FN ISI Export Format VR 1.0 PT J AU Bonne, G Mercuri, E Muchir, A Urtizberea, A Becane, HM Recan, D Merlini, L Wehnert, M Boor, R Reuner, U Vorgerd, M Wicklein, EM Eymard, B Duboc, D Penisson-Besnier, I Cuisset, JM Ferrer, X Desguerre, I Lacombe, D Bushby, K Pollitt, C Toniolo, D Fardeau, M Schwartz, K Muntoni, F TI Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene SO ANNALS OF NEUROLOGY ID INTERMEDIATE FILAMENT PROTEINS; CHROMATIN BINDING-SITE; NUCLEAR-MEMBRANE; ROD DOMAIN; CARDIOMYOPATHY; ENVELOPE; INTERACTS; DISEASE AB Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA tie, 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, racing from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease. C1 Grp Hosp Pitie Salpetriere, Inst Myol, INSERM, UR523, F-75651 Paris 13, France. Hop Cochin, Genet Mol Lab, F-75674 Paris, France. Hop St Vincent de Paul, Serv Neurol, F-75674 Paris, France. Dept Neurol, Angers, France. Dept Child Neurol, Lille, France. Hop Haut Leveque, Serv Neurol, Pessac, France. CHU Bordeaux, Serv Pediat, Bordeaux, France. Hammersmith Hosp, Imperial Sch Med, Dept Paediat, London, England. Univ Newcastle Upon Tyne, Dept Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Ist Ortoped Rizzoli, Neuromuscular Unit, Bologna, Italy. CNR, Ist Genet, I-27100 Pavia, Italy. Inst Human Genet, Greifswald, Germany. Univ Mainz Klinikum, Mainz, Germany. Neurol Klin & Poliklin, Dresden, Germany. Ruhr Univ Bochum, Neurol Klin & Poliklin, D-4630 Bochum, Germany. Univ Hamburg, Krankenhaus Eppendorf, Psychiat Klin, D-2000 Hamburg, Germany. RP Bonne, G, Grp Hosp Pitie Salpetriere, Inst Myol, INSERM, UR523, 47 Blvd Hop, F-75651 Paris 13, France. TC 133 PD AUG PY 2000 VL 48 IS 2 BP 170 EP 180 UT ISI:000088564700006 ER PT J AU Elson, GCA Lelievre, E Guillet, C Chevalier, S Plun-Favreau, H Froger, J Suard, I de Coignac, AB Delneste, Y Bonnefoy, JY Gauchat, JF Gascan, H TI CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex SO NATURE NEUROSCIENCE ID CILIARY NEUROTROPHIC FACTOR; AMYOTROPHIC-LATERAL-SCLEROSIS; LEUKEMIA INHIBITORY FACTOR; MOTOR-NEURONS; MICE LACKING; LIFR-BETA; CYTOKINE; FAMILY; SURVIVAL; DISEASE AB Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, CNTFR, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (CLC) and the soluble receptor cytokine-like factor-1 (CLF). CLF expression was required for CLC secretion, and the complex acted only on cells expressing functional CNTF receptors. The CLF/CLC complex activated gp130, LIFR and signal transducer and activator of transcription 3 (STAT3) and supported motor neuron survival. Our results indicate that the CLF/CLC complex is a second ligand for CNTFR with potentially important implications in nervous system development. C1 Ctr Immunol Pierre Fabre, F-74164 St Julien Genevois, France. CHU Angers, INSERM, E9928, F-49033 Angers, France. RP Gauchat, JF, Ctr Immunol Pierre Fabre, 5 Ave Napoleon III, F-74164 St Julien Genevois, France. TC 98 PD SEP PY 2000 VL 3 IS 9 BP 867 EP 872 UT ISI:000167177400012 ER PT J AU Roncali, J TI Oligothienylenevinylenes as a new class of multinanometer linear pi-conjugated systems for micro- and nanoelectronics SO ACCOUNTS OF CHEMICAL RESEARCH ID SOLUBLE THIENYLENEVINYLENE OLIGOMERS; BOND-LENGTH ALTERNATION; CONDUCTING POLYMERS; MOLECULAR WIRES; BANDGAP CONTROL; OLIGOTHIOPHENES; TETRATHIAFULVALENE; MACROMOLECULES; DONORS; UV/VIS AB This Account deals with the synthesis and characterization of monodisperse soluble oligothienylenevinylenes with chain lengths up to 100 Angstrom. The chain length dependence of the electronic and electrochemical properties both in solution and in the solid state are analyzed and discussed in the context of the potential use of oligothienylenevinylenes as molecular wires. Problems related to interchain interactions are illustrated by the analysis of the effects of structure on the reversible dimerization of cation radicals and by the synthesis of new series of end-substituted oligomers. C1 Univ Angers, CNRS, UMR 6501, F-49045 Angers, France. RP Roncali, J, Univ Angers, CNRS, UMR 6501, 2 Blvd Lavoisier, F-49045 Angers, France. TC 90 PD MAR PY 2000 VL 33 IS 3 BP 147 EP 156 UT ISI:000086154500003 ER PT J AU Legrand, E Chappard, D Pascaretti, C Duquenne, M Krebs, S Rohmer, V Basle, MF Audran, M TI Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis SO JOURNAL OF BONE AND MINERAL RESEARCH DE osteoporosis; men; bone histomorphometry; bone microarchitecture; bone mineral density; vertebral fractures ID SPINAL OSTEOPOROSIS; PATTERN FACTOR; ILIAC CREST; MEN; WOMEN; HISTOMORPHOMETRY; ARCHITECTURE; MECHANISMS; PREDICTION; PREVALENCE AB Some studies have indicated that the risk of fragility fractures in men increases as bone mineral levels decrease, but there is an overlap in the bone mineral density (BMD) measurements between patients with or without fractures. Furthermore, it has been suggested that the biomechanical competence of trabecular bone is dependent not only on the absolute amount of bone present but also on the trabecular microarchitecture. In the present study, 108 men (mean age 52.1 years) with lumbar osteopenia (T score < -2.5) were recruited to examine the relationships between BMD, architectural changes in trabecular bone, and the presence of vertebral fractures. Lumbar BMD was assessed from L2 to L4 in the anteroposterior view with dual-energy X-ray absorptiometry. At the upper left femur, hip BMD was measured at the transcervical site. Spinal X-ray films were analyzed independently by two trained investigators, and vertebral fracture was defined as a reduction of at least 20% in the anterior, middle, or posterior vertebral height. Transiliac bone biopsy specimens were obtained for all patients. Histomorphometric studies were performed on an image analyzer, and the following parameters were determined: trabecular bone volume (BV/TV), trabecular thickness (Tb.Th), number (Tb.N), and separation (Tb.Sp), interconnectivity index (ICI), characterization of the trabecular network (node count and strut analysis), and star volume of the marrow spaces. Spinal radiographs evidenced at least one vertebral crush fracture in 62 patients (group LI) and none in 46 patients (group I). After adjusting for age, body mass index, and BMD, there were no significant differences between the two groups in BV/TV, Tb.Th, or star volume. In contrast, the mean values of ICI, free end-to-free end struts (FF/TSL), and Tb.Sp were significantly higher, whereas Tb.N and node-to-node struts (NN/TSL) were lower in patients with at least one vertebral fracture. Logistic regression analysis showed that only ICI, FF/TSL, NN/TSL, and Tb.N were significant predictors of the presence of vertebral fracture: odds ratios for an alteration of 1 SD ranged from 1.7 (1.0-3.2) for NN/TSL to 3.2 (1.1-10.1) for ICI. Patients with at least three vertebral fractures (n = 23) were categorized as "multiple fractures." The results of logistic regression showed that spine BMD, BV/TV, and all architectural parameters were significant predictors of multiple vertebral fractures: odds ratios for an alteration of I SD ranged from 2.2 (1.1-4.6) for star volume to 3.7 (1.4-9.7) for ICI. These results strongly suggest that bone trabecular microarchitecture is a major and independent determinant of vertebral fractures in middle-aged men with osteopenia. C1 Univ Angers, Ctr Hosp, Lab Histol Embryol, Fac Med, Angers, France. Univ Angers, Ctr Hosp, Serv Med Interne & Endocrinol, Angers, France. Univ Angers, Ctr Hosp, Serv Rhumatol, Angers, France. RP Legrand, E, CHU Angers, Serv Rhumatol, F-49033 Angers, France. TC 89 PD JAN PY 2000 VL 15 IS 1 BP 13 EP 19 UT ISI:000084420800004 ER PT J AU Graham, MA Lockwood, GF Greenslade, D Brienza, S Bayssas, M Gamelin, E TI Clinical pharmacokinetics of oxaliplatin: A critical review SO CLINICAL CANCER RESEARCH ID METASTATIC COLORECTAL-CANCER; CARCINOMA CELL-LINES; FOLINIC ACID; PLATINUM COMPLEXES; PHASE-I; CISPLATIN; TRIAL; 5-FLUOROURACIL; CYTOTOXICITY; RESISTANT AB Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O'] platinum; Eloxatine) is a novel platinum coordination complex used for the treatment of metastatic colorectal carcinoma in combination with fluoropyrimidines. The objective of this review is to integrate the key data from multiple studies into a single, comprehensive overview of oxaliplatin disposition in cancer patients. The pharmacokinetics (PKs) of unbound platinum in plasma ultrafiltrate after oxaliplatin administration was triphasic, characterized by a short initial distribution phase and a long terminal elimination phase (t(1/2) 252-273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m(2) every 3 weeks or 85 mg/m(2) every 2 weeks. Interpatient and intrapatient variability in platinum exposure (area under the curve(0-48)) is moderate to low (33 and 5% respectively). In the blood, platinum binds irreversibly to plasma proteins (predominantly serum albumin) and erythrocytes. Accumulation of platinum in blood cells is not considered to be clinically significant. Platinum is rapidly cleared from plasma by covalent binding to tissues and renal elimination. Urinary excretion (53.8 +/- 9.1%) was the predominant route of platinum elimination, with fecal excretion accounting for only 2.1 +/- 1.9% of the administered dose 5 days postadministration. Tissue binding and renal elimination contribute equally to the clearance of ultrafilterable platinum from plasma. Renal clearance of platinum significantly correlated with glomerular filtration rate, indicating that glomerular filtration is the principal mechanism of platinum elimination by the kidneys. Clearance of ultrafilterable platinum is lower in patients with moderate renal impairment; however, no marked increase in drug toxicity was reported. The effect of severe renal impairment on platinum clearance and toxicity is currently unknown. Covariates such as age, sex, and hepatic impairment had no significant effect on the clearance of ultrafilterable platinum, and dose adjustment due to these variables is not required. Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation and is not subjected to CYP450-mediated metabolism. Up to 17 platinum-containing products have been observed in plasma ultrafiltrate samples from patients, These include several proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo-diaminocyclohexane platinum complexes, along with several other noncytotoxic products. Oxaliplatin does not inhibit CYP450 isoenzymes in vitro, Platinum was not displaced from plasma proteins by a variety of concomitant medications tested in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and irinothecan have been observed. These results indicate that the additive/synergistic antitumor activity observed with these agents is not due to major alterations in drug exposure, and the enhanced efficacy is likely to be mechanistically based. Together, these PK, biotransformation, drug-drug interaction analyses and studies in special patient populations provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition observed in patients. C1 Sanofi Synthelabo, Dept Clin Pharmcokinet & Drug Metab, Malvern, PA 19355 USA. Ctr Paul Papin, F-49033 Angers, France. Debiopharm SA, CH-1003 Lausanne, Switzerland. RP Graham, MA, Sanofi Synthelabo, Dept Clin Pharmcokinet & Drug Metab, 9 Great Valley Pkwy, Malvern, PA 19355 USA. TC 82 PD APR PY 2000 VL 6 IS 4 BP 1205 EP 1218 UT ISI:000086633500002 ER PT J AU Abenhaim, L Rossignol, M Valat, JP Nordin, M Avouac, B Blotman, F Charlot, J Dreiser, RL Legrand, E Rozenberg, S Vautravers, P CA Paris Task Force TI The role of activity in the therapeutic management of back pain - Report of the International Paris Task Force on Back Pain SO SPINE ID RANDOMIZED CLINICAL-TRIAL; PHYSICAL-ACTIVITY; RISK-FACTORS; PRIMARY-CARE; FOLLOW-UP; BEHAVIORAL-THERAPY; EXERCISE PROGRAM; NATURAL-HISTORY; HEALTHY-ADULTS; SICK LEAVE C1 Montreal Dept Publ Hlth, Montreal, PQ, Canada. McGill Univ, Ctr Clin Epidemiol & Community Studies, Montreal, PQ, Canada. Univ Tours, Hop Trousseau, Tours, France. NYU, Hosp Joint Dis, Inst Orthopaed, Occupat & Ind Orthopaed Ctr, New York, NY USA. Hop Henri Mondor, F-94010 Creteil, France. CHU Montpellier, Hop Lapeyronie, Montpellier, France. Ctr Hosp Emile Roux, Limeil Brevannes, France. CHU Bichat, Paris, France. Hop Hotel Dieu, Angers, France. Hop La Pitie Salpetriere, Paris, France. Hop Hautepierre, Strasbourg, France. RP Rossignol, M, Montreal Dept Publ Hlth, 1301 Sherbrooke St E, Montreal, PQ, Canada. TC 65 PD FEB 15 PY 2000 VL 25 IS 4 SU Suppl. S BP 1S EP 33S UT ISI:000085530600001 ER PT J AU Chaillous, L Lefevre, H Thivolet, C Boitard, C Lahlou, N Atlan-Gepner, C Bouhanick, B Mogenet, A Nicolino, M Carel, JC Lecomte, P Marechaud, R Bougneres, P Charbonnel, B Sai, P CA Diabete Insuline Orale grp TI Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial SO LANCET ID NOD MICE; T-CELLS; AUTOIMMUNE-DISEASES; ADOPTIVE TRANSFER; TRANSFER MODEL; B-CHAIN; SUPPRESSION; PREVENTION; TOLERANCE; MOUSE AB Background Oral administration of autoantigens can slow the progression of beta-cell destruction in non-obese diabetic mice. We investigated whether oral administration of recombinant human insulin could protect residual beta-cell function in recent-onset type 1 diabetes. Methods We enrolled 131 autoantibody-positive diabetic patients aged 7-40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss <10%, polyuria for <6 weeks). They were randomly assigned 2.5 mg or 7.5 mg oral insulin daily or placebo for 1 year, in addition to subcutaneous insulin therapy, Serum C-peptide concentrations were measured in the fasting state and after stimulation, to assess beta-cell function. Autoantibodies to beta-cell antigens were assayed. Analyses were by intention to treat. Findings Baseline C-peptide and haemoglobin A(1c) concentrations were similar in the three groups. During follow up, there were no differences between the groups assigned 2.5 mg or 7.5 mg oral insulin or placebo in subcutaneous insulin requirements, haemoglobin A(1c) concentrations, or measurements of fasting (mean at 12 months 0.18 [SD 0.17], 0.17 [0.17], and 0.17 [0.12] nmol/L) or stimulated C-peptide concentrations (glucagon-stimulated 0.39 [0.38], 0.37 [0.39], and 0.33 [0.24] nmol/L; meal-stimulated 0.72 [0.60], 0.49 [0.49], and 0.57 [0.51 nmol/L]. Neither age nor C-peptide concentration at entry influenced treatment effects. No differences were seen in the time-course or titres of antibodies