Showing papers by "CHU Ambroise Paré published in 2005"

Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria

Abstract: Hereditary coproporphyria (HCP), an autosomal dominant acute hepatic porphyria, results from mutations in the gene that encodes coproporphyrinogen III oxidase (CPO). HCP (heterozygous or rarely homozygous) patients present with an acute neurovisceral crisis, sometimes associated with skin lesions. Four patients (two families) have been reported with a clinically distinct variant form of HCP. In such patients, the presence of a specific mutation (K404E) on both alleles or associated with a null allele, produces a unifying syndrome in which hematological disorders predominate: 'harderoporphyria'. Here, we report the fifth case (from a third family) with harderoporphyria. In addition, we show that harderoporphyric patients exhibit iron overload secondary to dyserythropoiesis. To investigate the molecular basis of this peculiar phenotype, we first studied the secondary structure of the human CPO by a predictive method, the hydrophobic cluster analysis (HCA) which allowed us to focus on a region of the enzyme. We then expressed mutant enzymes for each amino acid of the region of interest, as well as all missense mutations reported so far in HCP patients and evaluated the amount of harderoporphyrin in each mutant. Our results strongly suggest that only a few missense mutations, restricted to five amino acids encoded by exon 6, may accumulate significant amounts of harderoporphyrin: D400-K404. Moreover, all other type of mutations or missense mutations mapped elsewhere throughout the CPO gene, lead to coproporphyrin accumulation and subsequently typical HCP. Our findings, reinforced by recent crystallographic results of yeast CPO, shed new light on the genetic predisposition to HCP. It represents a first monogenic metabolic disorder where clinical expression of overt disease is dependent upon the location and type of mutation, resulting either in acute hepatic or in erythropoietic porphyria.

Reperfusion of complex pulmonary arteriovenous malformations after embolization: report of three cases.

Abstract: The purpose of this report is to discuss the different mechanisms of reperfusion of pulmonary arteriovenous malformations (PAVMs) after embolization. Transcatheter embolotherapy is currently the first-line treatment of PAVMs to prevent neurologic complications or pulmonary hemorrhage. Initial good results can be expected but we report three cases of reperfusion of complex large PAVMs after coil embolization. After adequate embolization, reperfusion of PAVMs may occur by several mechanisms including recanalization of embolized arteries, recruitment of normal arterial branches, growth or enlargement and development of a systemic arterial supply.

Changes in crossbridge mechanical properties in diabetic rat cardiomyopathy.

Abstract: Diabetes mellitus is associated with an increased risk of heart failure, resulting from a specific cardiomyopathy independent of coronary atherosclerosis. It is not yet established whether altered myocardial function is related to changes in molecular mechanics of myosin. Accordingly, we investigated the total number, single force and kinetics of myosin crossbridges (CB) in a rat model of streptozotocin-induced diabetic cardiomyopathy. Experiments were conducted on left ventricular papillary muscles from male diabetic (D) Wistar (n = 16) and age-matched control (C) rats (n = 15). Mechanical indices including the maximum unloaded shortening velocity V(max) and the maximum total isometric tension normalized per cross-sectional area TF(max) were determined. Using A. F. Huxley's equations, we calculated the total cycling CB number per mm(2) Psi, the elementary force per single CB Pi, the maximum values of the rate constant for CB attachment f(1) and detachment g(1) and g(2), and the turnover rate of myosin ATPase per site k(cat). The D rats exhibited a 25% decrease in TF(max) and a 34% decrease in V(max) as compared to C. This contractile dysfunction was associated with a significant reduction in Psi (9.0 +/- 1.6 in D versus 11.4 +/- 1.9 10(9)mm(-2) in C, P < 0.001) without significant change in Pi (6.1 +/- 0.8 in D versus 6.3 +/- 0.9 pN in C, NS). In the 2 groups, TF(max) correlated positively with Psi (r = 0.76, P < 0.001 and r = 0.64, P < 0.01, in D and C respectively) but no relationship was found between TF(max) and Pi. As compared to C, D showed lower values of f(1), g(1) and g(2), and a slower turnover rate of myosin ATPase. Thus, present data suggested that the cardiac contractile impairment observed in streptozotocin-induced diabetic rat cardiomyopathy was mainly related to a decrease in active CB total number and CB kinetics alterations without significant change in CB single force.