TaqIB polymorphism in cholesterol ester transfer protein (CETP) gene predicts future cardiovascular death in patients experiencing an acute coronary syndrome

Background: Cholesterol ester transfer protein (CETP) plays a pivotal role in the remodelling of triglyceride (TG)-rich and high-density lipoprotein (HDL) particles. Sequence variations in the CETP gene may interfere with coronary atherosclerosis. However, clinical studies of various CETP polymorphisms have shown controversial data in coronary artery outcome. We aimed to investigate whether TaqIB CETP gene polymorphism could predict clinical outcome in a prospective cohort of patients hospitalized for an acute coronary syndrome (ACS). Methods: Two hundred and seventy consecutive Caucasian patients hospitalized for an ACS, and having a significant coronary artery disease in at least one major vessel (stenosis >50%), were prospectively enrolled and followed for 57 months. The mean age was 65.1±12.5 years, and 77% were males. One hundred and thirty-nine patients (51.5%) suffered from unstable angina at inclusion and 131 patients (48.5%) presented with an acute myocardial infarction (MI). The follow-up data were obtained from questionnaires. The major recurrent events recorded were 32 deaths comprising 28 cardiovascular deaths and 49 combined cardiovascular events (28 cardiovascular deaths, 19 non-fatal ACS and 2 non-fatal strokes). CETP genotyping was performed using a restriction fragment length polymorphism based method. Results: A significant relation was found between B2B2 genotype and combined cardiovascular end-point (p<0.02), mainly driven by a link with cardiovascular death (p<0.05). The hazard risk ratio for cardiovascular death associated with B2B2 genotype was 2.2 [95% confidence interval (CI): 1.01–4.94, p<0.05]. In multivariate analyses, no modification except for a significant interaction with statin therapy was observed by inclusion of potential confounders for the association of B2B2 genotype with cardiovascular death. Conclusions: These results suggest that patients homozygous for the B2 allele and not taking statin had a strong increase of recurrent cardiovascular event after an initial acute coronary event. This cardiovascular risk seems to be corrected with statin therapy. Clin Chem Lab Med 2009;47:1039–46.Peer Reviewe

Site-Specific Reduction of Oxidative and Lipid Metabolism in Adipose Tissue of 3′-Azido-3′-Deoxythymidine-Treated Rats

Although it is well accepted that treatment with some nucleoside reverse transcriptase inhibitors modifies both fat metabolism and fat distribution in humans, the mechanisms underlying these modifications are not yet known. The present investigation examined whether a decrease in oxidative capacity, induced by a chronic oral administration of 3′-azido-3′-deoxythymidine (AZT) in rats, could be associated with an alteration of the lipogenic capacity of white adipose tissues. The impact of obesity as a factor was then evaluated. Results showed that AZT treatment induced differential effects depending on anatomical localization. Indeed, in the inguinal adipose tissue, the specific activities of cytochrome c oxidase and fatty acid synthase, two rate-controlling enzymes in energy and lipogenic metabolisms, respectively, both decreased under AZT treatment, thus leading to a lowered cell lipid accumulation. Moreover, the AMP-activated protein kinase phosphorylation level tended to increase, thus implying that AZT causes an energy imbalance. Furthermore, the inguinal tissue of obese rats presented a sensitivity to AZT treatment that was higher than that of lean rats. In contrast, for epididymal tissue, no significant change in all these parameters could be detected under AZT treatment, regardless of the nutritional status of the animals. Taken together, these data demonstrate differential effects of AZT on subcutaneous adipose tissue and visceral white adipose tissue. It could be considered that the chronic decreases in energy and lipogenic metabolism of inguinal adipocyte, consecutive to AZT treatment, may lead, in the long term, to adipose tissue atrophy

Endogenous Sonic Hedgehog limits inflammation and angiogenesis in the ischaemic skeletal muscle of mice

Aims: Hedgehog (Hh) signalling has been shown to be re-activated in ischaemic tissues and participate in ischaemia-induced angiogenesis. Sonic Hedgehog (Shh) is upregulated by more than 80-fold in the ischaemic skeletal muscle, however its specific role in ischaemia-induced angiogenesis has not yet been fully investigated. The purpose of the present study was to investigate the role of endogenous Shh in ischaemia-induced angiogenesis. Methods and results: To this aim, we used inducible Shh knock-out (KO) mice and unexpectedly found that capillary density was significantly increased in re-generating muscle of Shh deficient mice 5 days after hind limb ischaemia was induced, demonstrating that endogenous Shh does not promote angiogenesis but more likely limits it. Myosin and MyoD expression were equivalent in Shh deficient mice and control mice, indicating that endogenous Shh is not required for ischaemia-induced myogenesis. Additionally, we observed a significant increase in macrophage infiltration in the ischaemic muscle of Shh deficient mice. Our data indicate that this was due to an increase in chemokine expression by myoblasts in the setting of impaired Hh signalling, using tissue specific Smoothened conditional KO mice. The increased macrophage infiltration in mice deficient for Hh signalling in myocytes was associated with increased VEGFA expression and a transiently increased angiogenesis, demonstrating that Shh limits inflammation and angiogenesis indirectly by signalling to myocytes. Conclusion: Although ectopic administration of Shh has previously been shown to promote ischaemia-induced angiogenesis, the present study reveals that endogenous Shh does not promote ischaemia-induced angiogenesis. On the contrary, the absence of Shh leads to aberrant ischaemic tissue inflammation and a transiently increased angiogenesis

Novel KHDRBS1-NTRK3 Rearrangement in a Congenital Pediatric CD34-Positive Skin Tumor: A Case Report

International audienceCutaneous spindle-cell neoplasms in adults as well as children represent a frequent dilemma for pathologists. Along this neoplasm spectrum, the differential diagnosis with CD34-positive proliferations can be challenging, particularly concerning neoplasms of fibrohistiocytic and fibroblastic lineages. In children, cutaneous and superficial soft-tissue neoplasms with CD34-positive spindle cells are associated with benign to intermediate malignancy potential and include lipofibromatosis, plaque-like CD34-positive dermal fibroma, fibroblastic connective tissue nevus, and congenital dermatofibrosarcoma protuberans. Molecular biology has been valuable in showing dermatofibrosarcoma protuberans and infantile fibrosarcoma that are characterized by COL1A1-PDGFB and ETV6-NTRK3 rearrangements respectively. We report a case of congenital CD34-positive dermohypodermal spindle-cell neoplasm occurring in a female infant and harboring a novel KHDRBS1-NTRK3 fusion. This tumor could belong to a new subgroup of pediatric cutaneous spindle-cell neoplasms, be an atypical presentation of a plaque-like CD34-positive dermal fibroma, of a fibroblastic connective tissue nevus, or represent a dermatofibrosarcoma protuberans with an alternative gene rearrangement