to insulin, glutamic acid decarboxylase, or islet antigen 2, Interpretation At the doses used in this trial, oral administration of insulin initiated at clinical onset of type 1 diabetes did not prevent the deterioration of beta-cell function. C1 CHU Nantes, F-44035 Nantes 01, France. CHU St Vincent de Paul, Paris, France. CHU Lyon, Lyon, France. CHU Necker, Paris, France. CHU Marseille, Marseille, France. CHU Angers, Angers, France. CHU Tours, Tours, France. CHU Poitiers, Poitiers, France. RP Chaillous, L, Hotel Dieu, Pl Alexis Ricordeau, F-44093 Nantes 01, France. TC 64 PD AUG 12 PY 2000 VL 356 IS 9229 BP 545 EP 549 UT ISI:000088820800011 ER PT J AU Bataille, B Delwail, V Menet, E Vandermarcq, P Ingrand, P Wager, M Guy, G Lapierre, F TI Primary intracerebral malignant lymphoma: report of 248 cases SO JOURNAL OF NEUROSURGERY DE primary central nervous system lymphoma; brain neoplasm; non-Hodgkin's lymphoma ID CENTRAL-NERVOUS-SYSTEM; NON-HODGKINS-LYMPHOMA; RETICULUM-CELL SARCOMA; HIGH-DOSE METHOTREXATE; PRIMARY CNS LYMPHOMA; RADIATION-THERAPY; INCREASING INCIDENCE; PROGNOSTIC FACTORS; CEREBRAL LYMPHOMA; BRAIN AB Object. The authors present a retrospective analysis of 248 immunocompetent patients with primary intracerebral lymphoma treated at 19 French and Belgian medical centers between January 1980 and December 1995. Methods. This study involved 127 female and 121 male patients with a median age of 61 years (range 2-88 years). All tumors available for review were classic diffuse non-Hodgkin's lymphoma, for which the phenotype was determined in 220 patients: 212 (96.4%) were B-cell and eight (3.6%) were T-cell type tumors. According to the Revised European-American classification of lymphoid neoplasms, most lesions were diffuse large cell rumors (62%). A total of 196 turners were reviewed in 127 patients for whom preoperative computerized tomography and magnetic resonance studies were available. There was a single lesion in 66% of the cases, with a supratentorial location in 87%. Tumor location in the basal ganglia, corpus callosum, or fornix, infiltration of the periventricular ependyma, or a mirror pattern, were strongly suggestive of a lesion of lymphomatous origin. The histological diagnosis was obtained after surgical resection in 116 patients, with the remainder undergoing biopsy sampling only. Of the 248 patients studied, 129 (52%) received chemotherapy plus radiation therapy, 60 (24%) received radiation therapy alone, 35 (14%) received chemotherapy alone? and 24 (10%) received no postsurgical treatment. Conclusions. Using univariate analysis, the authors determined prognostic factors that were significantly associated with a favorable impact on survival including age younger than 60 years, radiation therapy (without evidence of a dose-response relationship), radiation therapy combined with chemotherapy, and chemotherapy consisting of anthracycline. Partial surgical resection was all unfavorable prognostic factor. Multivariate analysis was used to confirm the independent prognostic value of radiation therapy, age, chemotherapy consisting of anthracyclines or methotrexate, and partial surgical resection. This European survey provides a reasonable basis for the treatment of primary intracerebral lymphoma with the following sequence: stereotactic biopsy sampling, chemotherapy with a methotrexate- and anthracycline-based regimen; followed by cranial irradiation. C1 Univ Poitiers, Sch Med, Dept Neurol Surg Radiat Oncol Radiol & Pathol, Poitiers, France. Univ Angers, Sch Med, Dept Neurol Surg, Angers, France. RP Bataille, B, Cite Hosp La Miletrie, Serv Neurochirurg, 350 Ave Jacques Coeur,BP 577, F-86021 Poitiers, France. TC 64 PD FEB PY 2000 VL 92 IS 2 BP 261 EP 266 UT ISI:000085032900005 ER PT J AU Claustres, M Guittard, C Bozon, D Chevalier, F Verlingue, C Ferec, C Girodon, E Cazeneuve, C Bienvenu, T Lalau, G Dumur, V Feldmann, D Bieth, E Blayau, M Clavel, C Creveaux, I Malinge, MC Monnier, N Malzac, P Mittre, H Chomel, JC Bonnefont, JP Iron, A Chery, M Des Georges, M TI Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France SO HUMAN MUTATION DE congenital absence of the vas deferens; CBAVD; cystic fibrosis; CF; CFTR; ABCC7; France ID CHLORIDE CHANNEL ACTIVITY; COMPLETE CODING REGION; BILATERAL ABSENCE; PARTIAL PENETRANCE; MOLECULAR-BASIS; GENE-MUTATIONS; GEOGRAPHIC-DISTRIBUTION; CYTOPLASMIC LOOP; MESSENGER-RNA; DISEASE AB We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 19 laboratories in France. We have analyzed 7,420 CF alleles, demonstrating a total of 310 different mutations including 24 not reported previously, accounting for 93.56% of CF genes, The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Only 11 mutations had relative frequencies > 0.4%, 140 mutations were found on a small number of CF alleles (from 29 to two), and 154 were unique. These data show a clear geographical and/or ethnic variation in the distribution of the most common CF mutations. This spectrum of CF mutations, the largest ever reported in one country, has generated 481 different genotypes, We also investigated a cohort of 800 French men with congenital bilateral absence of the vas deferens (CBAVD) and identified a total of 137 different CFTR mutations. Screening for the most common CF defects in addition to assessment for IVS8-5T allowed us to detect two mutations in 47.63% and one in 24.63% of CBAVD patients, In a subset of 327 CBAVD men who were more extensively investigated through the scanning of coding/flanking sequences, 516 of 654 (78.90%) alleles were identified, with 15.90% and 70.95% of patients carrying one or two mutations, respectively, and only 13.15% without any detectable CFTR abnormality. The distribution of genotypes, classified according to the expected effect of their mutations on CFTR protein, clearly differed between both populations. CF patients had two severe mutations (87.77%) or one severe and one mild/variable mutation (11.33%), whereas CBAVD men had either a severe and a mild/variable (87.89%) or two mild/variable (11.57%) mutations. Hum Mutat 16:143-156, 2000. (C) 2000 Wiley-Liss, Inc. C1 CHU Montpellier, Mol Genet Lab, CNRS, UPR 1142,Inst Biol, F-34060 Montpellier, France. Hop Debrousse, Lab Biochim Pediat, Lyon, France. Ctr Biogenet, Brest, France. Hop Henri Mondor, Biochim Lab, F-94010 Creteil, France. Grp Hosp Cochin, Lab Biochim & Genet Mol, Paris, France. Hop Calmette, Lab Biochim & Biol Mol, Lille, France. Hop Trousseau, Lab Biochim & Biol Mol, F-75571 Paris, France. Hop Purpan, Med Genet Lab, Toulouse, France. CHU Pontchaillou, Genet Mol Lab, Rennes, France. CHR Maison Blanche, INSERM, U314, Reims, France. Fac Med, Lab Biochim Biol Mol & Enzymol, Clermont Ferrand, France. CHU Angers, Serv Genet, Angers, France. Hop Tronche, Grenoble, France. Hop Timone, Ctr Diagnost Prenatal, Marseille, France. CHU Georges Clemenceau, Lab Biochim B, Caen, France. CHU Poitiers, Lab Genet Cellulaire & Mol, Poitiers, France. Hop Necker Enfants Malad, Paris, France. Grp Hosp Pellegrin, Bordeaux, France. CHU Brabois, Genet Lab, Vandoeuvre Nancy, France. RP Claustres, M, CHU Montpellier, Mol Genet Lab, CNRS, UPR 1142,Inst Biol, Blvd Henry IV, F-34060 Montpellier, France. TC 61 PY 2000 VL 16 IS 2 BP 143 EP 156 UT ISI:000088473500006 ER PT J AU Vilmer, E Suciu, S Ferster, A Bertrand, Y Cave, H Thyss, A Benoit, Y Dastugue, N Fournier, M Souillet, G Manel, AM Robert, A Nelken, B Millot, F Lutz, P Rialland, X Mechinaud, F Boutard, P Behar, C Chantraine, JM Plouvier, E Laureys, G Brock, P Uyttebroeck, A Margueritte, G Plantaz, D Norton, L Francotte, N Gyselinck, J Waterkeyn, C Solbu, G Philippe, N Otten, J TI Long-term results of three randomized trials (58831,58832,58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report SO LEUKEMIA DE long-term follow-up; acute lymphoblastic leukemia; childhood; EORTC ID CHILDREN; METHOTREXATE; CHEMOTHERAPY AB We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/-1.8% and 65% +/-1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6%+/-1% and 7%+/-1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2% +/- 0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of g-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/1, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial. C1 Hop Robert Debre, Dept Hematoimmunol, F-75019 Paris, France. Eortc Data Ctr, Brussels, Belgium. HUDE, Dept Hematooncol, Brussels, Belgium. Debrousse Hosp, Dept Immunohematopediatry, Lyon, France. Hop Robert Debre, Lab Genet Biochem, F-75019 Paris, France. Ctr Antoine Lacassagne, Dept Hematooncol, F-06054 Nice, France. Univ Ziekenhuis, Dept Pediat Hematooncol, Ghent, Belgium. CHU Purpan, Hematol Lab, Toulouse, France. CHR, Hematol Lab, Lille, France. Debrousse Hosp, Hematol Lab, Lyon, France. Childrens Hosp, Dept Hematol, Toulouse, France. CHR, Dept Hematol, Lille, France. J Bernard Hosp, Dept Hematol, Poitiers, France. Hautepierre, Dept Hematol, Strasbourg, France. CHU Angers, Dept Hematol, Angers, France. CHR Hotel Dieu, Dept Hematol, Nantes, France. CHRU, Dept Hematol, Caen, France. Amer Hosp, Dept Hematol, Reims, France. CHR La Citadelle, Dept Pediatry, Liege, Belgium. Hop St Jacques, Dept Hematol, F-25030 Besancon, France. UZ Gasthuisberg, Dept Pediat, Louvain, Belgium. A Villeneuve Hosp, Dept Oncohematol, Montpellier, France. CHR La Tronche, Dept Pediat, Grenoble, France. Escolar San Joao Hosp, Dept Pediat, Porto, Portugal. Esperance Clin, Dept Pediat, Montegnee, Belgium. AZ Middelheim, Dept Pediat, Antwerp, Belgium. AZ VUB, Dept Pediat, Brussels, Belgium. RP Vilmer, E, Hop Robert Debre, Dept Hematoimmunol, 48 Bd Serrurier, F-75019 Paris, France. TC 58 PD DEC PY 2000 VL 14 IS 12 BP 2257 EP 2266 UT ISI:000166207000031 ER PT J AU Bibby, DC Davies, NM Tucker, IG TI Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems SO INTERNATIONAL JOURNAL OF PHARMACEUTICS DE cyclodextrin; microspheres; polymer; modified release; mechanism ID IN-VITRO EVALUATION; ZERO-ORDER RELEASE; BETA-CYCLODEXTRIN; PHARMACEUTICAL APPLICATIONS; INCLUSION COMPLEXES; POLY(ACRYLIC ACID); SUSTAINED-RELEASE; ALPHA-CYCLODEXTRIN; SOLUTE SOLUBILITY; MICROSPHERES AB For many drug candidates a modified in vivo drug release is desired to improve efficacy, sustain effect or minimise toxicity. Polymeric delivery systems, such as microspheres, nanospheres and polymeric films, have been extensively researched in an attempt to achieve modified drug release. Cyclodextrins offer an alternative approach. These cyclic oligosaccharides have the ability to form non-covalent complexes With a number of drugs and in so doing alter their physicochemical properties. In addition, the primary and secondary hydroxyl groups of the native (alpha, beta, gamma-) cyclodextrins are potential sites for chemical modification. It follows that the incorporation of these agents into polymeric drug delivery systems, as physical mixtures, covalently bound conjugates or cross-linking agents, frequently permits a greater degree of control of drug release. This paper reviews the incorporation of Various cyclodextrins into polymeric formulations. The mechanisms by which cyclodextrin/polymer formulations act to modify drug release are considered. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 Univ Otago, Sch Pharm, Formulat & Drug Delivery Grp, Dunedin, New Zealand. RP Bibby, DC, Univ Angers, Fac Pharm, UPRES EA 2169, 16 Bd Daviers, F-49100 Angers, France. TC 54 PD MAR 20 PY 2000 VL 197 IS 1-2 BP 1 EP 11 UT ISI:000085847300001 ER PT J AU Delabaere, E Trinh, DT TI Spectral analysis of the complex cubic oscillator SO JOURNAL OF PHYSICS A-MATHEMATICAL AND GENERAL ID PERTURBATION-THEORY; REAL SPECTRUM; PT-SYMMETRY; HAMILTONIANS; EIGENVALUES; RESURGENCE AB Using the 'exact semiclassical analysis', we study the spectrum of a one-parameter family of complex cubic oscillators. The PT-invariance property of the complex Hamiltonians and the reality property of the spectrum are discussed. Analytic continuations of the spectrum in the complex parameter and their connections with the resonance problem for the real cubic oscillator are investigated. The global analytic structure of the spectrum yields a branch point structure similar to the multivalued analytic structure discovered by Bender and Wu for the quartic oscillator. C1 Univ Angers, Dept Math, CNRS, UMR 6093, F-49045 Angers 01, France. Coll Dalat, Dept Math, Dalat, Vietnam. RP Delabaere, E, Univ Angers, Dept Math, CNRS, UMR 6093, 2 Blvd Lavoisier, F-49045 Angers 01, France. TC 51 PD DEC 8 PY 2000 VL 33 IS 48 BP 8771 EP 8796 UT ISI:000165998400019 ER PT J AU Roche, PH Regis, J Dufour, H Fournier, HD Delsanti, C Pellet, W Grisoli, F Peragut, JC TI Gamma knife radiosurgery in the management of cavernous sinus meningiomas SO JOURNAL OF NEUROSURGERY DE cavernous sinus; cranial nerve; meningioma; gamma knife; radiosurgery; skull base ID CRANIAL BASE MENINGIOMAS; STEREOTAXIC RADIOSURGERY; SKULL BASE; RECURRENCE; NERVES AB Object. The authors sought to assess the functional tolerance and tumor control rate of cavernous sinus meningiomas treated by gamma knife radiosurgery (GKS). Methods. Between July 1992 and October 1998, 92 patients harboring benign cavernous sinus meningiomas underwent GKS. The present study is concerned with the first 80 consecutive patients (63 women and 17 men). Gamma knife radiosurgery was performed as an alternative to surgical removal in 50 cases and as an adjuvant to microsurgery in 30 cases. The mean patient age was 49 years (range 6-71 years). The mean tumor volume was 5.8 cm(3) (range 0.9-18.6 cm(3)). On magnetic resonance (MR) imaging the tumor was confined in 66 cases and extensive in 14 cases. The mean prescription dose was 28 Gy (range 12-50 Gy), delivered with an average of eight isocenters (range two-18). The median peripheral isodose was 50% (range 30-70%). Patients were evaluated at 6 months, and at 1, 2, 3, 5, and 7 years after GKS. The median follow-up period was 30.5 months (range 12-79 months). Tumor stabilization after GKS was noted in 51 patients, tumor shrinkage in 25 patients, and enlargement in four patients requiring surgical removal in two cases. The 5-year actuarial progression-free survival was 92.8%. No new oculomotor deficit was observed. Among the 54 patients with oculomotor nerve deficits, 15 improved, eight recovered, and one worsened. Among the 13 patients with trigeminal neuralgia, one worsened (contemporary of tumor growing), five remained unchanged, four improved, and three recovered. In a patient with a remnant surrounding the optic nerve and preoperative low vision (3/10) the decision was to treat the lesion and deliberately sacrifice the residual visual acuity. Only one transient unexpected optic neuropathy has been observed. One case of delayed intracavernous carotid artery occlusion occurred 3 months after GKS, without permanent deficit. Another patient presented with partial complex seizures 18; months after GKS. All cases of tumor growth and neurological deficits observed after GKS occurred before the use of GammaPlan. Since the initiation of systematic use of stereotactic MR imaging and computer-assisted modern dose planning, no more side effects or cases of tumor growth have occurred. Conclusions. Gamma knife radiosurgery was found to be an effective low morbidity-related tool for the treatment of cavernous sinus meningioma. In a significant number of patients, oculomotor functional restoration was observed. The treatment appears to be an alternative to surgical removal of confined enclosed cavernous sinus meningioma and should be proposed as an adjuvant to surgery in case of extensive meningiomas. C1 CHU Timone, Serv Neurochirurg Fonctionnelle & Stereotax, F-13385 Marseille 05, France. CH St Marguerite, Serv Neurochirurg, Marseille, France. CH Timone, Serv Neurochirurg, Marseille, France. CH Larrey, Serv Neurochirurg, Angers, France. RP Roche, PH, CHU Timone, Serv Neurochirurg Fonctionnelle & Stereotax, 264 Blvd St Pierre, F-13385 Marseille 05, France. TC 51 PD DEC PY 2000 VL 93 SU Suppl. 