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We have developed the surgical techniques of living donor liver transplantation (LDLT) for Budd-Chiari syndrome (BCS) and evaluated long-term outcomes including specific complications. BCS is characterized by hepatic outflow obstruction. Liver transplantation from living donors poses a unique challenge as liver replacement therapy does not replace the retrohepatic segment of inferior vena cava (IVC). We have performed 1105 LDLTs in 1055 patients from January 1990 to March 2005. Of these, nine patients (eight males and one female) underwent LDLT for BCS. Five out of nine patients underwent LDLT as a primary procedure and four patients had received other treatments before transplantation. Eight patients presented with chronic and one with fulminant liver failure. Predisposing factors were identified in three patients. IVC reconstruction without patch plasty was performed on four patients. Five patients needed cavoplasty using a replacement vein graft. Of the nine patients, seven are alive at a median follow-up of 58 months (range 1 month to 15.2 years) with two patients developing recurrent hepatic vein stenosis which were treated successfully with metallic stent placement. Two patients died: one from multiorgan failure and the other from pulmonary embolism secondary to disease recurrence. LDLT for BCS is highly effective by using modified cavoplasty and provides good long-term survival which may be obtained by life-long anticoagulant treatment and nonsurgical interventions.
BACKGROUND: The incidence of gallstones is higher in people who have undergone gastrectomy than in the general population, but the cause of this is unknown. METHODS: Between January 1992 and January 2003, 749 patients underwent ultrasonography of the gallbladder after gastrectomy for gastric cancer. A total of 2327 examinations were carried out. The incidence of gallstones was compared in subgroups of patients classified according to the type of reconstruction, extent of gastrectomy, whether the duodenum was excluded and type of lymph node dissection. RESULTS: The incidence of gallstones was significantly higher after total compared with partial gastrectomy (27.9 versus 7.8 per cent at 5 years; P < 0.001). Reconstruction with duodenal exclusion was associated with a significantly higher incidence than non-exclusion (25.1 versus 8.2 per cent at 5 years; P < 0.001). Patients who had lymph node dissection in the hepatoduodenal ligament had a significantly higher incidence of gallstones than those who did not (28.2 versus 7.5 per cent at 5 years; P < 0.001). In multivariate analysis that included type of reconstruction and lymph node dissection, lymph node dissection in the hepatoduodenal ligament was identified as the most significant risk factor for gallstone development (odds ratio 3.66 (95 per cent confidence interval 2.16 to 6.22); P < 0.001). CONCLUSION: Lymph node dissection in the hepatoduodenal ligament, total gastrectomy and exclusion of the duodenum are risk factors for gallstones after gastrectomy.
Metabolic liver disease can be cured by orthotopic liver transplantation. Some successful cases of whole or partial liver transplantation have been reported. Because liver function in these recipients is normal save for the production of the responsive metabolic factor, auxiliary partial orthotopic liver transplantation (APOLT) may produce a benefit. However, no experimental model of APOLT for metabolic liver diseases has been reported. We established a canine APOLT model to evaluate the clinical feasibility and efficacy of APOLT to cure hemophilia. The donor normal beagle dog was used to establish an APOLT model. A left lobe partial liver graft taken from the donor was orthotopically transplanted to the recipient after resection of the native left lobe preserving the native right lobe. Recipients showed no atrophy and comparable blood flow in both the graft and the native liver at the time of exploration after APOLT. Thus, APOLT was performed from a normal donor to a recipient with hemophilia A. In this recipient, blood factor VIII activity markedly increased after APOLT and was maintained for 7 weeks. No episode of bleeding was seen during the observation. In conclusion, a canine APOLT model was successfully established as evidenced by sustained production of factor VIII in a hemophilia recipient. These findings suggest the clinical feasibility and efficacy of APOLT for metabolic liver diseases.
The novel approach of tissue engineering to treat many forms of liver diseases using hepatocytes requires sufficient numbers and sustained survival of the transplanted cells. It has been shown that providing extracellular matrix components extracted from Engelbreth-Holm-Swarm cells (EHS-ECMs) to heterotopically transplanted hepatocytes allows significantly greater hepatocyte survival. We investigated the survival and morphology of hepatocytes and EHS-ECMs transplanted under the kidney capsule compared with hepatocytes with growth factor-reduced EHS-ECMs in mice. Both the EHS-ECMs and growth factor-reduced EHS-ECMs showed a large number of surviving hepatocytes under the kidney capsule without any intergroup differences. Histologically, transplanted hepatocytes in both groups retained their characteristic morphologies and formed small liver tissues. These data indicate that extracellular matrix components are the predominant factor in EHS-ECMs required to maintain hepatocytes at heterotopic sites.
