Validation of Baveno VI and Expanded-Baveno VI Criteria for predicting gastroesophageal varices in patients with alcoholic and non-alcoholic fatty liver disease.

Background and aims: Baveno VI and Expanded-Baveno VI Criteria were validated to rule out high-risk esophageal varices (HRV) and to prevent unneeded endoscopies in compensated advanced chronic liver disease (cACLD) mainly related to viral hepatitis. We aim to assess these criteria to rule out low- and high- risk varices in patients with cACLD secondary to alcoholic liver disease (ALD) and non- alcoholic fatty liver disease (NAFLD). Methods: Data were collected retrospectively from 2016 to 2020. Inclusion criteria were: NAFLD and /or ALD related cACLD, a liver stiffness measurement (LSM) ≥ 10 kPa and an esophagogastroduodenoscopy (EGD) within 12 months. Exclusion criteria were: use of non cardioselective ß-blockers, hepatic decompensation, previous variceal bleeding, portal thrombosis, liver cancer, or liver transplant. Results: One hundred and ninety-four patients were included in this study. Eighty-one patients (42%) met Baveno VI criteria and 103 (53%) met Expanded-Baveno VI criteria. Baveno VI criteria yielded a high negative predictive value (NPV ≥ 95%) for detecting HRV and varices of any size. Expanded-Baveno VI criteria yielded a high NPV ≥ 95% only for detecting HRV: the miss rate for varices of any size was 8%. Expanded-Baveno VI criteria could avoid more endoscopies than the original Baveno VI criteria to rule out HRV (53% versus 42%). Conclusion: In this study, both criteria showed high NPV to rule out HRV but only original Baveno VI criteria yielded a satisfactory high NPV to rule out varices of any size. Expanded-Baveno VI criteria could avoid more endoscopies to exclude HRV.

[Sertraline-induced chronic eosinophilic pneumonia]. / Pneumopathie chronique à éosinophiles induite par la sertraline.

INTRODUCTION: Sertraline is a selective serotonin reuptake inhibitor which is often used as first-line treatment for depression. Several patterns of interstitial lung disease attributable to sertraline have been reported in the literature. CASE REPORT: A 69-year-old patient, who had been taking sertraline to treat severe depression for 10 months, presented with a deterioration in his general condition and respiratory symptoms found to be associated with bilateral pneumonitis. An exhaustive assessment did not reveal any infectious or autoimmune aetiology. Transthoracic lung biopsy revealed a pattern of eosinophilic lung disease. Sertraline-induced lung toxicity was then suspected and this treatment was therefore stopped. The patient's symptoms resolved and the chest imaging normalized. CONCLUSIONS: Our observation suggests that sertraline was the cause of chronic eosinophilic pneumonia characterized by an insidious clinical presentation several months after starting the medication. Given its widespread prescription, we encourage any clinician facing this disease to pay attention to possible drug-induced origins of lung disease.

The changing pattern of cirrhosis in Belgium: a study based on two cohorts prospectively collected 15 years apart.

BACKGROUND AND STUDY AIM: The epidemiology of cirrhosis is evolving over the past decades in Western countries. The aim of this study was to assess the changes in the epidemiology of cirrhosis in our region by comparing two cohorts of patients diagnosed 15 years apart. PATIENTS AND METHODS: From the outpatient's liver clinics of our hospital and from January 1995 to December 2017, we consecutively recorded all patients with cirrhosis. From this registry, the current study compared two cohorts of patients diagnosed 15 years apart. Epidemiologic data and liver-related mortality were compared between both cohorts with a 3 to 8-year follow-up. RESULTS: During a 23-year period, 1151 patients consented to be included in the cirrhosis registry. The current study compared 197 patients with cirrhosis diagnosed from 1995 to 1999 (cohort C1) with 237 patients with cirrhosis diagnosed from 2010 to 2014 (cohort C2). Our results showed that in the cohort C2, compared with the cohort C1, the prevalence of NAFLD-related cirrhosis increased (C1 : 3% vs C2 : 16%, p< 0.0001) while the prevalence of HCV-related cirrhosis decreased (C1 : 22% vs C2 : 10%, p< 0.0001). In the more recent cohort, liver biopsy was less frequently performed (C1 : 65% vs C2 : 20%, p<0.0001). An intriguing finding was the increasing age at cirrhosis diagnosis for patients with alcohol-related cirrhosis (C1 : 52±11 years vs C2 : 57±10 years, p<0.0001). CONCLUSIONS: The epidemiology of cirrhosis has changed over time. Effective prevention strategies are needed to reduce the burden of liver disease.