3 BP 68 EP 73 UT ISI:000165730500015 ER PT J AU Michallet, M Tanguy, ML Socie, G Thiebaut, A Belhabri, A Milpied, N Reiffers, J Kuentz, M Cahn, JY Blaise, D Demeocq, F Jouet, JP Michallet, AS Ifrah, N Vilmer, E Molina, L Michel, G Lioure, B Cavazzana-Calvo, M Pico, JL Sadoun, A Guyotat, D Attal, M Cure, H Bordigoni, P Sutton, L Buzyn-Veil, A Tilly, M Leporrier, M Fegueux, N Dreyfus, F Rio, B Lutz, P Vernant, JP TI Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Societe Francaise de Greffe de Moelle (SFGM) SO BRITISH JOURNAL OF HAEMATOLOGY DE second allogeneic haematopoietic stem cell; transplantation; acute leukaemia; chronic leukaemia ID CHRONIC MYELOGENOUS LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; PERIPHERAL-BLOOD LYMPHOCYTES; CHRONIC MYELOID-LEUKEMIA; 2ND TRANSPLANTS; THERAPY; IMMUNOTHERAPY; RECURRENCE; REMISSION AB Although recurrent malignancy is the most frequent indication for second stem cell transplantation (2nd SCT), there are few reports that include sufficiently large numbers of patients to enable prognostic factor analysis. This retrospective study includes 150 patients who underwent a 2nd SCT for relapsed acute myeloblastic leukaemia (n = 61), acute lymphoblastic leukaemia (n = 47) or chronic myeloid leukaemia (n = 42) after a first allogeneic transplant (including 26 T-cell-depleted). The median interval between the first transplant and relapse, and between relapse and second transplant was 17 months and 5 months respectively. After the 2nd SCT, engraftment-occurred in 93% of cases, 32% of patients developed acute graft-vs.-host disease (GVHD) greater than or equal to grade II and 38% chronic GVHD. The 5-year overall and disease-free survival were 32 +/- 8% and 30 +/- 8%, respectively with a risk of relapse of 44 +/- 12% and a transplant-related mortality of 45 +/- 9%. In a multivariate analysis, ave factors were associated with a better outcome after 2nd SCT: age <16 years at second transplant; relapse occurring more than 12 months after the first transplant: transplantation from a female donor: absence of acute GVHD; and the occurrence of chronic GVHD. The best candidates for a second transplant are likely to be patients with acute leukaemia, in remission before transplant, in whom the HLA-identical donor was female and who relapsed more than 1 year after the first transplant. C1 Hop Edouard Herriot, Unite Greffe Cellules Souches Hematopoiet, Hematol Serv, F-69437 Lyon, France. Soc Greffe de Moelle, Unite Stat, Paris, France. Hop St Louis, Hematol Serv, Paris, France. Ctr Hosp Hotel Dieu, Hematol Serv, Nantes, France. Ctr Hosp Haut Leveque, Hematol Serv, Pessac, France. Hop Henri Mondor, Hematol Serv, F-94010 Creteil, France. Hop Jean Minjoz, Serv Hematol Adulte, F-25030 Besancon, France. Inst J Paoli I Calmettes, Unite Transplantat Medullaire, F-13009 Marseille, France. CHU Hotel Dieu, Serv Hematol Pediat, Clermont Ferrand, France. CHU Huriez, Hematol Serv, Lille, France. CHU Angers, Hematol Serv, Angers, France. Hop Robert Debre, Unite Hematol Immunol, F-75019 Paris, France. CHU Albert Michallon, Hematol Serv, Grenoble, France. Hop Enfants La Timone, Hematol Serv, Marseille, France. Hop Hautepierre, Serv Oncohematol, Strasbourg, France. Hop Necker Enfants Malad, Hematol Serv, Paris, France. Inst Gustave Roussy, Serv Hematol Adulte, Villejuif, France. Hop Jean Bernard, Hematol Serv, Poitiers, France. Hop Nord, Hematol Serv, St Etienne, France. CHU Purpan, Hematol Serv, Toulouse, France. Ctr Jean Perrin, Serv Oncohematol, Clermont Ferrand, France. Hop Brabois, Unite Transplantat Medullaire, Nancy, France. Hop La Pitie Salpetriere, Hematol Serv, Paris, France. Hop Necker Adultes, Hematol Serv, Paris, France. Ctr Henri Becquerel, Hematol Serv, F-76038 Rouen, France. CHU Caen, Hematol Serv, F-14000 Caen, France. CHU Montpellier, Hematol Serv, Montpellier, France. Hop Cochin, Serv Hematol, F-75674 Paris, France. Hop Hotel Dieu, Serv Hematol, F-75181 Paris, France. RP Michallet, M, Hop Edouard Herriot, Unite Greffe Cellules Souches Hematopoiet, Hematol Serv, F-69437 Lyon, France. TC 45 PD FEB PY 2000 VL 108 IS 2 BP 400 EP 407 UT ISI:000085970600030 ER PT J AU Benoit, JP Faisant, N Venier-Julienne, MC Menei, P TI Development of microspheres for neurological disorders: From basics to clinical applications SO JOURNAL OF CONTROLLED RELEASE DE anticancer drugs; biodegradable polymer; chemotherapy; drug delivery; microspheres; neuro-oncology; neurotrophic factors; transmitters ID NERVE GROWTH-FACTOR; BLOOD-BRAIN-BARRIER; MICROENCAPSULATED MONOSIALOGANGLIOSIDE GM1; BIODEGRADABLE POLYMER MICROSPHERES; CONTROLLED-RELEASE POLYMER; SOLVENT EVAPORATION METHOD; BCNU-LOADED MICROSPHERES; DRUG-CARRIER MATRICES; BIOERODIBLE POLYANHYDRIDES; POLY(D,L-LACTIDE-CO-GLYCOLIDE) MICROSPHERES AB Drug delivery to the central nervous system remains a challenging area of investigation for both basic and clinical neuroscientists. Numerous drugs are generally excluded from blood to blain transfer due to the negligible permeability of the brain capillary endothelial wall, which makes up the blood brain barrier in vivo. For several years, we have explored the potential applications of the microencapsulation of therapeutic agents to provide local controlled drug release in the central nervous system. Due to their size, these microparticles can be easily implanted by stereotaxy in discreet, precise and functional areas of the brain without damaging the surrounding tissue. This type of implantation avoids the inconvenient insertion of large implants by open surgery and can be repeated if necessary. We have established the compatibility of poly(lactide-co-glycolide) microspheres with brain tissues. Presently, the most developed applications concern Neurology and Neuro-oncology, with local delivery of neurotrophic factors and antimitotic drugs into neurodegenerative lesions and brain tumours, respectively. The drugs that had been encapsulated by our group included nerve growth factor (NGF), 5-fluorouracil (5-FU), idoxuridine and BCNU. Preclinical studies have been performed with each drug. Studies with NGF are reported as an example. A phase I/II clinical trial has been carried out in patients with newly diagnosed glioblastomas to assess the potentialities of 5-FU-loaded microspheres when intracranially implanted. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Angers, Fac Pharm, UPREA EA 2169, Angers, France. Univ Angers, Ctr Hosp, Serv Neurochirurg, Angers, France. RP Benoit, JP, Univ Angers, Fac Pharm, UPREA EA 2169, Angers, France. TC 44 PD MAR 1 PY 2000 VL 65 IS 1-2 BP 285 EP 296 UT ISI:000085933700026 ER PT J AU Escorsell, A Del Arbol, LR Planas, R Albillos, A Banares, R Cales, P Pateron, D Bernard, B Vinel, JP Bosch, J CA TEST Study Members TI Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: The TEST study SO HEPATOLOGY ID PLACEBO-CONTROLLED TRIAL; ESOPHAGEAL-VARICES; DOUBLE-BLIND; PORTAL-HYPERTENSION; SOMATOSTATIN; CIRRHOSIS; HEMORRHAGE; LIGATION; NITROGLYCERIN; EFFICACY AB Failure to control bleeding and early rebleeding account for the high mortality associated with variceal hemorrhage in cirrhosis. We compared endoscopic sclerotherapy to terlipressin, a drug that effectively controls acute bleeding while reducing in-hospital mortality. This multicenter randomized controlled trial included 219 cirrhotic patients admitted for endoscopy-proven acute variceal bleeding and randomized to receive repeated injections of terlipressin during 6 days (n = 105) or emergency sclerotherapy (n = 114). Success was defined as obtaining control of bleeding (24-hour bleeding-free period during the first 48 hours) and lack of early rebleeding (any further bleeding from initial control to 5 days later) and survival during the study. Both groups were similar at inclusion. Failure rate for terlipressin was 33% and 32% for sclerotherapy (not significant [NS]). Early rebleeding was responsible for 43% and 44% of failures, respectively. This high efficacy was observed in both Child-Pugh class A + B and Child-Pugh class C patients. Both treatments were similar regarding transfusion requirements, in-hospital stay, and 6-week mortality (26 vs. 19 patients). Side effects appeared in 20% of patients receiving terlipressin and in 30% of those on sclerotherapy (P = .06); being serious in 4% and 7%, respectively (NS). In conclusion, terlipressin and sclerotherapy are equally highly effective therapies achieving the initial control of variceal bleeding and preventing early rebleeding. Both treatments are safe, but terlipressin is better tolerated. Therefore, terlipressin may represent a first-line treatment in acute variceal bleeding until the administration of elective therapy, especially in hospitals where a skilled endoscopist is not available 24 hours a day. C1 Univ Barcelona, Hosp Clin, Dept Med, IDIBAPS,Liver Unit,IMD, E-08036 Barcelona, Spain. Univ Barcelona, Hosp Clin, Dept Med, IDIBAPS,Endoscopy Unit, E-08036 Barcelona, Spain. Univ Alcala de Henares, Hosp Ramon y Cajal, Dept Gastroenterol, Madrid, Spain. Univ Alcala de Henares, Clin Puerta Hierro, Dept Gastroenterol, Madrid, Spain. Hosp Univ Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain. Univ Complutense Madrid, Hosp Gen Gregorio Maranon, Dept Gastroenterol, Madrid, Spain. CHU Angers, Angers, France. CHU Jean Verdier, Intens Care Unit, Bondy, France. CHU Pitie Salpetriere, Paris, France. CHU Purpan, Toulouse, France. RP Bosch, J, Univ Barcelona, Hosp Clin, Dept Med, IDIBAPS,Liver Unit,IMD, C Villarroel 170, E-08036 Barcelona, Spain. TC 43 PD SEP PY 2000 VL 32 IS 3 BP 471 EP 476 UT ISI:000089091000004 ER PT J AU Coqueret, O Gascan, H TI Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21(WAF1/CIP1/SD11) SO JOURNAL OF BIOLOGICAL CHEMISTRY ID PROTEIN-TYROSINE-PHOSPHATASE; CILIARY NEUROTROPHIC FACTOR; DEPENDENT KINASES; INDUCED-DIFFERENTIATION; SIGNAL-TRANSDUCTION; CDK INHIBITORS; TGF-BETA; ACTIVATION; P21; CBP AB Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that induce gene activation in response to cytokine receptor stimulation, Following tyrosine phosphorylation, STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. Activation is transient, and down-regulation of STAT signaling occurs within a few hours. In the present study, we show that the cyclin-dependent kinase inhibitor p21(WAF1/CIP1/SD11) inhibits STAT3 transcriptional activation. Following leukemia inhibitory factor stimulation, p21(WAF1/CIP1/SD11) was found to associate with STAT3 proteins in coimmunoprecipitation and pull down assays. In vivo, overexpression of p21(WAF1/CIP1/SD11) reduced transcriptional activation by STAT3 proteins but did not modify DNA binding activity. Interestingly, pull down experiments showed that p21(WAF1/CIP1/SD11) could interact with the CREB-binding coactivator protein, and inhibition of STAT3 activity by p21(WAF1/CIP1/SD11) did not occur when CREB-binding protein was overexpressed, These results suggest a model by which p21(WAF1/CIP1/SD11) functions as an inhibitor of STAT3 signaling and highlight a new activity for this cyclin-dependent kinase inhibitor. C1 CHU Angers, INSERM, F-49033 Angers, France. RP Coqueret, O, CHU Angers, INSERM, E-9928,4 Rue Larrey, F-49033 Angers, France. TC 43 PD JUN 23 PY 2000 VL 275 IS 25 BP 18794 EP 18800 UT ISI:000087815900026 ER PT J AU Sainte-Laudy, J Sabbah, A Drouet, M Lauret, MG Loiry, M TI Diagnosis of venom allergy by flow cytometry. Correlation with clinical history, skin tests, specific IgE, histamine and leukotriene C4 release SO CLINICAL AND EXPERIMENTAL ALLERGY DE venom allergy; allergy diagnosis; histamine release; leukotriene release; flow cytometry; CD63 ID HUMAN BASOPHIL ACTIVATION; INTERLEUKIN-3; GENERATION; STINGS; BEE AB Background Potent allergens such as hymenoptera venoms are capable of inducing severe and life threatening clinical reactions. Percentage of false negative results obtained by the usual diagnostical methods is comprised between 10 and 25% Objective Evaluation of the sensitivity and the specificity of cellular tests and particularly evaluation of a new flow cytometric method. Methods Forty-five allergic patients having experienced a local, a systemic reaction or an anaphylactic shock and 10 controls having undergone hymenoptera stings without clinical reactions were selected on the basis of the clinical history, skin tests and specific IgE. Three cellular tests were performed on the same cell suspensions and in the presence of 2 ng/mL of rIL3: histamine release (RIA), leukotriene C4 release (ELISA) and basophil activation test (flow cytometry after double anti-IgE FITC, anti-CD63 PE labelling). Results As compared to the clinical history, sensitivities of skin tests, specific IgE, flow cytometry, histamine release and leukotriene release were, respectively; 85%, 88%, 100%, 89% and 100%. Flow cytometric analysis of basophil activation showed a significant decrease of the mean fluorescence density and number of IgE positive cells and a