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Biomedical subjects

L Bühler

Publications and source records attributed to L Bühler.

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

Coagulation and thrombotic disorders associated with pig organ and hematopoietic cell transplantation in nonhuman primates.

BACKGROUND: Efforts to achieve tolerance to transplanted pig organs in nonhuman primates by the induction of a state of mixed hematopoietic chimerism have been associated with disorders of coagulation and thrombosis. Activation of recipient vascular endothelium and platelets by porcine hematopoietic cells and/or activation of donor organ vascular endothelium and/or molecular differences between the species may play roles. Irradiation or drug therapy could possibly potentiate endothelial cell activation and/or injury. METHODS: We have investigated parameters of coagulation and platelet activation in nonhuman primates after (1) a regimen aimed at inducing mixed hematopoietic chimerism and tolerance (TIR that included total body irradiation, T cell depletion, and splenectomy; (2) pig bone marrow or pig peripheral blood mobilized progenitor cell transplantation (PCTx); and/or (3) pig organ transplantation (POTx). Five experimental groups were studied. Baboons were the recipient subjects in all groups except Group 1. Gp 1 Cynomolgus monkeys (n=6) underwent TIR + allotransplantation of hematopoietic cells and a kidney or heart or TIR + concordant xenotransplantation (using baboons as donors) of cells and a kidney; Gp 2 Baboons (n=4) underwent TIR with or without (+/-) autologous hematopoietic cell infusion; Gp 3 (n=12) PCTx+/-TIR; Gp 4 (n=5) POTx+/-TIR; Gp 5 (n=4) TIR + PCTx + POTx. Platelet counts, with plasma prothrombin time, partial thromboplastin time, fibrinogen levels, fibrin split products and/or D-dimer were measured. RESULTS: In the absence of a discordant (porcine) cellular or organ transplant (Groups 1 and 2), TIR resulted in transient thrombocytopenia only, in keeping with bone marrow depression from irradiation. PCTx alone (Group 3) was associated with the rapid development of a thrombotic thrombocytopenic (TTP)-like microangiopathic state, that persisted longer when PCTx was combined with TIR. POTx (+/-TIR) (Group 4) was associated with a gradual fall (over several days) in platelet counts and fibrinogen with disseminated intravascular coagulation (DIC); after graft excision, the DIC generally resolved. When TIR, PCTx and POTx were combined (Group 5), an initial TTP-like state was superseded by a consumptive picture of DIC within the first week, necessitating graft removal. CONCLUSIONS: Both PCTx and POTx lead to profound alterations in hemostasis and coagulation parameters that must be overcome if discordant xenotransplantation of hematopoietic cells and organs is to be fully successful. Disordered thromboregulation could exacerbate vascular damage and potentiate activation of coagulation pathways after exposure to xenogeneic cells or a vascularized xenograft.

Animals↗
PubMed2000

High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response.

