Biomedical subjects
Publications and source records attributed to R Touraine.
A 16-year-old Caucasian girl was admitted to hospital with acute renal failure and hemolytic anemia due to rhabdomyolysis following a 3-km walk. (31)P-magnetic resonance spectroscopy provided characteristic spectra of type VII glycogen storage disease (phosphofructokinase deficiency).
Hirschsprung disease (HSCR) is a common malformation of neural-crest-derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest-derived cells and of CNS but also in the development of midline structures in humans.
Explore the source record for details and available documents.
Metabolic suicide gene transfer is widely applied for gene therapy of cancer, and retroviral vectors expressing the herpes simplex virus thymidine kinase (HSV-tk) gene are commonly used in clinical trials. Most of these vectors contain positive selectable markers that undoubtedly facilitate the determination of viral titer and the identification of high-titer producer clones. However, the presence of additional transcriptional units may result in reduced expression of the gene of interest. The use of fusion genes expressing bifunctional proteins may help to overcome this problem. We have constructed a retroviral vector carrying the TNFUS69 chimeric gene, which originates from the fusion of the HSV-tk and neomycin phosphotransferase II genes, and evaluated the functional expression of the encoded fusion protein. In vitro, expression of the fusion gene conferred to target cells both resistance to neomycin and selective sensitivity to the antiherpetic drugs ganciclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine. Cells transduced with the fusion gene, however, showed reduced ability to phosphorylate ganciclovir compared with cells expressing the native HSV-tk. Therefore, although the fusion gene may be used as a constituent of retroviral cassettes for positive and negative selection in vitro, its usefulness for suicide gene transfer applications in vivo may depend upon the possibility of using (E)-5-(2-bromovinyl)-2'-deoxyuridine in a clinical context.
Aicardi syndrome is characterized by infantile spasms, agenesis of the corpus callosum and chorioretinal lacunae. This disorder affects mostly females with early embryonic lethality in males. We present a case of persistent hyperplastic primary vitreous (PHPV) in association with Aicardi syndrome in a 2-year-old girl.
Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB an EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.
Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the absence of submucosal and myenteric plexuses in a variable length of the gastrointestinal tract. Pedigrees and segregation analyses suggested the involvement of one or several dominant genes with low penetrance in HSCR. Considering that RET and glial cell line-derived neurotrophic factor (GDNF) mutations have been reported in the disease, we regarded the other RET ligand, neurturin (NTN), as an attractive candidate gene, especially as it shares large homologies with GDNF. Here, we report on the finding of a heterozygous missense NTN mutation in a large non-consanguineous family including four children affected with a severe aganglionosis phenotype extending up to the small intestine. Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation. This cascade of independent and additive genetic events fits well with the multigenic pattern of inheritance expected in HSCR, and further support the role of RET ligands in development of the enteric nervous system.
OBJECTIVE: The objective of the study was to evaluate the accuracy of MR cholangiography in showing the biliary tree in neonates and infants and to show preliminary applications in a pediatric population. SUBJECTS AND METHODS: MR cholangiography was performed with T2-weighted turbo spin-echo sequences (8000/300 [TR/TE], six or eight excitations). The study included seven patients with suspected bile duct disorders and 10 control individuals. RESULTS: In the control group, the extrahepatic bile ducts (EHBDs) were revealed by MR cholangiography in all patients. In one of the five patients with neonatal cholestasis, biliary atresia was excluded by identifying the entire EHBD on MR cholangiograms. In the four other patients with neonatal cholestasis, biliary atresia was suspected because the EHBD could not be seen on MR cholangiography. The diagnosis was confirmed in three of these four patients, in whom the MR finding was associated with significant periportal thickening. In the remaining patient, in whom periportal thickening was not seen, sclerosing cholangitis was diagnosed on biopsy. In the sixth patient with neonatal cholestasis, who had received a liver transplant, MR cholangiography showed biliary dilatation above the biliary-digestive anastomosis. In the seventh patient, a neonate with a prenatal diagnosis of hepatic cyst, MR cholangiography showed a choledochal cyst. CONCLUSION: MR cholangiography may become an important diagnostic tool in the detection of biliary atresia, congenital choledochal dilatation, and biliary complications in hepatic transplantation for pediatric patients.
