PubMed Health⌕ Search

Biomedical subjects

José Oberholzer

Publications and source records attributed to José Oberholzer.

At least 19 recordsLinked to original sources
PubMed2007

'Prope' tolerance in a noncompliant living related small bowel transplant recipient after severe rejection.

Advances in immunosuppression and surgical technique have greatly improved patient outcomes after intestinal transplantation. However, the procedure remains one of the most challenging among solid organ transplantation as a result of the high rate of acute rejection, sepsis, and posttransplantation lymphoproliferative disorder. Recently, clinical trials to explore tolerance protocols in humans have been initiated, including small bowel transplant recipients, with results not always reproducible. The concept of operational tolerance is more meaningful in the clinical setting when physiological stability of graft function is achieved in the absence of maintenance immunosuppression. We report the intriguing case of a living related small bowel transplant recipient who developed clinical "prope" tolerance to the graft after treatment of severe acute rejection despite continuous noncompliance with immunosuppressive therapy.

Adult↗
PubMed2007

Successful rescue of refractory, severe antibody mediated rejection with splenectomy.

Antibody-mediated rejection (AMR) commonly occurs after transplantation of ABO-incompatible and sensitized renal transplant. Treatment regimens commonly include a combination of plasmapheresis (PL) and intravenous immunoglobulin (IVIG). However, some cases of AMR remain refractory to treatment. We report a case series of four patients with AMR refractory to standard therapy (ST) who resolved after splenectomy. Four living donor kidney transplant recipients were diagnosed with AMR. Two patients were ABO incompatible, one was cross-match positive and one had no obvious predisposing factors. After failure of therapy with corticosteroids, PL, IVIG, Thymoglobulin, and Rituximab (three patients) or Campath (one patient), AMR was treated with laparoscopic splenectomy. After an average of 11 days of ST, laparoscopic splenectomy was performed for rescue. The urinary output improved immediately in all patients, serum creatinine levels decreased within 48 hr, and ABO titers fell in the ABO-incompatible patient and the cross-match became negative in the two sensitized patients. Splenectomy may play a role in the treatment of AMR refractory to ST.

Adult↗
PubMed2006

Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets.

Mesenchymal cells in the developing pancreas express the neural stem cell marker nestin and the transcription factor islet-1 (Isl-1). Using defined culture conditions we isolated on a single cell basis nestin producing cells from human pancreatic islets. These cells were immortalized with lentiviral vectors coding for telomerase and mBmi. They are positive for Isl-1 and nestin and have the potential to adopt a pancreatic endocrine phenotype with expression of critical transcription factors including Ipf-1, Isl-1, Ngn-3, Pax4, Pax6, Nkx2.2, and Nkx6.1 as well as the islet hormones insulin, glucagon, and somatostatin. In addition, they can be differentiated into human albumin producing cells in vivo when grafted into a SCID mouse liver. In accordance with a mesenchymal phenotype, the cells were also able to adopt adipocytic or osteocytic phenotypes in vitro. In conclusion, cultured pancreatic islets contain nestin and Isl-1 positive mesenchymal stem cells with multipotential developmental capacity.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2006

Hilar early division of the hepatic duct in living donor right hepatectomy: the probe-and-clamp technique.

The division of the hepatic duct is one of the most challenging passages of the donor hepatectomy. We report our experience with the early division, prior to the liver parenchyma resection, of the hepatic duct and the definition of the biliary anatomy with a probe inserted in the proper hepatic duct. From February 2002 to December 2004, 40 donors (25 male, 15 female; mean age 34, range 20-57) underwent right hepatectomy. The yield was a single duct in 24 donors (60%), two ducts in 12 donors (30%), and three ducts in one donor (2.5%), and three donors had aberrant anatomy yielding two ducts (7.5%). By means of a ductoplasty, a single orifice for the recipient biliary anastomosis was obtained in 77.5% of the cases. Three donors (7.5%) suffered a resection surface bile leak. The technique of hepatic duct probing and early division provides a precise definition of the biliary anatomy and facilitates one of the most challenging passages of the donor hepatectomy. This technique should also contribute to maximizing the preservation of the vascular supply of the hepatic duct and the yield of a single orifice for the recipient anastomosis. At a median follow-up of 21 months (range 10-44), neither short- nor long-term complications had been caused by the small donor choledochotomy.

Adult↗
PubMed2006

Living related segmental bowel transplantation: from experimental to standardized procedure.