significant increase of the number of CD63 positive cells. The 10 controls tested by flow cytometry were negative. Conclusion As compared to the clinical history and to the other parameters tested here, flow cytometry showed a high sensitivity and a high specificity. The excellent correlation observed between this method and the other cellular tests such as histamine and leukotriene release are in favour of the specificity of flow cytomery and in favour of the use of this method for venom allergy diagnosis. C1 Lab Pasteur Cerba, Unite Immunoallergol, Cergy Pontoise, France. Hop Angers, Dept Allergol, Angers, France. RP Sainte-Laudy, J, Lab Pasteur Cerba, Unite Immunoallergol, F-95066 Val Doise 09, France. TC 40 PD AUG PY 2000 VL 30 IS 8 BP 1166 EP 1171 UT ISI:000088445600016 ER PT J AU Debillon, T Gras-Leguen, C Verielle, V Winer, N Caillon, J Roze, JC Gressens, P TI Intrauterine infection induces programmed cell death in rabbit periventricular white matter SO PEDIATRIC RESEARCH ID TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID INTERLEUKIN-6; CEREBRAL HYPOXIA-ISCHEMIA; FACTOR-ALPHA; RISK-FACTORS; HISTOLOGIC CHORIOAMNIONITIS; INTRAVENTRICULAR HEMORRHAGE; CLINICAL CHORIOAMNIONITIS; AMPICILLIN-SULBACTAM; PRETERM LABOR AB An association between chorioamnionitis and periventricular leukomalacia has been reported in human preterm infants. However, whether this link is causal has not been convincingly established, and the underlying molecular mechanisms remain unclear. The objective of this study was to establish a reproducible model of cerebral white matter disease in preterm rabbits after intrauterine infection. Escherichia coli was inoculated into both uterine horns of laparotomized pregnant rabbits when gestation was 80% complete. The fetuses were delivered by cesarean section and killed 12, 24, or 48 h after the inoculation. Programmed cell death in the white matter was evaluated by hematoxylin-eosin-saffron staining and in situ fragmented DNA labeling (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). In a first group of 14 pregnant rabbits not treated with antibiotics, all fetuses delivered 48 h after inoculation were stillborn, whereas fetuses extracted 12 or 24 h after inoculation were alive. No significant cell death was detected in the live fetuses compared with the control noninfected rabbits. In a second group of five pregnant rabbits treated with ceftriaxone initiated 24 h after the inoculation and continued until cesarean section was performed 48 h after inoculation, 13 fetuses were alive, but all showed evidence of extensive programmed cell death in the white matter by hematoxylin-eosin-saffron staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. White matter damage became histologically detectable only 48 h after inoculation. Three of the 13 brains displayed periventricular white matter cysts mimicking human cystic periventricular leukomalacia. The high reproducibility of white matter damage in our model should permit further studies aimed at unraveling the molecular mechanisms of periventricular leukomalacia. C1 Hop Mere Enfant, Dept Perinatol, F-44093 Nantes 1, France. Univ Med, Lab Antibiol, F-44093 Nantes, France. Ctr Paul Papin, Lab Anatomopathol, F-49033 Angers 1, France. Hop Robert Debre, Serv Neurol Pediat, F-75019 Paris, France. Hop Robert Debre, INSERM, E9935, F-75019 Paris, France. RP Debillon, T, CHU Nantes, Hop Mere Enfant, Serv Reanimat Neonatale, F-44093 Nantes 1, France. TC 39 PD JUN PY 2000 VL 47 IS 6 BP 736 EP 742 UT ISI:000087127600008 ER PT J AU Grolleau, F Lapied, B TI Dorsal unpaired median neurones in the insect central nervous system: Towards a better understanding of the ionic mechanisms underlying spontaneous electrical activity SO JOURNAL OF EXPERIMENTAL BIOLOGY DE insect; dorsal unpaired median neurones; pacemaker activity; electrophysiology; ionic current ID COCKROACH PERIPLANETA-AMERICANA; CELLS DUM NEURONS; LOCUST METATHORACIC GANGLION; ADULT AMINERGIC NEURONS; NEUROSECRETORY-CELLS; SCHISTOCERCA-GREGARIA; MIGRATORY LOCUST; NEUROHORMONE-D; CA2+ CURRENTS; PHYSIOLOGICAL-CHARACTERISTICS AB The efferent dorsal unpaired median (DUM) neurones, which include octopaminergic neurones, are among the most intensively studied neurones in the insect central nervous system. They differ from other insect neurones in generating endogenous spontaneous overshooting action potentials. The second half of the 1980s is certain to be considered a turning point in the study of the ion channels underlying the electrical activity of DUM neurones. Recent advances made using the patch-clamp technique have stimulated an increasing interest in the understanding of the biophysical properties of both voltage-dependent and voltage-independent ion channels. Patch-clamp studies of DUM neurones in cell culture demonstrate that these neurones express a wide variety of ion channels. At least five different types of K+ channel have been identified: inward rectifier, delayed rectifier and A-like channels as well as Ca2+- and Na+-activated K+ channels. Moreover, besides voltage-dependent Na+ and Ca2+-sensitive Cl(-)channels, DUM neurones also express four types of Ca2+ channel distinguished on the basis of their kinetics, voltage range of activation and pharmacological profile. Finally, two distinct resting Ca2+ and Na+ channels have been shown to be involved in maintaining the membrane potential and in regulating the firing pattern. In this review, we have also attempted critically to evaluate these existing ion channels with regard to their specific functions in the generation of the different phases of the spontaneous electrical activity of the DUM neurone. C1 Univ Angers, UPRES EA 2647, RCIM, Neurophysiol Lab, F-49045 Angers, France. RP Lapied, B, Univ Angers, UPRES EA 2647, RCIM, Neurophysiol Lab, Rue Haute Reculee, F-49045 Angers, France. TC 37 PD JUN PY 2000 VL 203 IS 11 BP 1633 EP 1648 UT ISI:000087629000001 ER PT J AU Kaassis, M Oberti, F Burtin, P Boyer, J TI Argon plasma coagulation for the treatment of hemorrhagic radiation proctitis SO ENDOSCOPY ID PROCTOSIGMOIDITIS; EXPERIENCES; SUCRALFATE; THERAPY; APC AB Background and Study Aims: Chronic radiation proctitis is a complication of radiotherapy for malignant pelvic diseases. Rectal bleeding caused by radiation proctitis is difficult to manage. Argon plasma coagulation (APC) is an electrocoagulation technique that appears to be an effective and low-cost alternative to the use of lasers in gastrointestinal endoscopy, The aim of this study was to evaluate the efficacy of APC, as well as patients' tolerance of the procedure, in the treatment of bleeding radiation-induced proctitis, Patients and Methods: The charts of 16 patients with chronic radiation proctitis were analyzed retrospectively. Their average age was 73.5 (range 62-80), Fifteen patients had prostate cancer, and one had uterine cancer. The average time to onset of symptoms after radiotherapy was 15 months (range 6-36 months), All patients had intermittent or daily rectal bleeding, and three patients needed blood transfusions. The severity of bleeding was graded from 0 to 4, APC treatment was administered every month; the argon gas flow was set at 0.6 l/min with an electrical power setting of 40 W. Results: All patients were improved with APC treatment. A mean of 3.7 sessions was necessary to relieve symptoms. APC therapy resulted in a reduction in the mean severity score from 2.4 to 0.6. Seven patients had no recurrent rectal bleeding, and the bleeding was significantly reduced to occasional and negligible spotting (less than one bleeding episode per week) in nine patients. None of the patients required transfusions after treatment. During the follow-up period (average 10.7 months, range 8-28 months), one patient had a recurrence of rectal bleeding that required two repeat sessions. The tolerance was good, with no long-term treatment-related complications. Conclusions: APC is an effective, safe and well-tolerated treatment for rectal bleeding caused by chronic radiation proctitis, It should be considered as a first-line therapy for radiation proctitis. C1 Univ Hosp, Gastroenterol Unit, F-49033 Angers, France. RP Boyer, J, Univ Hosp, Gastroenterol Unit, 4 Rue Larrey, F-49033 Angers, France. TC 35 PD SEP PY 2000 VL 32 IS 9 BP 673 EP 676 UT ISI:000089092700002 ER PT J AU Lafont, A Dubois-Rande, JL Steg, PG Dupouy, P Carrie, D Coste, P Furber, A Beygui, F Feldman, LJ Rahal, S Tron, C Hamon, M Grollier, G Commeau, P Richard, P Colin, P Bauters, C Karrillon, G Ledru, F Citron, B Marie, FN Kern, M CA FROST Study Grp TI The French Randomized Optimal Stenting Trial: A prospective evaluation of provisional stenting guided by coronary velocity reserve and quantitative coronary angiography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY ID BALLOON ANGIOPLASTY; ARTERY DISEASE; BENESTENT-II; RESTENOSIS; IMPLANTATION; STENOSIS AB OBJECTIVES We sought to make a prospective comparison of systematic stenting with provisional stenting guided by Doppler measurements of coronary velocity reserve and quantitative coronary angiography. BACKGROUND Despite the increasing use of stents during percutaneous transluminal coronary angioplasty, it is unclear whether systematic stenting is superior to a strategy of provisional stenting in which stents are placed only in patients with unsatisfactory results or as a hail-out procedure. METHODS Two hundred fifty-one patients undergoing elective coronary angioplasty were randomly assigned either to provisional stenting (group 1, in which stenting was performed if postangioplasty coronary velocity reserve was <2.2 and/or residual stenosis greater than or equal to 35% or as hail-out) or to systematic stenting (group 2). The primary end point was the six-month angiographic minimal lumen diameter (MLD). Major adverse cardiac events were secondary end points (death, acute myocardial infarction and target lesion revascularization), RESULTS Stenting was performed in 48.4% of patients in group 1 and 100% of patients in group 2 (p < 0.01). Six months after angioplasty, the MLD did not differ between groups (1.90 +/- 0.79 mm vs. 1.99 +/- 0.70 mm, p = 0.39), as was the rate of binary restenosis (27.1% vs. 21.4%, p = 0.37). Among patients with restenosis, 13/32 (40.6%) in group 1 but 100% (25/25) in group 2 had in-stent restenosis (p < 0.01). Target lesion revascularization (15.1% vs. 14.4% in groups 1 and 2 respectively, p = 0.89) and major adverse cardiac events (15.1% vs. 16.0%, p 0.85) were not significantly different. CONCLUSIONS Systematic stenting does not provide superior angiographic results at six months as compared with provisional stenting. (C) 2000 by the American College of Cardiology. C1 Univ Paris 05, Hop Boucicaut, Dept Cardiol, F-75015 Paris, France. Hop Henri Mondor, F-94010 Creteil, France. Hop Bichat, F-75877 Paris, France. Hop Purpan, Toulouse, France. Hop Bordeaux Pessac, Bordeaux, France. Hop Angers, Angers, France. Hop Necker Enfants Malad, Paris, France. Hop Charles Nicolle, F-76031 Rouen, France. Hop Emile Muller, Mulhouse, France. Hop Cote Nacre, Caen, France. Clin St Martin, Caen, France. Hop Brabois, Nancy, France. Hop Antoine Beclere, Paris, France. Hop Cardiol, F-59037 Lille, France. Hop Lariboisiere, F-75475 Paris, France. Hop Broussais, F-75674 Paris, France. Hop Gabriel Montpied, Clermont Ferrand, France. St Louis Univ Ctr, St Louis, MO USA. RP Lafont, A, Univ Paris 05, Hop Boucicaut, Dept Cardiol, 78 Rue Convent, F-75015 Paris, France. TC 33 PD AUG PY 2000 VL 36 IS 2 BP 404 EP 409 UT ISI:000088491800007 ER PT J AU Spanggaard, H Prehn, J Nielsen, MB Levillain, E Allain, M Becher, J TI Multiple-bridged bis-tetrathiafulvalenes: New synthetic protocols and spectroelectrochemical investigations SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY ID CESIUM TETRATHIAFULVALENE; CATION RADICALS; TWIN DONOR; SALTS; ISOMERIZATION; CATENANES; DESIGN; UNITS AB Synthetic strategies for preparing dimeric tetrathiafulvalenes (TTFs) linked by either one, two, or four bridges have been developed. In particular, we report efficient few-step protocols for the preparation of face-to-face overlapped quadruple-bridged bis-TTFs. The ready interconversion of cis and trans TTFs in the presence of catalytic amounts of acid was implemented in one synthetic protocol as a way to control the isomeric outcome. The compounds were characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. Moreover, the X-ray crystal structure of the macrocycle 4b is presented and compared to semiempirical (PM3) geometry optimizations. Cyclic voltammetry and spectroelectrochemistry were used to describe the interactions established between two TTF units upon oxidation, that is, their ability to form mixed-valence complexes and pi-dimers either intra- or intermolecularly. The length, flexibility, and number of bridging units in a bis-TTF, as well as the specific TTF positions being connected, determine the extent of these interactions. Thus, rigid linkers enhance the formation of intermolecular mixed-valence complexes. For 4b, the absorption spectrum of this mixed-valence stale of TTF in solution has been recorded for the first time. Finally, preliminary complexation experiments with different electron-deficient molecules are described. C1 Odense Univ, Univ So Denmark, Dept Chem, DK-5230 Odense, Denmark. ETH Zurich, Organ Chem Lab, CH-8092 Zurich, Switzerland. Univ Angers, CNRS, UMR 6501, F-49045 Angers, France. RP Nielsen, MB, Odense Univ, Univ So Denmark, Dept Chem, Campusvej 55, DK-5230 Odense, Denmark. TC 32 PD OCT 4 PY 2000 VL 122 IS 39 BP 9486 EP 9494 UT ISI:000089690600017 ER PT J AU Raimundo, JM Blanchard, P Brisset, H Akoudad, S Roncali, J TI Proquinoid acceptors as building blocks for the design of efficient pi-conjugated fluorophores with high electron affinity SO CHEMICAL COMMUNICATIONS ID NARROW-BANDGAP; POLYMERS; THIOPHENE; LIGHT; OLIGOTHIOPHENES; COPOLYMERS; OLIGOMERS; UNITS AB The association of aromatic electron donor groups with proquinoid acceptors leads to pi-conjugated fluorophores combining tunable emission wavelength at constant geometry, high fluorescence efficiency and high electron affinity. C1 Univ Angers, CNRS, UMR 6501, F-49045 Angers, France. RP Roncali, J, Univ Angers, CNRS, UMR 6501, 2 Bd Lavoisier, F-49045 Angers, France. TC 31 PY 2000 IS 11 BP 939 EP 940 UT ISI:000087163600025 ER PT J AU Hideur, A Chartier, T Ozkul, C Sanchez, F TI Dynamics and stabilization of a high power