Magnetic resonance (MR) imaging and MR spectroscopy of nerve regeneration and target muscle energy metabolism in a model of prosthesis-guided reinnervation in rats.

RATIONALE AND OBJECTIVES: We monitored the regeneration of the rat sciatic nerve after its transection and the concomitant alteration in the high-energy phosphates content in the target tibialis anterior muscle. METHODS: Rat sciatic nerve was resected and the gap connected with a prosthesis of polytetrafluoroethylene. Progress of reinnervation was monitored by 1H MR imaging, whereas muscular energy metabolism was evaluated by localized 31P MR spectroscopy. RESULTS: Reconstitution between the nerve stumps was resumed 8-12 weeks postoperatively. The ratio of phosphocreatine to inorganic phosphate reached a plateau at 46% of the initial level approximately 8 weeks after the operation and recovered thereafter. Immediately after the surgery, muscular pH became slightly alkaline and returned to normal with the progress of reinnervation. CONCLUSION: Recovery of the muscular energy metabolism began after the reconnection of the severed nerve stumps. The combination of MR imaging and MR spectroscopy followed noninvasively the progress of reinnervation and muscular energy metabolism of the prosthesis-guided nerve regeneration.

Transhepatic balloon dilation of biliary strictures in liver transplant patients: a 10-year experience.

PURPOSE: The authors report their initial and long-term results using transhepatic balloon dilation to treat biliary strictures in liver transplant patients. PATIENTS AND METHODS: Over a 10-year period, 72 liver transplant patients with biliary strictures underwent 81 balloon dilation treatments. Anastomotic strictures were present in 56 patients; nonanastomotic strictures were present in 16. RESULTS: Initial technical success was achieved in 64 of 72 patients (89%). Balloon dilation failed in eight patients (11%), and they were treated surgically. Complications occurred in nine (12%) patients, and all were successfully treated. Within the first 6 months, five patients (6.9%) required surgical revision. Three patients (4.2%) underwent repeated liver transplantation; and five patients (6.9%) died. Fifty-one patients in whom balloon dilation was initially successful were available for at least a 6-month follow-up. Life-table analysis showed an overall 81% +/- 4.8 success rate at 6 months; it dropped to 70% +/- 6.2 at 6 years. For anastomotic strictures, it was 77% +/- 5.8 at 6 months and 66% +/- 7.3 at 6 years. For nonanastomotic strictures, it was 94% +/- 6.2 at 6 months, which dropped to 84% +/- 10 at 5 years. CONCLUSION: Transhepatic balloon dilation represents an effective and relatively safe treatment for biliary stricture in liver transplant recipients.

Early death or retransplantation in adults after orthotopic liver transplantation. Can outcome be predicted?

Early, reliable outcome prediction after a liver transplant would help improve organ use by minimizing unnecessary retransplantations. At the same time, early intervention in those cases destined to fail may ameliorate the high morbidity and mortality associated with retransplantation. The purpose of this study was to analyze several parameters that have been identified in the past as being associated with patient and graft outcome, and to try to develop a model that would allow us to make predictions based on data available in the early postoperative period. A total of 148 patients were followed in a prospective, observational study. Graft failure was defined as patient death or retransplantation within 3 months of surgery. Preoperative variables studied included patient demographics, need for life support, presence of ascites, serum bilirubin, serum albumin, prothrombin time, serum creatinine, and the results of the cytotoxic crossmatch. During the first 5 postoperative days, standard measurements included serum transaminases, serum bilirubin, ketone body ratio, prothrombin time, factor V, and serum lactate. Oxygen consumption was measured shortly after surgery, once the patients had rewarmed to 36 degrees C. There were 131 successful transplants (88.5%) and 17 failures (11.5%). Most of the variables studied were found to be associated with outcome (by univariate analysis) at different points in the early postoperative period. However, receiver operating characteristic curve analysis showed that the predictive ability of even the best parameter was not adequate to make decisions on individual patients. Multivariate analysis, using stepwise logistic regression, yielded a model with an overall accuracy of 92.7%. Again, receiver operating characteristic curve analysis suggested that this model did not achieve the discriminating power needed for routine clinical use. We are still not able to accurately predict outcome in the early posttransplant period. We must be very careful when evaluating parameters, or scoring systems, that are said to accomplish this. It is especially important in this era of cost containment, with its renewed pressures to guide therapy based on our perceived understanding of a patient's future clinical course.

Xenotransplantation rejection is antibody-mediated in both sensitized and nonsensitized recipients.

