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Biomedical subjects

P Moreau

Publications and source records attributed to P Moreau.

At least 37 records · Page 2Linked to original sources
PubMed2002

Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients.

The use of mycophenolate mofetil (MMF) for prophylaxis of aGVHD and/or for treatment of acute or chronic GVHD is increasing. However, the benefit of MMF as an alternative to commonly used immunosuppressive agents still needs to be assessed. We ran a retrospective study on 21 consecutive patients (median age, 36 years; range, 20-63) with aGVHD or extensive cGVHD following related (17) or unrelated (4) matched donor SCT (BM, 16; PBSC, 5) who received MMF (2 g/day) because of intolerance to or failure of CsA-containing combinations. Four of the six patients with aGVHD responded, and the response rate was 69% in cGVHD patients. We observed neither significant differences in terms of response rate for skin, liver and bowel nor dissociated response in cases of multiple organ involvement (67% of the patients). Response was the same for lichenoid and sclerodermatous skin cGVHD subtypes. No adverse effects, except diarrhea (three patients), were observed. However, 22 opportunistic or serious viral or bacterial infections occurred in 10 patients. Analysis of trough plasma levels showed a trend for a higher mean MPA concentration in patients responding to MMF. Our study highlights the high risk of infectious complications induced by the administration of MMF, an otherwise efficient and well-tolerated treatment for GVHD.

Acute Disease↗
PubMed2002

Potentiation of Fas-mediated apoptosis by an engineered glycosylphosphatidylinositol-linked Fas.

FasL and TRAIL are apoptotic ligands of the TNF-like cytokines family, acting via activation of the transmembrane death domain containing receptors Fas for FasL, and DR4 or DR5 for TRAIL. A glycosylphosphatidylinositol-linked TRAIL receptor called DcR1 behaves as a decoy receptor inhibiting TRAIL-mediated cell death in several cellular systems. We engineered and stably expressed a chimeric GPI-linked Fas receptor (Fas-GPI) in T-lymphocyte cell lines constitutively expressing functional transmembrane Fas. Surprisingly, despite lacking the death domain region of functional Fas, Fas-GPI was able to significantly increase Fas-mediated cell death triggered by membrane bound or soluble FasL, whereas engagement of Fas-GPI alone did not trigger apoptosis. This potentiating effect, but not transmembrane Fas activation, was selectively inhibited by protein kinase C activation with phorbol esters, demonstrating that Fas-GPI activated a specific synergistic signal transduction pathway. Fas-GPI and transmembrane Fas were localized in distinct membrane compartments, since Fas-GPI, but not transmembrane Fas, was found in the glycolipid-rich membrane microdomains. These results suggest that apoptosis induced by members of this ligand/receptors family may be differentially modulated through other and parallel signalling pathways.

Animals↗
PubMed2002

Long-term results (12 years) of high-dose therapy in 127 patients with de novo multiple myeloma.

This report describes the long-term outcome of a cohort of 127 de novo multiple myeloma patients treated with at least one course of high-dose therapy (HDT) in a single institution between June 1985 and December 1995, for whom the minimum follow-up duration for survivors is 6 years. The 12-year overall survival (OS) and event-free survival (EFS) rates are 24.9% and 3.1%, respectively, and the median survival and EFS are 49 and 17 months, respectively. Only four patients are alive and disease-free 79, 90, 132 and 153 after the first HDT, respectively. Three of them received a subsequent allogeneic bone marrow transplantation. Three factors significantly influence OS in this series: B2M at diagnosis, age, and the completion of a second HDT. The 10-year survival is 18.9% for the group of patients with B2M level >3 mg/l at diagnosis as compared with 41% for patients with B2M < or =3, with a median survival of 31 months vs 73 (P = 0.01). The 10-year survival is 23.4% for the group of patients aged >55 years as compared with 36.5% for patients aged <55 years, with a median survival of 34.5 months vs 70.5 (P = 0.04). The 10-year survival is 20.4% for the group of patients who did not receive a second HDT as compared with 35.2% for patients who completed a second HDT, with a median survival of 29 months vs 70 (P = 0.02). In this study we show that some patients treated with HDT experience durable remission and prolonged survival. This survival is significantly influenced by age (< or =55 years), B2M at diagnosis (< or =3 mg/l) and by the completion of two cycles of HDT.

Adult↗
PubMed2002

Simultaneous bilateral total hip arthroplasty in sickle cell disease.

