Search

Background. Graft-versus-host disease (GVHD) after liver transplantation is uncommon, and the outcome is almost always fatal. Since 1987, about 30 cases have been described, and patient survival is mostly exceptional. Methods. A 29-year-old man underwent retransplantation due to chronic cholestatic syndrome, 5 years after his first liver transplantation. Indication for the first liver transplantation was acute liver failure caused by exsiccosis. After the second transplantation, the patient had an initially uneventful course, developing thrombocytopenia at day 21 followed by skin rash and septic complications. Diagnosis of acute GVHD was made by using serological techniques for HLA-A and HLA-DRB and subsequently by fluorogenic sequence-specific primed polymerase chain reaction. In addition, donor lymphocytes were marked by immunohistochemical methods via biopsies of the skin. Immunosuppressive therapy was withdrawn to allow the patient's own immune system to eliminate donor cells. Results. By withdrawing the immunosuppressive therapy, clinical and morphological signs of GVHD vanished. The patient is doing well without recurrence 13 months after transplantation. Conclusion. Withdrawal of immunosuppressive therapy is a promising approach in the treatment of acute GVHD to allow the patient's immune system to reconstitute itself, reject offending lymphocytes, and avoid lethal septic complications.

Resection and end-to-end anastomosis of the trachea represent the preferred treatment for various benign and malignant diseases involving the trachea. Various studies have reported conflicting results with alternative techniques and suture materials for tracheal anastomosis. Our objective was to evaluate three frequently used techniques concerning stenosis rate and histological reaction in a large-animal species. Tracheal resection of 3 cm and end-to-end anastomosis were performed in 15 sheep with the use of three different techniques. In the first group, an interrupted suture with polyglactin, in the second group an interrupted suture with polydioxanone, and in the last group a continuous suture with polypropylene were used. The animals were killed 1, 2, 4, 8, and 24 weeks postoperatively. The luminal stenosis was determined by means of computerized planimetry. All three techniques appeared to be appropriate for tracheal anastomosis. The luminal stenosis developed within the first 8 weeks after surgery. A cross-sectional area of approximately 40–70% was finally achieved. Differences dependent on the suture material are less important than the technical details of the operation.

Cystic fibrosis transmembrane conductance regulator (CFTR) is a channel and regulator protein that is crucially involved in transepithelial ion transport. In the exocrine pancreas, the CFTR-mediated secretion of an electrolyte-rich fluid is a major but as yet incompletely understood function. We show here that the peptide guanylin is a specific activator of CFTR function in the human pancreas implicating regulation of pancreatic electrolyte secretion. Guanylin and its affiliated signaling and effector proteins including guanylate cyclase C, cGMP-dependent protein kinase II, CFTR, and the epithelial Cl-/HCO3- exchanger, anion exchanger 2, are highly expressed in the human pancreas. Guanylin is localized specifically to the typical centroacinar cells and proximal duct cells which, based on its additional presence in the pancreatic juice, is obviously released luminally into the pancreatic ducts. The guanylin receptor and the respective functional downstream proteins are all confined to the apical membrane of the duct cells implicating an as yet unknown route of luminal regulatory pathway of electrolyte secretion in the ductal system. Functional studies in two different human pancreatic duct cell lines expressing the CFTR Cl- channel that is functionally intact in CAPAN-1 cells but defective (delta F508) in CFPAC-1 cells clearly identify guanylin as a specific regulator of pancreatic CFTR channel function. Whole-cell patch-clamp recordings in CAPAN-1 cells revealed that forskolin induces an increase of Cl- conductance mediated by cAMP. In contrast, guanylin increased Cl- conductance in the same cells via cGMP but not cAMP; the respective membrane current was largely blockable by the sulfonylurea glibenclamide. In CFPAC-1 cells, however, neither guanylin nor forskolin produced a current activation. Based on the present findings we conclude that guanylin is an intrinsic pancreatic regulator of Cl- current activation in pancreatic duct cells via cGMP and CFTR. Remarkably, in the pancreas guanylin may exert its function through an intriguing luminocrine mode via the pancreatic juice.