BACKGROUND: In pig-to-primate organ transplantation, hyperacute rejection can be prevented, but the organ is rejected within days by acute vascular rejection, in which induced high-affinity anti-Gal alpha1-3Gal (alphaGal) IgG and possibly antibodies directed against new porcine (non-alphaGal) antigenic determinants are considered to play a major role. We have explored the role of an anti-CD40L monoclonal antibody in modifying the humoral response to porcine hematopoietic cells in baboons pretreated with a nonmyeloablative regimen. METHODS: Porcine peripheral blood mobilized progenitor cells obtained by leukapheresis from both major histocompatibility complex-inbred miniature swine (n=7) and human decay-accelerating factor pigs (n=3) were transplanted into baboons. Group 1 baboons (n=3) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with ATG, complement depletion with cobra venom factor, short courses of cyclosporine, mycophenolate mofetil, porcine hematopoietic growth factors, and anti-alphaGal antibody depletion by immunoadsorption before transplantation of high doses (2-4 x 10(10)/cells/kg) of peripheral blood mobilized progenitor cells. In group 2 (n=5), cyclosporine was replaced by eight doses of anti-CD40L monoclonal antibodies over 14 days. The group 3 baboons (n=2) received the group 1 regimen plus 2 doses of anti-CD40L monoclonal antibodies (on days 0 and 2). RESULTS: In group 1, sensitization to alphaGal (with increases in IgM and IgG of 3- to 6-fold and 100-fold, respectively) and the development of antibodies to new non-alphaGal porcine antigens occurred within 20 days. In group 2, no sensitization to alphaGal or non-alphaGal determinants was seen, but alphaGal-reactive antibodies did return to their pre- peripheral blood mobilized progenitor cells transplant levels. In group 3, attenuated sensitization to alphaGal antigens was seen after cessation of cyclosporine and mycophenolate mofetil therapy at 30 days (IgM 4-fold, IgG 8-30-fold), but no antibodies developed against new porcine determinants. In no baboon did anti-CD40L monoclonal antibodies prevent sensitization to its own murine antigens. CONCLUSIONS: We believe these studies are the first to consistently demonstrate prevention of a secondary humoral response after cell or organ transplantation in a pig-to-primate model. The development of sensitization to the murine elements of the anti-CD40L monoclonal antibodies suggests that nonresponsiveness to cell membrane-bound antigen (e.g., alphaGal) is a specific phenomenon and not a general manifestation of immunological unresponsiveness. T cell costimulatory blockade may facilitate induction of mixed hematopoietic chimerism and, consequently, of tolerance to pig organs and tissues.

Animals↗
PubMed2000

Human islet transplantation: lessons from 13 autologous and 13 allogeneic transplantations.

BACKGROUND: A series of 13 islet autotransplantations and 13 islet allotransplantations performed between 1992 and 1999 at the University Hospital of Geneva are presented. Factors affecting the outcome are analyzed. METHODS: Islet autotransplantation has been performed in seven patients with chronic pancreatitis and in six patients with benign tumors undergoing extensive pancreatectomy. Islet allografts were performed in C-peptide-negative patients simultaneously or after a kidney or lung transplantation. Each recipient received islets from one to four donors. Panel-reactive antibodies were monitored by microlymphocytotoxicity test. RESULTS: Eleven of 13 patients who underwent autotransplantation maintained insulin independence for 6 months to 5 years. Two years after autologous islet transplantation, five of nine patients were insulin independent with an glycosylated hemoglobin of 5.9%. Three late islet failures occurred in patients with chronic pancreatitis. Islet yield was significantly lower in patients with chronic pancreatitis than in patients with benign tumors (2044 equivalent islet number/gram resected pancreas versus 5184 equivalent islet number/gram; P=0.037). In islet allotransplantation, no early graft loss was found. All 13 patients who underwent allotransplantation had basal C-peptide levels above 0.3 nmol/L for 3 months to 5 years. Mean glycosylated hemoglobin decreased from 9.1% before transplantation to 5.5% at month 3. Insulin independence was achieved in two type I diabetic patients. In four of six patients with graft failure, the graft had induced panel-reactive antibodies. CONCLUSIONS: In islet autotransplantation, the reduced number of islets that can be isolated from fibrotic pancreata may be the major limiting factor. In islet allotransplantation, early graft function can now be consistently achieved. Islet allografts seem to be highly immunogenic, and chronic islet failure cannot be prevented consistently by conventional immunosuppression.

Autoimmunity↗
PubMed1999

Xenotransplantation--state of the art--update 1999.