side-pumped Yb-doped double-clad fiber laser SO OPTICS COMMUNICATIONS DE fiber lasers; high power; side-pumping; dynamics; nonlinear effects ID MU-M; OUTPUT AB We present an experimental study of the dynamics of a high power Yb3+-doped double-clad fiber laser in various optical configurations operating in the 1.08 mum wavelength. The fiber is side-pumped with a high power laser diode using the V-groove technique. Different self-pulsing regimes are identified resulting from third-order nonlinear effects. The influence of the cavity losses on the dynamical behavior is also investigated. In addition, we show that the system is efficiently stabilized in a unidirectional ring cavity where Brillouin backscattering is suppressed. (C) 2000 Published by Elsevier Science B.V. C1 Univ Rouen, CNRS CORIA UMR 6614, Grp Opt Optron, F-76821 Mt St Aignan, France. RP Sanchez, F, Univ Angers, Lab POMA, 2 Bd Lavoisier, F-49000 Angers, France. TC 29 PD DEC 15 PY 2000 VL 186 IS 4-6 BP 311 EP 317 UT ISI:000165983200012 ER PT J AU Benaouf, G Parisi, L TI Genetics of host-pathogen relationships between Venturia inaequalis races 6 and 7 and Malus species SO PHYTOPATHOLOGY DE Malus x domestica ID SCAB RESISTANCE; AVIRULENCE GENE; LINKAGE MAPS; VF GENE; APPLE; POPULATIONS; MARKERS AB Resistance to scab originating from Malus floribunda clone 821 is the most widely form of resistance used in apple breeding programs. A dominant gene, named Vf, was introgressed from this clone into recent cultivars, although the genetic determinants of the resistance of M. floribunda 821 are apparently more complex than a single gene. The appearance of new races overcoming the resistance of cultivars with the Vf gene, the parental clone, or both made it possible to undertake a genetic analysis of host-pathogen interactions. The segregation of resistance in progenies of crosses from 'Golden Delicious' x M. floribunda 821 and 'Golden Delicious' x 'Idared' into five strains of Venturia inaequalis-races 1 (strains 104, 1093, and 301), 6 (strain 302), and 7 (strain 1066)-demonstrated the existence of a second dominant gene in M. floribunda 821. This gene, independent of Vf, was named Vfh because it seemed to induce a hypersensitive reaction. The results obtained with strain 1066, virulent to M, floribunda 821, allowed identification of another dominant gene, Vg, responsible for the resistance of 'Golden Delicious' to this strain. Vg is also carried by 'Florina', which was selected for its Vf resistance. The pathogenicity of a progeny originating from a cross between V. inaequalis strains 1066 and 301, characterized in vitro on leaf disks of differential genotypes, revealed two independent avirulence genes involved in the pathogenicity toward the Vg and VS genes, respectively. These avirulence genes were named Avr Vg and Avr Vf. The host-pathogen interactions detected are consistent with a gene-for-gene relationship. C1 INRA, Ctr Angers, Unite Pathol Vegetale & Phytobacteriol, F-49071 Beaucouze, France. RP Parisi, L, INRA, Ctr Angers, Unite Pathol Vegetale & Phytobacteriol, BP 57, F-49071 Beaucouze, France. TC 29 PD MAR PY 2000 VL 90 IS 3 BP 236 EP 242 UT ISI:000085499400005 ER PT J AU Hunault, M Bauer, KA TI Recombinant factor VIIa for the treatment of congenital factor VII deficiency SO SEMINARS IN THROMBOSIS AND HEMOSTASIS DE factor VIIa; factor VII deficiency; bleeding disorder ID COAGULATION-FACTOR-VII; ACTIVATED FACTOR-VII; BOVINE FACTOR-VII; TISSUE FACTOR; FACTOR-IX; CONTINUOUS-INFUSION; BLOOD-COAGULATION; HAGEMAN-FACTOR; PLASMA; QUANTITATION AB Factor VII deficiency is a rare autosomal bleeding disorder with a highly variable hemorrhagic predisposition, Severe bleeding, including hemarthroses, may be encountered when plasma factor VII levels are below 1%, Patients have prolonged prothrombin times, and the final diagnosis is established by quantitative factor VII assays. Some patients have true deficiencies, that is, very low factor VII activity and low factor VII antigen (crossreacting material) levels (CRM-); others have normal antigen levels but low activity (CRM+). Still others have reduced antigen levels (CRMR). There is a rather poor correlation between clinical symptoms and factor VII activity levels in plasma. Treatment of these patients consists of fresh frozen plasma, prothrombin complex concentrates, or factor VII concentrates. Recombinant activated factor VII (rFVIIa) is a very useful alternative, and several patients have been treated successfully. Because of the short half-life of factor VIIa, repeated doses have to be administered, and continuous infusion may be even better, Antibodies to factor VII have been reported but seem to be rather rare. From the available data it appears that rFVIIa is a safe and effective treatment modality for patients with congenital factor VII deficiency. C1 VA Boston Healthcare Syst, Dept Med, Hematol Oncol Sect, Boston, MA USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. CHU Angers, Serv Malad Sang, Angers, France. RP Bauer, KA, Vet Adm Med Ctr W Roxbury, 1400 VFW Pkwy, Boston, MA 02132 USA. TC 28 PY 2000 VL 26 IS 4 BP 401 EP 405 UT ISI:000165399900008 ER PT J AU Chanson, P Boerlin, V Ajzenberg, C Bachelot, Y Benito, P Bringer, J Caron, P Charbonnel, B Cortet, C Delemer, B Escobar-Jimenez, F Foubert, L Gaztambide, S Jockenhoevel, F Kuhn, JM Leclere, J Lorcy, Y Perlemuter, L Prestele, H Roger, P Rohmer, V Santen, R Sassolas, G Scherbaum, WA Schopohl, J Torres, E Varela, C Villamil, F Webb, SM TI Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly SO CLINICAL ENDOCRINOLOGY ID LONG-TERM TREATMENT; SLOW-RELEASE LANREOTIDE; GROWTH-HORMONE; SOMATOSTATIN; TOLERABILITY; PHARMACOKINETICS; EPIDEMIOLOGY; MULTICENTER; MANAGEMENT; BIM-23014 AB BACKGROUND AND OBJECTIVE The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin(R) LAR(R), Novartis Pharma AG) and lanreotide SR (Somatuline(R), Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values less than or equal to 6.5 mU/l (2.5 mug/l) and less than or equal to 2.6 mU/l (1.0 mug/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly. C1 CHU Bicetre, Serv Endocrinol & Malad Reprod, F-94275 Le Kremlin Bicetre, France. Novartis Pharma AG, Clin Res & Dev, Basel, Switzerland. Hop Lariboisiere, F-75475 Paris, France. Hop La Pitie Salpetriere, Paris, France. CHU Grenoble, F-38043 Grenoble, France. Hop Lapeyronie, Montpellier, France. CHU Rangueil, F-31054 Toulouse, France. Hotel Dieu, Nantes, France. Ctr Hosp Reg & Univ Lille, F-59037 Lille, France. Hop Maison Blanche, Reims, France. Hop Bois Guillaume, Bois Guillaume, France. Hop Brabois, Vandoeuvre Nancy, France. Hop Sud, Rennes, France. Ctr Hosp Henri Mondor, Creteil, France. Hop Haut Leveque, Pessac, France. Ctr Hosp Reg & Univ, Angers, France. Hop Neurocardiol, Lyon, France. Univ Klin Koln, Klin & Poliklin Innere Med 2, Cologne, Germany. Univ Klin Dusseldorf, Dusseldorf, Germany. LMU, Klinikum Innenstadt, Med Klin, Munich, Germany. Hosp Reina Sofia, Cordoba, Spain. Hosp Clin San Cecilio, Granada, Spain. Hosp Cruces, Baracaldo, Spain. Hosp Ramon y Cajal, E-28034 Madrid, Spain. Hosp Univ Virgen Rocio, Dept Endocrinol, Seville, Spain. Hosp Santa Cruz & San Pablo, E-08025 Barcelona, Spain. RP Chanson, P, CHU Bicetre, Serv Endocrinol & Malad Reprod, 78 Rue Gen Leclerc, F-94275 Le Kremlin Bicetre, France. TC 28 PD NOV PY 2000 VL 53 IS 5 BP 577 EP 586 UT ISI:000165401500006 ER PT J AU Cimon, B Carrere, J Vinatier, JF Chazalette, JP Chabasse, D Bouchara, JP TI Clinical significance of Scedosporium apiospermum in patients with cystic fibrosis SO EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES ID PSEUDALLESCHERIA-BOYDII; DISEASE; FUNGI AB The incidence of airway colonization by Scedosporium apiospermum and of related sensitization was investigated prospectively in 128 patients with cystic fibrosis over a 5-year period, and results were compared with clinical data. Scedosporium apiospermum, recovered from sputum samples in 11 of 128 (8.6%) patients, was the most frequent filamentous fungus after Aspergillus fumigatus. Counterimmunoelectrophoresis, used to detect scedosporiosis serologically, was positive in 27 of 128 (21.1%) patients. The discrepancy between the mycological and serological results may be related to immune cross-reactions between Scedosporium apiospermum and Aspergillus fumigatus. However, symptoms of allergic bronchopulmonary disease were observed in two patients chronically colonized by Scedosporium apiospermum. The results clearly demonstrate that the frequency of this fungus is largely underestimated and that it may trigger an inflammatory response, thus suggesting a pathogenic role in patients with cystic fibrosis. C1 CHU Angers, Lab Parasitol Mycol, F-49033 Angers 01, France. Hop Renee Sabran, F-83406 Hyeres, France. RP Cimon, B, CHU Angers, Lab Parasitol Mycol, 4 Rue Larrey, F-49033 Angers 01, France. TC 28 PD JAN PY 2000 VL 19 IS 1 BP 53 EP 56 UT ISI:000085351300011 ER PT J AU Menei, P Pean, JM Nerriere-Daguin, V Jollivet, C Brachet, P Benoit, JP TI Intracerebral implantation of NGF-releasing biodegradable microspheres protects striatum against excitotoxic damage SO EXPERIMENTAL NEUROLOGY DE drug delivery; microsphere; nerve growth factor; striatum; excitotoxic injury; Huntington's disease ID NERVE GROWTH-FACTOR; BASAL FOREBRAIN NEURONS; HUNTINGTONS-DISEASE; QUINOLINIC ACID; RODENT MODEL; CHOLINERGIC NEURONS; MESSENGER-RNA; RAT STRIATUM; POLY(D,L-LACTIDE-CO-GLYCOLIDE) MICROSPHERES; STEREOTAXIC IMPLANTATION AB Intrastriatal implantation of genetically modified cells synthesizing nerve growth factor (NGF) constitutes one way to obtain a long-term supply of this neurotrophic factor and a neuronal protection against an excitotoxic lesion. We have investigated if NGF-loaded poly (D,L-lactide-co-glycolide) microspheres could represent an alternative to cell transplantations. These microspheres can be implanted stereotaxically and locally release the protein in a controlled and sustained way. In order to test this paradigm, the NGF release kinetics were characterized in vitro using radiolabeled NGF, immunoenzymatic assay, and PC-12 cells bioassay and then in vivo after implantation in the intact rat striatum, These microspheres were thus implanted into the rat striatum 7 days prior to infusing quinolinic acid. Control animals were either not treated or implanted with blank microspheres. The extent of the lesion and the survival of ChAT-, NADPH-d-, and DARPP-32-containing neurons were analyzed, In vitro studies showed that microspheres allowed a sustained release of bioactive NGF for at least 1 month. Microspheres implanted in the intact striatum still contained NGF after 2.5 months and they were totally degraded after 3 months. After quinolinic acid infusion, the lesion size in the group treated with NGF-releasing microspheres was reduced by 40% when compared with the control groups. A marked neuronal sparing was noted, principally concerning the cholinergic interneurons, but also neuropeptide Y/somatostatin interneurons and GABAergic striatofuge neurons, These results indicate that implantation of biodegradable NGF-releasing microspheres can be used to protect neurons from a local excitotoxic lesion and that this strategy may ultimately prove to be relevant for the treatment of various neurological diseases. (C) 2000 Academic Press. C1 CHU Angers, Serv Neurochirurg, Dept Neurosurg, INSERM U298, F-49033 Angers 01, France. Sch Pharm, UPRES EA 2169, Angers, France. INSERM U437, Nantes, France. RP Menei, P, CHU Angers, Serv Neurochirurg, Dept Neurosurg, INSERM U298, F-49033 Angers 01, France. TC 27 PD JAN PY 2000 VL 161 IS 1 BP 259 EP 272 UT ISI:000085666300024 ER PT J AU Mouneyrac, C Geffard, A Amiard, J Amiard-Triquet, C TI Metallothionein-like proteins in Macoma balthica: effects of metal exposure and natural factors SO CANADIAN JOURNAL OF FISHERIES AND AQUATIC SCIENCES ID OYSTERS CRASSOSTREA-GIGAS; SCALLOP MIZUHOPECTEN-YESSOENSIS; BINDING PROTEINS; CADMIUM ACCUMULATION; MOLECULAR WEIGHT; MYTILUS-EDULIS; BIOACCUMULATION; MERCURY; SILVER; CONTAMINATION AB Biological processes involved in the tolerance acquired by populations chronically exposed to metal pollution in the environment were examined in baltic clams (Macoma balthica) originating from both industrialized and clean areas and in clams exposed experimentally to metals. It has been shown previously that clams surviving Ag and Hg exposure at LT50 did not protect themselves by accumulating smaller amounts of metals than clams that failed to survive, so attention was focussed on the physicochemical forms of storage of the accumulated metals. Silver was found to be predominantly bound to insoluble forms and Cd and Hg to soluble forms. In both controls and contaminated clams, a metallothionein-like protein (MTLP) has been shown to be present, the concentrations of which did not depend on the geographical origin of the clams. The significant relationship between metal and MTLP concentrations shown in the baltic clams suggests that the induction of this protein could provide a useful tool for the biomonitoring of metal pollution. The influence of natural factors (season, weight), however, must be taken into account when interpreting such data. C1 Univ Nantes, ISOMer, Fac Pharm, Serv Ecotoxicol, F-44035 Nantes 1, France. IRFA Dept Sci Vie & Terre, Lab Ecol Anim, F-49100 Angers, France. RP Amiard-Triquet, C, Univ Nantes, ISOMer, Fac Pharm, Serv Ecotoxicol, EA 2663,1 Rue Gaston Veil, F-44035 Nantes 1, France. TC 27 PD JAN PY 2000 VL 57 IS 1 BP 34 EP 42 UT ISI:000084870600005 ER PT J AU Siepmann, J Peppas, NA TI Hydrophilic matrices for controlled drug delivery: An improved mathematical model to predict the resulting drug release kinetics (the "sequential layer" model) SO PHARMACEUTICAL RESEARCH DE controlled release; diffusion; hydrophilic matrix; hydroxypropyl methylcellulose (HPMC); modeling; swelling ID POLYMER DISENTANGLEMENT CONCENTRATION; DIFFUSION LAYER; DOSAGE FORMS; FORMULATION VARIABLES; HPMC GELS; TABLETS; DISSOLUTION; MECHANISMS; NMR; COEFFICIENTS AB Purpose. The aims of this study were (i)to elucidate the transport mechanisms involved in drug release from hydrophilic matrices; and (ii) to develop an improved mathematical model allowing quantitative predictions of the resulting release kinetics. Methods. Our previously presented model has been substantially modified, by adding: (i) inhomogeneous swelling; (ii) poorly water-soluble drugs; and (iii) high initial drug loadings. The