Background and aims: Despite a decreasing incidence of primary gastric carcinoma over the last decade, the incidence of early gastric cancer has remained unchanged. Some aspects of the surgical treatment (e.g., extent of resection, lymphadenectomy) are still controversially discussed in the literature. Patients/methods: Between May 1986 and July 1999, 87 patients were operated upon due to primary early gastric adenocarcinoma. All patients data were analyzed retrospectively. Results: Of 626 patients with primary gastric carcinoma, 87 (13.9%) had an early carcinoma (54 men, 33 women; median age 61 years). In all patients, curative (R0-) gastrectomy could be performed, total in 62 patients (71.4%) and subtotal in 25 patients (28.6%). Postoperative morbidity was 23% and mortality 4.5%. Mucosal tumors were found in 34 (39.1%) and submucosal in 53 (60.9%) patients. Multicentricity was present in eight cases (9.1%). Twelve patients (13.8%) had lymph-node metastases. The 5-year survival rate was 88.8%. The submucosal infiltration, the lymph-node infiltration, the histological type, and the tumor size had no statistically significant impact on prognosis. Conclusion: Radical resection of early gastric cancer cured most of the patients, irrespective of lymph-node metastases or tumor size. Multicentricity, increasing incidence of proximal cancers, and low mortality suggest that total gastrectomy may be indicated. Patients with early gastric cancer may benefit from D2-lymphadenectomy, but this has to be assessed in further randomized studies, in particular for those with small mucosal tumors.

Background/aims: Quantification of α1-fetoprotein (AFP) mRNA in the blood using reverse transcriptase polymerase chain reaction (RT-PCR) could be a useful tool in monitoring the dynamics of minimal residual disease in patients with hepatocellular carcinoma (HCC). Since all available assays do not take into account the efficiency of cell separation, RNA extraction and reverse transcription, a competitive RT-PCR assay for quantification of AFP mRNA in relation to the housekeeping gene glyceraldehyde phosphate dehydrogenase (GAPDH) was established. Patients and methods: Peripheral blood of 22 patients and bone marrow aspirates of 11 patients with hepatocellular carcinoma was monitored perioperatively. Eighteen patients with other hepatic tumours or non-malignant hepatic diseases and 26 healthy blood donors served as controls. Messenger RNA contents were calculated relative to the content of GAPDH mRNA as an indicator of total cell count. Results: Among HCC patients, 6 of 22 (26%) were positive for AFP mRNA before operation with values ranging from 2 ag/100 fg to 36 ag/100 fg GAPDH mRNA (mean 14). Among bone marrow samples, AFP mRNA was detectable in 5 of 11 (45%) cases, with 4 ag/100 fg to 23 ag/100 fg GAPDH (mean 9). However, AFP mRNA was also detectable in 3 of 18 (17%) control patients and in 2 of 26 (8%) healthy blood donors. Perioperative findings were highly variable. Conclusion: AFP mRNA is not a specific marker for circulating malignant hepatocytes. Whether definition of a cut-off level or the use of a multimarker-PCR will provide more useful data remains to be established.

Organs transplanted between phylogenetically disparate species, such as from the pig into the primate, are subject to intragraft deposition of preformed recipient immunoglobulin M (IgM) antibodies with subsequent complement activation finally leading to complete and rapid destruction of the xenograft (hyperacute graft rejection, HAR). Current therapeutic strategies for abrogation of HAR include pretransplant antibody absorption by specific or nonspecific extracorporeal column perfusion, ex vivo donor organ perfusion, the administration of substances interfering with complement activation, or even the genetic alteration of the donor. Here, in the pig to cynomolgus monkey species combination, we are describing an experimental model for abrogation of HAR by using large, relative to the recipient weight, oversized donor kidneys as xenotransplants. Porcine kidney xenotransplantation (n = 15) was performed using large white pigs of different weights and ages as organ donors and cynomolgus monkeys as recipients. In grafts with an organ weight below 50 g (20 to 48 g, median 25 g), primary nonfunction (PNF) of the porcine kidney was observed in 11 out of 12 cases and complete HAR in 5 out of 12 experiments. In contrast, none of three grafts with a donor organ weight70 g showed signs of HAR or PNF. In one animal, a second porcine kidney from the same donor (23 g) was successfully transplanted immediately after HAR and subsequent removal of a first porcine kidney (20 g). By using appropriate immunohistochemistry stainings of reperfusion biopsies, profound deposition of recipient natural antibodies in both small and large xenografts was shown, with only scarce deposition of C3 and C5b-9 in the latter, indicating only incomplete intragraft activation of the complement cascade in these organs. Intraoperative cardiac output (CO) measurements performed in 7 experiments demonstrated a 20 to 50% decrease in CO following reperfusion in 6 out of 7 grafts irrespective of the donor organ weight. The intraoperative decrease in CO was not associated with perioperative morbidity or mortality. The use of oversized doner kidneys can enable the study of a variety of immunologic and physiologic sequela beyond HAR associated with life-supporting discordant primate kidney transplantation.