Organ transplantation is limited by the number of cadaveric human donor organs that become available. Xenotransplantation - the transplantation of organs and tissues between animal species - would supply an unlimited number of organs and offer many other advantages. The pig has been identified as the most suitable donor animal. Pig organs, when transplanted into humans or nonhuman primates, are, however, rejected hyperacutely within minutes by antibody-mediated complement activation. Human anti-pig antibodies have been identified as being directed against galactose alpha 1-3galactose (alpha Gal) epitopes on pig vascular endothelium. Methods have been successfully developed to prevent hyperacute rejection. These include (i) depletion or inhibition of recipient antibodies or complement and (ii) development of transgenic pigs that express a human complement-regulatory protein (e.g. hDAF). The persistence or return of anti-pig antibody, however, even following the use of hDAF pig organs, eventually leads to what has been variously termed "acute vascular rejection" or "delayed xenograft rejection", which is again believed to be largely antibody-dependent. Nevertheless, experimental pig-to-primate organ xenotransplantation now results in transplant function for days and weeks rather than minutes. Little is yet known of the nature of the acute cellular rejection response that is anticipated to follow, and of any subsequent chronic rejection that may develop. Tolerance to both the alpha Gal epitope and to swine leukocyte antigens (SLA) is being explored using gene therapy techniques and by the induction of hematopoietic cell chimerism. The development of genetically engineered pigs that do not express the alpha Gal epitope is also being pursued. Considerable progress has been made in recent years, but experimental results do not yet warrant the initiation of a clinical trial of organ xenotransplantation. However, trials are already underway of pig cell transplants in patients with diabetes and neurodegenerative conditions, such as Parkinson's disease.

Animals↗
PubMed1999

Autologous bone marrow transplantation for recurrent malignant lymphoma after liver transplantation.

BACKGROUND: Cancer chemotherapy in chronic carriers of hepatitis B virus is known to promote viral replication, and, when immunosuppressive treatment is stopped, the return of immune competence can be followed by a fulminant hepatitis. Liver transplantation may be required and has been successfully performed for this condition. However, malignancy recurrence after transplantation has not been reported yet. METHODS AND RESULTS: We here report the case of an asymptomatic hepatitis B surface antigen carrier who developed a malignant lymphoma, which was treated by chemotherapy. After cessation of chemotherapy, he developed a fulminant hepatitis, requiring liver transplantation. Three years later, he developed a recurrent malignant lymphoma, which was treated successfully by autologous bone marrow transplantation. In order to prevent viral replication, lamivudine and intermittent administration of fresh-frozen plasma highly concentrated in anti-HBs immunoglobulin was initiated before the bone marrow transplantation. The patient remains well 12 and 56 months after autologous bone marrow and liver transplantation, respectively. CONCLUSIONS: This experience suggests that all hepatitis B surface antigen-positive patients for whom chemotherapy is indicated would benefit from prophylactic antiviral hepatitis B virus therapy. Furthermore, successful autologous bone marrow transplantation is possible after liver transplantation.

Bone Marrow Transplantation↗
PubMed1999

Different responses of human anti-HLA and anti-alphagal antibody to long-term intravenous immunoglobulin therapy.

Concentrated human immunoglobulin (IVIG) has been administered intravenously in the treatment of autoimmune disorders and to reduce anti-HLA antibodies in highly sensitized patients awaiting organ transplantation. It has also been shown, in experimental animals, to prevent the hyperacute rejection of discordant xenografts, possibly by anticomplement activity. The aim of the present study was to assess the effect of IVIG therapy on both acquired anti-HLA antibodies and natural antigalactose alpha1-3 galactose (alphaGal) antibodies in five patients awaiting heart transplantation. Five patients placed on mechanical circulatory support who had developed high HLA panel-reactive antibodies (PRA) or in whom the percentage of PRA was increasing rapidly were treated weekly with 500 mg/kg IVIG, which contained 1% of anti-alphaGal IgG. Levels of PRA, anti-alphaGal IgG and IgM, and serum cytotoxicity to pig cells were measured before, during, and after therapy. PRA percentages in the five patients were initially 85%, 53%, 23%, 19% and 19% (mean 39%). Mean PRA fell by 66% after 3 months of therapy (to a mean PRA of 14%), and by 96% after 6 months therapy (to a mean PRA of 2%). Anti-alphaGal antibody levels and serum cytotoxicity to pig aortic endothelial cells did not change significantly. These results confirm the effectiveness of IVIG therapy in reducing PRA in HLA highly sensitized patients. It is likely that IVIG does not contain the relevant anti-HLA antibody, resulting in an accelerated catabolism of native alloantibodies. However, as IVIG contains a normal level of anti-alphaGal IgG, catabolism of anti-alphaGal IgG is not modified, as it is being continuously replaced. To achieve a decrease in the anti-alphaGal IgG level it would be necessary to use IVIG depleted of this antibody.

