Clinical Phenotype in an Early-Onset French Pediatric Population: Charcot-Marie-Tooth's Disease Type 2A.

Charcot-Marie-Tooth's disease type 2A (MCT2A), induced by mutation of the mitofusin 2 (MFN2) gene represents the main cause of MCT2. The aim of this study is to provide details of the clinical and electromyographic phenotype of MCT2A in a pediatric population. We conducted a French multicenter retrospective study, including all children with a genetic diagnosis of MCT2A. Thirteen MCT2A children were included with a beginning of symptoms before the age of 10 years ("early-onset group"). We report two new mutations: c.1070 A → T (p.Lys357.Met) and c.280 C → G (p.Arg94Gly). The evolution of the disease is marked by a fast worsening for three patients with loss of motor autonomy, while the evolution is relatively stable for eight patients. The group of early-onset MCT2A seems more heterogeneous than previously described, with a nonconstant severe phenotype.

Modelling of marine debris pathways into UK waters: Example of non-native crustaceans transported across the Atlantic Ocean on floating marine debris.

The long-distance transfer of non-native, potentially invasive species via floating marine debris is an increasing threat to biodiversity and conservation efforts. To address the lack of understanding around mechanisms and pathways of species transfer via marine debris, a novel modelling approach was applied to recreate the likely trajectory and source of a large piece of debris fouled by non-native species collected from UK marine waters. This approach applied the Oil Spill Contingency and Response (OSCAR) simulation tool, an adapted oil spill modelling programme, which was informed by a combination of biological trait information for the foulant species, marine debris characteristics and hydrodynamic data. The modelling output suggested an origin in the Western Atlantic, a scenario concurrent with the known distribution of the foulant species. This modelling approach represents a valuable tool with which to determine the origin and trajectory of invasive species transferred via marine debris.

Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency.

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa protein termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-mediated transformation of T cells likely involves the deregulated expression of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression or activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular factors HEB-1 and p67SRF. An additional distinguishing characteristic of HTLV-I infection is the profound state of viral latency that is present in circulating primary leukemic T cells. In this study, we demonstrate that HTLV-I Tax can physically associate with p100, the product of the Rel-related NF-kappa B2 gene, both in transfected cells and in HTLV-I-infected leukemic T-cell lines. Furthermore, the physical interaction of Tax with p100 leads to the inhibition of Tax-induced activation of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the normally nuclearly expressed Tax protein. In contrast, a mutant of Tax that selectively fails to activate nuclear NF-kappa B expression does not associate with p100. Together, these results suggest that the cytoplasmic interplay of Tax and p100 may play an important role in the initiation and maintenance of HTLV-1 latency observed in adult T-cell leukemia.

Human T-cell leukemia virus type I Tax activation of NF-kappa B/Rel involves phosphorylation and degradation of I kappa B alpha and RelA (p65)-mediated induction of the c-rel gene.

The tax gene product of human T-cell leukemia virus type I (HTLV-I) is a potent transcriptional activator that both stimulates viral gene expression and activates an array of cellular genes involved in T-cell growth. Tax acts indirectly by inducing or modifying the action of various host transcription factors, including members of the NF-kappa B/Rel family of enhancer-binding proteins. In resting T cells, many of these NF-kappa B/Rel factors are sequestered in the cytoplasm by various ankyrin-rich inhibitory proteins, including I kappa B alpha. HTLV-I Tax expression leads to the constitutive nuclear expression of biologically active NF-kappa B and c-Rel complexes; however, the biochemical mechanism(s) underlying this response remains poorly understood. In this study, we demonstrate that Tax-stimulated nuclear expression of NF-kappa B in both HTLV-I-infected and Tax-transfected human T cells is associated with the phosphorylation and rapid proteolytic degradation of I kappa B alpha. In contrast to prior in vitro studies, at least a fraction of the phosphorylated form of I kappa B alpha remains physically associated with the NF-kappa B complex in vivo but is subject to rapid degradation, thereby promoting the nuclear translocation of the active NF-kappa B complex. We further demonstrate that Tax induction of nuclear c-Rel expression is activated by the RelA (p65) subunit of NF-kappa B, which activates transcription of the c-rel gene through an intrinsic kappa B enhancer element. In normal cells, the subsequent accumulation of nuclear c-Rel acts to inhibit its own continued production, indicating the presence of an autoregulatory loop. However, the pathologic action HTLV-I Tax leads to the deregulated and sustained nuclear expression of both NF-kappa B and c-Rel, a response that may contribute to HTLV-I-induced T-cell transformation.

The transcriptionally active factors mediating the effect of the HTLV-I Tax transactivator on the IL-2R alpha kappa B enhancer include the product of the c-rel proto-oncogene.