Background. The expression of RET/PTC chimeras was demonstrated in 10% to 20% of sporadic papillary thyroid carcinomas (PTCs), whereas rearrangements of NTRK1 were detected less frequently. Some investigators have hypothesized that RET/PTC activation is preferentially associated with slow-growing tumors of low malignancy in elderly patients; other studies support the contrary. Methods. Expression analysis of RET and NTRK1 was performed by duplex reverse transcription-polymerase chain reaction in tumor tissues from 119 patients with PTC. Samples with suspected rearrangements were further analyzed for the expression of the hybrid messenger RNAs RET/PTC 1 to RET/PTC 7 and for known NTRK1 chimeras, respectively. Results. Seventeen of 119 tumors (14.3%) revealed somatic rearrangements of RET; NTRK1-derived hybrids were demonstrated in 15 cases (12.6%). In patients with RET/PTC chimeras, a statistically not significant tendency towards younger age, lower recurrence rate, and improved survival was observed, despite increased incidence of lymph node metastasis. Cumulative survival analysis of NTRK1 rearrangement-positive individuals demonstrated a worse outcome when compared with patients with expression of RET hybrids (P =.055). Conclusions. The high incidence of yet uncharacterized NTRK1 hybrid mRNAs in our patient cohort leads to the speculation that activating chromosomal rearrangements of several tyrosine kinase receptors may be a common feature of PTCs and that the expression of distinct chimeras may potentially be of prognostic significance. (Surgery 2000;128:984-93.)

The incidence of proximal gastric third carcinoma (PGC) has been rising in recent years. Classification and surgical therapy remain controversial.Between May 1986 and October 1997, 532 patients were operated for primary gastric carcinoma. All patient data were analyzed retrospectively comparing findings in patients with PGC and those with distal gastric carcinoma (DGC).Two hundred fifty patients had a PGC, and 282 patients had a DGC. The rate of RO resections was 79.3% for PGC and 81.6% for DGC. In 93.9% of the patients with PGC total gastrectomy was performed; for DGC total gastrectomy was done in 74.5% of patients. Postoperative morbidity and mortality were 29.2% for PGC and 23.8% for DGC, and 3.2% for PGC and 3.5% for DGC, respectively. Patients with advanced tumor stages (stage III and IV) were more common in the PGC group (73.3% vs. 53.6% in DGC). After RO resection, the 5-year survival rate was 33.2% for PGC and 59.7% for DGC.There was no significant difference between the rates of RO resections for PGC and DGC. Total gastrectomy can be performed with low postoperative morbidity and mortality. PGC and DGC represent the same tumor entity, and prognosis is similar, but due to more advanced tumor stages, the long-term survival is worse for patients with PGC than for those with DGC. Left retroperitoneal lymphadenectomy may be indicated for PGC.

KIDNEYS from pigs transgenic for human decay accelerating factor (h-DAF) have been shown not to be hyperacutely rejected when transplanted into nonhuman primates. In the initial reports on the use of h-DAF kidneys profound anemia was the reason for termination of the experiments in most of the monkeys. This was probably due to either species incompatibility of the porcine erythropoietin in the recipient cynomolgus monkeys, the induction of neutralizing anti-pig erythropoietin antibodies, or cyclophosphamide bone marrow toxicity. We have developed a life-supporting kidney xenotransplantation model with bilateral ligature of the recipients’ native ureters but preservation of the native kidneys, thus allowing ongoing recipient erythropoietin production.

Background. Ex situ liver surgery allows liver resection and vascular reconstruction in patients who have liver tumors located at critical sites. Only a small series of studies about ex situ liver surgery is available in the literature. No long-term results have been published. Methods. Twenty-four patients were considered for ex situ liver surgery because conventional liver surgery was considered impossible or too hazardous. The patients' ages were 51.3 ± 7.5 years. Indications were various primary and secondary liver malignancies and benign liver tumors in 2 patients. Results. In 22 of 24 patients, the ex situ liver resection and subsequent autotransplantation were performed. The anhepatic periods in these patients lasted for 5.6 ± 1.1 hours. In the remaining 2 patients, autotransplantation was not possible and allogenic liver transplantation was performed 17 and 19 hours after hepatectomy. In 4 patients, liver failure occurred after autotransplantation and required transplantation. The confluens between hepatic veins and the inferior vena cava was reconstructed in 5 patients. Fifteen patients survived the postoperative period and were discharged after 36.5 ± 16 days. The median survival time of 6 patients who had metastases of colonic carcinoma was 21 months. The 2 patients with benign liver disease are alive 9 and 5 years after ex situ surgery. Conclusions. Extended liver resections with difficult reconstructions of the hepatic venous confluens are feasible by ex situ liver surgery and subsequent autotransplantation. However, the early postoperative mortality rate is high, especially in patients with cholestatic livers. Early tumor recurrence remained the problem in these patients with extended local tumor spread. Ex situ liver surgery should only be performed in selected patients. (Surgery 2000;127:520–7.)

Durch die Verwendung von transgenen Spendertieren mit Expression humaner Komple-mentregulatoren kann die nach diskordanter Xenotransplantation auftretende hyperakute Abstosungsreaktion (HAR) inhibiert werden. In den hier vorgestellten Untersuchungen analysierten wir den Einflus der Expression von h-DAF im Spenderorgan auf das Xeno-transplantatuberleben in einem Primatenmodell.