This study analyzes the mechanisms involved in xenotransplantation rejection between closely related species. Hamster hearts were transplanted heterotopically into both normal rats and rats previously sensitized by the transfusion of donor blood. Sequential ultrastructural and immunohistochemical analyses were performed on the grafts, spleens, and sera. The data obtained support the view that induced antibodies directed against the xenograft endothelium play a very important role in producing graft damage. Moreover, the demonstration of antibodies against myocyte determinants suggests that it is possible, in this particular model, that the antiendothelial antibodies are not the only ones involved in the injury process.

Hepatic resection for cystic lesions of the liver.

OBJECTIVE: The purpose of this study was to report the authors' experience with hepatic resection for cystic lesions of the liver. SUMMARY BACKGROUND DATA: Past experience with aspiration, sclerosing therapy, internal drainage, fenestration, and marsupialization are of limited value. Hepatic resection has evolved into a safe operation over the last two decades. METHODS: A retrospective study of 44 patients with various cystic lesions of the liver (polycystic disease, 2; solitary or multiple congenital cysts, 19; biliary cystadenoma, 6; cystadenocarcinoma, 3; squamous cell carcinoma, 3; Caroli's disease, 5; and hydatid cyst, 6) was performed. RESULTS: After 7 trisegmentectomies, 24 lobectomies, 6 left lateral segmentectomies, and 7 nonanatomical hepatic resections, only 1 operative death occurred in a Jehovah's Witness. Symptomatic relief was complete and permanent in all of the patients with benign congenital or parasitic hepatic cysts, except for the two patients with polycystic disease of the liver. One of the 3 patients with adenocarcinoma and 3 patients with squamous cell carcinoma of the cyst wall died of tumor recurrence between 3 and 14 months after hepatic resection. CONCLUSIONS: Hepatic resection is safe and effective for cystic lesions of the liver. Symptomatic relief is complete and permanent after hepatic resection, except in cases of diffuse polycystic disease of the liver. Liver transplantation should be considered for diffuse polycystic disease of the liver when the symptoms are extremely severe.

FK 506 pre-treatment is associated with reduced levels of tumor necrosis factor and interleukin 6 following hepatic ischemia/reperfusion.

Using a rat model, the effect of pre-treatment with FK 506 on hepatic ischemia/reperfusion injury was investigated. All control animals died within 72 h of the ischemia/reperfusion injury. Pre-treatment of the animals with FK 506 (0.3 mg/kg in 0.5 ml saline) administered intravenously improved survival. The most striking protection against fatal ischemia/reperfusion injury was achieved in rats that were given FK 506 6 and 24 h prior to the induction of the hepatic ischemic insult (70% and 80% 10-day survival rates, respectively). The hepatoprotective effect of FK 506 was assessed further in a second experiment in which the serum levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were measured. These results suggest that a 60-min period of hepatic ischemia and subsequent reperfusion triggers the release of both TNF and IL-6, and that FK 506 pre-treatment (6 h before the ischemic episode) significantly inhibits the production and/or release of these two cytokines compared to untreated controls. These data provide additional information concerning the immunosuppressive and hepatoprotective activities of FK 506. Based upon these data, it is probable that FK 506 attenuates hepatic ischemia/reperfusion injury, at least in part, by reducing TNF and IL-6 levels.

The protective effect of FK506 pretreatment against renal ischemia/reperfusion injury in rats.

The effect of pretreatment with FK506 on renal ischemia and reperfusion (I/R) injury was investigated using a rat model. Animals were assigned to one of two groups (20 rats each). Group 1 animals (controls) received 0.5 ml saline while group 2 animals received FK506 (0.3 mg/kg), administered intravenously 24 hr prior to the induction of renal ischemia. A 60-min period of ischemia of the right kidney was induced, and upon reperfusion a left nephrectomy was performed. Blood samples for estimation of BUN, creatinine, and tumor necrosis factor were collected on days 0 (preischemia), 1, 2, 3, 5, 7, and 10 (postischemia). Rats were sacrificed after day 10 and renal tissue was examined histologically. All animals survived the ischemic episode. FK506 pretreatment significantly reduced the serum levels of BUN (P less than 0.02), creatinine (P less than 0.02), and TNF (P less than 0.05) as compared with that seen in controls. Histologically, at day 10, the kidneys showed the expected sequelae of prior renal I/R with various degrees of tubular damage. However, no objective differences were evident between the two groups. Based upon these data, it can be concluded that (1) FK506 pretreatment ameliorates the functional renal injury associated with I/R, (2) renal ischemia induces the release of TNF, and (3) FK506 pretreatment results in a significant inhibition of TNF production. These data suggest that the release of TNF may be responsible for the increasing of BUN and creatinine levels seen after renal I/R and that pretreatment of renal donors with FK506 may improve renal function in the immediate post-transplant period.

Liver transplantation for arteriohepatic dysplasia (Alagille's syndrome).