INTRODUCTION: Living donor bowel transplantation has recently emerged as a valuable alternative to cadaver bowel transplant. We herein present our single-center experience with this procedure. MATERIALS AND METHODS: From April 1998 to October 2004, 12 living donor intestinal transplants were performed in 11 patients (7 males, 4 females; average age, 26 years). Four of the patients were children under 5 years. A segment of distal ileum 150 to 180 cm long in pediatric recipients and 200 cm long in adult was used. The immunosuppressive protocol consisted of induction with thymoglobulin and maintenance with tacrolimus with or without mycophenolate mofetil and steroids. RESULTS: All donors recovered well and did not experience any early or late complications. The overall 1- and 3-year patient survival was 82% with a graft survival of 75%. In the last 8 patients, transplanted after January 2000, the 1-year patient and graft survival has been 100% and 88%, respectively. The median hospital stay was 36 days (range, 13-290 days). During the first year after transplant only, the patient who received a totally mismatched graft experienced one episode of rejection (8%). All the surviving patients are currently supported by enteral diet without fluid requirements. CONCLUSIONS: Living donor bowel transplantation is a valuable strategy in the treatment of irreversible intestinal failure. The results have improved over the years thanks to increased experience of the team.

Adult↗
PubMed2006

Routine left robotic-assisted laparoscopic donor nephrectomy is safe and effective regardless of the presence of vascular anomalies.

The classic approach to donor nephrectomy consists of preferential procurement of the kidney without vascular anomalies. We studied the effect of routine procurement of the left kidney regardless the presence of multiple arteries on the outcomes of robotic-assisted laparoscopic living donor nephrectomy (LLDN) with particular reference to the incidence of urological complications. From August 2000 to July 2005, 209 left LLDNs were performed. We analyzed the outcomes of donors and recipients in relation to the presence of multiple vessels versus normal anatomy. We divided the patients into two groups: group A (n = 148) with normal vascular anatomy and group B (n = 61) with vascular anomalies. In the donors, no significant difference in conversion to open surgery rate, blood loss, length of stay, was noted between the two groups; operative time and warm ischemia time were slightly higher in group B. One-year patient survival was 98% in both groups while the 1-year graft survival was 96.6% in group A and 96% in group B. Only one urological complication was noted in the group with normal anatomy (0.7%) versus none in the group with multiple arteries. Left kidney procurement using robotic-assisted laparoscopic technique is safe and effective, even in the presence of vascular anomalies.

Adolescent↗
PubMed2006

Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets.

High glucose concentrations have a dual effect on beta-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to beta-cell production of interleuking (IL)-1beta in human pancreatic islets. Fas, a death receptor regulated by IL-1beta, is involved in glucose-induced beta-cell apoptosis. Fas engagement can be switched from death signal to induction of proliferation when the caspase 8 inhibitor, FLICE-inhibitory protein (FLIP), is active. Here, we show that IL-1beta at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1beta concentrations (0.01-0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1beta (2-5 ng/ml) had the reverse effects. A similarly bimodal induction of FLIP, pancreatic duodenal homeobox (PDX)-1, and Pax4 mRNA expression, as well as glucose-stimulated insulin secretion, was observed. In contrast, Fas induction by IL-1beta was monophasic. Low IL-1beta also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1beta. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1beta-stimulated beta-cell proliferation. Consistent with our in vitro results, IL-1beta knockout mice displayed glucose intolerance along with a decrease in islet Fas, FLIP, Pax4, and PDX-1 transcripts. These findings indicate that low IL-1beta levels positively influence beta-cell function and turnover through the Fas-FLIP pathway and that IL-1Ra production prevents harmful effects of high IL-1beta concentrations.

Animals↗
PubMed2006

Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1.

Type 2 diabetes is characterized by a deficit in beta-cell mass, and its incidence increases with age. Here, we analyzed beta-cell turnover in islets from 2- to 3- compared with 7- to 8-month-old rats and in human islets from 53 organ donors with ages ranging from 17 to 74 years. In cultured islets from 2- to 3-month-old rats, the age at which rats are usually investigated, increasing glucose from 5.5 to 11.1 mmol/l decreased beta-cell apoptosis, which was augmented when glucose was further increased to 33.3 mmol/l. In parallel, beta-cell proliferation was increased by both 11.1 and 33.3 mmol/l glucose compared with 5.5 mmol/l. In contrast, in islets from 7- to 8-month-old rats and from adult humans, increasing glucose concentrations from 5.5 to 33.3 mmol/l induced a linear increase in beta-cell death and a decrease in proliferation. Additionally, in cultivated human islets, age correlated positively with the sensitivity to glucose-induced beta-cell apoptosis and negatively to baseline proliferation. In rat islets, constitutive expression of Fas ligand and glucose-induced Fas receptor expression were observed only in 7- to 8-month-old but not in 2- to 3-month-old islets, whereas no age-dependent changes in the Fas/Fas ligand system could be detected in human islets. However, pancreatic duodenal homeobox (PDX)-1 expression decreased with age in pancreatic tissue sections of rats and humans. Furthermore, older rat islets were more sensitive to the high-glucose-mediated decrease in PDX-1 expression than younger islets. Therefore, differences in glucose sensitivity between human and 2- to 3-month-old rat islets may be due to both differences in age and in the genetic background. These data provide a possible explanation for the increased incidence of type 2 diabetes at an older age and support the use of islets from older rats as a more appropriate model to study glucose-induced beta-cell apoptosis.

