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R Mage

Publications and source records attributed to R Mage.

At least 19 recordsLinked to original sources
PubMed2004

Islet of Langerhans allogeneic transplantation at the University of Geneva in the steroid free era in islet after kidney and simultaneous islet-kidney transplantations.

AIMS: We report a single-center experience of islet allogeneic transplantation in islet after kidney (IAK) and simultaneous islet-kidney (SIK) type 1 diabetic recipients using a steroid-free immunosuppressive regimen. METHODS: Eight patients received 12 islet infusions in 5 IAK and 3 SIK procedures. Median age was 51 years (range, 30-58 years) with a male:female ratio of 2:6. IAK was considered only for patients with a stable kidney function and a creatinine clearance level >60 mL/min. SIK was considered for patients with a counterindication for simultaneous kidney-pancreas transplantation. Immunosuppression was based on sirolimus/tacrolimus combined with daclizumab induction. Two consecutive infusions of >5000 islet equivalents (IEQ)/kg were planned. RESULTS: Five patients completed the transplantation course, whereas 3 patients received only 1 islet infusion. All patients have functional grafts (C-peptide >166 pmol/L) at 6-month median follow-up. Of 5 patients who completed their transplantation course 4 became insulin independent. HbA1c and fructosamine decreased over time, showing improved metabolic control. Severe adverse events were observed in 4 patients. One SIK patient died after OKT-3 treatment of severe kidney rejection. CONCLUSIONS: The Edmonton immunosuppressive protocol can be applied for patients undergoing either IAK or SIK procedures, with a high rate of graft function and insulin independence. Morbidity is higher than among patients undergoing solitary islet transplantation for type 1 brittle diabetes.

Adult↗
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↗
PubMed2000

[Natural biological risks and military biological risks].

The Iraqi biological program, the activities of sect Aum in Japan and the extensive endemicity of plague prove the existence of military, terrorist and natural biological risks. Among the agents of natural risk (viruses, bacteria.), plague is induced by modification of the ecosystem. Present since 1921 in the high plateau of Madagaskar, the disease evolves under two modes, endemic (natural) or epidemic (urban). Since the control of endemicity is impossible, the decrease of incidence will be obtained by the control of the animal reservoir. The military risk is part of the history of armed conquests. Anthrax and botulinum toxins, are the most toxic agents, banned by the Convention of London (1972). In 1995, 4 years after the end of Gulf war, UNSCOM obtained from authorities the inventory of Iraqi biological program, with details on the militarization of toxins and spores. These furtive weapons, are produced with limited technological skills, often in dual manufactures and are difficult to control.

Adult↗
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

Does hepatocyte transplantation in a chemically induced acute hepatic failure make sense?

PURPOSE: Acute hepatic insufficiency (AHF) is one of the major challenges of intensive care medicine. Liver transplantation is the current solution to unsuccessful medical management. Owing to the lack of organ donors, other methods such as hepatocyte transplantation (HcTX) and bioartificial livers need to be explored. The aim of our experimental study is to evaluate the effect of hepatocyte transplantation on the survival in AHF animals intoxicated with D-Galactosamine (D-Gal). METHODS: The first step consists of the determination of the dose of D-Gal needed to induce at least 80% mortality between 48 and 72 hours. Two groups of a single strain of male Wistar rats are then compared, one being intoxicated with D-Gal (control group), the other receiving and HcTX in the splenic parenchyma 48 hours after intoxication. RESULTS: The required dose to achieve AHF is 3 gr/kg body weight (Gr. 0). Survival rates are as follow: Gr. 1: D0: 93%; from D1 to D28: 13%. Gr. 2: D0: 80%; D1 and D2: 33%; D3: 20%; D4: 13%, from D5 to D28: 6%. (D0 = Day of transplantation). Liver enzymes show a peak of deterioration at 24 hours, then return to normal values in both groups. Histological examination of those animals still alive and sacrificed on day 28 demonstrates a restitutio ad integrum of hepatic structure. In Group 2, it is possible to observe remaining living hepatocytes in the splenic parenchyma. CONCLUSIONS: When HcTX is performed 48 hours after D-Gal intoxication, i.e., when the animals begin to develop AHF symptoms, animal survival only significantly improves between days 0 and 3. Unlike other trials, we cannot demonstrate an improvement in long-term survival. Thus, according to this particular experimental model, HcTX is not an alternative for the treatment of AHF.