BACKGROUND: Hepatocellular carcinoma (HCC) commonly develops in patients with chronic hepatitis. Intrahepatic recurrence after hepatectomy often includes nodules of new tumour in the liver remnant. The aim of this study was to examine hepatitis-related factors that might predict this type of recurrence. METHODS: The influence of various hepatitis-related factors on intrahepatic recurrence of HCC was studied by multivariate analysis in 138 patients who underwent curative resection and were followed for more than 2 years. RESULTS: The Cox proportional hazard model showed that histological evidence of fibrosis of the underlying liver was the most significant predictive factor for intrahepatic recurrence (P = 0.001). Serum albumin level was also significantly associated with recurrence (P = 0.038). The relative risks of histological fibrosis and low serum albumin levels were 8.9 and 1.7 respectively. Among tumour-related factors, only tumour size was significantly associated with recurrence (P = 0.017). Major hepatectomy was also an independent risk factor for intrahepatic recurrence (P = 0.004). CONCLUSION: Histological evidence of fibrosis and low serum albumin levels are useful predictors of intrahepatic recurrence after hepatectomy, presumably owing to metachronous multifocal tumour in the liver remnant.
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BACKGROUND: In clinical organ transplantation monoclonal antibodies (mAb) to different surface molecules of immunocompetent cells become integral parts of the immunosuppressive therapy. In this study, a mAb against the rat leukocyte common antigen CD45 (RT7) was tested for its immunosuppressive potency after a single perioperative injection. METHODS: Binding and depleting properties of the anti-RT7 mAb were investigated by flow cytometry. In the fully major histocompatibility complex-disparate heart and skin transplantation models (LEW [RT1l]--> LEW.1W [RT1u]), a single dose of anti-RT7 mAb (10 mg/kg) was administered intravenously (day -1). To characterize the long-term acceptance of heart allografts second set skin transplantation (day 100), mixed lymphocyte reaction studies (day 100) and reverse transcriptase-polymerase chain reaction analysis for intragraft cytokine expression (day 200) were performed. RESULTS: The anti-RT7 mAb bound to nearly all hematopoietic lineage cells, but particularly T and NK cells, and profoundly depleted these cells in circulation and lymphoid tissues. Anti-RT7 mAb-treated rats showed long-term acceptance of heart allografts (>200 days; n=12), whereas untreated recipients rejected allografts by day 8 (n=6). In contrast to hearts, primary skin allograft survival was only moderately prolonged. Animals with stable heart allograft acceptance showed normal in vitro lymphocyte proliferation responses to donor and third party antigen. These recipients also acutely rejected second set donor-strain skin grafts without inducing rejection of persisting heart allografts. Reverse transcriptase-polymerase chain reaction analysis of intragraft cytokines showed up-regulation of Fas-ligand and IL-4 mRNA in long-surviving heart allografts. CONCLUSIONS: The findings demonstrate that a single injection of an anti-RT7 mAb in the rat can induce stable long-term acceptance of heart allografts by transient but profound T-cell depletion. Local immunoregulatory mechanisms seem to play a role for maintenance of long-term graft acceptance.
Recent studies suggest that cytotoxic T-lymphocytes expressing p38 mitogen-activated protein kinase (p38MAP kinase) contribute to allograft rejection in clinical heart transplantation. Interleukin-2 (IL-2), a potent T cell mitogen, activates the p38MAP kinase pathway, resulting in phosphorylation of target transcription factors. In this study we investigated the expression of activated p38MAP kinase in intragraft cell infiltrates following rat heterotopic small bowel transplantation and examined the effects of the immunosuppressant FK506 on intragraft expression of activated p38MAP kinase and allograft rejection. Allografts receiving FK506 (0.5 mg/kg per day i. m.) for 7 days as primary anti-rejection therapy had a significant reduction in histopathological evidence of allograft rejection on Day 7, compared to allograft controls. In addition, Western blotting analysis of intragraft cell infiltrates showed a reduction in the expression of activated p38MAP kinase in allografts treated with FK506. We conclude that intragraft cell infiltrate expression of activated p38MAP kinase is an important marker of acute rejection in this animal model of small bowel transplantation, and that FK506 is an effective immunosuppressant, in this situation, that may act in part by preventing the activation of p38MAP kinase.