OBJECTIVE: To evaluate the concept of surgical decompression of the biliary tree by peripheral hepatojejunostomy for palliative treatment of jaundice in patients with irresectable malignant tumors of the liver hilum. SUMMARY BACKGROUND DATA: Jaundice, pruritus, and recurrent cholangitis are major clinical complications in patients with obstructive cholestasis resulting from malignant tumors of the liver hilum. Methods for palliative treatment include endoscopic stenting, percutaneous transhepatic drainage, and surgical decompression. The palliative treatment of choice should be safe, effective, and comfortable for the patient. METHODS: In a retrospective study, surgical technique, perioperative complications, and efficacy of treatment were analyzed for 56 patients who had received a peripheral hepatojejunostomy between 1982 and 1997. Laparotomy in all of these patients had been performed as an attempt for curative resection. RESULTS: Hepatojejunostomy was exclusively palliative in 50 patients and was used for bridging to resection or transplantation in 7. Anastomosis was bilateral in 36 patients and unilateral in 20. The 1-month mortality in the study group was 9%; median survival was 6 months. In patients surviving >1 month, a marked and persistent decrease in cholestasis was achieved in 87%, although complete return to normal was rare. Among the patients with a marked decrease in cholestasis, 72% had no or only mild clinical symptoms such as fever or jaundice. CONCLUSIONS: Peripheral hepatojejunostomy is a feasible and reasonably effective palliative treatment for patients with irresectable tumors of the liver hilum. In patients undergoing exploratory laparotomy for attempted curative resection, this procedure frequently leads to persistent-although rarely complete-decompression of the biliary tree. In a few cases it may also be used for bridging to transplantation or liver resection after relief of cholestasis.

BACKGROUND: Donor-specific blood transfusion prior to transplantation has been demonstrated to prolong allograft survival. This study compared the effect of donor-specific blood transfusion after kidney, heart, pancreas, and skin allotransplantation in congenic rats of reciprocal strain combinations across a major histocompatibility complex barrier. STUDY DESIGN AND METHODS: Whole donor-specific and third-party blood was administered to the prospective graft recipients 14 and 7 days before the transplantation of kidney, heart, pancreas, and skin. Rejection was defined by cessation of organ-specific function (i.e., uremia, cessation of heartbeat, and recurrence of diabetes). The survival of skin grafts was monitored visually. All allografts were histologically assessed immediately after rejection or at the end of a 100-day observation period. RESULTS: Donor-specific blood transfusion leads to permanent acceptance of all renal allografts. LEW.1U heart allografts were accepted by LEW.1A recipients, but they were rejected in the reciprocal situation. Survival of pancreas and skin allografts was not significantly prolonged. Third-party blood had no effect on allograft survival. CONCLUSION: The beneficial effect of donor-specific blood transfusion depends on both the kind of transplanted organ and the genetic incompatibility involved. The precise mechanisms responsible for the remarkable organ-specific differences remain unknown.

Little is known about hearing impairment in patients after organ transplantation. Few cases of hearing loss associated with different immunosuppressants have been published. To evaluate severe hearing impairment in patients after liver transplantation (OLT), all living adult patients in need of a hearing aid were analyzed. Out of 521 transplanted patients, 25 (5%) were identified with hearing aids. Nine (36%) of these patients either suffered from hearing loss prior to OLT or experienced risk factors such as ototoxic drugs. Of the remaining 16 patients who developed severe hearing loss after OLT (64%), half were men. Mean age was 42 +/- 18 years at OLT, which took place 8 +/- 4 years ago. Main transplantation indication was virus-induced cirrhosis (44%). In 14/16 (88%) patients, the hearing aid was bilateral. In 50% of patients, the hearing aid was necessary within 2 years post-OLT. Additional tinnitus was present in 9/16 patients (56%), otalgia in three patients (19%). Four patients (25%) reported a history of sudden deafness. In three of them, an association with high levels of calcineurin inhibitors was found. The proportion of patients receiving tacrolimus (50%) was relatively higher than those receiving cyclosporine (50%) compared to control patients (28% respectively 64%, P < .05). In conclusion, a high incidence of severe hearing loss was found in patients after liver transplantation. In most patients, onset of hearing loss is early and bilateral, suggesting a dose-dependent toxicity. The pathogenetic role of different immunosuppressants remains to be evaluated.