Animals↗
PubMed1998

Effects of glucose on chemically induced acute hepatic failure in rats.

TOPIC: Acute hepatic failure (AHF) is a physiopathological entity difficult to reproduce experimentally but necessary to evaluate new therapies such as bioartificial liver (BAL) or hepatocyte transplantation (HcTX). Two main animal models are available: surgical or chemical induction of an AHF. Many authors have assessed BAL or HcTX with such models and observed increased survival rate in the treated groups. However, during AHF, severe hypoglycemia takes place. Some authors have shown that adjunction of glucose in beverage after surgically induced AHF may induce by itself an improvement of survival rate. METHOD: The purpose of the present study is to test if the adjunction of glucose leads to the same effect in an AHF chemically induced by D-Galactosamine (D-Gal). A group of animals (rats) receiving glucose 20% as beverage immediately after intoxication (Group 1), is compared with a control group receiving tap water (Group 2). RESULTS: The required dose to achieve AHF is 2.75 g/kg body weight (Gr. 0). Survival rates are as follows: Gr. 1: Day 3:20%; day 5: 10%; day 8: 0%. Gr. 2: Day 3: 0%. The difference in survival rate is not statistically significant between the two groups. Liver enzymes peak at 24 hours, then return to normal values; blood sugar levels show no difference between groups. Histological examination of Gr. 0 animals surviving and sacrificed on day 28 shows restitutio ad integrum of hepatic structure. CONCLUSION: Glucose adjunction does not alter survival rate. We can conclude that this particular model of AHF is reliable.

Animals↗
PubMed1997

[Islands of Langerhans autotransplantation after pancreatic resection for benign pathology].

One way to prevent the occurrence of insulin-dependent diabetes after major pancreatic resection is to perform islet of Langerhans autotransplantation. Thus far, we have performed nine autotransplantations. The last three autotransplantations were performed in patients with benign tumoral pathology (one corporeal mucinous cyst, one isthmic insulinoma and one corporeal cystadenoma). In these three cases, we performed a distal 40%, 75% and 80% pancreatectomy respectively, since enucleation was not indicated or not feasible. After resection and removal of the tumoral lesion, pancreatic segments were injected intraductally with collagenase and digested according to a modified semi-automated Ricordi's technique. We obtained 105,000, 415,000 and 144,300 non-purified islets which were then embolized into the liver by intraportal injection during the same operative procedure. After surgery, all patients were insulin-independent. There was no morbidity or mortality. In a patient who presented acute pancreatitis of the residual pancreas five months after transplantation, insulin therapy was introduced. More than one year after the graft, the two other patients remain insulin-independent. In conclusion, we propose islet autotransplantation after pancreatic resection for benign focal pathology, to prevent or delay the occurrence of insulin-dependent diabetes.

Adult↗
PubMed1996

[Isolation and cryopreservation of human islets of Langerhans].

Islet transplantation represents an alternative to whole pancreas transplantation for the treatment of patients suffering from diabetes type I. The transplantation of a sufficient number of islets is an essential condition for successful allograft. Islet cryopreservation allows the storage of islet preparations for subsequent pooling, at the time of transplantation, of cryopreserved islets with a fresh preparation in order to increase the mass of transplanted pancreatic endocrine tissue. From May 1994 to April 1995, islets were isolated from 22 human pancreases using a modified automated method, and 19 preparations were cryopreserved. The function of cryopreserved islets was tested in vitro (static incubation and perifusion). The results of static incubation experiments confirmed that the insulin secretion of cryopreserved human islets in response to glucose stimulation was comparable to the response of islets that have not been frozen. In static incubation experiments, the mean (+/- SEM) insulin secretion of islets, prior to cryopreservation, was 239.3 (+/- 58.9) and 479.5 (+/- 59.5) pg/islet/15 min at 2.8 mM glucose and 16.7 mM glucose respectively. The mean (+/- SEM) insulin secretion of cryopreserved islets was 274 (+/- 103.2) and 468.5 (+/- 191.9) pg/islet/15 min at 2.8 mM and 16.7 mM glucose respectively. The perifusion experiments also demonstrated a significant increase of insulin secretion from cryopreserved islets perifused with a stimulating glucose concentration. Our experiments allow us to envisage the use of cryopreserved islet preparations for allotransplantation in diabetic patients.