Adolescent↗
PubMed2005

Treatment of acetaminophen-induced acute liver failure in the mouse with conditionally immortalized human hepatocytes.

BACKGROUND/AIMS: Liver failure is a life threatening condition currently treated by palliative measures and, when applicable, organ transplantation. The use of a bioartificial organ capable of fulfilling the main functions of the liver would represent an attractive alternative. However, the shortage of suitable donor cells, and their limited growth ability have impeded the development of this strategy. We investigated whether lentiviral vectors allow for conditional immortalization of human hepatocytes and whether these immortalized hepatocytes could reverse lethal acute liver failure. METHODS: We exposed primary human hepatocytes to Cre-excisable lentiviral vectors coding for SV40T Antigen, telomerase, and/or Bmi-1 and tested the functionality of the resulting cell lines. Therapeutic potential of immortalized hepatocytes were tested in a murine model of acetaminophen-induced hepatic injury. RESULTS: The immortalized hepatocytes grew continuously yet were non-tumorigenic, stopped proliferating when exposed to Cre recombinase, and conserved defining properties of primary hepatocytes, including the ability to secrete liver-specific proteins and to detoxify drugs. The implantation of encapsulated immortalized human hepatocytes rescued mice from lethal doses of acetaminophen. CONCLUSIONS: Lentiviral vectors represent tools of choice for immortalization of non-dividing primary cells, and lentivirally immortalized human hepatocytes are promising reagents for cell-based therapy of acute liver failure.

Acetaminophen↗
PubMed2005

Islet transplantation: current status and future directions.

Pancreatic islet transplantation has gone a long way to finally enter the armamentarium of today's clinicians for the battle against diabetes. The proof of principle has been made and current clinical islet transplant trials need to further refine this attractive treatment modality. We review the post-Edmonton era, the selection of islet transplant recipients, the production of islet grafts, and the need for immunosuppression and procedure-related risks. The success of islet transplantation and expansion of clinical trials with islet networks are also discussed.

Clinical Trials as Topic↗
PubMed2005

Increased risk of post-transplant diabetes mellitus despite early steroid discontinuation in Hispanic kidney transplant recipients.

Early steroid discontinuation (ESD) has been associated with a lower incidence of post-transplant diabetes mellitus (PTDM). We retrospectively reviewed the incidence of PTDM in relation to racial groups in kidney transplant recipients treated with ESD. Between January 2002 and September 2003, 125 consecutive primary adult kidney transplants were performed. Group A (n = 91) had steroids discontinued on postoperative day 6 and maintenance immunosuppression of Tacrolimus and mycophenolate mofetil. Group B (n = 34), received the same immunosuppression but was maintained on steroids indefinitely. Induction consisted of thymoglobulin in African-Americans; all others received Simulect. At 1 yr, patient/graft survival, serum creatinine and rate of acute rejection were similar in both groups. The incidence of PTDM was significantly lower in group A (7%) compared with group B (26%, p = 0.0209). The incidence of PTDM in group A was limited to Hispanic patients with a family history of diabetes mellitus. African-Americans and Caucasians in group A did not experience PTDM (p = 0.005 compared with African-American in group B). Our steroid free protocol nearly eliminated the incidence of PTDM in African-Americans and Caucasians, but was still associated with significant rate of PTDM in Hispanic recipients. Alternative immunosuppression may benefit this population.

Adult↗
PubMed2005

Early discontinuation of steroids is safe and effective in pediatric kidney transplant recipients.

