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Articles by Gordon A. Francis
Total Records ( 2 ) for Gordon A. Francis
  D. Meeike Kusters , Barbarba A. Hutten , Brian W. McCrindle , David Cassiman , Gordon A. Francis , Claude Gagne , Daniel Gaudet , Katherine M. Morrison , Gisle Langslet , John J. Kastelein and Albert Wiegman
 

Background

Statin therapy is recommended for children with familial hypercholesterolemia (FH), but most children do not reach treatment targets.

Objective

Here we present the design and results at baseline of the ongoing CHARON study, to evaluate the safety and efficacy of rosuvastatin.

Methods

This study comprises an international 2-year open label, titration-to-goal study in 198 children with heterozygous FH aged 6 to 18 years, with rosuvastatin in a maximum dose of 10 mg (<10 years of age) or 20 mg (older children). In addition, 64 unaffected siblings were enrolled as controls. The primary efficacy outcome is the change from baseline in low-density lipoprotein cholesterol, and the secondary outcome is the change in carotid intima-media thickness (c-IMT) in patients with FH compared with their siblings. The primary safety outcomes are growth and sexual maturation; secondary outcomes are the change in other lipoprotein levels and the incidence of adverse events, discontinuation rates, and abnormal laboratory values.

Results

At baseline, mean age of patients with FH was 12.1 ± 3.3 years, 44% were boys, and mean low-density lipoprotein cholesterol levels were 6.1 ± 1.3 mmol/L (235.9 ± 48.7 mg/dL). Mean c-IMT was 0.399 mm (95% CI, 0.392-0.406 mm) in children with FH versus 0.377 (95% CI, 0.366-0.388 mm) in unaffected siblings (P = .001).

Conclusions

At baseline, as expected according to on previous observations, children with FH proved to have a greater c-IMT than their healthy siblings. These differences had already occurred at a very young age, which emphasizes the importance of considering early statin initiation in this high-risk population.

  Julie C. Robichaud , Gordon A. Francis and Dennis E. Vance
  Phosphatidylethanolamine N-methyltransferase (PEMT) is a liver-specific enzyme that converts phosphatidylethanolamine to phosphatidylcholine (PC). Mice that lack PEMT have reduced plasma levels of PC and cholesterol in high density lipoproteins (HDL). We have investigated the mechanism responsible for this reduction with experiments designed to distinguish between a decreased formation of HDL particles by hepatocytes or an increased hepatic uptake of HDL lipids. Therefore, we analyzed lipid efflux to apoA-I and HDL lipid uptake using primary cultured hepatocytes isolated from Pemt+/+ and Pemt–/– mice. Hepatic levels of the ATP-binding cassette transporter A1 are not significantly different between Pemt genotypes. Moreover, hepatocytes isolated from Pemt–/– mice released cholesterol and PC into the medium as efficiently as did hepatocytes from Pemt+/+ mice. Immunoblotting of liver homogenates showed a 1.5-fold increase in the amount of the scavenger receptor, class B, type 1 (SR-BI) in Pemt–/– compared with Pemt+/+ livers. In addition, there was a 1.5-fold increase in the SR-BI-interacting protein PDZK1. Lipid uptake experiments using radiolabeled HDL particles revealed a greater uptake of [3H]cholesteryl ethers and [3H]PC by hepatocytes derived from Pemt–/– compared with Pemt+/+ mice. Furthermore, we observed an increased association of [3H]cholesteryl ethers in livers of Pemt–/– compared with Pemt+/+ mice after tail vein injection of [3H]HDL. These results strongly suggest that PEMT is involved in the regulation of plasma HDL levels in mice, mainly via HDL lipid uptake by SR-BI.
 
 
 
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