OBJECTIVES: The authors evaluated the experience and results of a single center in surgical treatment of proximal bile duct carcinoma. SUMMARY BACKGROUND DATA: Whenever feasible, surgery is the appropriate treatment in proximal bile duct carcinoma. To improve survival rates and with special regard to liver transplantation, the extent of surgical radicalness remains an open issue. PATIENTS AND METHODS: Retrospective analysis of 249 patients who underwent surgery for proximal bile duct carcinoma via the following procedures: resection (n = 125), liver transplantation (n = 25), and exploratory laparotomy (n = 99). Survival rates were calculated according to the Kaplan-Meier method, uni- and multivariate analysis of prognostic factors, and log rank test (p < 0.05). RESULTS: Survival rates after resection and liver transplantation are correlated with international Union Against Cancer (UICC) tumor stage (resection: overall 5-year, 27.1%; stage I and II, 41.9%; stage IV, 20.7%; liver transplantation: overall 5-year, 17.1%; stage I and II, 37.8%; stage IV, 5.8%). Significant univariate prognostic factors for survival after liver resection were lymph node involvement (N category), tumor stage, tumor-free margins, and vascular invasion; for transplantation, they were local tumor extent, N category, tumor stage, and infiltration of liver parenchyma. For resection and transplantation, a multivariate analysis showed prognostic significance of tumor stage and tumor-free margins. CONCLUSION: Resection remains the treatment of choice in proximal bile duct carcinoma. Whenever possible, decisions about resectability should be made during laparotomy. With regard to the observation of long-term survivors, liver transplantation still can be justified in selected patients with stage II carcinoma. It is unknown whether more radical procedures, such as liver transplantation combined with multivisceral resections, will lead to better outcome in advanced stages. With regard to palliation, surgical drainage of the biliary system performed as hepatojejunostomy can be recommended.

Nach grosen bauchchirurgischen Eingriffen oder Polytrauma besitzt ein fruhzeitiges enterales Nahrungsangebot in der postoperativen Phase moglicherweise einen gunstigen Effekt durch Verminderung der Katabolie und Verhinderung der bakteriellen Translokation [1]. Fur die Aufrechterhaltung der gastrointestinalen Barrierefunktion spielen Kohlenhydrate und ihre Resorption im Dunndarm eine zentrale Rolle. An einem tierexperimentellen Modell wurde die gestorte Barrierefunktion des Darmes bei fehlender enteraler Nahrungszufuhr durch Bestimmung der Genexpression von Glukosetransportern bestimmt. Es wurde untersucht, in welcher Weise die Genexpression der verschiedenen Hexosetransporter SGLT1 und GLUT2 durch die enterale Nahrungspassage reguliert wird [2].

Back pain is a frequent and often ominous clinical sign in patients with ductal pancreatic cancer.From 1971 to 1993 a pancreatic carcinoma could be resected in 192 patients, whereas 261 patients underwent either probatory laparotomy alone or palliative bypass procedures. In a retrospective study including uni- and multi-variate survival analysis we have determined the impact of preoperative back pain on both resectability and long-term prognosis after resection.Among the presenting symptoms of patients with ductal pancreatic cancer back pain was a predictive sign of irresectability. In the presence of preoperative back pain the long-term prognosis after resection of the tumour was also significantly impaired. In a multivariate analysis it could be demonstrated that the prognostic impact of back pain was as strong as the influence of residual tumour, tumour grading, and tumour size.Back pain often indicates irresectability of ductal pancreatic carcinoma and also impairs the long-term prognosis even after curative resection.

Resection was performed in 85 patients with ampullary and in 150 with ductal pancreatic head carcinoma. Curative resection was achieved in 98 and 87 per cent respectively. Patient survival at 5 years after exclusion of hospital deaths was 38 versus 16 per cent respectively. The patients were compared retrospectively in a multivariate survival analysis. For patients with pancreatic carcinoma, residual tumour stage, tumour size and grading were independent prognostic factors, but for those with ampullary carcinoma only tumour size was a prognostic factor. Lymph node metastasis impaired prognosis, but this effect was demonstrable for both groups only after univariate analysis. The Union Internacional Contra la Cancrum classification system was not a reliable parameter of prognosis after resection of ampullary carcinoma. Patients with ampullary cancer appear to have a better prognosis intrinsically than those with pancreatic head tumours, and not simply because they present at an earlier stage. The difference in prognosis cannot be explained sufficiently by a differential importance of the various survival variables.