In pediatric kidney transplantation, steroid induced growth retardation and cushingoid features are of particular concern. In children, gradual steroid withdrawal late after kidney transplantation increases the risk of rejection. In this pilot study, we investigated the outcome of pediatric renal transplantation with an early steroid withdrawal protocol. This is a retrospective case-control study of pediatric renal transplants with age-matched historical control. Groups were comparable in terms of HLA matching, donor type and graft ischemia time. In the steroid withdrawal group (SWG, n = 13), induction therapy included mycophenolate mofetil (MMF) and a 5-day course of steroids with Thymoglobulin in 11 and basiliximab in two other patients. In the steroid group (SG, n = 13), in addition to steroids, four patients were given basiliximab, eight were given Thymoglobulin, and one OKT3. Maintenance therapy included tacrolimus (SWG n = 11, SG n = 3) or cyclosporine (SWG n = 2, SG n = 10). Azathioprine was given to all the patients in the SG, except the last two patients of this series who were prescribed MMF. MMF was given to all in the SWG. Patient and graft survival rates were 100% in both groups. In the SWG, no acute rejection episode was detected. In the steroid group, three patients (25%) presented with an acute rejection episode. All but one patient in either group showed immediate graft function. Patients in the steroid-withdrawal group exhibited a significantly higher creatinine clearance at 6 and 12 months post-transplant (95.8 +/- 23.3 vs. 71.3 +/- 21.9, p = 0.03; and 91.3 +/- 21.6 vs. 69.6 +/- 28.6, p = 0.04). In the SWG delta BMI was significantly lower and delta height Z score was significantly higher, and we observed significantly less hyperlipidemia, body disfigurement, and need for anti-hypertensive medication. Early steroid withdrawal in pediatric renal transplant recipients is efficacious and safe and does not increase risk of rejection, preserving optimal growth and renal function, and reducing cardiovascular risk factors.

Antibodies, Monoclonal↗
PubMed2005

Effect of microcapsule composition and short-term immunosuppression on intraportal biocompatibility.

With higher nutrient and oxygen supply and close contact to blood, the portal vein is a possible alternative to the peritoneal cavity for transplantation of encapsulated cells. Data regarding intraportal biocompatibility of microcapsules are lacking. Microcapsules were built from five alginate types differing in their molar mass and mannuronic/guluronic acid ratios by complex formation with divalent cations (barium or calcium) or mixtures of divalent cations and polycations. They were injected in the portal vein of rats, and cellular and fibrotic pericapsular infiltration thickness was measured 3 and 7 days after implantation. Overgrowth was characterized using various stainings or immunohistochemistry (hematoxylin and eosin, Giemsa, ED-1 for monocyte/macrophage, alpha-actin for myofibroblasts, CD31 for endothelial cells). The impact of short-term immunosuppression (gadolinium-chloride IV 20 mg/kg/day on days--1 and 4 as well as 10 days of rapamycin PO 1 mg/kg/day, tacrolimus PO 3 mg/kg/day, or combinations of rapamycin/tacrolimus or gadolinium/tacrolimus) was further assessed 3, 7, and 42 days after implantation. Overall, overgrowth increased from day 3 to day 7 (p < 0.05). Three and 7 days after implantation, polycation-containing microcapsules induced more reaction than microbeads (p < 0.0001 and p < 0.01). Considering polycation-free beads, barium-alginate induced the weakest reaction. Biocompatibility of microbeads was independent of mannuronic/guluronic acid ratio and molar mass of the alginate. Infiltration was mainly a monocyte/macrophage-rich foreign body reaction, but an eosinophil-containing immunoallergic reaction was also observed. Short-term immunosuppression significantly reduced infiltration in all conditions and up to 42 days after implantation. Biocompatibility after intraportal infusion was best for barium-alginate microbeads and poorest for polycation-containing microcapsules. Short- and long-term overgrowth could be significantly reduced by short-term immunosuppression.

Alginates↗
PubMed2004

Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma.

An increasing number of patients with hepatocellular carcinoma (HCC) are undergoing evaluation for listing for liver transplantation. Criteria for selection require ongoing review for suitability. A consecutive series of 40 patients with HCC within the standard Milan criteria (single tumors n = 19 < 5 cm, or up to 3 tumors < 3 cm) and beyond (Extended Criteria; single tumors n = 21 < 7.5 cm, multiple tumors < 5 cm) underwent liver transplant with a sirolimus-based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitors and steroids. At 44.3 +/- 19.3 months (mean +/- standard deviation) follow-up, 1- and 4-year survivals (Kaplan-Meier) are 94.1 +/- 5.7% and 87.4 +/- 9.3%, in the Milan group, respectively, and 90.5 +/- 6.4% and 82.9 +/- 9.3% in the Extended Criteria group, respectively. Five patients died during follow-up, only 1 from recurrent HCC. Five tumor recurrences have occurred at median 17 (mean 22 +/- 17) months posttransplant, 1 in the Milan group and 4 in the Extended Criteria group. Median survival in the patients with recurrent tumor is 42 months (mean 45 +/- 25), and the median postrecurrence survival is 15.5 months (mean 23 +/- 16). The rate of patients who were alive and free of tumor at 1 and 4 years is 94.1 +/- 5.7% and 81.1 +/- 9.9%, respectively, in the Milan group and is 90.5 +/- 6.4% and 76.8 +/- 10.5%, respectively, in the Extended Criteria group. Five patients had sirolimus discontinued for toxicity, while 24 of 35 surviving patients have sirolimus monotherapy immunosuppression. In conclusion, the Milan criteria for liver transplantation in the presence of HCC can be carefully extended without compromising outcomes. This sirolimus based immunosuppression protocol appears to have beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity.