validity of the improved model has been tested experimentally using hydroxypropyl methylcellulose (HPMC)-matrices, containing either a poorly or a freely water-soluble drug (theophylline or chlorpheniramine maleate) at various initial loadings in phosphate buffer pH 7.4 and 0.1 N HCl, respectively. Results. By overcoming the assumption of homogeneous swelling we show that the agreement between theory and experiment could be significantly improved. Among others, the model could describe quantitatively even the very complex effect on the resulting relative release rates (first slowing down, then accelerating drug release) observed when increasing the initial loading of poorly water-soluble drugs. Conclusions. The practical benefit of this work is an improved design model that can be used to predict accurately the required composition and dimensions of drug-loaded hydrophilic matrices in order to achieve desired release profiles, thus facilitating the development of new pharmaceutical products. C1 Free Univ Berlin, Coll Pharm, D-12169 Berlin, Germany. Purdue Univ, Sch Chem Engn, W Lafayette, IN 47907 USA. RP Siepmann, J, Univ Angers, Fac Pharm, Pharm Galen Lab, 16 Blvd Daviers, F-49100 Angers, France. TC 26 PD OCT PY 2000 VL 17 IS 10 BP 1290 EP 1298 UT ISI:000165879700019 ER PT J AU Tuech, JJ Pessaux, P Rouge, C Regenet, N Bergamaschi, R Arnaud, JP TI Laparoscopic vs open colectomy for sigmoid diverticulitis - A prospective comparative study in the elderly SO SURGICAL ENDOSCOPY-ULTRASOUND AND INTERVENTIONAL TECHNIQUES DE laparoscopy; colon; elderly patients; sigmoid diverticulitis; high-risk patients ID COLORECTAL SURGERY; CHOLECYSTECTOMY; PNEUMOPERITONEUM; HEMODYNAMICS; RISK AB Background: The aim of this prospective comparative study was to assess the outcome of laparoscopic and open colectomy for sigmoid diverticulitis in patients aged greater than or equal to 75 years. Methods: From January 1993 to December 1998, all patients 75 years of age and older undergoing an elective colectomy for sigmoid diverticulitis were included in the study. The patients were divided into the following two groups: group 1 (n = 22) consisted of patients who underwent a laparoscopic procedure; group 2 (n = 24) consisted of patients who underwent an open procedure. Results: In group 1, there were 12 women and 10 men with a mean age of 77.2 years (range, 75-82); in group 2, there were 14 women and 10 men with a mean age of 78 years (range, 76-84) (p = 0.37). There was no difference between the groups in ASA classification. The operative time was shorter in group 2 (136 vs 234 mins). The postoperative period during which parenteral analgesics were required (5.4 vs 8.2 days, p = 0.001), postoperative morbidity (18% vs 50%, p = 0.02), postoperative length of hospital stay (13.1 vs 20.2 days, p = 0.003), and the inpatient rehabilitation (6 vs 15 patients, p = 0.01) were significantly shorter for group 1 than for group 2. There were no perioperative deaths. The conversion rate was 9% in group 1. Conclusion: The data from the present study suggest that laparoscopic colectomy for sigmoid diverticulitis can be applied safely to older patients with fewer complication, less pain, shorter hospital stay, and a more rapid return to preoperative activity levels than that seen with open colorectal resection. C1 Angers Univ Hosp, Dept Digest Surg, F-49000 Angers, France. RP Tuech, JJ, Angers Univ Hosp, Dept Digest Surg, 4 Rue Larrey, F-49000 Angers, France. TC 26 PD NOV PY 2000 VL 14 IS 11 BP 1031 EP 1033 UT ISI:000165706100012 ER PT J AU Barrat, JA Blichert-Toft, J Gillet, P Keller, F TI The differentiation of eucrites: The role of in situ crystallization SO METEORITICS & PLANETARY SCIENCE ID RARE-EARTH ELEMENTS; DIOGENITE PARENT BODY; CUMULATE EUCRITES; SOLAR-SYSTEM; PARTITION-COEFFICIENTS; GENETIC-IMPLICATIONS; MINERAL CHEMISTRY; ALKALI ELEMENTS; CORE FORMATION; PIPLIA-KALAN AB We report on major and trace element analyses of 17 eucrites, including three cumulate eucrites (Binda, Moore County, and Serra de MagC), determined by, respectively, inductively-coupled plasma atomic emission spectrometry and inductively-coupled plasma mass spectrometry. The results obtained for Binda and Moore County are consistent with the model of Treiman (1997) for the formation of cumulate eucrites, which holds that these meteorites were produced from a eucritic melt. Our sample of Serra de Mage contains unusually large amounts of pyroxene and probably an accessory phase rich in heavy rare earth elements and is therefore not representative of this eucrite as known from literature data. Our results for the noncumulate eucrites Bereba, Bouvante, Cachari, Caldera, Camel Donga, Ibitira, Jonzac, Juvinas, Lakangaon, Millbillillie, Padvarninkai, Pasamonte, Sioux County, and Stannern are in good agreement with literature data. The observed decoupling between major and trace elements for noncumulate eucrites can be explained by in situ crystallization during the differentiation of an asteroidal magma ocean. This model can further account for both the Nuevo Laredo and the Stannern trends but has as a consequence that none of the analyzed eucrites represents a primary melt. C1 Univ Angers, Fac Sci, F-49045 Angers, France. Ecole Normale Super Lyon, CNRS UMR 8515, Lab Sci Terre, F-69364 Lyon 7, France. Inst Dolomieu, CNRS UMR 5025 UJF, F-38031 Grenoble, France. RP Barrat, JA, Univ Angers, Fac Sci, 2 Bd Lavoisier, F-49045 Angers, France. TC 26 PD SEP PY 2000 VL 35 IS 5 BP 1087 EP 1100 UT ISI:000089736400021 ER PT J AU Corzo, G Escoubas, P Stankiewicz, M Pelhate, M Kristensen, CP Nakajima, T TI Isolation, synthesis and pharmacological characterization of delta-palutoxins IT, novel insecticidal toxins from the spider Paracoelotes luctuosus (Amaurobiidae) SO EUROPEAN JOURNAL OF BIOCHEMISTRY DE baculovirus; insecticidal toxins; scorpion toxins; sodium channel; spider toxins ID FUNNEL-WEB SPIDER; IMPROVED BACULOVIRUS INSECTICIDE; SODIUM CURRENT INACTIVATION; PLECTREURYS-TRISTIS SIMON; PRIMITIVE HUNTING SPIDER; SCORPION ALPHA-TOXIN; AMINO-ACID-SEQUENCE; TIME-OF-FLIGHT; MU-AGA-IV; RECOMBINANT BACULOVIRUS AB Four novel insecticidal toxins were isolated from the venom of the spider Paracoelotes luctuosus (Araneae: Amaurobiidae) and named delta-palutoxins IT1 to IT4. The four toxins are homologous 36-37 amino acid peptides reticulated by four disulfide bridges and three have amidated C-terminal residues. The delta-palutoxins are highly homologous with the previously described mu-agatoxins and curtatoxins (77-97%). The four peptides demonstrated significant toxicity against larvae of the crop pest Spodoptera litura (Lepidoptera: Noctuidae) in a microinjection bioassay, with LD50 values in the 9-50 mu g per g of insect range. This level of toxicity is equivalent to that of several of the most active scorpion toxins used in the development of recombinant baculoviruses, and the delta-palutoxins appear to be insect specific. Electrophysiological experiments demonstrated that delta-palutoxin IT1, the most active toxin acts by affecting insect sodium channel inactivation, resulting in the appearance of a late-maintained sodium current, in a similar fashion to insecticidal scorpion alpha and alpha-like toxins and is thus likely to bind to channel receptor site 3. However, delta-palutoxin IT1 was distinguished by its lack of effect on peak sodium conductance, on the early phase of sodium current inactivation and the absence of a shift in the activation voltage of the sodium channels. delta-Palutoxins are thus proposed as new insecticidal toxins related to the alpha and alpha-like scorpion toxins. They will be useful both in the development of recombinant baculoviruses in agrochemical applications and also as molecular probes for the investigation of molecular mechanisms of insect selectivity and structure and function of sodium channels. C1 Suntory Inst Bioorgan Res, Shimamoto, Osaka 6188503, Japan. Univ Angers, Neurophysiol Lab, Angers, France. Nicholas Copernicus Univ, Biophys Lab, Torun, Poland. Amer Cyanamid Co, Princeton, NJ 08540 USA. RP Corzo, G, Suntory Inst Bioorgan Res, Wakayamadai 1-1-1, Shimamoto, Osaka 6188503, Japan. TC 26 PD SEP PY 2000 VL 267 IS 18 BP 5783 EP 5795 UT ISI:000089715100016 ER PT J AU Turbiez, M Frere, P Blanchard, P Roncali, J TI Mixed pi-conjugated oligomers of thiophene and 3,4-ethylenedioxythiophene (EDOT) SO TETRAHEDRON LETTERS DE oligomers; oligothiophene; electrochemistry; optical properties ID CONDUCTING POLYMERS; BANDGAP; POLY(THIOPHENES) AB Conjugated oligomers based on various combinations of thiophene and 3,4-ethylenedioxythiophene (EDOT) moieties have been synthesised. Comparison of the optical and electrochemical properties shows that the introduction of a bis-EDOT core in the middle of the system produces a decrease of the HOMO-LUMO gap which is attributed to an enhancement of the planarity and rigidity of the pi-conjugated system. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 CNRS, UMR 6501, Inst Mol & Mat Organ, F-49045 Angers, France. RP Frere, P, CNRS, UMR 6501, Inst Mol & Mat Organ, 2 Blvd Lavoisier, F-49045 Angers, France. TC 26 PD JUL 15 PY 2000 VL 41 IS 29 BP 5521 EP 5525 UT ISI:000088200200019 ER PT J AU Siepmann, J Kranz, H Peppas, NA Bodmeier, R TI Calculation of the required size and shape of hydroxypropyl methylcellulose matrices to achieve desired drug release profiles SO INTERNATIONAL JOURNAL OF PHARMACEUTICS DE controlled release; geometry; hydrophilic matrix; hydroxypropyl methylcellulose; modeling ID SWELLING-CONTROLLED RELEASE; PENETRANT DIFFUSION; SWELLABLE POLYMERS; DISSOLUTION; DISENTANGLEMENT; REPTATION; SOLUTE; MODELS AB The aim of this study was to develop methods for the design of hydroxypropyl methylcellulose (HPMC) tablets with specified drugs profiles. This was achieved by the use of a mathematical model developed to predict the release kinetics of water-soluble drugs from HPMC matrices. The required model parameters were determined experimentally for propranolol HCl and chlorpheniramine maleate in 0.1 N HCl and phosphate buffer pH 7.4, respectively. Then, the effects of the dimensions and aspect ratio (radius/height) of the tablets on the drug release rate were evaluated. Independent experiments were conducted to verify the theoretical predictions. Acceptable agreement between theory and experiment was found, irrespective of the type of release medium and drug. However, statistical analysis revealed a structure in the resulting residuals. Drug release rates are overestimated at the beginning and underestimated at the end of the process. Possible explanations and modifications of the model are thoroughly discussed. Both. theoretical and experimental data showed that a broad spectrum of drug release patterns can be achieved by varying the size and shape of the tablet. The effect of the initial matrix radius on release was found to be more pronounced than the effect of the initial thickness. The practical benefit of the proposed method is to predict the required size and shape of new controlled drug delivery systems to achieve desired release profiles. thus significantly facilitating the development of new pharmaceutical products. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Free Univ Berlin, Coll Pharm, D-12169 Berlin, Germany. Purdue Univ, Sch Chem Engn, W Lafayette, IN 47907 USA. RP Siepmann, J, Univ Angers, Pharm Galen Lab, Fac Pharm, 16 Blvd Daviers, F-49100 Angers, France. TC 26 PD MAY 25 PY 2000 VL 201 IS 2 BP 151 EP 164 UT ISI:000087826200002 ER PT J AU Modrowski, D Basle, M Lomri, A Maric, PJ TI Syndecan-2 is involved in the mitogenic activity and signaling of granulocyte-macrophage colony-stimulating factor in osteoblasts SO JOURNAL OF BIOLOGICAL CHEMISTRY ID HEPARAN-SULFATE PROTEOGLYCAN; FIBROBLAST GROWTH-FACTOR; CELL-SURFACE; MOLECULAR-CLONING; GM-CSF; N-SYNDECAN; MEMBRANE; BINDING; KINASE; PHOSPHORYLATION AB We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) binds to heparan sulfate proteoglycans expressed at the surface of osteoblastic cells and that the mitogenic activity of this cytokine is dependent on the presence of fully sulfated proteoglycans, In this study, we determined if GM-CSF interacts with syndecans, a family of cell surface heparan sulfate proteoglycans. Human primary osteoblasts were found to express syndecan-2 and -4 but few syndecan-1 transcripts and proteins. Recombinant human GM-CSF coupled to biotin was found to bind to syndecan-2. Immunocytochemical transmission electron microscope analysis showed co-localization of syndecan-2 and GM-CSF at the cell membrane surface. Syndecan-2 also co-localized at the cell surface and co-immunoprecipitated with the GM-CSF receptor alpha chain, suggesting a strong interaction between the cytokine, its receptor, and syndecan-2, Phosphorylation of tyrosine residues in syndecan-2 associated with the alpha chain of the GM-CSF receptor was increased after cell stimulation by GMCSF. Antisense oligonucleotides that reduced specifically the expression of syndecan-2 inhibited the mitogenic activity of GM-CSF and the activation of extracellular signal-regulated kinase-l induced by the cytokine. Our results indicate functional interactions between syndecan-2 and GM-CSF in osteoblasts, and we propose that syndecan-2 plays a role as a co-receptor for this cytokine. C1 Hop Lariboisiere, INSERM, CNRS, Unite 349, F-75475 Paris 10, France. Univ Angers, Lab Histol Embryol, F-49045 Angers, France. RP Modrowski, D, INSERM, U349, 2 Rue Ambroise Pare, F-75475 Paris 10, France. TC 25 PD MAR 31 PY 2000 VL 275 IS 13 BP 9178 EP 9185 UT ISI:000086206500017 ER PT J AU Harousseau, JL Witz, B Lioure, B Hunault-Berger, M Desablens, B Delain, M Guilhot, F Le Prise, PY Abgrall, JF Deconinck, E Guyotat, D Vilque, JP Casassus, P Tournilhac, O Audhuy, B Solary, E TI Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leukemia: Results of a randomized trial of the Groupe Ouest-Est Leucemies Aigues Myeloblastiques SO JOURNAL OF CLINICAL ONCOLOGY ID BONE-MARROW TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; STEM-CELL TRANSPLANTATION; HEMATOPOIETIC GROWTH-FACTORS; 1ST COMPLETE REMISSION; ELDERLY PATIENTS; PHASE-III; POSTREMISSION CHEMOTHERAPY; INDUCTION TREATMENT; COOPERATIVE GROUP AB Purpose: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucemies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR). Patients and Methods: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 mu g/kg. Results: In the