Adult↗
PubMed1995

[Islets of Langerhans allografts in the pig: initial results].

Islet of Langerhans transplantation represents a promising treatment of diabetes. Use of porcine islets for xenotransplantation could offer a solution to shortage of organ donors. However, isolation of pig islets remains a real challenge because of their marked fragility. Using a modified automated method for islet isolation, we performed 10 intraportal islet allografts in pigs. Surgically pancreatectomized pigs were transplanted with purified islet preparations pooled from pancreases of 3 donors (slaughter-house pigs, age 5-8 months). Six recipients were not immunosuppressed and four received an immunosuppressive treatment of Cyclosporine and Azathioprine. In the first group (non-immunosuppressed recipients), insulin secretion was observed for a mean of 4.8 days after transplantation. In the second group (with immunosuppressive treatment) the recipients sustained an insulin secretion for 6-9 days. However, in both groups liver biopsies showed signs of acute rejection and destruction of the transplanted islets. Pig islet allotransplantation, using as recipients surgically pancreatectomized pigs, can be considered as a suitable model to assess the functional results of mass islet isolation. We were able to reverse diabetes transitory in a large animal, by transplantation of purified pig islet preparations. However, even when an immunosuppressive treatment was administered to the recipients, rejection seemed to represent an important factor in the functional outcome of the islet grafts.

Animals↗
PubMed1995

[Mechanism of rejection of islet of Langerhans xenografts].

For immediately vascularised xenografts, the presence of preformed antibodies associated with the activation of the complement induces a hyperacute humoral rejection in discordant combinations. For neovascularised xenografts, such as the islets of Langerhans, the absence of an initial vascularisation prevents the acute humoral rejection and there is some evidence to suggest that the rejection is cell mediated. To analyse the influence of species response to cellular transplantation, we compared the functional outcome and the immunohistochemical analysis of concordant and discordant xenotransplated islets with allotransplanted islets of Langerhans. In the concordant xenotransplantation experiment, rat (Sprague Dawley) purified islets (N = 600) were transplanted under the kidney capsule of streptozotocin diabetic mice. In the discordant experiment, purified human islets (N = 1000), in the allotransplantation model Balb mouse islets (N = 600) were transplanted under the kidney capsule of C57BL/6 mice. Daily blood glucose levels were monitored until rejection occurred (blood glucose > 11 mMol/L) and kidney biopsies were taken every second day for immunohistological examination. In allotransplanted mice, rejection occurred after a mean of 15 +/- 4 days, in concordant xenotransplanted mice after a mean of 10 +/- 3 days and in the discordant xenotransplanted mice after a mean of 8 +/- 1 days. The immunohistological analysis showed in both xenotransplantation models a deposit of IgM and C3 surrounding the grafted cells, starting at day 1 and persisting until rejection, associated with the presence of Mac-1 positive cells. The intensity of the humoral response was moderate to important in the concordant group, but very strong and unchanged until rejection in the disconcordant group. An invasion with CD4+ and CD8+ cells started between day 4 and 6 in both groups, progressively increasing until rejection. In the allotransplantation model, no humoral response was detectable and the cellular response started between day 10 and 12 after transplantation. We conclude, that a cellular response is involved in the rejection process of both concordant and discordant xenotransplanted islets of Langerhans. Compared to an allotransplantation model, the humoral response does not destroy the function of transplanted islets, but could trigger or accelerate the cell-mediated response.

Animals↗