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Objectives: We report the first survey on French physicians and patients participating to assess motivations prior enrolment and benefits and constraints perceived after participation., Method: Twenty physicians were interviewed and 37 patients completed a questionnaire during clinical study participation., Results: If the main patient's motivation is altruistic, physician wish their own patient feel better. After participation, patient is satisfied with being part of a research effort and contributing to medical science. Effect of trial treatment on physical well-being seems less pronounced. Main constraint is the randomisation to placebo group. For physicians, the main benefit is getting research experience and training. Main constraints are logistical. Otherwise, perceptions on the same clinical trial depend on participant. In fact, physician usually overestimates constraints of clinical trial for patient., Conclusion: The knowledge of patients and physicians perceptions of clinical trials and its taking into account should probably reduce difficulties in the recruitment in France.

Unlabelled: OBJECTIVE - METHOD: The purpose of this review is to explore the expectations of patients and physicians prior to participate to a clinical trial and their positive or negative experiences after participating. A systematic review of Medline database from 1966 to 2005 identified 79 papers reported patients and physicians perceptions of clinical trials (only 3 in French), whom 27 English surveys conducted on patients and physicians., Results: If primary patients' motivation for enrolment was altruistic, physicians wish to help their patient. After enrolment, the most perceived positive benefit for patients and physicians are, respectively, the emotional improvement and the greater opportunity for personal benefit offered to enrolled patients. Most physicians' negative experience included logistical difficulties while patients are unease with randomisation and often uncomfortable with medical procedures. Unlike patients, all physicians' expectations seem to be fulfilled., Conclusion: The knowledge of patients' and physicians' perception of participation may improve recruitment in clinical trials.

The plasma lipolysis of triglyceride (TG)-rich lipoproteins is mainly due to the activity of lipoprotein lipase (LPL). Albeit important for our analysis of certain physiopathological situations, the determination of the magnitude of LPL-dependent lipolysis is not easy to perform. This essentially results from the binding of LPL to the luminal surface of vascular endothelium. The measurements of the whole putative LPL activity have been achieved after injection of heparin, a procedure that releases LPL from endothelium. However, the physiopathological relevance of this postheparin lipolysis assay (PHLA) remains questionable because it has never been demonstrated that the bulk of endothelium-bound LPL was active. It has been recently shown that a small part of LPL is associated to circulating lipoproteins in nonheparinized plasma, raising the possibility that the lipolysis mediated by this circulating LPL might reflect the overall LPL-dependent TG hydrolysis in plasma. To address this question, we developed a new lipolysis assay in which the very low density lipoprotein (VLDL)-bound LPL-dependent VLDL-TG hydrolysis (LVTH) was directly determined through the measurement of nonesterified fatty acid (NEFA) release during in vitro incubations. LVTH measurements were performed in control subjects, in type 2 diabetics, and in either heterozygous or homozygous LPL-deficient patients. In the latter group, LVTH values were extremely low. Those of heterozygous patients and of diabetics were similarly decreased by about 40% with respect to control group. Plasma TG concentrations exhibited an inverse relationship with LVTH level. In a subgroup of subjects, LVTH and PHLA were positively correlated and the inverse correlation of LVTH with plasma or VLDL-TG concentration was stronger than that obtained with PHLA. To further study the validity of this new assay, we measured LVTH in nine subjects who were studied for their catabolism of VLDL labeled with stable isotope. No relation was observed between the direct hepatic removal of VLDL and LVTH, whereas the latter was strikingly correlated with the rate of conversion of VLDL to intermediary density lipoprotein. Collective consideration of these findings strongly suggests that LVTH is a physiologically relevant index which could advantageously replace the measurements of PHLA in numerous physiopathological situations.