G-CSF group, the median duration of neutropenia (< 0.5 x 10(9)/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P < .001) and after ICC 2 (20 v 28 days, P < .001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P < .001; 29 v 34 days after ICC 2, P < .001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC 1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm. Conclusion: G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome. (C) 2000 by American Society of Clinical Oncology. C1 Univ Nantes, Dept Hematol, F-44035 Nantes 1, France. Univ Hosp, Dept Hematol, Nancy, France. Univ Hosp, Strasbourg, France. Univ Hosp, Angers, France. Univ Hosp, Amiens, France. Univ Hosp, Tours, France. Univ Hosp, Poitiers, France. Univ Hosp, Rennes, France. Univ Hosp, Brest, France. Univ Hosp, Besancon, France. Univ Hosp, St Etienne, France. Univ Hosp, Reims, France. Univ Hosp, Bobigny, France. Univ Hosp, Clermont Ferrand, France. Ctr Hosp, Colmar, France. Univ Hosp, Dijon, France. RP Harousseau, JL, Univ Nantes, Dept Hematol, 1 Pl Alexis Ricordeau, F-44035 Nantes 1, France. TC 24 PD FEB PY 2000 VL 18 IS 4 BP 780 EP 787 UT ISI:000085401800010 ER PT J AU Metais, I Aubry, C Hamon, B Jalouzot, R Peltier, D TI Description and analysis of genetic diversity between commercial bean lines (Phaseolus vulgaris L.) SO THEORETICAL AND APPLIED GENETICS DE genetic diversity; molecular markers; common bean; germplasm ID FRAGMENT-LENGTH-POLYMORPHISMS; VNTR CORE SEQUENCES; DNA MARKERS; PCR; AMPLIFICATION; PRIMERS; WILD; SIMILARITY; ORIGIN; PROBES AB The effectiveness of RFLP, DAMD-PCR, ISSR and RAPD markers in assessing polymorphism and relationships between 24 commercial lines of Phaseolus vulgaris L.was evaluated. We have used a Phaseolus-specific minisatellite sequence as a probe, which enabled 23 of the bean lines tested to be fingerprinted. Based on the sequence information obtained, primers corresponding to the bean-specific minisatellite core sequence were used in subsequent PCR amplifications. Our observations indicated that while the DAMD-PCR was sensitive in detecting genetic variation between bean species and between accessions of P. vulgaris, when used alone it may be limited in its ability to detect genetic variation among cultivated bean lines due to the low number of loci amplified. Only one out of the five ISSR primers tested was efficient in generating multiple band profiles, which was insufficient to distinguish all the different bean lines. Reproducible RAPD profiles were obtained, and these allowed us to differentiate all the genotypes tested with seven primers. We ultimately used only results from RFLP and RAPD markers to explore the genetic diversity among commercial bean lines. Both analyses led to the same clustering of the bean lines according to their geographical origins (United States or Europe). With respect to the European lines, the results obtained from RAPD data also enable the lines to be clustered according to their creators. C1 UFR Sci, Genet Lab, F-49045 Angers, France. RP Peltier, D, UFR Sci, Genet Lab, 2 Bd Lavoisier, F-49045 Angers, France. TC 23 PD DEC PY 2000 VL 101 IS 8 BP 1207 EP 1214 UT ISI:000166060400006 ER PT J AU Pessaux, P Arnaud, JP Ghavami, B Flament, JB Trebuchet, G Meyer, C Huten, N Champault, G CA Soc Francaise Chirurgie Laparoscop TI Laparoscopic antireflux surgery: comparative study of Nissen, Nissen-Rossetti, and Toupet fundoplication SO SURGICAL ENDOSCOPY-ULTRASOUND AND INTERVENTIONAL TECHNIQUES DE fundoplication; gastroesophageal reflux diesase; laparoscopy; Nissen; Nissen-Rossetti; Toupet ID GASTROESOPHAGEAL REFLUX DISEASE; RANDOMIZED TRIAL; FLOPPY NISSEN AB Background: The aim of this retrospective study was to compare the results of Nissen, Nissen-Rossetti, and Toupet laparoscopic fundoplication in terms of gastroesophageal reflux disease (GERD). Methods: From 1992 to 1996, 1,470 laparoscopic fundoplications were performed using one of three procedures: Nissen (n = 655), Nissen-Rossetti (n = 423), and Toupet(n = 392). Preoperative checkup included esophagogastroduodenoscopy in 1,437 patients (97.7%), esophageal manometry in 934 patients (63.5%), and 24-h pH-metry in 799 patients (54.3%). The results were estimated at 1 month, 3 months, and 2 years. Patients unable to visit the hospital center were contacted by telephone. Results: The three groups were quite similar regarding demographic data such as age, gender, preoperative clinical symptoms, and duration of GERD. One death (0.07%) occurred. At 3 months, there were no differences among the three groups concerning conversion, morbidity, dysphagia, early reintervention, or postoperative length of stay. The length of surgery was more important in the Toupet procedure. In the Nissen group, there were fewer Visick grade I patients but more Visick grade III patients. At 2 years, the recurrence and reintervention rates were similar. The overall residual severe dysphagia rate was 0.35% (n = 5). In the Nissen group, there were fewer Visick grade I patients but more in Visick grade II patients. There was no difference in Visick grade III and IV among the groups. More than 90% of the patients were satisfied (Visick I + Visick II), with no significant difference among the three groups. Conclusions: The results of this study do not differ significantly from the data reported in the Literature, suggesting such surgical techniques are effective and well tolerated, and that both can be properly used in the treatment of GERD. C1 CHU Angers, Dept Visceral Surg, F-49033 Angers 01, France. RP Arnaud, JP, CHU Angers, Dept Visceral Surg, 4 Rue Larrey, F-49033 Angers 01, France. TC 23 PD NOV PY 2000 VL 14 IS 11 BP 1024 EP 1027 UT ISI:000165706100010 ER PT J AU Pessaux, P Tuech, JJ Derouet, N Rouge, C Regenet, N Arnaud, JP TI Laparoscopic cholecystectomy in the elderly - A prospective study SO SURGICAL ENDOSCOPY-ULTRASOUND AND INTERVENTIONAL TECHNIQUES DE elderly; high-risk patients; laparoscopic cholecystectomy ID ACUTE CHOLECYSTITIS; MANAGEMENT AB Background: The aim of this prospective study was to determine the feasability and the complications or benefits of laparoscopic cholecystectomy (LC) in the patients older than 75 years. Methods: From January 1992 to July 1998, a total of 863 patients underwent LC, of these patients, 102 patients older than 75 years (group 1) were compared with 761 younger patients (group 2). Results: In the elderly, 35.3% were at high surgical risk (American Society of Anesthesiology [ASA] III and ASA TV). The conversion rate to open cholecystectomy (OC) was 21.6%. The mean length of hospital stay was 6.9 days for both laparoscopy and conversion. Morbidity and mortality rates were 13.7% and 1%, respectively. No patient suffered intraoperative cardiopulmonary complication, and there was no reoperation in the elderly. Conclusions: Elderly patients experience more complications and longer duration of hospital stay than younger patients. However, our results compare favorably with other OC studies in elderly patients. C1 CHU Angers, Dept Visceral Surg, F-49033 Angers 01, France. RP Tuech, JJ, CHU Angers, Dept Visceral Surg, 4 Rue Larrey, F-49033 Angers 01, France. TC 23 PD NOV PY 2000 VL 14 IS 11 BP 1067 EP 1069 UT ISI:000165706100021 ER PT J AU Lievre, M Gueyffier, F Ekbom, T Fagard, R Cutler, J Schron, E Marre, M Boissel, JP CA The INDANA Steering Comm TI Efficacy of diuretics and beta-blockers in diabetic hypertensive patients - Results from a meta-analysis SO DIABETES CARE ID RANDOMIZED CLINICAL-TRIALS; ISOLATED SYSTOLIC HYPERTENSION; CORONARY HEART-DISEASE; HIGH BLOOD-PRESSURE; ANTIHYPERTENSIVE THERAPY; CARDIOVASCULAR EVENTS; INTERVENTION TRIAL; MILD HYPERTENSION; METAANALYSIS; MORTALITY AB OBJECTIVE - To review the effectiveness of diuretic or beta-blocker-based treatment of hypertension in diabetic patients. RESEARCH DESIGN AND METHODS - A meta-analysis on individual patient data was performed on four trials of the treatment of hypertension in which diabetic patients were included and treated with first-line diuretics or beta-blockers. The main outcomes were the relative risk of death, fatal or nonfatal stroke, fatal or nonfatal coronary events, and major cardiovascular events. RESULTS - There were 92 diabetic patients who received first-line beta-blockers and 1,008 who received diuretics. In the control groups, diabetic patients had nearly twice the risk of any outcome when compared with nondiabetic patients. The same blood pressure reduction was achieved under treatment in the diabetic and nondiabetic patients, except for systolic pressure, which decreased more in the nondiabetic patients at 1 year. In the 15,843 nondiabetic patients, the risk of all four outcomes was reduced significantly in the treated group. In the 2,254 diabetic patients, the risk reduction was significant only for fatal and nonfatal stroke (36%, P = 0.011) and major cardiovascular events (20%, P = 0.032),but not for death (5%, P = 0.65) and fatal or nonfatal coronary events (15%, P = 0.23). However, no heterogeneity was detected between diabetic patients and nondiabetic patients for any outcome. The numbers of outcomes avoided for 1,000 patients treated for 5 years were higher in diabetic patients (e.g., 38 major cardiovascular events) than with nondiabetic patients (e.g., 28 major cardiovascular events). CONCLUSIONS - These results show that hypertensive diabetic patients benefit from first-line treatment with diuretics. No conclusion can be drawn for beta-blockers, owing to the small sample size. C1 Univ Lyon 1, Lyon Hosp, Dept Clin Pharmacol, Equipe Accueil 643, Lyon, France. Dept Community Hlth Sci, Dalby Lund, Sweden. Hypertens & Cardiovasc Rehabil Unit, Louvain, Belgium. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Hosp Angers, Angers, France. RP Lievre, M, Fac Med HRT Laennec, Serv Pharmacol Clin, Rue Guillaume Paradin,BP 8071, F-69376 Lyon 08, France. TC 23 PD APR PY 2000 VL 23 SU Suppl. 2 BP B65 EP B71 UT ISI:000086273600011 ER PT J AU Allain, P Heudi, O Cailleux, A Le Bouil, A Larra, F Boisdron-Celle, M Gamelin, E TI Early biotransformations of oxaliplatin after its intravenous administration to cancer patients SO DRUG METABOLISM AND DISPOSITION ID MASS-SPECTROMETRY; IN-VITRO; PLATINUM; PHARMACOKINETICS; CARBOPLATIN; BINDING; PLASMA; LEAD AB This article deals with the fate of oxaliplatin 1 and 3 h after its i.v. administration (130 mg/m(2)) to three patients. Its binding to plasma proteins and penetration into red blood cells were monitored by chromatography on-line with inductively coupled plasma mass spectrometry. Oxaliplatin biotransformations in plasma ultrafiltrate (PUF) and in urine were studied by chromatography coupled to inductively coupled plasma mass spectrometry or to electrospray ionization mass spectrometry. In plasma, four platinum (Pt) compounds were found. The peaks at 200 and 160 kDa corresponding to gamma-globulins contained 40% of the Pt bound; the peak at 60 kDa corresponding to albumin contained 40% of the Pt found. The peak <2 kDa could correspond to oxaliplatin, to its degradation products, or to adducts between Pt compounds and low-molecular-weight species such as glutathione, L-methionine, and L-cysteine. In PUF and urine, oxaliplatin itself, its degradation products, Pt-(dach)Cl-2, [Pt(dach)(OH2)Cl](+), and species that have the same retention times as Pt(dach)(methionine) and [Pt(dach)](2)(glutathione) were found. One hour after infusion, oxaliplatin in PUF and urine represented 12 and 50% of the total Pt, respectively. Three hours after infusion, oxaliplatin, undetectable in PUF, represented 10% of total Pt in urine. Inside red blood cells, two Pt compounds were found. The Pt peak at 60 kDa corresponding to hemoglobin and the peak <2 kDa corresponding to low-molecular species contained, respectively, 60% and 40% of Pt found. This study demonstrates that in the first hours after its infusion, oxaliplatin, in addition to other Pt compounds, is present in plasma and urine and that Pt is bound to albumin, gamma-globulins, and hemoglobin. C1 CHU Angers, Lab Pharmacol & Toxicol, F-49033 Angers 01, France. Ctr Reg Lutte Contre Canc, Ctr Paul Papin, Dept Med Oncol, Angers, France. Ctr Reg Lutte Contre Canc, Ctr Paul Papin, Dept Clin Pharmacol, Angers, France. RP Allain, P, CHU Angers, Lab Pharmacol & Toxicol, F-49033 Angers 01, France. TC 22 PD NOV PY 2000 VL 28 IS 11 BP 1379 EP 1384 UT ISI:000089909400019 ER PT J AU Raimundo, JM Blanchard, P Ledoux-Rak, I Hierle, R Michaux, L Roncali, J TI Huge enhancement of the quadratic nonlinear optical susceptibility in push-pull chromophores based on bridged dithienylethylene spacers SO CHEMICAL COMMUNICATIONS ID BOND-LENGTH ALTERNATION; HIGHLY EFFICIENT; THERMAL-STABILITY; BANDGAP; HYPERPOLARIZABILITIES; DERIVATIVES; ACCEPTOR; POLYENES; POLYMERS; DONOR AB Replacement of the open chain dithienylethylene pi-conjugating spacer by its bridged analog in push-pull NLO-phores produces a dramatic increase of the quadratic hyperpolarisability. C1 Univ Angers, CNRS, UMR 6501, F-49045 Angers, France. Ecole Normale Super, Lab Photon Quant & Mol, F-94235 Cachan, France. RP Roncali, J, Univ Angers, CNRS, UMR 6501, 2 Bd Lavoisier, F-49045 Angers, France. TC 22 PY 2000 IS 17 BP 1597 EP 1598 UT ISI:000088914800019 ER PT J AU Alexander, J Hirschowitz, A TI An asymptotic vanishing theorem for generic unions of multiple points SO INVENTIONES MATHEMATICAE ID LINEAR-SYSTEMS; INVERSE SYSTEM; SYMBOLIC POWER; HORACE METHOD; INTERPOLATION; SINGULARITIES; SURFACES; CURVES C1 Univ Angers, Dept Math, F-49000 Angers, France. Univ Nice, Dept Math, F-06034 Nice, France. RP Alexander, J, Univ Angers, Dept Math, F-49000 Angers, France. TC 22 PD MAY PY 2000 VL 140 IS 2 BP 303 EP 325 UT ISI:000087197000003 ER PT J AU Lunel, F Cadranel, JF Rosenheim, M Dorent, R Di-Martino, V Payan, C Fretz, C Ghoussoub, JJ Bernard, B Dumont, B Perrin, M Gandjbachkh, I Huraux, JM Stuyver, L Opolon, P TI Hepatitis virus infections in heart transplant recipients: Epidemiology, natural history, characteristics, and impact on survival SO GASTROENTEROLOGY ID POLYMERASE CHAIN-REACTION; NON-B-HEPATITIS; C VIRUS; LIVER-DISEASE; NON-A; BIOPSY PROCEDURES; VIRAL-B; TRANSMISSION; RNA; PREVALENCE AB Background & Aims: We have observed a high prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in heart transplant recipients (HTRs). The aim of this study was to assess the epidemiology, natural history, and clinical and biological characteristics of viral hepatitis in