Simultaneous bilateral uncemented total hip arthroplasty for avascular necrosis of the femoral head resulting from sickle cell disease was performed in 18 consecutive patients (36 hips). The patients were followed 2 to 10 years (mean, 5.7 years). All patients showed improvement in postoperative hip scores compared with preoperative scores for pain, range of motion, and function. There were 2 immediate postoperative complications related to sickling of red blood cells. One intraoperative fracture of the proximal femur occurred. There was 1 superficial and 1 deep infection. There was no femoral stem loosening, but 1 protrusio acetabuli occurred. One acetabular cup was revised for instability. Heterotopic ossification developed in 2 patients. Simultaneous bilateral total hip arthroplasty in sickle cell disease is a good option in a select group of patients with adequate hydration and ventilation in the perioperative and postoperative periods.

Adult↗
PubMed2001

Allogeneic hematopoietic stem-cell transplantation after nonmyeloablative preparative regimens: impact of pretransplantation and posttransplantation factors on outcome.

PURPOSE: To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens. PATIENTS AND METHODS: Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days. RESULTS: Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% +/- 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% +/- 12% and 38% +/- 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration. CONCLUSION: This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.

Adolescent↗
PubMed2001

Phosphatidylserine delivery to endoplasmic reticulum-derived vesicles of plant cells depends on two biosynthetic pathways.

Vesicles formed from endoplasmic reticulum (ER) by a cell-free system of leek cells (Allium porrum) are enriched in phosphatidylserine (PS), especially species containing very long chain fatty acids (VLCFA, at least 20 carbon atoms). In plant cells, PS is formed either by PS synthase or the serine exchange enzyme, although it is not known which pathway(s) contribute(s) to PS delivery in the ER-derived vesicles (EV), nor to what extent this occurs. Taking advantage of a cell-free system, we have shown that PS enrichment originates mainly from the serine exchange enzyme which is the only pathway that synthesizes the VLCFA-PS species. On the other hand, both enzymes synthesize PS with long chain fatty acids (up to 18 carbon atoms), but these species are given to the EV by PS synthase.

Endoplasmic Reticulum↗
PubMed2001

Longitudinal study of bacterial, viral, and fungal infections in adult recipients of bone marrow transplants.

The epidemiology of infections was studied in a retrospective cohort of 446 recipients of bone marrow transplants (BMTs; 92 of which were allogeneic and 354 of which were autologous) during 1993--1996. Infections that were microbiologically documented in 274 recipients included bacteremia, urinary tract infections, cytomegalovirus viremia, fungemia, invasive aspergillosis, and catheter-related infections. During the period of neutropenia, no differences were found between recipients of allogeneic BMTs and recipients of autologous BMTs with regard to the incidence and the nature of infection. After patients underwent engraftment, bacteremia, cytomegalovirus viremia, and invasive aspergillosis were significantly more common in recipients of allogeneic BMTs than in recipients of autologous BMTs. Deaths caused by infection were uncommon and were mainly the result of invasive aspergillosis. Therefore, empirical antimicrobial therapy should be the same for recipients of both allogeneic and autologous BMTs during the period of neutropenia; after engraftment, more attention should be paid to the risk of infection in allogeneic BMT recipients, particularly with regard to detection and prevention of invasive aspergillosis.

Adolescent↗
PubMed2001

Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy.

A careful prognostic evaluation of patients referred for high-dose therapy (HDT) is warranted to identify those who maximally benefit from HDT as well as those who clearly fail current HDT and are candidates for more innovative treatments. In a series of 110 patients with myeloma who received HDT as first-line therapy, times to event (disease progression and death) were studied through proportional hazard models, in relation to different prognostic factors, including a chromosome 13 fluorescence in situ hybridization (FISH) analysis using a D13S319 probe. Delta13 was detected in 42 patients (38%). Follow-up time among surviving patients and survival time were 48 +/- 3 and 51 +/- 7 months, respectively (median +/- SE). In the univariate analysis, Delta13 was the most powerful adverse prognostic factor for all times to event, especially for the survival time (P <.0001) and was followed by beta2-microglobulin (beta2m) levels 2.5 mg/L or higher (P =.0001). The comparison of survival prognostic models including beta2m 2.5 mg/L or greater and another factor favored the Delta13/beta2m combination. In 22 patients (20%) with no unfavorable factor, the median survival time was not reached at 111 months. In contrast, among 55 patients (50%) with one unfavorable factor and 33 patients (30%) with 2 unfavorable factors, median survival times were 47.3 +/- 4.6 months and 25.3 +/- 3.2 months, respectively (P <.0001). We conclude that delta13, adequately detected by FISH analysis, is a very strong factor related to poor survival, especially when associated with a beta2m level of 2.5 mg/L or higher. Routine FISH Delta13 assessment is strongly recommended for patients considered for HDT.