Adult↗
PubMed1999

Management of bleeding pseudoaneurysms in patients with pancreatitis.

BACKGROUND: Bleeding pseudoaneurysm is a rare but frequently fatal complication in patients with pancreatitis. METHOD: The medical records of ten patients who presented to this institution with a bleeding pseudoaneurysm between 1978 and 1997 were reviewed retrospectively. Six patients had chronic pancreatitis and four had acute pancreatitis. The splenic artery was involved in six cases, a pancreaticoduodenal artery in two, the gastroduodenal artery in one and the cystic artery in one. RESULTS: Computed tomography (CT) revealed the bleeding pseudoaneurysm in all patients (n = 6) with chronic pancreatitis but in only one of three with acute pancreatitis. Arteriography always gave the correct diagnosis. Seven patients underwent pancreatic resection as an emergency (n = 3) or within 48 h (n = 4), and survived. Three patients presenting with acute pancreatitis and massive bleeding underwent transcatheter arterial embolization. Two of them had a favourable outcome and one died from a recurrent haemorrhage 7 days later. Overall, two patients suffered significant perioperative complications and one died. CONCLUSION: CT is accurate in the diagnosis of pseudoaneurysms complicating pseudocysts. Primary resection of the pseudoaneurysm, which frequently requires pancreatic resection, is the treatment of choice. Angiography followed by transcatheter embolization is effective, but should be rapidly followed by operation.

Abdominal Pain↗
PubMed1999

Management of true aneurysms of the pancreaticoduodenal arteries.

OBJECTIVE: To review the authors' recent experience and that of the literature since 1973 and to provide management guidelines for true aneurysms of the pancreaticoduodenal arteries (PDA). SUMMARY BACKGROUND DATA: True aneurysms of the PDA are rare, with a total of only 52 cases reported since 1973. METHODS: Six patients were admitted to the authors' institution between 1985 and 1995 for rupture of a true aneurysm of the PDA. They were analyzed with regard to the mode of presentation, preoperative workup, management, and outcome. RESULTS: All patients had severe epigastric pain from retroperitoneal hemorrhage. Computed tomography scanning and angiography were performed in all cases. Aneurysms ranged from 0.7 to 1.2 cm (median 0.9 cm). The celiac axis was stenotic or occluded in five cases. Three patients underwent emergency pancreatoduodenectomy. Two of them survived. In one case, section of the median arcuate ligament was associated with the procedure, and the patient died from an aortic dissection. Embolization was performed in the last three patients. The procedure was definitive in two cases. In one, hemorrhage recurred 8 days later and required surgical ligation of the bleeding artery. CONCLUSIONS: The authors recommend rapid treatment of all true aneurysms of the PDA. Because most of these aneurysms result from a stenosis of the celiac axis, selective embolization may help to preserve patency of the PDA and should, therefore, be the primary therapeutic choice in ruptured aneurysms. Close follow-up is mandatory because of possible recurrent bleeding. Appropriate and expeditious management of true PDA aneurysms should help reduce the mortality rate.

Aged↗
PubMed1998

[Hemosuccus pancreaticus: a rare cause of upper gastrointestinal hemorrhage].

