Myogenic Disease and Metabolic Acidosis: Consider Multiple Acyl-Coenzyme A Dehydrogenase Deficiency.

BACKGROUND: Multiple acyl-coA dehydrogenase deficiency (MADD) is a rare, inherited, autosomal-recessive disorder leading to the accumulation of acylcarnitine of all chain lengths. Acute decompensation with cardiac, respiratory or hepatic failure and metabolic abnormalities may be life-threatening. CASE PRESENTATION: A 29-year-old woman presented with severe lactic acidosis associated with intense myalgia and muscle weakness. The clinical examination revealed symmetric upper and lower limb motor impairment (rated at 2 or 3 out of 5 on the Medical Research Council scale) and clear amyotrophy. Laboratory tests had revealed severe rhabdomyolysis, with a serum creatine phosphokinase level of 8,700 IU/L and asymptomatic hypoglycemia in the absence of ketosis. Electromyography revealed myotonic bursts in all four limbs. The absence of myositis-specific autoantibodies ruled out a diagnosis of autoimmune myositis. Finally, Acylcarnitine profile and gas chromatography-mass spectrometry analysis of organic acids led to the diagnosis of MADD. A treatment based on the intravenous infusion of glucose solutes, administration of riboflavin, and supplementation with coenzyme Q10 and carnitine was effective. Lipid consumption was strictly prohibited in the early stages of treatment. The clinical and biochemical parameters rapidly improved and we noticed a complete disappearance of the motor deficit, without sequelae. CONCLUSION: A diagnosis of MADD must be considered whenever acute or chronic muscle involvement is associated with metabolic disorders. Acute heart, respiratory or hepatic failure and metabolic abnormalities caused by MADD may be life-threatening, and will require intensive care.

Effects of smoking status and MADRS retardation factor on response to low frequency repetitive transcranial magnetic stimulation for depression.

BACKGROUND: Despite growing evidence supporting the clinical interest of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD), little is known regarding the effects of clinical and sociodemographic factors on the clinical outcome in patients. METHODS: We retrospectively investigated the effects of clinical (using the 3-factor model of the Montgomery-Åsberg depression rating scale [MADRS] encompassing dysphoria, retardation and vegetative symptoms) and sociodemographic characteristics of participants on clinical outcome in a sample of 54 TRD patients receiving low frequency rTMS (1Hz, 360 pulses) applied over the right dorsolateral prefrontal cortex combined with sham venlafaxine. RESULTS: Responders (n=29) displayed lower retardation baseline scores (13.6±2.9) than non-responders (15.6±2.9; n=25; P=0.02). We also observed a significant difference between the numbers of ex-smokers in responders and non-responders groups; all ex-smokers (n=8) were responders to rTMS (P=0.005). CONCLUSION: Low MADRS retardation factor and ex-smoker status is highly prevalent in responders to low frequency rTMS. Further studies are needed to investigate the predictive value of these factors.

SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme.

Oxygen and nutrient limitation are common features of the tumor microenvironment and are associated with cancer progression and induction of metastasis. The inefficient vascularization of tumor tissue also limits the penetration of other serum-derived factors, such as lipids and lipoproteins, which can be rate limiting for cell proliferation and survival. Here we have investigated the effect of hypoxia and serum deprivation on sterol regulatory element-binding protein (SREBP) activity and the expression of lipid metabolism genes in human glioblastoma multiforme (GBM) cancer cells. We found that SREBP transcriptional activity was induced by serum depletion both in normoxic and hypoxic cells and that activation of SREBP was required to maintain the expression of fatty acid and cholesterol metabolism genes under hypoxic conditions. Moreover, expression of stearoyl-CoA desaturase, the enzyme required for the generation of mono-unsaturated fatty acids, and fatty acid-binding protein 7, a regulator of glioma stem cell function, was strongly dependent on SREBP function. Inhibition of SREBP function blocked lipid biosynthesis in hypoxic cancer cells and impaired cell survival under hypoxia and in a three-dimensional spheroid model. Finally, gene expression analysis revealed that SREBP defines a gene signature that is associated with poor survival in glioblastoma.

Evaluation of the Faraday angle by numerical methods and comparison with the Tore Supra and JET polarimeter electronics.

On the Tore Supra tokamak, a far infrared polarimeter diagnostic has been routinely used for diagnosing the current density by measuring the Faraday rotation angle. A high precision of measurement is needed to correctly reconstruct the current profile. To reach this precision, electronics used to compute the phase and the amplitude of the detected signals must have a good resilience to the noise in the measurement. In this article, the analogue card's response to the noise coming from the detectors and their impact on the Faraday angle measurements are analyzed, and we present numerical methods to calculate the phase and the amplitude. These validations have been done using real signals acquired by Tore Supra and JET experiments. These methods have been developed to be used in real-time in the future numerical cards that will replace the Tore Supra present analogue ones.

Comparative evaluation of hepatitis C virus RNA quantitation by branched DNA, NASBA, and monitor assays.