Severe obesity exposes one to an increased risk of cardiovascular mortality. Gastroplasty has been shown to induce substantial weight loss and to improve the atherogenic profile of severely obese subjects. However, vitamin deficiencies after gastroplasty have been reported. Because hyperhomocysteinemia, an independent risk factor for cardiovascular disease, is influenced by nutritional status (and especially by folate intake), we hypothesized that a marginal folate deficiency induced by gastroplasty could promote hyperhomocysteinemia. Thus, plasma homocysteine concentrations were measured by high-performance liquid chromatography in 53 severely obese patients (body mass index = 42 +/- 1), before and 1 yr after vertical gastroplasty. Plasma homocysteine concentrations increased, on an average, from 9.9 +/- 0.4 to 12.8 +/- 0.6 micromol/L (P < 0.0001). This increase in homocysteine levels was observed in two thirds of the subjects, leading to clear-cut hyperhomocysteinemia (>15 micromol/L) in 32%. The changes in homocysteine concentrations were correlated to weight loss (P < 0.001) and to decrease in plasma folate concentrations (P < 0.01). Whereas gastroplasty induced a mean 32-kg weight loss and a striking improvement in conventional risk factors, the occurrence of iatrogenic hyperhomocysteinemia might hamper the benefit of surgery on cardiovascular risk in most of the patients. Our results further support use of a systematic efficient folate supplementation after gastroplasty.

Only a few cases of type I hyperlipidemia occurring in patients with autoimmune disease have been reported. We describe the case of a 35-yr-old woman suffering from severe type I hyperchylomicronemia. A combination of various hypolipidemic treatments, including strict hypolipidemic dietary therapy and administration of fibrates or n-3 fatty acids, was inefficient. Because of a history of familial autoimmunity, we introduced an immunosuppressive therapy that resulted in consistent long term and stable remission. Two attempts to reduce the immunosuppressor dose resulted in major relapses. To explain the defect of chylomicron hydrolysis, we investigated the postheparin plasma lipase activities. Hepatic triglyceride lipase activity was normal, whereas that of lipoprotein lipase (LPL) was reduced to about 30% of normal. Immunosuppressive therapy resulted in a complete and durable normalization of LPL activity. Using Western blot analysis, we found in the plasma of the patient a circulating IgG specifically directed against LPL, which became undetectable during immunosuppressive therapy. Western blot analysis revealed that the whole circulating anti-LPL autoantibody was bound to chylomicrons. Proteins extracted from patient's chylomicrons were able to induce a dose-related inhibition of LPL activity in vitro, whereas that of hepatic triglyceride lipase remained unchanged. These data constitute the first description of autoimmune hyperchylomicronemia due to an exclusive defect of LPL activity, and they show that a complete remission has been obtained after immunosuppressive therapy. Finally, our finding that the anti-LPL autoantibody is bound to chylomicrons emphasizes their previously unrecognized ability to transport LPL, already described for other lipoprotein fractions.

The aim of our work was to determine whether fatty acid modifications in smooth muscle cell phospholipids affect cholesterol efflux and desorption. [3H]Cholesterol was used to label cholesterol pools in the whole cell or selectively in the plasma membrane. Cells were incubated for 12 h in order to increase oleate, linoleate, arachidonate, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in phospholipids. Cholesterol efflux was monitored using native or tetranitromethane modified high-density lipoprotein3 (HDL3). When all cholesterol pools were labeled, the efflux from cells treated with different fatty acids were not different. Plasma membrane cholesterol efflux remained unchanged after oleate, linoleate or arachidonate treatments, but was markedly increased after EPA and DHA enrichment, both with native HDL3 and with tetranitromethane-high-density lipoprotein. These results suggest that the positive effects of n-3 fatty acid consumption on the atherosclerotic process could be linked in part to an increase in plasma membrane cholesterol efflux from vascular smooth muscle cells.

One of the key features of atherosclerosis formation and progression is 'dedifferentiation' of contractile arterial smooth muscle cells (SMC) in synthetic cells. In primary cultures and subcultures before 10 and after 200 passages, SMC exhibit contractile-like, synthetic and transformed phenotypes, respectively, providing a good model for studying dedifferentiation process in vitro: the rationale for comparing these phenotypes of SMC in vivo rests in similar changes in cytoenzymatic and cytoskeletal features. In vivo, dedifferentiated SMC are transformed into foam cells by accumulating lipids. Thus, the aim of this study was to determine whether cholesterol metabolism undergoes changes in dedifferentiated cells and the three cultured phenotypes were compared in regard to their cholesterol efflux mechanisms. Phenotypic changes were shown to be associated with decrease in intracellular cholesterol apoprotein mediated efflux and translocation but also with decrease in high affinity binding sites for native HDL. Thus, the dedifferentiation process triggers a need for increased supply of cholesterol for membrane synthesis and efflux down-regulation mechanisms are aimed at maximizing cholesterol availability to the cell. Plasma membrane cholesterol efflux, which seems to be apoprotein-independent, decrease slightly with cell dedifferentiation suggesting either modifications in the dedifferentiated cell membranes physical properties. Taken together, these different results showed that dedifferentiation of arterial SMC is associated with decrease in the different steps of the efflux process, which could constitute one of the early events in their foam cell transformation.

