PubMed Health⌕ Search

Biomedical subjects

Philippe Morel

Publications and source records attributed to Philippe Morel.

85 records · Page 5Linked to original sources
PubMed2002

Highly efficient lentiviral vector-mediated transduction of nondividing, fully reimplantable primary hepatocytes.

Gene therapy is an attractive approach for the treatment of liver disease. We demonstrate that a so-called third-generation human immunodeficiency virus (HIV)-derived vector system can govern the efficient delivery, integration, and stable expression of a transgene into primary human hepatocytes in the complete absence of cell division. We also show that rodent hepatocytes exhibit a significant degree of resistance to HIV vector-mediated transduction, a phenotype that is particularly pronounced in murine hepatocytes and that results from a block in the immediate-early phase of infection. We finally describe a methodology, that allows very high rates of transduction through minimal in vitro manipulation, in which hepatocytes are kept in suspension and reimplanted within a few hours of harvest with a fully preserved engraftment potential. These results have immediate implications for the treatment of liver diseases by the transplantation of genetically modified hepatocytes, an approach that could be applied to a number of hereditary and acquired hepatic disorders.

Animals↗
PubMed2002

Prostaglandin E(1) protects human liver sinusoidal endothelial cell from apoptosis induced by hypoxia reoxygenation.

Hepatic ischemia-reperfusion injury is an important cause of graft dysfunction after liver transplantation. Liver sinusoidal endothelial cells (LSECs) are particularly sensitive to ischemia-reperfusion injury and undergo apoptosis. This study investigates the protective role of PGE(1) on apoptosis of LSEC during hypoxia-reoxygenation in vitro. Hypothermia-hypoxia followed by reoxygenation triggered LSEC apoptosis, and prostaglandin PGE(1) protected LSEC from apoptosis in a dose-dependent manner. The release of matrix metalloproteinases (MMPs) and nitric oxide (NO) by LSECs were increased after hypoxia reoxygenation. Both the MMP inhibitor BB3103 and the NO inhibitor LNAM effectively decreased LSEC apoptosis, suggesting a separate role of MMPs and NO in hypoxia-reoxygenation-induced LSEC apoptosis. PGE(1) down-regulated NO production by inhibiting the expression of inducible NO synthase in LSEC. PGE(1) also inhibited MMP-2 release from LSEC during hypoxia reoxygenation. These results indicate that the protection of LSECs from apoptosis by PGE(1) in hepatic ischemia-reperfusion injury is mediated by inhibiting inducible NO synthase and MMP release.

Alprostadil↗
PubMed2002

Regional extra-corporeal circulation to protect transplanted kidney and pancreas from ischemia during vascular reconstruction.

The development of severe aorto-ilio-femoral atherosclerotic disease in a patient with a previous double transplantation, kidney and pancreas, is a major surgical challenge. The transplanted organs have to be protected from extensive ischemia during the vascular reconstructive procedure and achieve optimal revascularization. The surgical management of a complex case where regional extra-corporeal circulation was used to protect transplanted pancreas and kidney during aorto-bifemoral vascular grafting in a 39 yr old diabetic patient is described. Regional femoro-femoral extra-corporeal circulation with an oxygenator is a safe technique that allows time for the proximal revascularization, minimizes the warm organ ischemia time and results in preservation of organ function.

Adult↗
PubMed2002

Natural history of long-term lung injury in mouse experimental pancreatitis.

OBJECTIVE: In patients suffering from acute pancreatitis, the pathogenesis of pancreatitis-associated lung injury is not completely understood. Several rodent models of pancreatitis-associated lung injury suggested that activated neutrophils and the release of proinflammatory mediators after the activation of inflammatory cells within the pancreas might play an important role in translating the pancreatic inflammation to the lungs. In this study, we examined the natural history of pancreatitis-associated lung injury during an entire week. SUBJECTS: Mice were administered 12 hourly intraperitoneal injections of a supramaximal dose of cerulein. MEASUREMENTS AND MAIN RESULTS: The severity of pancreatitis was time-dependent, with a maximal injury by 12-24 hrs after the start of cerulein administration. Pancreatitis was associated with a significant lung injury characterized by a rise in lung microvascular permeability, sequestration of neutrophils within the lungs, and a marked thickening of alveolar membranes. Within the lungs, the peak of macrophage inflammatory peptide-2, which attracts inflammatory cells within the injured area, preceded the peaks of both tumor necrosis factor-alpha and intercellular adhesion molecule-1. Moreover, histologic injury peaked by 12 hrs, with a full recovery at day 7. Serum macrophage inflammatory peptide-2 concentrations were significantly correlated with the occurrence of pulmonary leakage. Lung macrophage inflammatory peptide-2 concentrations peaked 12 hrs before pancreatic concentrations. CONCLUSIONS: Mediators released by the pancreas into the blood during acute pancreatitis induce within the lungs the chronological expression of macrophage inflammatory peptide-2, tumor necrosis factor-alpha, and intercellular adhesion molecule-1.