We report on a patient with alcoholic chronic pancreatitis and intermittent upper gastrointestinal haemorrhage. Old blood was seen in the duodenum but no bleeding source could be identified by endoscopy. Computed tomography scanner and angiography disclosed an arterial pseudoaneurysm of the pancreatic tail, and left splenopancreatectomy was performed. In cases of upper gastrointestinal haemorrhage, the pancreas should be considered as a bleeding source if endoscopies remain negative and the patient presents with chronic pancreatitis.

Aneurysm, False↗
PubMed1998

[Long-term follow-up of 9 islets of Langerhans autografts after resection of the pancreas].

INTRODUCTION: Preservation of physiological endocrine pancreatic function represents a major problem in pancreatectomised patients. In 40 to 100%, pancreatic resection can result in diabetes, which is often difficult to manage. Islet autotransplantation has been proposed to prevent this severe metabolic consequence. PATIENTS AND METHODS: Between March 1992 and January 1997 we performed 9 human islet autotransplantations in Geneva. The patients comprised 6 males and 3 females aged 40 to 81 years (median: 51 years). The pancreatectomy was total in 3 cases, subtotal (95%) in 2 cases and partial (40-80%) in the others. Indications for resection were alcohol-induced chronic pancreatitis (6 cases) and focal benign pancreatic pathologies (3 cases). After collagenase digestion, unpurified islets were injected intraportally and embolised into the liver. Patient metabolic status was regularly tested by 24-hour serum glucose profile, measurement of glycosylated haemoglobin, oral and intravenous glucose tolerance tests and glucagon stimulation test. RESULTS: Immediately after autotransplantation, one patient had persistent insulin-dependent diabetes. Among the 8 patients who were insulin-independent soon after the graft, 4 presented a progressive deterioration of endocrine pancreatic function and required insulin therapy 5, 8, 24 and 36 months after the graft. Currently, 4 patients are insulin-independent: three of them have normal glucose tolerance tests (24, and 48 months after the graft) and the last presented with glucose intolerance 22 months after the graft but still does not require exogenous insulin. CONCLUSION: Islet autotransplantation can be considered a useful therapeutic option serving to prevent or delay the occurrence of surgically-induced diabetes. In our opinion, islet autotransplantation should be offered to any non diabetic patient needing to undergo major pancreatic resection.

Adult↗
PubMed1998

[Isolation of the pig islets of Langerhans: evaluation of in vitro and in vivo function].

Pig islets are considered the best alternative to human islets in the treatment of insulin-dependent diabetes. Pigs could represent a potential islet donor for xenotransplantation in humans because of the close similarity between human and porcine insulin and the theoretically unlimited availability of porcine pancreas. From November 1991 to January 1997 we performed 221 pig islet isolations from 3 pig sources: group 1: minipigs (age 9-18 months) and white pigs (3-8 months), group 2: large white pigs (5-8 months), group 3: large white pigs (12-24 months). Islets were isolated according to a semi-automated method using enzymatic digestion and purification through discontinuous Euro-Ficoll gradients. The pancreases were surgically removed in our laboratory for group 1, while pancreases from groups 2 and 3 were removed at the slaughterhouse with an average warm ischemia time of 15 minutes. In vitro islet function was assessed by static incubations and perifusions, and in vivo islet function by transplantation under the kidney capsule of nude diabetic mice. The results were as follows: [table: see text] Insulin secretion increased twofold after in vitro glucose stimulation. We obtained restoration of euglycemia in diabetic mice which survived > 3 months after the graft and returned to diabetes after nephrectomy. This study shows that our isolated pig islets are viable and functional in vitro and in vivo after transplantation.

Animals↗
PubMed1998

[Splenic vein thrombosis and chronic pancreatitis: therapeutic approach].