An overproduction of VLDL by the liver and a slower clearance of these lipoproteins are usually seen in diabetic patients. There is correlation between insulin resistance and plasma triglyceride concentration. Triglyceride may influence an early step in the insulin action pathway and alternatively, insulin resistance may cause hypertriglyceridemia. Hyperinsulinemia and/or hypertriglyceridemia may play a strong role in the cardiovascular risk of patients with type II diabetes. There is an important need to conduct trials to define therapy that can reduce the risk of cardiovascular complications.

The non enzymatic glucosylation (NEG) of proteins is a complex chemical reaction resulting in the formation of a stable bond between a glucose molecule and a protein aminogroup. In diabetics, hyperglycaemia may induce a large increase of NEG. Although the NEG of apolipoproteins remains moderate because of their short half-life, it may alter some of their properties. The NEG of LDL apo B induces a decrease of their catabolism due to a lowering of their binding to the LDL receptor. Glucosylated LDL can accumulate in macrophages, thereby facilitating the development of foam cells. The LDL NEG may also cause other processes including apo B oxidation and production of anti-LDL antibodies. The HDL NEG which essentially corresponds to that of apo A-I, induces a shortening of their half-life. In vitro, the NEG of apo A-I results in a decrease of its interaction with HDL surface. Finally, the binding of glucosylated HDL3 to HDL receptors is decreased in cultured fibroblasts. Since the level of lipoprotein NEG in vivo is moderate, the question as to whether this process may affect quantitatively the metabolic behaviour of lipoproteins and participate to the development of atheroma in diabetic patients, has not been clearly answered.

The association B blocking agent-lithium salt is used for the therapy of some severe hyperthyroidism with cardiotoxicosis. Separately, both drugs depress intracardiac conduction. However by recording the potentials of the His bundle in anesthetized dogs, a potential cardiotoxicity of this association is unlikely since sinusal automaticity alone is importantly slowed. But, these results need further confirmation in man.

Ophthalmic Graves' disease is a peculiar clinical condition, characterized by ocular symptoms, without thyrotoxicosis. A survey of 22 observed cases is discussed. This condition is 25 times less frequent than classical Graves' disease. The eye symptoms include upper lid retraction, exophthalmos, and severe ophthalmopathy. Unilateral symptoms are frequent (16 out of 22). A negative T3 suppression test was found in half of the patients. LATS was detectable in 3 out of 17 of the cases. The stimulation of TSH secretion by TRH was normal in 3 out of 6 of the cases. When the tests were combined and repeated, a positive response was found in 8 out of 9 of the exophthalmic patients, and in 3 out of 9 of the patients with lid retraction. Appreciation of the course of the disease necessitates a prolonged follow-up; transformation into classical thyrotoxicosis have been observed. Our clinical studies bring into focus the relationship of ocular symptoms with Graves' disease and Hashimoto's disease.

In diabetic patients, hyperglycaemia results in the non enzymatic glycation of many proteins. We studied the glycation of HDL of patients with either type 1 or type 2 diabetes compared with that of control subjects. Although a basal glycation was detectable in HDL of normal individuals, this increased by about 400% in HDL of both groups of diabetic patients. The degree of HDL glycation was positively correlated with blood glucose concentration. All the HDL apoproteins were glycated but the glycation of apo A-I represented about 80% of the total HDL. These data were compared to those obtained in vitro after incubation of normal apo A-I either as free molecular species or as phospholipid/apo A-I complex, in the presence of glucose (0 to 80 mmol/l) at 37 degrees C. The resulting apo A-I glycation was dependent upon both time of incubation and glucose concentration and was largely increased in the presence of phospholipids. These data suggest that the in vivo glycation of HDL apoproteins might depend upon glucose concentration but might also be partly influenced by their lipid environment.