Thirteen out of 268 children (less than 18 years old) underwent hepatic transplantation (OLT) for end-stage liver disease (ESLD) associated with arteriohepatic dysplasia (AHD). Seven children are alive and well with normal liver function. Six children died, four within 11 days of the operation and the other two at 4 and 10 months after the OLT. Vascular complications with associated septicemia were responsible for the deaths of three children. Two died of heart failure and circulatory collapse, secondary to pulmonary hypertension and congenital heart disease. The remaining patient died of overwhelming sepsis not associated with technical complications. Seven patients had a portoenterostomy or portocholecystostomy early in life; five of these died after the OLT. Severe cardiovascular abnormalities in some of our patients suggest that complete hemodynamic monitoring with invasive studies should be performed in all patients with AHD, especially in cases of documented hypertrophy of the right ventricle. The improved quality of life in our surviving patients confirms the validity of OLT as a treatment of choice in cases of ESLD due to AHD.

FK 506 reduces the injury experienced following renal ischemia and reperfusion.

The effect of FK 506 pretreatment on renal ischemia and reperfusion (I/R) injury was investigated. Adult male rats were assigned to one of two groups (20 animals each). Group 1 (controls) received 0.5 mL saline while group 2 received FK 506 (0.3 mg/kg) intravenously 24 h prior to the induction of renal ischemia. After a 60-min period of ischemia of the right kidney, a left nephrectomy was performed. Blood for BUN, creatinine, and tumor necrosis factor (TNF) was obtained prior to ischemia and on days 1, 2, 3, 5, 7, and 10. All surviving animals were sacrificed at day 10. FK 506 pretreatment reduced the serum levels of BUN (p less than .02), creatinine (p less than .02) and TNF (p less than .05) as compared to that seen in controls. Based upon these data, it appears that: (a) renal ischemia induces the release of TNF; (b) FK 506 pretreatment inhibits TNF production; and (c) FK 506 reduces renal injury association with I/R.

Antibody binding to endothelial and epithelial antigens triggers pig-to-rabbit xenograft rejection and its absence results in atypical complement deposition.

In pig-to-rabbit kidney xenograft (PRKX), endothelial antigen determinants (EAD) are immediately recognized by IgG and IgA, while IgM does not react with them. The purpose of this study was to investigate the different roles of IgG, IgA, IgM, and complement in the hyperacute rejection of a PRKX model. Nine isolated Landrace pig kidneys were each perfused with 10 ml normal New Zealand rabbit serum. Perfusates (serum A) were collected after discarding the first 0.5 ml. Serum A and rabbit complement were then incubated for 30 min with frozen sections of normal pig kidney. After washing with buffer solution all the specimens were treated for immunohistochemistry. Three frozen sections of normal Landrace pig kidney and three samples of normal New Zealand rabbit serum were used as controls. Immunohistochemical analysis of the nine perfused kidneys demonstrated IgG, IgA and C3 deposition on the peritubular and glomerular vascular endothelium. No IgM reactivity was shown. In the frozen sections exposed to serum A, immunofluorescence showed minimal IgG, IgA and C3 reactivity while IgM deposition was clearly evident on the tubular epithelium. Immunofluorescence of frozen sections exposed to rabbit complement, done by fluorescein-labeled goat anti-rabbit C3 antibodies were positive only in the glomerular endothelium. The same rabbit complement was active in antibody dependent cytotoxicity on human T cells. Our results indicated that in the PRKX model, IgG and IgA acted as preformed antibodies recognizing endothelial EAD. IgM did not bind to any endothelial molecules, but recognized antigens located on the brush border of the tubular epithelium. Furthermore, in this model, absence of antigen-antibody complexes resulted in atypical complement deposition.

Obstructive dilatation of extrahepatic recipient and donor bile ducts complicating orthotopic liver transplantation: imaging and laboratory findings.

Biliary obstruction in liver transplants is most commonly due to stricture at the biliary anastomosis. The native common bile duct typically is normal. We retrospectively studied 28 patients with choledochocholedochostomy anastomoses who had marked native and donor extrahepatic bile duct dilatation associated with clinical evidence of biliary obstruction. Operative cholangiograms were compared with postoperative cholangiograms obtained a mean of 50 weeks (range, 2-246 weeks) later. Mean caliber of the native common bile duct increased from 7.5 +/- 2.0 mm on operative cholangiograms to 14.8 +/- 3.9 mm on postoperative cholangiograms (p less than .001). Mean caliber of the donor common hepatic duct increased from 5.9 +/- 1.3 mm on operative cholangiograms to 12.8 +/- 3.8 mm on postoperative cholangiograms (p less than .001). Dilatation of the cystic duct remnant was seen in 15 patients. All patients had surgical revision to choledochojejunostomy with improved results of liver function studies in most cases. Diffuse dilatation of native and donor extrahepatic bile ducts may develop in liver transplant recipients. Typical features include native and donor extrahepatic ducts greater than 12 mm in diameter and a dilated cystic duct remnant on postoperative cholangiography in a patient with otherwise unexplained hepatic dysfunction.

