfred Hospital, the results of liver transplantation (LTx) for HCC were analysed and the patient actuarial survival was compared with that of those LTx patients without malignancy. RESULTS: A total of 441 LTx were performed in 404 patients between January 1986 and April 1998. Twenty-four LTx recipients (22 men; two women) of mean age 49 (15-62) years had HCC. Twenty-one had underlying aetiology for their cirrhosis (hepatitis B: n = 9; hepatitis C: n = 8; hepatitis B and C: n = 1; haemochromatosis: n = 1; autoimmune hepatitis: n = 1; alcoholism: n = 1), while three patients had cryptogenic cirrhosis. Six patients had incidental tumours and another two cases were of the fibrolamellar type. The average tumour size and tumour number were 2.9 (0.4-11.5) cm and 1.3 (1-4), respectively. Operative mortality was 4.2% (1/24). The HCC recurrence appeared in one (4.2%) patient (with a 11.5-cm HCC) who died 18 months after LTx. A further two patients died (one graft failure from recurrent hepatitis C and one from fungal sepsis) during follow-up. The overall 1- and 3-year actuarial patient survival rates were 87% and 76%, respectively, and that of patients with benign causes (n = 369) were 77% and 72% (P = NS). CONCLUSION: With careful patient selection, long-term tumour-free patient survival can be achieved. The results support an active transplant programme for selected HCC.

Adolescent↗
PubMed1998

Kinetics of intragraft cytokine expression, cellular infiltration, and cell death in rejection of renal allografts compared with acceptance of liver allografts in a rat model: early activation and apoptosis is associated with liver graft acceptance.

BACKGROUND: Liver transplants in the rat strain combination PVG-to-Dark Agouti are spontaneously tolerated, whereas kidney transplants in the same strain combination are rejected in 7-9 days. METHODS: To identify organ-specific differences that might yield further information about the mechanism of tolerance induction in this strain combination, liver or kidney grafts, spleen, and draining lymph nodes were harvested at days 1, 3, 5, and 7, and examined by immunohistochemistry, terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay, and reverse transcriptase-polymerase chain reaction for interferon-gamma, interleukin (IL)-2, IL-4, and IL-10. RESULTS: Renal allograft rejection was associated with the progressive development of an intense mononuclear cell infiltrate. Markers of lymphocyte activation and cytokine up-regulation appeared from day 3, and many apoptotic parenchymal cells were noted on days 5-7, at the peak of rejection. Conversely, liver allograft tolerance was associated with more rapid infiltration by activated T cells and earlier increases in cytokine expression, but with a more limited degree of cellular infiltration. Concurrent with the early activation, high levels of apoptosis were found in areas of leukocyte infiltrate, paralleling the disappearance of activated T cells from the graft between days 3 and 5. CONCLUSIONS: Apoptosis of infiltrating leukocytes in liver allografts may represent an important process in the induction of spontaneous liver transplant tolerance and may underlie the abortive nature of the effector response observed within tolerated livers. In contrast, activated cells in renal allografts in the same strain combination survive and proliferate, express high levels of cytokines, and are efficient in bringing about graft destruction.

Animals↗
PubMed1998

Conversion of pancreas allograft rejection to acceptance by liver transplantation.

BACKGROUND: Liver allografts of PVG(RT1c)-->DA(RT1a) are spontaneously accepted, whereas pancreas, heart, and kidney allografts are rejected. Our previous studies have shown that simultaneous liver and pancreas transplantation prevents pancreas allograft rejection. The aim of this study was to examine the effect of liver transplantation on subsequent pancreas allografts and on ongoing pancreas rejection. METHODS: Heterotopic, duct-ligated segmental pancreas grafts were transplanted into streptozotocin-induced diabetic recipients (60 mg/kg body weight i.p.) with or without orthotopic liver grafting at different times. Experimental design was as follows. Group 1 received PVG-->PVG pancreas syngrafts (n=6); group 2, PVG-->DA pancreas allografts (n=7); groups 3-5, PVG-->DA pancreas allografts followed by liver transplantation on day 2 (n=6), on day 4 (n=5), and on day 6 (n=5), respectively, group 6, PVG-->DA pancreas allografts after liver transplantation at 4 weeks (n=6). RESULTS: The results showed that pancreas allografts in group 2 were rejected from postoperative day 7 to 13. Liver transplantation prevented subsequent pancreas allograft rejection in group 6. Ongoing pancreas rejection was reversed by liver transplantation with subsequent graft acceptance in groups 3-5. Significant graft-infiltrating lymphocyte apoptosis was demonstrated at 2 weeks in pancreas transplants associated with liver grafting. Graft-versus-host disease was not detected in the pancreas recipients. CONCLUSIONS: We conclude that pancreas allografts in the PVG-->DA combination are rejected rapidly with median survival time of 9 days. Liver transplantation can protect subsequent pancreas grafts from rejection and reverse ongoing pancreas graft rejection with subsequent pancreatic acceptance. Graft-infiltrating lymphocyte apoptosis may be associated with the process of graft acceptance.

Animals↗