Actuarial Analysis↗
PubMed2001

Long-term complications of total body irradiation in adults.

PURPOSE: To report long-term pulmonary, thyroid, and ocular complications in patients who had conditioning regimens including total body irradiation (TBI) before bone marrow transplantation (BMT). METHODS AND MATERIALS: Between June 1986 and December 1995, 478 patients received TBI in our institution. The present study includes 186 adult patients who had complete remission lasting one year or more after BMT. There were 108 males and 78 females. Median age was 36.5 years (range 15-60). Initial diagnoses were lymphomas (50%), acute lymphoid leukemias (16%), acute myeloid leukemias (16%), chronic myeloid leukemia (13%), aplastic anemia (3%), and myelodysplasia (2%). At the time of BMT, 43.5% of patients were in complete response and 56.5% in partial response. Treatment consisted of a single dose TBI at 10 Gy in 9% and fractionated TBI delivering 12 to 13.5 Gy in 6 fractions in 91%. From 1986 to October 1991, TBI was performed in lateral position with 9 MV energy (57% of patients) and thereafter in alternate prone and supine positions with 15 MV energy (43%). Chemical conditioning regimen was cyclophosphamide (60 mg/kg at D-4 and D-3) in 69% and CBV (cyclophosphamide 1500 mg/m(2) from D-6 to D-3, BCNU 300 mg/m(2) at D-6, VP-16 200 mg/m(2) from D-6 to D-4) in 25%. Fifty eight percent of patients received autologous and 42% allogeneic BMT. All patients had clinical, biologic, and functional examinations at one-year intervals. RESULTS: Median follow-up from BMT was 49 months (range 12-136). Late pulmonary effects were observed only in functional explorations, without clinical effect, including restrictive syndrome in 8% and alteration in the diffusing capacity of carbon monoxide in 12%. No patient showed clinical thyroid symptoms, and 10% developed biologic dysfunction: hypothyroidism (6.5%), thyroiditis (3%), and Basedow disease (0.5%). Ocular complications occurred in 29.5%, including cataract (15%), dry syndrome (13%), and keratitis (1.5%). In univariate and multivariate analysis, pulmonary complications were statistically increased by chronicle graft vs. host disease (GVHD) vs. no (p = 0.02), prone and supine vs. lateral TBI position (p = 0.02), and with 15 MV vs. 9 MV beam energy (p = 0.02). Cataract occurred less frequently with fractionated than with single-dose TBI (p = 0.000002). No differences were observed regarding age, sex, initial diagnosis, status at the time of BMT, conditioning chemotherapy regimen, and total dose of TBI. CONCLUSION: From this retrospective study it was shown that long-term complications of TBI were not symptomatic in most patients. The role of parameters of irradiation and especially position of treatment and beam energy should be emphasized and assessed with a longer follow-up.

Adolescent↗
PubMed2001

Altered HLA-G transcription in pre-eclampsia is associated with allele specific inheritance: possible role of the HLA-G gene in susceptibility to the disease.

Pre-eclampsia is a disorder of human pregnancy occurring in 5-10% of all births, and represents the leading cause of infant morbidity and mortality and maternal death. In pre-eclampsia, invasion of fetal trophoblasts into maternal arteries during early pregnancy is shallow or absent. Here we examined the hypothesis that HLA-G, a non-classical class I HLA expressed in cytotrophoblasts, may act as a key gene in pre-eclampsia. We analysed HLA-G at the level of transcription and genotyped a silent CAC-CAT polymorphism in exon 3 and a 14-bp insertion/deletion in the 3' untranslated region. A deficit in levels of the HLA-G3 transcript was observed in mild pre-eclampsia compared to normal placentas. The distribution of HLA-G polymorphisms was different between normal and pre-eclampsia samples. A correlation between the alteration in transcription of the HLA-G gene and certain HLA-G genotypes was also observed. Thus we provide the first evidence for a possible role of HLA-G in genetic susceptibility to, and pathogenesis of pre-eclampsia.

Alleles↗
PubMed2001

Pelvic limb-salvage surgery for malignant tumors.

Thirteen patients with primary malignant tumors of the pelvis underwent internal hemipelvectomy. The diagnoses were: Ewing's sarcoma 7, osteosarcoma 4, chondrosarcoma 1, and malignant fibrous histiocytoma 1. No megaprostheses or massive allografts were used for reconstruction. Six patients underwent resection only with no reconstruction, 5 had strut grafts inserted to restore the pelvic ring, 1 had an autoclaved autograft of the acetabulum and 1 had an ilio-femoral arthrodesis. No patients were lost to follow-up. Nine patients died from their disease after an average of 23 months (range 2 to 72 months). The 4 survivors (3 free of disease) have an average follow-up of 84 months (range 60 to 120 months).