HTRs. Methods: From 1983 to 1992, 874 patients underwent heart transplantation at the Pitie-Salpetriere Hospital, Paris, France, 459 of whom qualified for analysis. A total of 140 patients had posttransplantation hepatitis B, C, or non-A-E. Sixty-nine patients developed HBV infection, 49 HCV infection, 11 HBV-HCV coinfection, and 11 non-A-E hepatitis, Results: HBV was transmitted nosocomially from patient to patient, most likely during endomyocardial biopsies. HCV was mainly transmitted through blood transfusions or the transplanted organ. Clinical and biological findings after 2 years of follow-up showed that 3 patients with an HBV genotype A precore mutant had severe or subfulminant hepatitis and that patients with HBV and HCV infection always progressed to chronicity. In general, patients had mild alanine aminotransferase level increases, a high level of viral replication, and few severe histologic Lesions, except for patients infected by precore HBV mutants. Patients coinfected by HBV and HCV tended to have more severe liver lesions. The survival rate 5 years after transplantation in patients with viral hepatitis (HBV, 81%; HCV, 89%; HBV and HCV coinfection, 100%; non-A-E hepatitis, 73%) was similar to that in patients without liver test abnormalities (76%). The actuarial survival curve was also similar in patients with or without liver test abnormalities. Conclusions: In our experience, histologic liver lesions do not progress rapidly in patients with post-heart transplant infection caused by HBV or HCV. HBV or HCV infection seems to have little impact on the 5-year survival rate of HTRs. C1 CHU Angers, Serv Bacteriovirol, F-49033 Angers, France. Ctr Hosp Creil, Hepatol Unit, Creil, France. Hop Paris, Estab Transfus Sanguine Assistance Publ, Paris, France. Hop La Pitie Salpetriere, Paris, France. Innogenet, Ghent, Belgium. Sante Publ, Paris, France. Chirurg Cardiaque, Paris, France. Hepatogastroenterol, Paris, France. RP Lunel, F, CHU Angers, Serv Bacteriovirol, 4 Rue Larrey, F-49033 Angers, France. TC 21 PD OCT PY 2000 VL 119 IS 4 BP 1064 EP 1074 UT ISI:000089847800022 ER PT J AU Brisset, MN Cesbron, S Thomson, SV Paulin, JP TI Acibenzolar-S-methyl induces the accumulation of defense-related enzymes in apple and protects from fire blight SO EUROPEAN JOURNAL OF PLANT PATHOLOGY DE chemical control; Erwinia amylovora; beta-1,3-glucanases; peroxidases; systemic resistance; CGA 245704 ID SYSTEMIC ACQUIRED-RESISTANCE; DISEASE RESISTANCE; BENZOTHIADIAZOLE; PATHOGENS; CUCUMBER; PLANTS; BETA-1,3-GLUCANASE; ASSOCIATION; PEROXIDASE; INDUCTION AB Acibenzolar-S-methyl (Novartis) is a chemical inducer of systemic acquired resistance in several annual plants. The ability of this novel chemical to induce resistance was studied in a perennial plant (apple) affected by fire blight caused by Erwinia amylovora. Acibenzolar-S-methyl (100 and 200 mg/l active ingredient) protected Golden Delicious seedlings, scions and trees from artificial infection when applied before inoculation. The protection of apple seedlings was similar to the protection obtained with the standard for fire blight control, plantomycin (100 mg/l streptomycin sulfate), applied immediately before inoculation. The mean levels of control in scions in the greenhouse and in trees in orchards were approximately 69% and 50%, respectively. The protection of apple seedlings was constantly associated with the activation of two families of defense-related enzymes, peroxidases and beta-1,3-glucanases. Accumulation of both enzymes was induced locally in treated leaves and systemically, especially for beta-1,3-glucanases, in upper untreated leaves, and was sustained for at least 17 days. These results suggest that acibenzolar-S-methyl promotes induced systemic resistance in apple by increasing defense-related compounds. This chemical could provide a new approach of control of fire blight but its practical use needs further investigation. C1 INRA, Ctr Angers, Unite Ameliorat Especes Fruitieres & Ornementales, F-49071 Beaucouze, France. INRA, Ctr Angers, Unite Pathol Vegetale & Phytobacteriol, F-49071 Beaucouze, France. Utah State Univ, Dept Biol, Logan, UT 84322 USA. RP Brisset, MN, INRA, Ctr Angers, Unite Ameliorat Especes Fruitieres & Ornementales, 42 Rue Georges Morel,BP 57, F-49071 Beaucouze, France. TC 21 PD JUL PY 2000 VL 106 IS 6 BP 529 EP 536 UT ISI:000088588100004 ER PT J AU Hambli, R Potiron, A TI Finite element modeling of sheet-metal blanking operations with experimental verification SO JOURNAL OF MATERIALS PROCESSING TECHNOLOGY DE Von Mises yield criterion; finite element modeling; material shearing mechanisms AB In order to accurately simulate sheet-metal cutting processes by material shearing mechanisms, such as blanking and punching processes, a finite element model valid for the numerical description of such processes has been developed. Damage and crack propagation have been taken into account by means of an elastoplastic constitutive law. To study the effects of variation of processes parameters on the geometry of sheared edges and the force-punch penetration evolution, we have implemented the algorithm of calculation by means of users routine (UMAT) of ABAQUS/Standard finite element code. Final results of the FEM simulation agree with the experimental ones. (C) 2000 Published by Elsevier Science S.A. All rights reserved. C1 ISTIA, LASQUO, F-49000 Angers, France. ENSAM, LPMI, F-49035 Angers, France. RP Hambli, R, ISTIA, LASQUO, 62 Ave Notre Dame Lac, F-49000 Angers, France. TC 21 PD MAY 15 PY 2000 VL 102 IS 1-3 BP 257 EP 265 UT ISI:000086949300039 ER PT J AU Pessaux, P Tuech, JJ Rouge, C Duplessis, R Cervi, C Arnaud, JP TI Laparoscopic cholecystectomy in acute cholecystitis - A prospective comparative study in patients with acute vs chronic cholecystitis SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES DE acute cholecystitis; gallbladder; laparoscopic cholecystectomy; optimal timing ID RANDOMIZED TRIAL; CHOLELITHIASIS; MANAGEMENT AB Background: The aim of this prospective study was to compare the outcome of laparoscopic cholecystectomy (LC) in patients with acute cholecystitis versus those with chronic cholecystitis and to determine the optimal timing for LC in patients with acute cholecystitis. Methods: From January 1991 to July 1998, 796 patients (542 women and 254 men) underwent LC. In 132 patients (67 women and 65 men), acute cholecystitis was confirmed via histopathological examination. These patients were divided into two groups. Group 1 (n = 85) had an LC prior to 3 days after the onset of the symptoms of acute cholecystitis, and group 2 (n = 47) had an LC after 3 days. Results: There were no mortalities. The conversion rates were 38.6% in acute cholecystitis and 9.6% in chronic cholecystitis (p < 10(-8)). Length of surgery (150.3 min vs 107.8 min; p < 10(-9)) postoperative morbidity (15% vs 6.6%; p = 0.001), and postoperative length of stay (7.9 days vs 5 days; p < 10(-9)) were significantly different between LC for acute cholecystitis and elective LC, For acute cholecystitis, we found a statistical difference between the successful group and the conversion group in terms of length of surgery and postoperative stay. The conversion rates in patients operated on before and after 3 days following the onset of symptoms were 27% and 59.54b, respectively (p = 0.0002). There was no statistical difference between early and delayed surgery in terms of operative time and postoperative complications. However, total hospital stay was significantly shorter for group 1. Conclusions: LC for acute cholecystitis is a safe procedure with a shorter postoperative stay, lower morbidity, and less mortality than open surgery. LC should be carried out as soon as the diagnosis of acute cholecystitis is established and preferably before 3 days following the onset of symptoms. Early laparoscopic cholecystectomy can reduce both the conversion rate and the total hospital stay as medical and economic benefits. C1 Dept Visceral Surg, F-49100 Angers, France. RP Arnaud, JP, Dept Visceral Surg, 4 Rue Larrey, F-49100 Angers, France. TC 21 PD APR PY 2000 VL 14 IS 4 BP 358 EP 361 UT ISI:000086678300010 ER PT J AU Pean, JM Menei, P Morel, O Montero-Menei, CN Benoit, JP TI Intraseptal implantation of NGF-releasing microspheres promote the survival of axotomized cholinergic neurons SO BIOMATERIALS DE cholinergic neuron; drug delivery; microsphere; nerve growth factor; neuroprotection; eurotrophic factor ID NERVE-GROWTH-FACTOR; BIODEGRADABLE MICROSPHERES; POLY(D,L-LACTIDE-CO-GLYCOLIDE) MICROSPHERES; STEREOTAXIC IMPLANTATION; BRAIN; RATS; STABILITY; DELIVERY; LESIONS; PATHWAY AB Neurotrophic factors therapy requires their precise delivery to the targeted neuronal population. For this purpose, a wide range of strategies have been developed, and among them the stereotaxic implantation of biodegradable microparticles. To assess the in vivo activity of NGF-releasing PLGA microspheres, unloaded and NGF-loaded microparticles were implanted in the rat brain, near the septal cholinergic neurons, axotomized by an unilateral transection of the fornix-fimbria. Histological analysis at two and six weeks after implantation revealed a non-specific astro- and micro-glial reaction around the microspheres, identical for both unloaded and NGF-loaded microspheres. No neuronal toxicity was noticed, and healthy looking neurons were observed in contact with the microspheres. In the non-treated animals, the percentage of axotomized surviving neurons, when compared to the controlateral intact side, was 31 +/- 2 and 27 +/- 1% at two and six weeks, respectively. Unloaded microspheres caused no protective nor neurotoxic effects (40 +/- 9 and 39 +/- 6% of surviving cholinergic neurons at two and six weeks, respectively). In contrast, NGF-loaded microspheres showed a significant effect on the survival of axotomized cholinergic neurons at two and six weeks after implantation (66 +/- 9 and 61 +/- 5% when compared to the controlateral intact side, respectively). These results show that PLGA microparticles present no neurotoxicity and release sufficient amounts of bioactive NGF to significantly limit the lesion-induced disappearance of cholinergic neurons in the septum during at least six weeks. PLGA microparticles can be used in the future to administer neurotrophic factors in central nervous system disorders. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Fac Pharm, UPRES EA 2169, F-49100 Angers, France. CHU Angers, Serv Neurochirurg, F-40033 Angers, France. RP Menei, P, Fac Pharm, UPRES EA 2169, 16 Blvd Daviers, F-49100 Angers, France. TC 20 PD OCT PY 2000 VL 21 IS 20 BP 2097 EP 2101 UT ISI:000088712700011 ER PT J AU King, GJ Maliepaard, C Lynn, JR Alston, FH Durel, CE Evans, KM Griffon, B Laurens, F Manganaris, AG Schrevens, T Tartarini, S Verhaegh, J TI Quantitative genetic analysis and comparison of physical and sensory descriptors relating to fruit flesh firmness in apple (Malus pumila Mill.) SO THEORETICAL AND APPLIED GENETICS DE apple; fruit; firmness; texture; QTL analysis; genes ID TRAIT LOCI; TOMATO; QTLS AB Texture is a major component of consumer preference for eating-quality in apple. A quantitative genetic analysis of traits associated with fruit-flesh firmness was carried out. This was based on segregation in an unselected mapping population replicated at six sites and harvested over 2 years. Different methods of assessment were compared, and a principal components analysis carried out. Instrumental measures used were Magness-Taylor penetrometer readings, stiffness by acoustic resonance, and a range of sensory descriptors assessed by a trained panel. There were good correlations between some measures, although stiffness was poorly correlated. Whilst genotype by environment effects were large, significant effects were attributable to the genotype, and these were used to detect QTLs. Significant QTLs were detected on seven linkage groups, with large effects on linkage groups L01, L10 and L16. Whilst there was a pool: correlation between acoustic stiffness and other measures, the significant and suggestive QTL detected for stiffness on linkage group L10 did represent a subset of significant QTLs detected for the penetrometer measure. The use of sensory assessment proved valuable in detecting QTLs representing different attributes of fruit texture. The possibility of interaction between significant QTLs: fur fruit texture and other strongly selected traits such as scab resistance and fruit acidity is addressed. C1 Hort Res Int, Warwick CV35 9EF, England. DLO, CPRO, Ctr Plant Breeding & Reprod Res, NL-6700 AA Wageningen, Netherlands. Hort Res Int, Maidstone ME19 6BJ, Kent, England. Ctr Rech Angers, INRA, Stn Ameliorat Especes Fruitieres & Ornamentales, F-49070 Beaucouze, France. Pomol Inst Naoussa, Naoussa 59200, Makedonia, Greece. Katholieke Univ Leuven, Louvain, Belgium. Univ Bologna, Dipartimento Colture Arboree, I-40126 Bologna, Italy. RP King, GJ, Hort Res Int, Warwick CV35 9EF, England. TC 20 PD MAY PY 2000 VL 100 IS 7 BP 1074 EP 1084 UT ISI:000087586500010 ER PT J AU Moreau, MF Gallois, Y Basle, MF Chappard, D TI Gamma irradiation of human bone allografts alters medullary lipids and releases toxic compounds for osteoblast-like cells SO BIOMATERIALS DE bone allograft; lipids; peroxidated lipids; lipofuschine; osteoblast; bone bank; biomaterial; bone substitute ID FREE-RADICALS; TRABECULAR BONE; RABBITS; BANK; ACID; RESORPTION; PRODUCTS; BIOLOGY; DISEASE; GRAFTS AB The uncertainties about the transmission of prion proteins from xenogenic grafts prepared from bovine bone has led to the reconsideration of allogenic bone as a grafting material. Allografting is a complementary technique to autografting nowadays when large bone volumes are necessary. Several preparation techniques have been proposed. Fresh-frozen, freeze-dried and gamma irradiation are the most common. However, a large amount of lipids is present in the medullary spaces (near 70% in weight for a human femoral head). They are known to strongly influence the biocompatibility of the bone graft. The exact changes of lipids upon the sterilization and storage processes are poorly known. The aims of the present study were to appreciate the effects of gamma irradiation on medullary lipids and to identify the cytotoxicity of gamma-irradiated bank bone with/without lipid on cultures of osteoblast-like cells. Bone cores from 8 femoral heads retrieved during prosthesis surger