[PERSONALIZED APPROACH TO LIPID-LOWERING THERAPY]. / APPROCHE PERSONNALISÉE DU TRAITEMENT DES DYSLIPIDÉMIES.

Individualized therapeutic strategy of dyslipidemias, classically relies upon a phenotypic approach. The pattern of lipid profile allows the choice of the best pharmacological option (statin, fibrate) and the patient's clinical risk profile allows the definition of therapeutic goals, especially LDL cholesterol target levels. Dyslipidemias have a major genetic component, which is best illustrated by familial hypercholesterolemia, with its two heterozygous and homozygous forms. There is a huge between-subject variability in the response to lipid-lowering therapies (especially to statins) and ongoing pharmacogenetic and pharmacogenomic studies should help to better understand this inter-individual heterogeneity. The recent discovery of mutations in the PCSK9 rene opened new perspectives regarding the understanding of some forms of familial hypercholesterolemia and led to the development of monoclonal antibodies that selectively inhibit PCSK9. These PCSK9 inhibitors allow, when combined to a statin, drastic reductions in LDL cholesterol concentrations, even when familial hypercholesterolemia is present. They are currently tested in large prospective controlled trials aiming to demonstrate a significant reduction in the residual cardiovascular risk in statin-treated patients.

Dietary supplementation contributes to lifestyle improvement in hypercholesterolemic patients in real-life contexts.

AIMS: Assess the evolution of cardiovascular lifestyle behaviors in hypercholesterolemic patients concomitantly with changes in their daily intake of phytosterol-supplemented yoghurt (Phyto-SY). METHODS: Nationwide prospective observational study conducted in general practices across France and Spain. Each practitioner suggested lifestyle changes to five consecutive patients with hypercholesterolemia (whether or not they were taking hypocholesterolemic drugs) and recommended daily consumption of Phyto-SY. The study design involved an inclusion visit, a patient's self-monitoring assessment after 1 month, and a final visit after 4 months. Primary evaluation criterion: changes in dietary habits assessed by a standardized Nutritional Lifestyle score. Secondary criteria: changes in lipid profile, anthropometry (waist circumference) and lifestyle behavior. RESULTS: A total of 2376 hypercholesterolemic patients (of whom 54.8% were women) were included. The average age was 56.2 years old. The Nutritional Lifestyle score improved from 15.4 ± 5.4 to 8.7 ± 4.0 (p < 0.0001). Total cholesterol decreased by 10.6% (<0.0001), HDL-C increased by 8.0% (<0.0001), and LDL-C fell by 12.7% (<0.0001). Similar results were observed in patients treated with statins and those who were not. Frequency of walking (>30 min) increased from 59.3% to 78.3% (p < 0.0001). The overweight rate decreased from 22.8% to 17.5% (p < 0.0001) and waist circumference from 94.6 ± 13.3 cm to 93.0 ± 12.8 cm (p < 0.0001). Nutritional Lifestyles and other lifestyle markers' improvement were parallel to adherence to Phyto-SY adherence. CONCLUSION: Improvements in Nutritional Lifestyle scores, which included regular consumption of Phyto-SY over 4 months, was significantly linked to healthier lifestyles and to beneficial modifications in atherogenic lipid profiles, which reflected patient empowerment in a 'real life' context.

D-dimer cut-off adjusted to age performs better for exclusion of pulmonary embolism in patients over 75 years.