BACKGROUND: At this time, folinic acid (FA) is commercially available as the racemic mixture d,l-FA, whose biological activity is supported by natural l-FA. The administration of d,l-FA results in the accumulation of d-FA in plasma relative to the active l-FA form; in vitro studies have shown that d-FA can compete with the polyglutamation of methotrexate (MTX). PURPOSE: Our purpose was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture d,l-FA with the pure l-FA in rescue of high-dose MTX therapy (5 g/m2) in children with acute lymphocytic leukemia (ALL). METHODS: Eighteen children with ALL were entered in this trial, which was planned with a crossover design. Four cycles of MTX were administered to each patient, and rescue was achieved orally every 6 hours at a dose of 12 mg/m2 for d,l-FA and 6 mg/m2 for pure l-FA. The d,l-FA and l-FA rescues were alternated from one cycle to the next. d-FA, l-FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific high-performance liquid chromatography assay. RESULTS: Considering total active folate levels (l-FA + 5-MTHF), mean residual concentrations were similar for rescue by d,l-FA and l-FA, after two and six intakes, respectively: 92 and 186 nM for d,l-FA rescue versus 100 and 184 nM for l-FA rescue. Intra-individual comparison of total active folates (l-FA + 5-MTHF) did not show any significant difference between d,l-FA rescue and l-FA rescue. After administration of d,l-FA, the accumulation of d-FA in plasma was confirmed. For both types of FA rescue, MTX terminal half-lives were identical (average value, 13.9 hours). Considering each type of toxic effect (hematologic, hepatic, renal, and digestive), there was no significant difference in the proportion of toxic cycles following l-FA rescue or d,l-FA rescue. CONCLUSION: The administration of the pure l-FA, compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, leads to equivalent treatment tolerance, and avoids the plasma accumulation of d-FA.
BACKGROUND: Sclerodermatous chronic graft-versus-host disease is a disabling complication after allogeneic bone marrow transplantation from HLA-identical sibling donors. Only a few series of patients have been reported and the dermatologic features have never been extensively described. OBJECTIVE: The purpose of the study was to describe clinical and biologic features of chronic sclerodermatous graft-versus-host disease and to compare them with scleroderma. METHODS: We reviewed 196 patients grafted between April 1973 and July 1987 with survival times sufficient to be at risk of chronic graft-versus-host disease. Seven had the sclerodermatous form. RESULTS: Most patients had disseminated sclerosis of the trunk and the proximal portions of the limbs. In two cases, atrophy of the skin was predominant, corresponding with a severe clinical evolution. Periorbital pigmentation was observed as an initial manifestation in three cases. Visceral manifestations resembled those observed in scleroderma but histologic and immunologic studies demonstrated clear differences. Response to therapy was variable. CONCLUSION: Chronic sclerodermatous graft-versus-host disease may realize two different patterns. Major atrophy is associated with a more severe progression.
Pyoderma gangrenosum (PG) consists of extensive necrotic ulceration with bluish and purplish red margins. This disease is often associated with ulcerative colitis, systemic, hematologic or rheumatic diseases. However post-surgical idiopathic PG can occur. One post-mastectomy case is reported. PG can first be suspected on clinical appearance and the lack of a specific etiology. PG is a diagnosis of exclusion that is made only after other possibilities have been ruled out. The treatment is surgical excision and systemic corticosteroids.
On the occasion of the "Journées Dermatologiques de Paris", in March 1988 we designed a survey to evaluate the sterile practices of French dermatologists in the "AIDS era". During the two days meeting, attended by 2,584 participants, 472 questionnaire forms were filled in (answer rate 18.5 p. 100). Among responders 43 p. 100 were exclusively office-based, 13 p. 100 only worked in hospitals, and 44 p. 100 were practicing both in office and hospital. The overall utilisation of gloves by French dermatologists remained highly variable, depending on the procedure. For example 6.7 p. 100 of responders reported never using gloves for excisions, 13 p. 100 for shave biopsies, 18 p. 100 for punch biopsies, 40 p. 100 for curettage and 47 p. 100 for electrocoagulation. Five per cent of the dermatologists surveyed did not sterilize their curettes regularly and 42 p. 100 their electrocoagulation needles. Heat sterilization was the most commonly used, in 69 p. 100 of cases for curettes and 42 p. 100 for electrocoagulation needles. On the other hand, chemical tray sterilization was used in 58 p. 100 of the cases for electrocoagulation needles, and in 31 p. 100 for curettes. For chemical sterilization, 63 p. 100 of responders used alcohol, 15 p. 100 glutaraldehyde, 15 p. 100 sodium hydrochloride, and 7 p. 100 other agents, mainly quartenary ammonium compounds. Twelve per cent of the physicians surveyed have adopted the practice of using a single electrocoagulation needle, belonging to each patient, for long term repeated procedures.(ABSTRACT TRUNCATED AT 250 WORDS)
Dermatomyositis (DM) is an inflammatory myopathy with a severe prognosis mainly determined by its association with malignancy. We present the results of a study of 32 adults with DM. Our aim was to define predictive signs of cancer and establish prognostic factors according to patient survival. Thirteen (41%) of the 32 patients had DM associated with malignancy. After 7 years of follow-up, the overall mortality rate was 52%. Mortality was higher for patients with malignancy. Cutaneous necrosis and an elevated erythrocyte sedimentation rate appeared as potential markers of associated malignancy. Classic signs of poor prognosis, such as age and association with cancer were found. Interestingly, extensive cutaneous lesions on the trunk and an elevated erythrocyte sedimentation rate were also more frequent among the patients who died. Our results demonstrate that selected groups of patients with DM, in part defined by cutaneous signs, have a poor prognosis.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.