Im Zeitraum von 1971–1993 wurden an der Medizinischen Hochschule Hannover 466 Patienten wegen eines duktalen Pankreaskarzinoms operiert dabei konnte bei 192 eine Tumorresektion vorgenommen werden. Dies entspricht einer Resektionsquote von 41%. An diesen Patienten wurden durch univariate and multivariate Faktorenanalyse die Einflusfaktoren auf die Prognose nach Tumorresektion analysiert. Eine erweiterte Resektion um Gefase oder Organe war in 40% der Falle (n=77) erforderlich. Dies ermoglichte bei 85% der Patienten eine RO-Resektion. Die Operationsletalitat nahm uber den gesamten Zeitraum deutlich ab and lag in den Jahren von 1985–1993 bei 3,5%. Die 5-Jahres-Uberlebensrate betrug 13,4% mit einer medianen Uberlebenszeit von 10,9 Monaten. Bei univariater Analyse war die Prognose mit zunehmender Tumorgrose sowie lymphatischer and hamatogener Metastasierung eingeschrankt. Es bestand eine signifikante Korrelation zwischen dem UICC-Tumorstadium und der Prognose, die ebenfalls signifikant vom Residualtumorstatus und dem Tumorgrading abhing. Operationserweiterungen bei der Pankreasresektion hatten dagegen keinen signifikanten Einflus auf die Prognose. In einer multivariaten Analyse nach dem Cox-Modell erwiesen sich jedoch nur der Residualtumorstatus, die Tumorgrose und das Tumorgrading als Faktoren von unabhangiger prognostischer Relevanz. Die lymphogene und hamatogene Metastasierung zeigten keinen unabhangigen Einflus auf die Prognose nach Resektion eines duktalen Pankreaskarzinoms.

It has already been shown that insulin cells studied under experimental conditions exhibit differences in insulin immunoreactivity and insulin release. The aim of this study, therefore, was to investigate whether insulin cells themselves exhibit morphological abnormalities after transplantation. Insulin cells in rat pancreas isografts with preserved or suppressed exocrine secretion were studied immunocytochemically and ultrastructurally and compared with those of unoperated rats. In isografts with preserved exocrine secretion, cortical insulin cells connected to the exocrine parenchyma or to glucagon or somatostatin cells expressed mostly dense immunoreactivities for insulin and amylin. In addition, medullary insulin cells connected only to other insulin cells displayed faint immunoreactivities for both constituents as found in unoperated animals. After duct ligation, however, pancreatic ducts and elongated capillaries extended into the islets. Corresponding to the stages of islet fragmentation, the heterogeneity among insulin cells underwent changes and was finally abolished. Ultrastructurally, differences in the number of secretory granules paralleled the heterogeneity in insulin immunoreactivity. It is interesting to note that the heterogeneity among insulin cells is preserved after transplantation, indicating that this phenomenon might be of physiological relevance. The heterogeneity may implicate differences in insulin storage and release as found in insulin cells under normal conditions.

The preservation of pancreatic B-cells is essential to ensure normal endocrine function of whole pancreas transplants. At present, however, it is unknown whether or not pancreatic B-cells in allografts display intercellular variations in insulin immunoreactivity and ultrastructure. It is also not clear whether the GLUT2 glucose transporter immunoreactivity is maintained in the plasma membrane after transplantation, as in B-cells under normal conditions. Therefore, pancreatic tissue of isografts and allografts, with or without signs of chronic rejection, was examined in streptozotocin-diabetic rats 10 to 100 days after transplantation by means of immunocytochemistry and electron microscopy. In isografts with preserved exocrine secretion pancreatic B-cells of larger islets exhibited normal heterogeneities in insulin immunoreactivity and in the number of secretory granules, whereas in isografts with suppressed exocrine secretion the heterogeneity was altered or abolished depending on the stage of islet dissociation. Differences in insulin immunoreactivity and ultrastructure were also observed in B-cells of tolerated allografts or those with signs of chronic rejection. In contrast to the localization of the GLUT2 glucose transporter under physiological conditions, GLUT2 glucose transporter immunoreactivity was not restricted to the pancreatic B-cell membrane but was also detected in the cytoplasm after transplantation. The cytoplasmic GLUT2 glucose-transporter localization developed in a time-dependent manner. It was evident 10 days after transplantation in isografts and was detectable still 100 days after transplantation in tolerated as well as in chronically rejected allografts. Interestingly, B-cells in the allografts with a dense insulin immunoreactivity exhibited GLUT2 glucose transporter expression in both localizations, whereas B-cells with a faint insulin immunoreactivity exhibited GLUT2 glucose transporter only in the plasma membrane. This may indicate a relation between the functional state of the pancreatic B-cells and the distribution of the GLUT2 glucose transporter in the cell. The heterogeneity between B-cells in pancreatic isografts and allografts implicates differences in the functional state of the B-cells with respect to insulin storage and release.