INTRODUCTION: A D-dimer (DD) test improves the diagnosis of PE (PE) when combined with clinical scores. However, as DD levels increase physiologically with age, this testing has less specificity in older patients. Douma et al. (1). proposed the use of an age adjusted DD cut-off to increase the specificity of this test. METHODS: We performed chart reviews of patients, older than 75 years, hospitalized for suspicion of PE in 2010-2011 (n = 165). PE was assessed with either pulmonary scintigraphy (PS, n = 64) and/or pulmonary computed tomography (PC, n = 101). We compared the specificity, sensitivity and false negatives rates of an age adjusted DD cut-off level ("ADC" = (patient's age x 0.01) microg/ml) with those of the conventional cut off level ("CDC" = 0.5 microg/ml). RESULTS: PE was confirmed in 45 cases. In the 120 patients with no PE (negative PS or PC), 7 cases had CDC below cut-off levels, while 28 cases had an ADC below cutoff level. The use of the ADC thus increased the specificity (ADC: 23% vs CDC: 6%, p = 0.0001), and this was obtained without significant loss of sensitivity (ADC: 96% vs CDC: 98%, ns). Patients were clinically assessed with the revised Geneva scores. In the negative PE group, the number of patients classified with low, moderate or high clinical probability of PE were 31, 81 and 8, respectively. The percentage of patients with DD values below cut-off values was 4%, 0.8% and 0.8%, respectively using the CDC and 9%, 12% and 2.5% using the ADC. CONCLUSIONS: In this age group, the specificity of ADC was found superior to that of the CDC. The clinical use of the ADC might be associated with less useless diagnosis procedures, without significant increase in rate of diagnosis failure.

[How I treat ... dyslipidemia according to the cardiovascular risk profile]. / Comment je traite ... une dyslipidémie en fonction du profil de risque cardiovasculaire.

The new guidelines from the European Atherosclerosis Society and the European Society of Cardiology include a number of new items. Here we demonstrate their application in several different clinical examples. We focus on the 4 items most pertinent for medical practice: 1) the stratification of risk of cardiovascular disease into 4 categories ('very high', 'high', 'moderate' and 'low risk'), involving--for primary prevention cases--the use of the SCORE table, which has been calibrated for Belgium and where the risk can be adjusted according to HDL cholesterol and the presence of other risk factors; 2) the choice of more stringent therapeutic targets for LDL cholesterol (< 70 mg/dl for 'very high' risk patients, 100 mg/dl for 'high' risk patients and 115 mg/dl for patients at 'moderate' risk); 3) the choice of other therapeutic targets (non-HDL cholesterol and apolipoprotein B levels) for patients at 'very high' or 'high' risk with combined dyslipidaemia; and 4) follow-up of lipid parameters and muscular and hepatic enzymatic profiles.

[New European guidelines for the management of dyslipidaemia in cardiovascular prevention]. / Les nouvelles recommandations Européennes pour le traitement des dyslipidémies en prévention cardiovasculaire.

The new guidelines from the European Atherosclerosis Society and the European Society of Cardiology include a number of updated items. In this paper, we summarize 4 of these changes that we consider to be the most pertinent. Firstly, cardiovascular risk is now stratified according to 4 (previously 2) categories: "very high risk" (patients with cardiovascular disease, patients with diabetes > 40 years old who have at least one other risk factor, patients with kidney failure, or patients in primary prevention with a SCORE value > or = 10%); "high risk" (patients in primary prevention with a SCORE value > or = 5% and < 10% or patients with a particularly serious risk factor such as familial hypercholesterolaemia or patients with diabetes < 40 years old without any other risk factor); "moderate risk" (primary prevention with SCORE > or = 1% and < 5%); and "low risk" (primary prevention with SCORE < 1%). The SCORE value for patients in primary prevention is estimated using the SCORE table (calibrated for Belgium). Risk in this table may now be corrected according to HDL cholesterol level. Secondly, the therapeutic targets for each category are now more stringent: LDL cholesterol < 70 mg/dl (or reduced by at least 50%) if the risk is "very high"; < 100 mg/dl if the risk is "high"; and < 115 mg/dl if the risk is "moderate". Thirdly, for patients at "high" or "very high" risk, particularly in patients with combined dyslipidaemia, two further therapeutic targets should be considered: non-HDL cholesterol and apolipoprotein B levels. Fourthly, the follow-up of efficacy (lipid profile) and tolerance (hepatic and muscular enzymes) is described in more details so as to harmonize case management in clinical practice.

Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization.

UNLABELLED: Since heterozygous familial hypercholesterolemia (HeFH) is a disease that exposes the individual from birth onwards to severe hypercholesterolemia with the development of early cardiovascular disease, a clear consensus on the management of this disease in young patients is necessary. In Belgium, a panel of paediatricians, specialists in (adult) lipid management, general practitioners and representatives of the FH patient organization agreed on the following common recommendations. 1. Screening for HeFH should be performed only in children older than 2 years when HeFH has been identified or is suspected (based on a genetic test or clinical criteria) in one parent.2. The diagnostic procedure includes, as a first step, the establishment of a clear diagnosis of HeFH in one of the parents. If this precondition is satisfied, a low-density-lipoprotein cholesterol (LDL-C) levelabove 3.5 mmol/L (135 mg/dL) in the suspected child is predictive for differentiating affected from non-affected children. 3. A low saturated fat and low cholesterol diet should be started after 2 years, under the supervision of a dietician or nutritionist.4. The pharmacological treatment, using statins as first line drugs, should usually be started after 10 years if LDL-C levels remain above 5 mmol/L (190 mg/dL), or above 4 mmol/L (160 mg/dL) in the presence of a causative mutation, a family history of early cardiovascular disease or severe risk factors. The objective is to reduce LDL-C by at least 30% between 10 and 14 years and, thereafter, to reach LDL-C levels of less than 3.4 mmol/L (130 mg/dL). CONCLUSION: The aim of this consensus statement is to achieve more consistent management in the identification and treatment of children with HeFH in Belgium.

Co-administration of ezetimibe and simvastatin in acute myocardial infarction.

BACKGROUND: Recent trials in acute myocardial infarction indicate that intensive and early statin therapy that lowers low-density lipoprotein cholesterol (LDL-C) to < or = 70 mg dL(-1) is beneficial. The combination of statins with ezetimibe, a newly developed cholesterol-absorption inhibitor, can lead to a further reduction in LDL-C of up to 26%. In this study, we examined the rapidity and intensity of the lipid-lowering effect of ezetimibe co-administered with simvastatin immediately after myocardial infarction. MATERIALS AND METHODS: Sixty patients admitted for acute myocardial infarction were randomized to receive either simvastatin 40 mg (SIMVA), a combination of simvastatin 40 mg and ezetimibe 10 mg (EZE/SIMVA), or no lipid-lowering drugs (NLLD) and had their lipid levels assessed 2, 4 and 7 days later. RESULTS: At baseline, cardiovascular risk factors were similar in all three groups [mean (SD) LDL-C of 141 (36) mg dL(-1)]. At days 2 , 4 and 7 there was no significant change in mean LDL-C levels in the NLLD group (-10%, -6%, and -9%, all P > 0.09), while there were significant reductions with SIMVA (-15%, -27%, and -25%, respectively, all P < 0.001 vs. day 0) and even greater reductions with co-administration of EZE/SIMVA (-27%, -41%, and -51%, respectively, all P < 0.001 vs. day 0). The percentages of patients achieving LDL-C below 70 mg dL(-1) at days 4 and 7 were substantially greater with EZE/SIMVA (45% and 55%, respectively) than with SIMVA (5% and 10%, respectively), while no NLLD patient reached this goal. Triglyceride levels showed a progressive increase in the NLLD group (+45% at day 7, P < 0.05 vs. day 0), no change in the SIMVA group, but a decrease in the EZE/SIMVA group (-17% at day 7, P < 0.05 vs. day 0). No significant difference in HDL-C levels, tolerability, or clinical events was observed between the three groups. CONCLUSIONS: The co-administration of ezetimibe 10 mg with simvastatin 40 mg, by inhibiting cholesterol absorption and production, allowed more patients with acute myocardial infarction to reach LDL-C < or = 70 mg dL(-1) as early as the fourth day of treatment. The effects of such rapid and intense reduction in LDL-C on cardiovascular morbidity and mortality need to be evaluated in future clinical endpoint studies.