The transactivator HTLV-I Tax activates the promoter of the gene coding for the interleukin 2 alpha-chain receptor (IL-2R alpha) via a kappa B site that can bind several protein species of the rel family. Tax1 strongly activates the enhancer activity of this motif, in both epithelial HeLa and lymphoid Jurkat cells. This activation was not observed in undifferentiated embryocarcinoma F9 cells. Overexpression of the p50, p65 and Rel proteins in these cells showed that significant activation of the IL-2R alpha kappa B site was observed only with Rel and Rel plus p65. Moreover, whereas both Tax and phorbol 12-myristate 13-acetate (PMA) are able to efficiently induce the binding of NF-kappa B to the IL-2R alpha kappa B site, PMA is functionally inactive. Using the DNA affinity precipitation assay, we observed that Tax1 is able to efficiently induce the binding of Rel, whereas PMA is not. This established a clear difference between both stimuli, indicating that Rel is the functionally active factor. We conclude from these results that the functional activity of members of the rel family is regulated by their interaction with DNA and that Rel can be a potent transcriptional activator on specific kappa B sites.

[Congenital hepatic fibrosis disclosed late by hepatic encephalopathy]. / Fibrose hépatique congénitale tardivement révélée par une encéphalopathie hépatique.

A case of hepatic encephalopathy revealing congenital hepatic fibrosis in a 47-year-old woman is reported. The characteristic features of this observation were: a) the long clinical latency of a congenital disease usually discovered in childhood or in adolescence; b) the existence of hepatocellular insufficiency which appeared without any other reason than an ordinary infection; c) the absence of digestive bleeding or portacaval shunt, factors always found in the rare, previously described cases of encephalopathy in congenital hepatic fibrosis.

[Pharmacokinetics of cimetidine in ascitic cirrhotics]. / Pharmacocinétique de la cimétidine chez le cirrhotique ascitique.

Eleven patients with ascitic cirrhosis and eleven patients without liver disease received 200 mg of cimetidine orally and intravenously. Plasma concentrations of cimetidine were analysed by high pressure liquid chromatography. No differences were observed in cimetidine half-life (2.53 +/- 0.63 and 2.33 +/- 0.40 h) between the two groups. Cimetidine clearance was diminished by about 30 p 100 in cirrhotic patients (0.426 +/- 0.138 vs. 0.649 +/- 0.163 l/h/kg). The apparent volume of distribution was also significantly diminished (1.50 +/- 0.44 vs. 2.14 +/- 0.55 l/kg) in patients with cirrhosis and ascites.

[Evolution of serum gammaglutamyl transpeptidase activity in treated hyperthyroid and hypothyroid patients]. / Evolution de l'activité sérique gammaglutamyl transpeptidase (GGT) au cours des hyperthyroïdies et des hypothyroïdies traitées.

The pattern of gammaglutamyl transpeptidase levels was studied in the sera of 25 subjects with hyperthyroidism and 11 subjects with hypothyroidism, before and after treatment, and in 14 age- and sex-matched control subjects. Gammaglutamyl transpeptidase levels were significantly increased in hyperthyroidism (65 +/- 59 U/l) (p less than 0.01) and significantly decreased under treatment (40 +/- 27 U/l) (p less than 0.001). Before treatment, gammaglutamyl transpeptidase levels correlated with alkaline phosphatase levels and 5'-nucleotidase levels, the correlation persisting after treatment with 5'-nucleotidase. Alkaline phosphatase levels significantly increased under treatment (p less than 0.01). The percentages of gammaglutamyl transpeptidase variation correlated with thyroxine (r = 0.44, p less than 0.03), triiodothyronine (r = 0.47, p less than 0.02) and latent fixation capacity (r = 0.44, p less than 0.03) variations. Subjects with hypothyroidism had significantly decreased gammaglutamyl transpeptidase levels before treatment (18 +/- 9 U/l, p less than 0.01). Alkaline phosphatase levels were significantly decreased before treatment, and significantly increased after treatment. For all subjects with hyperthyroidism of hypothyroidism, the percentages of gammaglutamyl transpeptidase variations correlated with thyroxine (r = 0.48, p less than 0.003) and triiodothyronine (r = 0.39, p less than 0.016) variations. These results suggest that variations in gammaglutamyl transpeptidase levels in hyperthyroidism and hypothyroidism are, at least in part, in relation with variations in thyroid hormone levels.

[Pharmacokinetics of alcohol after 3-hour intravenous infusion with and without cimetidine in 10 healthy non-alcoholic subjects]. / Pharmacocinétique de l'alcool après perfusion intraveineuse de trois heures avec et sans cimétidine chez dix sujets sains non alcooliques.