OBJECTIVE: Organ allografts contain passenger leukocytes that are transferred to the recipient with the transplantation, but their functional relevance to the recipient's immune system is still controversial. MATERIALS AND METHODS: To clarify the functional capacity of passenger leukocytes, we attempted to enhance their effect in rat heart allograft recipients by selective depletion of recipient leukocytes using a monoclonal antibody (mAb) against a recipient-specific allotype of CD45 (RT7(a)). RESULTS: Although antibody treatment of the recipient alone led to profound lymphopenia and reversible myelosuppression, additional transplantation of an major histocompatibility complex-incompatible heart graft from an RT7(b) donor led to lethal aplastic anemia in the recipients. This lethal effect was completely abrogated by postoperative anti-CD3 treatment of the recipient and was partially abrogated or delayed by depletion of passenger leukocytes through additional anti-RT7(b) antibody treatment of the recipient or gamma-irradiation of the graft. CONCLUSIONS: The results suggest a role for both donor and recipient-type T cells for the induction of aplastic anemia in this model. The study shows that, under defined conditions, allogeneic passenger leukocytes in a heart graft can have a profound effect on the recipient's immune system and bone marrow.
BACKGROUND: Although hepatectomy has been accepted as a therapeutic option for the primary tumor of hepatocellular carcinoma (HCC), what role the second liver resection will play in the clinical care of patients with intrahepatic recurrence of HCC after the initial resection has not been well evaluated. STUDY DESIGN: In a retrospective review of the 6-year period between January 1991 and December 1996, records were examined of 94 patients who underwent curative liver resection for HCC. Of these, 57 patients had isolated recurrent disease to the liver; 12 of the 57 patients underwent repeat surgical resection and 45 patients received nonsurgical ablative therapy. Clinical data for these patients were reviewed for operative morbidity and mortality, survival, disease-free survival, and pattern of failure. RESULTS: There were no perioperative deaths during repeat liver resections for recurrent HCC. Operative morbidity in the second resection was comparable to the initial resection. The disease-free survival rate after the second hepatectomy was 31% at 2 years, significantly lower than that after initial hepatectomy (62%) (p = 0.009). The overall survival rate after the second hepatectomy was 90% at 2 years, in contrast to 70% after nonsurgical ablative treatment for recurrent HCC (p = 0.253). CONCLUSIONS: Although the second liver resection for recurrent HCC can be performed safely and may improve survival, the disease-free survival rate after such resection therapy is low. This likelihood of further recurrences encourages studies for the selection of patients who may benefit from repeat liver resection.
Methanol extract (RM-ext) obtained from the dried rhizome of Rheum undulatum was screened for activity in experimental models of type I allergy. RM-ext exhibited the inhibition on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and an antigen-induced histamine release from rat peritoneal mast cells. Among nine stilbenes isolated from RM-ext, seven inhibited the histamine release. Rhapontigenin (compound 1), piceatannol (2) and piceatannol 3'-beta-D-glycoside (6) with oral administration showed the inhibition on PCA. Compounds 1 and 2 exhibited the inhibitory effect on sheep red blood cell-induced delayed-type hyper sensitivity (SRBC-DTH) of type IV allergic model. These results indicated that the rhizome of Rheum undulatum inhibits the allergic reactions and that these inhibitory effects may be partially attributable to the stilbenes mentioned above.
Foam fractionation is a simple, inexpensive method for separating and purifying proteins. Typically, a dilute bromelain solution with a pH ranging from 2.0 to 7.0 foams very well when bubbles are introduced into a foam fractionation column. It was observed, however, that the dilute enzyme solution only foamed between approximately pH 2.0 and 3.0 when the inner wall of the fractionation column was coated with a natural contaminant (okra residue). We studied the separation ratio and the protein mass recovery to explore the effect of a natural antifoaming agent on the foam fractionation of a dilute bromelain solution. The control variables used in this process were the initial bulk solution pH, which ranged from 2.0 to 7.0, and the superficial air velocity, which varied between 1.7 and 6.2 cm/s.
Cystic fibrosis (CF) affects the function of multiple organs. The inability to maintain luminal hydration of ducts leads to their plugging and destruction of the affected organs. An exacerbating problem is the acidic pH of the fluid produced by CF patients' secretory glands. This is best documented for pancreatic secretion. Alkaline fluid secretion requires vectorial transport of electrolytes and of HCO(3)(-). The mechanism of HCO(3)(-) secretion by cystic fibrosis transmembrane conductance regulator (CFTR) expressing cells is not well understood. In the present communication we discuss results suggesting that CFTR itself can transport large amounts of HCO(3)(-) and that HCO(3)(-) transport by CFTR is mediated by a coupled, Cl(-)-dependent process that is different from a simple HCO(3)(-) conductance.