Several studies have shown a relationship between pretreatment hepatitis C virus (HCV) viral load and the response to interferon (IFN) therapy, creating a need for quantitative HCV-RNA assays. Here, we compared three commercial methods: nucleic acid sequence-based amplification NASBA (Organon), branched DNA 2.0 (bDNA) (Chiron), and Monitor (Roche), with reverse-transcription polymerase chain reaction (RT-PCR) as the reference. We assessed sensitivity and reproducibility on a well-characterized panel of sera (EUROHEP), a Chimp Rodney plasma pool, and samples from IFN-treated and -untreated patients with chronic hepatitis C caused by different HCV genotypes. The reproducibility of the NASBA and bDNA methods was slightly better than that of Monitor, especially for genotypes 2 and 4. NASBA had the highest sensitivity (99% vs. 94% and 88% with Monitor and bDNA, respectively), especially for the follow-up of patients on IFN. NASBA gave the highest HCV-RNA concentrations, which were approximately 10-fold more than with the bDNA assay and 100-fold more than with the Monitor kit. The linearity, tested on the chimp Rodney plasma pool, was better with bDNA for high viral load than with NASBA and Monitor, although for low concentration of HCV RNA, bDNA was negative. Pretreatment viral load was lower in patients who had a sustained virological response to IFN, although the bDNA method was not sensitive enough to quantify all pretreatment samples. This study indicates that gene amplification methods (NASBA or Monitor) have better sensitivity than bDNA assays for quantification of HCV RNA in patients with chronic HCV infection, although the bDNA and NASBA methods are more likely to quantify all genotypes. Prospective studies are needed to demonstrate the usefulness of quantitative assays for the follow-up of patients with chronic hepatitis C.

Flow cytometric study of DNA distribution in cytopunctures of benign and malignant breast lesions.

One hundred seventy-eight cytopunctures of mammary lesions were obtained for cytologic diagnosis and flow cytometric (FCM) analysis of the nuclear DNA content. All lesions were excised and evaluated histologically; 106 were carcinomas and 72 were benign lesions. The benign lesions showed a diploid DNA content, with one exception. Among the 106 carcinomas, 35 (33%) were diploid, 14 (13%) were tetraploid and 57 (54%) were aneuploid. For 79 carcinomas, the relationship between ploidy and (1) "T" and "N" of TNM staging, (2) the histologic grading of Scarff, Bloom and Richardson, (3) axillary nodal involvement, (4) the presence of estrogen and progesterone receptors, (5) age and (6) menopausal status was investigated. The percentage of aneuploidy was significantly higher (P less than .05) in grade III tumors as compared to grade I tumors. There was no significant relationship between aneuploidy and the other factors. However, a trend was observed between the lack of steroid receptors and a high probability of the tumor being aneuploid. FCM DNA analysis was also carried out on breast carcinomas obtained at surgery in 40 patients for whom FCM DNA analysis had previously been performed on breast cytopuncture specimens. The FCM DNA analyses were found to be best performed on the samples obtained by cytopuncture, which may increase the yield of tumor cells.

Tissue glycolytic enzymes in primary breast cancer patients receiving adjuvant chemotherapy.

Primary breast cancers from 85 patients undergoing post-surgical adjuvant chemotherapy were analyzed for five glycolytic enzymes: lactate dehydrogenase (LDH); phosphohexose isomerase (PHI); glucose-6-phosphate dehydrogenase (G-6PD); pyruvate-kinase (PK); and 6-phospho-gluconate dehydrogenase (6-PGD). The purpose of this study was to determine whether biochemical parameters could offer a prognostic index to determine outcome of therapy. The patients were followed up to a maximum of 54 months; during this period 30 of them developed recurrent or metastatic disease. The enzyme activities were expressed by the three following reference parameters: units/g proteins, units/g tissue weight and units/mg DNA. Two methods of analysis were compared: firstly, univariate analysis using life tables; and secondly, multivariate analysis using the Cox's model, where enzyme levels were tested for each mode of expression in addition to node status, histological features, receptor and menopausal status. Life table analyses appear limited when subsets of patients were studied because the sample size tends to become too small to warrant firm conclusions. Using the Cox's model, a prognostic index 1 was proposed, including the number of involved nodes and the product of logarithms of G-6PD and 6-PGD expressed as units/mg DNA. Compared to the number of involved nodes, this index gives a slightly better discrimination of the patients at 2 yr after mastectomy.

Glycolytic enzymes in human breast carcinoma cytosols: the influence of commonly used reference parameters.

The activities of selected glycolytic enzymes in breast tumor tissues were examined based on earlier studies showing a relationship between therapy and/or prognosis of breast cancer and tissue enzyme. In the present study, five glycolytic enzymatic activities (pyruvate kinase [PK], glucose-6-phosphate dehydrogenase [G6PD], phosphohexose-isomerase [PHI], lactate dehydrogenase [LDH], and 6-phospho-glucocate dehydrogenase [6PGD]) were measured in the cytosol (105,000 g) of 57 breast carcinomas and 22 benign breast lesions. Nucleic acids and DNA were also determined. The results were related to the wet weight of the tissue, to total and tissue cytosol proteins, and to DNA. The various means of expressing the results were compared. The correlations were satisfactory except for PHI and LDH. In these cases, this might have been due to blood contamination. The enzyme activities content was lower in the benign breast lesions than in the breast carcinomas irrespective of the way the results were expressed.