Correlation between genotype,metabolic data,and clinical presentation in carnitine palmitoyltransferase 2 (CPT2) deficiency

Carnitine palmitoyltransferase 2 (CPT2) deficiency, the most common inherited disease of the mitochondrial long-chain fatty acid (LCFA) oxidation, may result in distinct clinical phenotypes, namely a mild adult muscular form and a severe hepatocardiomuscular disease with an onset in the neonatal period or in infancy. In order to understand the mechanisms underlying the difference in severity between these phenotypes, we analyzed a cohort of 20 CPT2-deficient patients being affected either with the infantile (seven patients) or the adult onset form of the disease (13 patients). Using a combination of direct sequencing and denaturing gradient gel electrophoresis, 13 CPT2 mutations were identified, including five novel ones, namely: 371G>A (R124Q), 437A>C (N146T), 481C>T (R161W), 983A>G (D328G), and 1823G>C (D608H). After updating the spectrum of CPT2 mutations (n=39) and genotypes (n=38) as well as their consequences on CPT2 activity and LCFA oxidation, it appears that both the type and location of CPT2 mutations and one or several additional genetic factors to be identified would modulate the LCFA flux and therefore the severity of the disease.     

Lipid peroxidation and free radicals. Role in cellular biology and pathology

Membrane phospholipids attack by oxygen free radicals, i.e. lipidoperoxidation, occurs in normal cellular life. This free radicals attack is controlled by a protective system, both enzymatic (superoxide dismutase, catalase, glutahione peroxidase) and non enzymatic (vitamine E). Imbalance between attack and defense can explain many pathological events. In these events, the oxidation products of unsaturated fatty acids are of fundamental importance, in particular those derived from arachidonic acid (prostaglandins, prostacyclins, thromboxanes and leukotrienes).     

Maladies surrénaliennes infracliniques : cas du phéochromocytome silencieux et de la maladie d’Addison infra-clinique

The silent pheochromocytoma, a hidden form of pheochromocytoma, exposes the patient to an increased risk of mortality if the diagnosis is not etablished on time. Biological diagnosis of pheochromocytoma can be difficult. Catecholamine secretion is dependent on tumor size and a large number of physiological, pharmacological, lifestyle modifications and sampling conditions influence the measurement of urinary and plasma metanephrines. The prevalence of pheochromocytoma is 2% among adrenal incidentaloma smaller than 3 cm (2/3 of tumors). Recent studies suggest the almost zero risk of pheochromocytoma among these tumors if they are hypodense (<10 housfield units) on adrenal tomography. Addison's disease is a pathology affecting about 1 in 8000. Immunopathology is still unknown, but some elements advocated the hypothesis of a predominant cell-mediated immunity in particular Interferon-gamma production by CD4 T lymphocytes in the presence of an epitope from the 21-hydroxylase, as well as IgG1 subtype produced by activated B lymphocytes, autoantibodies do appear to be a simple marker of the disease. Subclinical Addison's disease is defined by the presence of anti-21-hydroxylase autoantibodies, without clinical symptoms. It evolves faster to the clinical phase in young subjects, male, having high levels of autoantibodies and with an initially impaired adrenal function. Dosage of ACTH, plasma renin active, and basal cortisol and after Synacthen allow to discriminate the subjects with low or high risk of evolution and establish an appropriate monitoring.     

Endocarditis due to Coxiella burnetti despite the absence of obvious exposure

Q?fever is an ubiquitous zoonotic disease caused by Coxiella burnetti, an intracellular Gram negative bacteria. It may present as an acute or a chronic disease course. Endocarditis due to Coxiella burnetti represents 1 to 5% of all infectious endocarditis. We report a 41-year-old man without obvious exposure history, who presented with a Q fever endocarditis.     

Troglitazone inhibits cyclin D1 expression and cell cycling independently of PPARgamma in normal mouse skin keratinocytes

Troglitazone is one of the thiazolidinedione (TZD) class of anti-diabetic drugs and a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma). Troglitazone and other PPARgamma ligands have been shown to inhibit cell proliferation and induce cell cycle arrest in a variety of cancer cells, and have been considered as potential tumor preventive and tumor therapeutic agents. Little is known, however, about how normal or initiated cells respond to these agents during mouse skin carcinogenesis. We report here that troglitazone and another TZD, ciglitazone, dramatically inhibited mitogen-induced cellular proliferation in normal mouse skin primary keratinocytes and in the C50 keratinocyte cell line. This was accompanied by induction of cell cycle G1 phase arrest and suppression of cyclin D1, cdk4, and cdk2 expression. Troglitazone suppressed cyclin D1 expression at multiple levels. In addition, we demonstrated that PPARgamma was not expressed at functional levels in cultured mouse skin keratinocytes, and that the inhibitory effects of troglitazone on cellular proliferation and cyclin D1 expression in these cells were PPARgamma-independent. Given the important role of keratinocyte proliferation in skin carcinogenesis, our data suggest that TZD may be useful tumor preventive agents in skin.