Adolescent↗
PubMed2001

Phosphatidylserine increase in rat liver endomembranes during the acute phase response.

The acute phase response (APR) is responsible for great changes in protein and lipid metabolism. For example, marked changes are observed in the metabolism of fatty acids, triglycerides, cholesterol and sphingolipids. Those lipids are partly recovered in the lipoproteins and subsequently in the plasma. Beside these lipid families, nothing is known about phospholipids and their synthesis in endomembranes during the APR. Our studies show that phosphatidylserine synthesis is stimulated during the APR and that this lipid is increased in the endoplasmic reticulum (ER) and the ER-derived vesicles.

Acute-Phase Reaction↗
PubMed2001

HLA-G: a shield against inflammatory aggression.

Recent developments in the field of HLA-G research have revealed that, besides its involvement during pregnancy, HLA-G is expressed in peripheral tissues during pathological processes, such as viral infections, malignancies and organ transplantation. Here, we discuss recent findings regarding the influence of HLA-G on the T helper (Th) cytokine balance (favoring Th2-type responses), and the expression of HLA-G during chronic, cutaneous inflammatory diseases, such as psoriasis and atopic dermatitis. We propose a novel role for HLA-G as a tissue-protective molecule in inflammatory responses.

Cytokines↗
PubMed2001

Transient involvement of endothelin in hypertrophic remodeling of small arteries.

OBJECTIVE: This study was designed to evaluate the capacity of norepinephrine (NE) to induce hypertrophic remodeling of small arteries in rats, and to determine the involvement of endothelin (ET) to initiate and maintain it. DESIGN AND RESULTS: Treatment with NE (2.5 microg/kg per min) for 14 or 28 days produced a similar inward hypertrophic remodeling, characterized by a smaller lumen, but increased media thickness and cross-sectional area. Arterial stiffness was reduced. Histological evaluation confirmed the hypertrophic nature of remodeling. Concomitant administration of LU135252 (ET-receptor antagonist) for the first 14 days of NE administration prevented the development of hypertrophy, without altering arterial mechanics. Treatment with the same antagonist from day 14 to day 28 of NE or angiotensin II (Ang II) treatment failed to regress established vascular hypertrophy. In contrast, normalization of arterial structure was observed with prazosin, an alpha-adrenergic blocker. Endothelin content in small mesenteric arteries showed a transient elevation following chronic NE administration. CONCLUSIONS: Increased circulating NE levels are associated with hypertrophic remodeling of small arteries, in which ET plays an initiating role. However, the maintenance of vascular hypertrophy is ET-independent, either in the presence of augmented circulating levels of NE or Ang II. Thus, early rather than late treatment with ET-receptor antagonists may be a preferable approach to limit small artery-mediated end-organ damage in cardiovascular diseases.

Angiotensin II↗
PubMed2001

Norepinephrine-induced aortic hyperplasia and extracellular matrix deposition are endothelin-dependent.

BACKGROUND: Sympathetic hyperactivity is observed in several disease states and may contribute to cardiovascular hypertrophic remodeling. Endothelin has been suggested to be a mediator of hypertrophy. OBJECTIVE: To examine the involvement of endothelin in maintaining the growth response induced by exogenous norepinephrine. DESIGN AND METHODS: Rats were treated with norepinephrine (2.5 microg/Kg per min subcutaneously) for 2 and 4 weeks, alone or in association with the selective endothelin-A (ETA) receptor antagonist, darusentan (LU135252, 30 mg/Kg per day orally) for weeks 3 and 4. RESULTS: Increases in medial cell number and accumulation of collagen and elastin characterized norepinephrine-induced aortic remodeling. These effects occurred without marked changes of mean arterial pressure, but may be related to enhanced pressure variability in addition to direct effects of norepinephrine. Inhibition of ETA receptors by darusentan reversed aortic alterations produced by infusion of norepinephrine. Evaluation of medial apoptosis did not reveal any significant change in any group at 4 weeks. CONCLUSIONS: Antagonism of ETA receptors effectively and rapidly reversed norepinephrine-induced aortic structural and compositional changes, suggesting a central role of endothelin in mediating this response. Thus, ETA receptor antagonists may help to regress large artery remodeling in conditions of increased circulating catecholamine concentrations.

Animals↗