The aim of this study is to examine the effect of hyperthermia on tumour necrosis factor-alpha (TNF-alpha) resistance in L929-11E cells. L929-11E is a TNF-alpha resistant variant derived from L929 cells, a commonly used model for TNF-alpha study. Based on the results from flow cytometry and Western blotting, hyperthermia (43 degrees C, 3 h) was found to induce apoptosis, mitochondrial potential (delta psi(m)) depolarization and release of cytochrome c in L929-11E cells. Similar responses were found in L929 cells when treated with TNF-alpha. Heating at 43 degrees C for 1 h did not significantly damage the mitochondria of L929-11E cells but partially reversed their resistance to TNF-alpha. When L929-11E cells were sequentially treated with heating (43 degrees C, 1 h) and TNF-alpha, a more severe damage in mitochondria was observed. Taken together, our results indicate (1) hyperthermia induced apoptosis in L929-11E cells via mitochondrial damages in a way very similar to the action of TNF-alpha in L929 cells, (2) hyperthermia could be used to overcome TNF-alpha resistance by altering mitochondrial activities and (3) L929-11E and its parental cells provide a useful model in elucidating the signalling linkage between TNF-alpha receptor and mitochondria.
Hyperthermia is a potential anti-cancer regimen but the mode of action is far from clear. Based on the flow cytometric analysis with FITC-annexin V and propidium iodide, apoptosis was found to be the major form of cell death after the treatment with hyperthermia (43 degrees C, 3 h) and/or recombinant murine tumour necrosis factor-alpha (TNF-alpha, 50 ng/ml) in L929 cells. Since mitochondria are thought to play a key role in apoptosis, experiments were done to assess their role in the hyperthermia-mediated apoptosis. Our results indicate that hyperthermia was able to depolarize the mitochondrial membrane potential (delta psi m) and release cytochrome c to the cytoplasm, in a way very similar to the action of TNF-alpha. With the use of cyclosporin A to inhibit the delta psi m dissipation, the cytotoxicity mediated by hyperthermia or TNF-alpha was suppressed. Taken together, our results indicate that hyperthermia and TNF-alpha can induce apoptosis in L929 cells and the mitochondrial dysfunction plays a key role in the cell death process.
The average mass composition of cosmic rays with primary energies between 10(17) and 10(18) eV has been studied using a hybrid detector consisting of the High Resolution Fly's Eye (HiRes) prototype and the MIA muon array. Measurements have been made of the change in the depth of shower maximum and the muon density as a function of energy. The results show that the composition is changing from a heavy to lighter mix as the energy increases.
BACKGROUND: Donor leukocytes may exert positive immunoregulatory effects on allograft acceptance. Most recent studies have focused on pretreatment protocols. In this study, the effect of postoperative infusion of donor leukocytes on graft survival and the phenotypic and functional requirements for infused cells were investigated in fully major histocompatibility complex (MHC)-mismatched rat heart transplant models. METHODS: LEW (RT1l) heart grafts were implanted heterotopically into abdomens of LEW.1W (RT1u), and different types of cells were infused postoperatively. Immunohistochemistry was used to evaluate histopathological changes of grafts. RESULTS: In the absence of any immunosuppressive agents, a single dose of viable donor spleen cells (SC), but not bone marrow cells, was able to prolong heart allograft survival to about 21 days, while they were rejected promptly at day 7 in controls. Infusion of T cell-depleted donor SC, irradiated donor SC or third-party (BN) SC showed no effect on graft survival. Compared with resting cells, neither in vitro nor in vivo prestimulation of infused donor SC improved graft survival. Clinical signs of graft-versus-host reaction were not observed in all above groups. Histology showed remarkable reduction in the severity of graft infiltrate and interleukin-2 receptor-positive cells in grafts of cell-treated animals. Postoperative infusion of SC of F1 generation between different strain combinations showed two requirements for infused cells to be effective: (1) expression of donor-type MHC antigens and (2) strong alloreactivity against the host MHC antigens. CONCLUSION: Postoperative infusion of viable donor SC can lead to allospecific down-regulation of alloreactivity by a graft-versus-host-associated effect.