10% of chronic pancreatitis (CP) cases are complicated by splenic vein thrombosis (SVT) which is responsible for upper digestive haemorrhages. To improve our approach to treatment we reviewed 30 cases of SVT associated with CP treated in our centre from 1985 to 1995. 14 patients were treated conservatively. Six of them were refused for surgery due to extension of splenic vein thrombosis into the portal vein. Two patients without extrinsic compression of the vein were treated with anticoagulants. 16 patients were treated by surgery with low morbidity and without mortality. The standard treatment in fourteen cases was splenopancreatectomy. The average follow-up of seven years shows that these patients have preserved their body mass index (BMI). The results suggest that early surgical intervention is beneficial in preventing progression of SVT to the portomesenteric vein.

Adult↗
PubMed1998

[Pancreatic pseudocysts: choice of treatment?].

Pseudocysts of the pancreas may require drainage or resection during their evolution. External drainage can be considered as a treatment of first resort with low related morbidity. It also offers a means of treating patients with major contraindications for surgery. In our experience, however, only 55% of external drainages prove successful. Therefore, surgical treatment, even at the cost of low-rate morbidity, remains the only final treatment for complications linked to pseudocysts of the pancreas. In the long term, however, these results depend on the etiology of the pseudocysts.

Adult↗
PubMed1998

Inhibition of leukocyte adherence and transendothelial migration in cultured human liver vascular endothelial cells by prostaglandin E1.

Primary graft dysfunction is a major complication of orthotopic liver transplantation, and hepatic ischemic reperfusion injury is considered to be its major determinant cause. Although oxygen free radicals play an important role, leukocytes, cytokines, and adhesion molecules also contribute to hepatic ischemic reperfusion injury. Prostaglandin E1 (PGE1) has been shown to protect against impairment and dysfunction of transplanted livers in various experimental models as well as in clinical liver transplantation. In this study, the role of PGE1 on leukocyte adherence and transendothelial migration was investigated in cultured human liver vascular endothelial cells (HLVEC). Our results indicated that stimulated, but not resting, leukocytes exhibited high adhesion and transmigration capacity. HLVEC incubated with tumor necrosis factor (TNF) promoted leukocyte adherence and transendothelial migration. PGE1 inhibited leukocyte adherence to HLVEC when it was preincubated with either HLVEC or leukocytes. Moreover, PGE1 also suppressed stimulated leukocyte transendothelial migration in a dose-dependent manner. The inhibitory activity of PGE1 was further investigated on both HLVEC and leukocytes with attention to adhesion molecules. On HLVEC, PGE1 down-regulated TNF-induced expression of endothelial cell leukocyte adhesion molecule 1 and vascular adhesion molecule 1, but not intercellular adhesion molecule 1. On leukocytes, PGE1 inhibited expression of CD11a/CD18 and membrane-bound TNF on PHA-stimulated leukocytes. PGE1 also suppressed TNF release from the stimulated leukocytes. These results indicated that inhibition of leukocyte adherence and transendothelial migration is one of the mechanisms by which PGE1 protects liver grafts.

Alprostadil↗
PubMed1998

Management of true aneurysms of the splenic artery.

BACKGROUND: Splenic artery aneurysms (SAA) are detected with increasing frequency but their management still remains controversial. This paper relates our experience in the outcome and management of ruptured aneurysms of the splenic artery. METHODS: Between 1977 and 1996, 8 patients presented to our institution with a ruptured SAA. Their ages ranged from 25 to 72 years (mean 55 ys). RESULTS: All patients presented with rupture as the first sign of SAA. One patient was at 32 weeks of gestation and rupture suggested placental abruption. Three patients required cardiopulmonary reanimation prior to surgical procedures. Splenopancreatectomy (n = 4), splenectomy (n = 2), and ligation of the splenic artery (n = 1) were performed. Seven of the 8 patients survived. Size of aneurysms ranged from 2 cm to 3.5 cm (mean 3 cm). CONCLUSIONS: SAA may rupture at any age. Diagnosis during pregnancy rests upon a high index of suspicion. The mortality rate remains low if immediate resuscitation is performed and an aggressive surgical approach is taken.

Adult↗