Carcinoma, Hepatocellular↗
PubMed2004

Activation of human macrophages by allogeneic islets preparations: inhibition by AOP-RANTES and heparinoids.

During transplantation, pancreatic islets release chemokines which promote macrophage attraction, hampering engraftment of islets. The aim of this study was to modulate chemotaxis and the immune response of human macrophages induced by islets. Human monocyte-derived macrophages of healthy subjects were exposed to supernatants of human islets. Chemotaxis, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) release were evaluated. To modulate migration, human macrophages were incubated in the presence of aminooxypentane-regulated on activation, normal, T-cell expressed, and secreted (AOP-RANTES), a potent antagonist of CCR5. Chemotactic activity of islets supernatant was modulated by the addition of heparin or heparinoids [pentosan and calix[8S]arene (C8S)]. AOP-RANTES significantly reduced, in a dose-dependent manner, macrophage chemotaxis and cytokine release induced by islets supernatant. The chemotactic index was reduced from 3.05 +/- 0.27 to 0.71 +/- 12, TNF-alpha from 1205 +/- 52 to 202 +/- 12 pg/ml, and IL-1beta from 234 +/- 12 to 10 +/- 6 pg/ml. The trapping of chemokines by heparinoids reduced the chemotactic activity of islets supernatant from 3.05 +/- 0.27 to 1.2 +/- 0.1 with heparin or pentosan and to 1.72 +/- 0.22 with C8S, and also decreased the TNF-alpha release by human macrophages from 1205 +/- 35 to 1000 +/- 26 (C8S), 250 +/- 21 (heparin) and 320 +/- 19 (pentosan) pg/ml, and IL-1beta from 234 +/- 13 to 151 +/- 5 (C8S), 50 +/- 3 (heparin) and 57 +/- 4 (pentosan) pg/ml. In conclusion, AOP-RANTES and heparinoids inhibit human macrophage activation and migration induced by islets supernatant.

Adult↗
PubMed2004

Are criteria for islet and pancreas donors sufficiently different to minimize competition?

Islet and pancreas transplantation may compete for a limited number of organs. We analyzed records from the national Swiss transplant registry during a 4-year period to investigate the proportion of donors that are suitable for islet and pancreas transplantation. Suitability for pancreas transplantation was mainly defined as: age 10-45 years; weight <or= 80 kg; BMI <or= 25 kg/m(2); amylasemia <or= 150 U/l; ICU stay <or= 3 days and absence of severe hypotension (MAP <or= 60 mmHG). Between 1.1.1997 and 31.12.2000, data of 407 donors were collected, from which 321 donors were included in the study. Thirty-three (10%), 143 (45%), and 23 (7%) donors fulfilled the criteria for pancreas, islet transplantation, and both procedures, respectively. Giving priority to pancreas transplantation and accepting the absence of one selection criterion, 90 (28%) pancreas and 100 (31%) islet donors were identified. We conclude that with current allocation policies prioritizing pancreas transplantation, pancreas and islet transplantation may coexist with little competition.

Adult↗
PubMed2004

Steroid avoidance in liver transplantation.

Corticosteroids have always played a valuable role in transplantation. Unfortunately, they are subject to a wide range of side effects, such as hyperlipidemia, hypertension, diabetes mellitus, osteoporosis, growth retardation and Cushingoid appearance. Steroids may also exacerbate problems that existed before surgery, including malignancy, hepatitis B and hepatitis C. New, powerful immunosuppressants have allowed steroid use to be reduced or avoided altogether, but use of these regimens is not simple and may be associated with late acute rejection and recurrence of autoimmune disease. The present review examines the rationale for steroid avoidance in liver transplantation and assesses the new regimens that are currently being developed.

Animals↗