is produced by free radical catalyzed oxidation of arachidonic acid. ADMA and 15(S)-8-iso-PGFza are excreted by the kidneys. Quantification of 1 5(S)-8-iso-PGF2, in the circulation and in urine is a proven method to assess oxidative stress in humans. ADMA has been shown to be present in orthotopic human liver transplantation (OLT) and F2-isoprostanes to be overproduced in the hepatorenal syndrome.2 In the present study we quantified in patients (3 women, 9 men, age 47 ? 13 years) suffering from end-stage liver disease immediately prior to OLT circulating and excretory levels of ADMA by high performance liquid chromatography3 and GC-tandem MS,* respectively, and of 15($-8-i~o-PGF~, by GC-randem MS.5 Five of the patients were in Child-Pugh stage B. Healthy volunteers served as controls. Approval for the study protocol was obtained from the local Institutional Review Board for Studies in Humans. Informed consent was obtained from each patient. We measured elevated ADMA concentrations in the patients' plasma(5.3 t 3.4vs.0.54 2 0.1 pmol/L, P< .O5;Fig. l).Theplasma levels of L-arginine (41.5 ? 7.8 pmol/L) and the biologically inactive symmetric dimethylarginine (SDMA; 0.53 ? 0.20 pmol/L) were normal. Urinary excretion of ADMA in the patients was statistically significantly (P < .05) enhanced compared with that of the control group (5.6 2 1.5 vs. 3.4 t 1.1 pmol/mmol creatinine; Fig. 1). Circulating levels of free plus esterified 1 5(S)-8-iso-PGFzu were 3.2-fold elevated in the patients in comparison with those of healthy volunteers (244 -t 263 vs. 77 2 23 pg/mL; P = .00639). In the patients, 1.5-fold increased levels of urinary 15(S)-8-iso-PGFza were found in comparison with those of the control group (135 ? 83 vs. 88 t 40 nmollmol creatinine; P = .0398). Our results suggest that hepatic dysfunction is a prominent determinant of ADMA concentration in patients suffering from liver diseases. This is supported by the finding that, in the rat, the liver plays an important role in the metabolism of ADMA by taking up large amounts from the systemic circulation.6 Dimethylarginine dimethylaminohydrolase (DDAH) is highly expressed in the liver and removes ADMA by metabolization to L-citrulline. The highly elevated ADMA plasma levels measured in the patients suffering from hepatic disease presumably reflect deteriorated hepatic DDAH activity, to which increased oxidative stress and excessive local production of tumor necrosis factor a could contribute. Elevated ADMA plasma concentration has been recognized as an important risk factor for cardiovascular disease. Accumulation of ADMA in chronic renal failure' and end-stage hepatic failure could be a causative factor in the development of multiple organ failure. High plasma ADMA concentration in critically ill patients has been shown to be an independent risk factor regarding intensive care unit mortality.* Imbalanced ADMA pathway and elevated oxidative stress may contribute to liver pathology and multiple organ failure. The authors thank Bibiana Schubert, MariaTheresia Suchy, and Frank-Mathias Gutzki for excellent technical assistance. Acknowledgment

Die Immunogenitat eines Transplantats ist abhangig von Art und Umfang der Histoin- kompatibilitat zwischen Spender und Empfanger, wobei Antigene des Haupthistokompa- tibilitatskomplexes (MHC), insbesondere MHC-Klasse II Molekule, einen besonders starken Stimulus zur Induktion von Abstosungsreaktionen darstellen. Daruber hinaus finden sich organspezifische Muster der Immunantwort auf ein Transplantat. Bei der kombinierten Transplantation unterschiedlicher Organe besteht eine komplexe immunologische Situation, in der Interaktionen zwischen den Immunreaktionen stattfinden konnen. An einem genetisch definierten Modell der individuellen und kombinierten Transplantation von Niere und Langerhansschen Inseln an der Ratte haben wir untersucht, welchen Einflus MHC Klasse II Antigene auf die Immunogenitat des individuellen Transplantats haben, und in wieweit eine donorspezifische Nierentransplantation das Uberleben Langerhansscher Inseln beeinflust.

Background The genetic background of papillary thyroid carcinoma (PTC) has been elucidated by the identification of somatic translocations of the tyrosine kinases RET and NTRK1. Expression of RET/PTC chimeras has been demonstrated in 10–25 per cent of sporadic PTCs while rearrangements of NTRK1 were detected less frequently. Based upon the limited data available, some investigators have hypothesized that RET/PTC activation is preferentially associated with slow growing tumours of low malignancy in elderly patients, while other studies support the contrary. Methods Tumour tissues from 115 patients with sporadic PTC were harvested at operation and snap frozen. Following RNA extraction, expression analysis of the RET proto-oncogene as well as the NTRK1 gene was performed by multiplex reverse transcriptase–polymerase chain reaction. Samples with suspected rearrangements of the genes were further analysed for expression of the hybrid messenger RNAs RET/PTC1 to RET/PTC4, and for known NTRK1 chimeras. Clinical data of all patients were documented in an extensive database of thyroid carcinomas maintained by this research group. Results Twenty-one (18 per cent) of 115 tumour samples revealed somatic rearrangements of RET while translocations of the NTRK1 gene were demonstrated in 2 per cent of all samples analysed to date. The mean age of all patients was 52 (range 14–86, median 54) years and that of patients positive for RET rearrangements was 49 (range 14–82, median 49) years. Nine of 21 RET-rearranged tumours showed aggressive behaviour with locally invasive tumour growth and infiltration of adjacent structures such as muscles, vessels and trachea. Tumour samples without detectable RET translocations were associated with organ-exceeding tumour growth in only 20 per cent of cases. Conclusion These data represent one of the most comprehensive studies on gene translocations and their clinical significance in PTC. In accordance with international publications, an incidence of 2 per cent of NTRK1 rearrangements and 18 per cent of RET translocations is reported, which is in contrast to other national reports of low rearrangement rates. Somatic translocations were associated with tumours demonstrating aggressive behaviour in almost half of patients with PTC in all age groups, indicating a prognostic role of oncogenic RET/PTC activation.