Acute Disease↗
PubMed2002

Molecular detection of circulating beta-cells after islet transplantation.

Islet transplantation is a promising treatment for type 1 diabetes. However, islet grafts are submitted to multiple injuries, including immunosuppressive drug toxicity, hyperglycemia, hypoxia, unspecific inflammatory reactions, as well as allo- and autoimmune destruction. Therapeutic approaches to these damage mechanisms require early detection of islet injury, which is currently not feasible because of the lack of efficient markers. Based on the hypothesis of islet dissociation and release of islet cells into the circulation during islet injury, we designed a highly sensitive and specific molecular assay, able to detect two beta-cells per milliliter of venous blood by RT-PCR of insulin mRNA. We report that circulating beta-cells can be demonstrated up to 10 weeks after intraportal islet transplantation, as assessed after six islet grafts in four type 1 diabetic patients. Furthermore, our results suggest that the time during which circulating islet cells can be detected may depend on the graft environment and the immunosuppressive regimen. This test may allow better estimation of islet cell loss and identification of factors involved in islet graft injury.

Adult↗
PubMed2002

Reduction of blood glucose variability in type 1 diabetic patients treated by pancreatic islet transplantation: interest of continuous glucose monitoring.

OBJECTIVE: To compare the glycemic profiles of patients with type 1 diabetes treated with either an implantable insulin pump or pancreas or islet transplantation by the means of the continuous glucose monitoring system (CGMS; Minimed, Sylmar, CA). RESEARCH DESIGN AND METHODS: The CGMS enabled recording of subcutaneous glucose concentrations (range 2.2-22 mmol/l) over 72 h (288 measurements per day). Over 3 days, 26 patients with type 1 diabetes were connected to a CGMS: 10 patients were treated with intraperitoneal insulin infusion through an implantable pump (IPII), 9 patients were treated with simultaneous pancreas-kidney transplantation (SPK), and 7 patients were treated with pancreatic islet transplantation after kidney grafting (IAK). All SPK patients and four IAK patients were insulin independent, whereas three IAK patients had partial graft function and reduced exogenous insulin needs. Glucose control was evaluated by the mean glucose concentration, glucose variability, and the number and duration of hypoglycemic events (<3.3 mmol/l) over 3 days. RESULTS: The mean glucose concentration and the glucose variability in SPK and IAK patients were significantly lower than those observed in patients treated with IPII: 5.38 +/- 1.12 and 5.83 +/- 0.81 vs. 7.81 +/- 1.55 mmol/l (P < 0.001) and 1.40 +/- 0.42 and 1.32 +/- 0.53 vs. 3.47 +/- 1.66 mmol/l (P < 0.001), respectively. Furthermore, the mean glucose concentration and the glucose variability were comparable between SPK and IAK patients. Over 3 days, no hypoglycemic events were observed in SPK patients and insulin-independent IAK patients. A total of 4.12 +/- 1.66 hypoglycemic events were detected in the IPII patient group, whereas only 0.66 +/- 0.57 events were observed in IAK patients with partial graft function (P < 0.001). The duration of the hypoglycemic events was significantly longer in IPII patients as compared with IAK patients: 64 +/- 33 vs. 30 +/- 15 min for the day period and 130 +/- 62 vs. 30 +/- 27 min for the night period (P < 0.001). CONCLUSIONS: Use of subcutaneous CGMS confirms that islet transplantation can be as efficient as pancreas transplantation in restoring good metabolic control and reducing blood glucose variability. Metabolic improvement due to use of an implantable insulin pump requires insulin delivery by a closed loop.

Adult↗
PubMedDate not supplied

Preoperative concomitant hyperfractionated radiotherapy and gemcitabine for locally advanced rectal cancers: a phase I-II trial.