FK 506 ameliorates the hepatic injury associated with ischemia and reperfusion in rats.

The effect of FK 506 on regeneration of the liver was studied in rats after a two-thirds partial hepatectomy after 60 min of ischemia of the unresected liver. The animals were divided into three distinct groups of 10 rats each. Group 1 (controls) received 0.5 ml saline solution intravenously 30 min after the induction of ischemia. Groups 2 and 3 were injected with FK 506 (0.3 mg/kg) intravenously 30 min after and 24 min before the induction of hepatic ischemia, respectively. The hepatic content of ATP and serum levels of ALT and lactate dehydrogenase were determined on each animal. In addition, the histological appearance and mitotic activity of the remnant liver was determined at regular 24-hr intervals after hepatic ischemia. All 10 control animals died within 72 hr. Treatment with FK 506 resulted in improved survival in groups 2 and 3 (30% and 80%, respectively). The improved survival seen in the FK 506-treated animals was reflected by a restoration of hepatic ATP content, a reduction in the serum levels of ALT and lactate dehydrogenase, an amelioration of hepatic necrosis and neutrophilic infiltration and an increase in the mitotic activity of the liver. These results suggest that FK 506 ameliorates the hepatic injury associated with ischemia/reperfusion and has a potent stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective agent when administered to organ donors before graft harvesting.

The spectrum of portal vein thrombosis in liver transplantation.

Thrombosis of the portal vein with or without patency of its tributaries used to be a contraindication to orthotopic liver transplantation (OLTX) until quite recently. Rapid progress in the surgical technique of OLTX in the last few years has demonstrated that most patients with portal vein thrombosis can be safely and successfully transplanted. Presented here is a series of 34 patients with portal vein thrombosis transplanted at the University of Pittsburgh since 1984. The various techniques used to treat various forms of thrombosis are described. The survival rate for this series was 67.6% (23 of 34 patients). Survival was best for patients who underwent phlebothrombectomy or placement of a jump graft from the superior mesenteric vein. The survival rate also correlated with the amount of blood required for transfusion during surgery. Overall it is concluded that a vast majority of the patients with thrombosis of the portal system can be technically transplanted and that their survival rate is comparable to that of patients with patent portal vein.

Morphological and functional evaluation of peripheral nerve regeneration in the rat using an expanded polytetrafluoroethylene (PTFE) microprosthesis.

The aim of our study was to evaluate in the rat the ability of a polytetrafluoroethylene microprosthesis (PTFE), to guide the peripheral nerve regeneration between the two extremities of a transected sciatic nerve. In 15 adult male Wistar rats, weighing 200 g, a segment of the right sciatic nerve was resected, leaving a gap of about 1 cm, bridged with microprosthesis, using our original microsurgical technique. Neurophysiological evaluations were performed at 6 and 9 months post-operatively to study the distal motor latency either in the right sciatic nerve or in the unoperated control side. In all the rats myoelectrical responses with an increased latency of the operated side were produced from the interosseous muscle of the foot. The animals were sacrificed 9 months post surgery. Histological sections at the level of the graft were done in all the rats, and in 10 animals biopsies of the tibialis anterior muscle (TA) of each side were performed. An active process of axonal regeneration was documented inside the graft, with no infiltration of nerve fibers through the wall of the prosthesis. A connective fibrous reaction was present around the external wall of the graft. Muscle biopsies showed definite signs of muscle reinnervation, with residual features of variable degree of denervation. These findings stress and confirm the ability of the PTFE graft to allow effective regeneration in a peripheral nerve gap in the rat.

FK 506 ameliorates the hepatic injury associated with ischemia.

Ischemic damage of the allograft liver is a major problem in clinical liver transplantation. Therefore the identification of hepatoprotective agents is a high priority at most liver transplantation programs. FK 506, a potent new immunosuppressive agent has been reported to possess hepatotrophic activity. To evaluate the putative hepatotrophic activity of FK 506 on experimental hepatic ischemia, rats were subjected to a subtotal hepatectomy following experimental ischemia and subsequent rat survival was assessed. FK 506 (0.3 mg/Kg) administered intravenously 24 hours prior to the induction of hepatic ischemia, reduced the subsequent mortality rate from 100% among controls given saline to only 20% (P less than 0.001). This observation demonstrates that FK 506 enhances the regenerative response of the liver to ischemic injury and may, in addition to its immunologic activity have hepatotrophic activity as well.