Ethanol metabolism was studied in ten male non-alcoholic subjects following the constant intravenous infusion of ethanol (1.2 g/kg) administered during three hours with and without cimetidine. Pharmacokinetic analysis was performed on the pseudolinear portion of the elimination curve. The mean peak ethanol concentrations were not significantly different with and without cimetidine. There was no acceleration of ethanol metabolism at high concentrations: the ethanol elimination rate was similar above and under 17 mM, with and without cimetidine. Cimetidine administration had no effect on pharmacokinetic parameters of ethanol (area under the curve, Km and Vm). The fact that the ethanol elimination rate is similar whatever be its concentration and the absence of modifications of the pharmacokinetic parameters by cimetidine are not in favor of an important role of the microsomal ethanol oxidizing system (MEOS) in the ethanol metabolism of nonalcoholic subjects. The data do not allow to examine the role of MEOS in ethanol metabolism after chronic alcohol consumption.

[Changes in circulating lymphocyte subsets in alcoholic hepatopathies. Respective role of alcohol, hepatocellular insufficiency and malnutrition]. / Etude des modifications des sous-populations lymphocytaires circulantes au cours des hépatopathies alcooliques. Rôle respectif de l'alcool, de l'insuffisance hépato-cellulaire et de la dénutrition.

Peripheral lymphocyte subpopulations have been quantified by a direct and indirect, immunofluorescence technique, using monoclonal antibodies, in 22 patients with continued heavy drinking, hepatocellular dysfunction (spider angiomata, ascites, and factor V decrease) (group I), in 16 patients with a history of heavy drinking and abstinence maintained for at least 6 months and hepatocellular dysfunction (group II) and in 28 patients admitted for continued heavy drinking, without hepatocellular dysfunction (group III). Sixteen normal subjects were studied as controls. The total number of lymphocytes and T lymphocytes (OKT3+) were significantly reduced (p less than 0.001) in groups I and II. A significant decrease of B lymphocytes was observed in group II (p less than 0.02). The OKT8+ lymphocytes were significantly reduced in group I (p less than 0.01) and in group II (p less than 0.001); the decrease of the OKT4+ lymphocytes was significant in group II (p less than 0.01) only. The OKT4/OKT8 ratio was higher in group I (p less than 0.05) and group II (p less than 0.01) than in the control group. Normal values of total lymphocytes, B lymphocytes, T lymphocytes subsets and OKT4/OKT8 ratio were observed in group III. In group III, the lymphocyte subpopulations and OKT4/OKT8 ratio were similar in patients with or without abnormalities of liver function tests. In group I and II, no correlation was found between the lymphocyte subpopulations or the OKT4/OKT8 ratio and factor V or nutritional status assessed by anthropometrical and biological tests. T-cell imbalance in alcoholic liver disease does not seem to be related to alcohol consumption, factor V decrease or malnutrition.

[Evaluation of decontamination procedures used at digestive endoscopy units in Gironde]. / Evaluation des procédures de décontamination utilisées dans les centres d'endoscopie digestive de Gironde.

Decontamination procedures used for endoscopes were noted in 23 digestive endoscopy units, public and private, in the department of Gironde and compared to recommended procedures. Serial, bacteriological samples were obtained from one esogastroscope and one colonoscope in each unit, after upper endoscopy and colonoscopy diagnostic procedures at the end of the endoscopy session. Six units of 23 used complete decontamination procedures. In the 17 other units, principal errors of decontamination procedures were: inadequate cleaning of internal channel of scopes (12 units) and lack of utilization of glutaraldehyde between each endoscopy (8 units). Bacteriological samples were negative in 11/12 endoscopes after a complete decontamination procedure and in 8/39 after an inadequate procedure (p less than 0.01). Complete procedures are efficacious but not used often enough. Information and changes in endoscopic practices are necessary in digestive endoscopy units.

LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma.

Human clear cell renal cell carcinoma (CCC) remains resistant to therapies. The transcription factor LIM-class homeobox gene Lim1 is required for normal organogenesis, including nephrogenesis, by regulating cell movements, differentiation and growth. Its expression is controlled partly by the sonic hedgehog-Gli signaling pathway, which we have recently shown to be reactivated in human CCC. So far, no study has assessed whether Lim1 may be associated with tumorigenesis. Using a panel of human CCC cell lines expressing or not the von Hippel-Lindau tumor suppressor gene and 44 tumor/normal tissues pairs, we found that Lim1 is constitutively and exclusively reexpressed in tumors. Through Lim1 silencing or overexpressing, we show that Lim1 is a growth and survival factor in human CCC, at least through the activation of oncogenic pathways including the phosphoinositide kinase-3/Akt and nuclear factor-kappaB pathways. More importantly, in nude mice bearing human CCC tumors, Lim1 silencing abolished tumor growth through the same mechanism as in vitro. In Lim1-depleted cells and tumors, cell movements were substantially impaired because of the inhibition of expression of various proteins involved in metastatic spread, such as paxillin or tenascin-C. These findings establish that the developmental marker Lim1 acts as an oncogene in cancer cells and targeting Lim1 may constitute an innovative therapeutic intervention in human CCC.