PURPOSE: The purpose of this study was to determine the maximum tolerated dose of gemcitabine when it was administered concomitantly with hyperfractionated radiotherapy before surgery in patients with locally advanced rectal cancers and to investigate the midterm efficacy of such a regimen. PATIENTS AND METHODS: Thirty-seven patients with stage II-III tumors as assessed by computed tomography/echoendoscopy were enrolled. Radiotherapy consisted of 50 Gy given in two daily fractions of 1.25 Gy over 4 weeks. The starting dose of gemcitabine was 10 mg/m(2)/day (in a 30-minute i.v. perfusion) twice weekly with planned escalation steps of 5 mg/m(2)/day. Surgery was planned at 6 weeks after the end of radiotherapy. Main end-points of the study were complete pathological tumor response, the rate of clear margin resection, and actuarial locoregional control and disease-free survival. The median follow-up for all patients was 32 months (range: 10-51 months). RESULTS: At the level of 45 mg/m(2), two of four patients presented with dose-limiting rectal toxicities (severe acute proctitis requiring hospitalization in the immediate postradiotherapy period). Thus, the gemcitabine biweekly dose of 40 mg/m(2) was considered to be the maximum tolerated dose. Among the 36 patients who underwent surgery, 17 (47%) had a marked pathological response, including six patients (17%) with a microscopically complete response and 11 (30%) with only microscopically residual carcinoma of less than 1 cm. All of them had clear surgical margins. At 3 years, actuarial overall survival rate was 85%, locoregional control was 94.5%, and disease-free survival was 67%. DISCUSSION: The present study determined the recommended dose of gemcitabine to be 40 mg/m(2) when administered concurrently twice a week with 50 Gy hyperfractionated radiotherapy for the preoperative treatment of locally advanced rectal cancers. The encouraging pathological response rate and the very low locoregional recurrence rate suggest that this innovative approach merits further investigation.

Adult↗
PubMedDate not supplied

Long-term renal function after liver transplantation is related to calcineurin inhibitors blood levels.

BACKGROUND: Renal dysfunction is common after liver transplantation (LT). The aim of our study was to assess the prevalence of renal dysfunction 5 yr after LT and to identify risk factors for the development of this complication. PATIENTS AND METHODS: A total of 134 adult patients underwent LT from 1987 to 1998 and 74.6% of them were alive 5 yr after. Pre-LT, 1 and 5 yr post-LT renal function were calculated by Cockroft and modification of diet in renal disease (MDRD) formula. Since 1987 glomerular filtration rate (GFR) has been measured by radiolabeled tracers clearance (RTC). Risk factors for GFR < 50 mL/min were analyzed using a multivariate logistic regression model. RESULTS: Mean pre-LT GFR was 79 and 85 mL/min with Cockroft and MDRD respectively; 11% of the patients had a GFR or= 150 microg/L or tacrolimus (FK) >or= 10 microg/L at 1 yr and CyA >or= 100 microg/L or FK >or= 8 microg/L at 5 yr. CONCLUSION: 5 yr after LT, patients have lost 26% of their initial GFR and 25% of them have a GFR < 50 mL/min. This complication is predicted by high levels of calcineurin inhibitors (CNI). Therefore CNI levels should be reduced as low as possible and use of alternative drugs should be considered.

Adolescent↗
PubMedDate not supplied

Long-term results of radical resection for locally advanced duodenal adenocarcinoma.

BACKGROUND/AIMS: Duodenal adenocarcinomas are uncommon tumors characterized by non-specific symptoms and late diagnosis. The objective of this study was to assess long-term results of locally advanced duodenal adenocarcinoma treated by surgical resection. METHODOLOGY: A retrospective study, over a 10-year period, identified 9 patients (mean age 65 years) treated for duodenal carcinoma. RESULTS: Out of nine patients who were treated for duodenal adenocarcinoma, 8 underwent R0 resection (5 pancreaticoduodenectomies, 1 total pancreaticoduodenectomy and 2 segmental duodenal resections). All of them had tumor of stage II or III according to TNM classification. Median follow-up was 104 months (range 25 to 185). Five patients had lymph node metastases (stage III) at the time of surgery. Two- and five-year survival rates were 100% and 75%, respectively for the whole group. No correlation between lymph node status and survival was found. CONCLUSIONS: Radical surgical resection for locally advanced duodenal adenocarcinomas provides good long-term results in terms of patient survival, even for N1 tumors (stage III).

Adenocarcinoma↗