In inbred streptozocin-induced diabetic rats, the long-term function of different endocrine pancreatic isografts was compared. Isolated islets transplanted into the portal vein showed a progressive deterioration of function over time. In contrast, islets under the kidney capsule sustained a constant long-term function controlling all clinical signs of diabetes. Recipients of kidney subcapsular islets displayed normal growth rate, peripheral serum glucose and insulin levels, and metabolic parameters. However, their functional reserve was markedly reduced as revealed by diminished glucose tolerance and reduced insulin-secreting capacity after an intravenous glucose challenge. Vascularized whole-organ pancreatic grafts with portal venous drainage led to complete normalization of all parameters determined in this study. This study showed that the long-term function of islets transplanted under the kidney capsule is superior compared with islets transplanted into the portal vein.

The significance of portal venous drainage after whole-pancreas transplantation both for metabolic control and development of diabetic nephropathy was investigated. Streptozotocin-diabetic inbred LEW rats received a duct-ligated pancreas graft with either systemic or portal venous drainage and were followed for up to one year. Normal and untreated diabetic rats (n=18 in each group) served as controls. Irrespective of the route of venous drainage pancreas transplants normalized the diabetic polyuria, polyphagia, and polydipsia. Growth rates and general health did not differ from normal rats. Pancreas transplantation with portal venous drainage furthermore normalized nonfasting blood glucose and peripheral insulin levels, and intravenous glucose tolerance. Pancreas transplantation with systemic venous drainage, however, was associated with peripheral hyperinsulinemia, slightly elevated nonfasting blood glucose levels, and supranormal K-values in intravenous glucose tolerance tests. Though portal venous drainage was associated with better metabolic control than systemic venous drainage, both techniques of pancreas transplantation proved equally effective to prevent the development of diabetic glomerular membrane thickening determined 6 and 12 months posttransplant.

Die adequate chirurgische Versorgung der exokrinen Sekretion nach Transplantation des vaskularisierten Pankreas ist noch immer umstritten. Grundsatzlich kann die exokrine Sekretion des Transplantats entweder durch Obstruktion der Pankreasausfuhrungsgange unterdruckt oder durch Drainage in den Gastrointestinal- oder Urogenitaltrakt erhalten werden. Am Modell der isogenen Pankreastransplantation bei Streptozotocin-diabetischen Ratten wurde der Einflu\ der erhaltenen oder unterdruckten exokrinen Sekretion auf die Qualitat der endokrinen Transplantatfunktion bestimmt. Die exokrine Sekretion wurde entweder durch pankreatikoduodenale Transplantation erhalten oder durch Gangligatur unterdruckt. Die Qualitat der endokrinen Transplantatfunktion wurde durch Bestimmung der nichtnuchtern-Blutzuckerwerte, der intravenosen Glukosetoleranz, der peripheren Insulinspiegel, des Wasser-und Futterverbrauchs sowie der Urin- und Stuhlproduktion ermittelt. Die Unterdruckung der exokrinen Sekretion induzierte im Transplantat eine vollstandige Atrophie des Azinusgewebes, eine Proliferation der Pankreasausfuhrungsgange, eine interstitielle Zellinfiltration sowie eine Fragmentation von Langerhans-Inseln. Trotz dieser fundamentalen Umbauvorgange im Transplantat konnte keine Beeintrachtigung der endokrinen Transplantatfunktion innerhalb der Beobachtungszeit von 1 Jahr festgestellt werden. Pankreastransplantate mit erhaltener und unterdruckter exokriner Sekretion normalisierten gleichermasen die diabetische Hyperglykamie, die eingeschrankte Glukosetoleranz, die periphere Hypoinsulinamie, sowie die Polydipsie, Polyphagie und Polyurie, und sie ermoglichten eine normale korperliche Entwicklung diabetischer Empfanger eines Pankreastransplantats. Aus diesen Ergebnissen kann gefolgert werden, das die Unterdruckung der exokrinen Sekretion zu keiner Beeintrachtigung der endokrinen Funktion von Pankreastransplantaten fuhrt.