Case report: acute pancreatitis induced by Clozapine.

Two percent of acute pancreatitis are drug induced. In the present paper, we reported the case of a 39 year-old patient with chronic-hallucinatory schizophrenia who developed symptomatic pancreatitis during the clozapine dose titration performed to reach the therapeutic range. Diagnosis of pancreatitis was suggested by clinical examination and abnormal laboratory values of pancreatic enzymes and confirmed by C-T scan and ultrasonography. The causal incrimination of clozapine in this case seems likely as all other possible causes of pancreatitis were excluded, as AP developed shortly after the introduction of the drug and as the pancreatic enzymes normalized after clozapine was stopped. No rechallenge to confirm the causal relationship was however attempted. So far, only eight cases of acute pancreatitis have been reported in association with clozapine use. Clozapine is an atypical antipsychotic drug which belongs to the chemical class of dibenzodiazepines. The mechanism by which clozapine could produce acute pancreatitis remained unclear. Nevertheless, we advocate a careful biological follow-up (measuring periodically the concentrations of amylase, lipase and triglycerides) during the treatment by clozapine.

Impact of genetic defects on coronary atherosclerosis in patients suspected of having familial hypercholesterolaemia.

BACKGROUND: In the present study we assessed whether the presence of genetic mutations typical of familial hypercholesterolaemia (FH) was associated with greater atherosclerosis in the coronary vessels in patients with severe hypercholesterolaemia and a family history of early cardiovascular disease. MATERIALS AND METHODS: Two hundred and thirty-five patients selected for having severe hypercholesterolaemia and a family history of cardiovascular disease were classified as FH (57 men and 38 women) or non-FH (84 men and 56 women) according to a genetic analysis of the LDL-R or ApoB genes. Coronary atherosclerosis was evaluated by performing a thoracic CT scan and exercise stress testing. RESULTS: Familial hypercholesterolaemia individuals had a significantly higher prevalence of coronary calcification than the non-FH patients from among both the men (OR = 3.90; 95% CI 1.86-8.19; P < 0.001) and the women (OR = 2.34; 95% CI 1.01-5.48; P = 0.05). In exercise stress testing, ECG abnormalities suggestive of cardiac ischaemia were found with a higher prevalence in the FH patients than the non-FH patients from among both the men (OR 6.15; 95% CI 2.16-17.5; P < 0.001) and the women (OR 4.76; 95% CI 0.91-24.6; P = 0.06). All differences were statistically significant after adjusting for age and cholesterol and for most classical risk factors that differed between the FH and non-FH groups. CONCLUSION: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, the presence of a genetically ascertained FH is associated with a higher prevalence of coronary artery calcifications and a positive exercise stress test. These results suggest that despite a similar phenotype, patients carrying mutations suggestive of FH may have a greater cardiovascular risk than patients without these mutations.

Impact of genetic defects on atherosclerosis in patients suspected of familial hypercholesterolaemia.

BACKGROUND: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, we assessed whether patients with mutations of low-density lipoprotein (LDL) receptor and apolipoprotein B genes related to familial hypercholesterolaemia (FH) have a different degree of atherosclerosis than those without such mutations. METHOD: In our lipid clinics, 273 patients were selected on the basis of a severe hypercholesterolaemia (cholesterol above 95th percentile) and a family history of early cardiovascular disease. By molecular genetic test, 122 patients were classified as FH. Atherosclerosis was evaluated by the ultrasonographic measurement of intima-media thickness (IMT) in the carotid and femoral arteries. RESULT: Despite the fact that non-FH individuals had a higher prevalence of obesity, hypertension, diabetes and hypertriglyceridaemia, FH individuals had significantly greater carotid and femoral IMT than non-FH patients: difference between carotid and femoral IMT, respectively, 0.19 mm (95% CI, 0.08-0.29; P < 0.001) and 0.20 mm (95% CI, 0.09-0.35; P = 0.001), respectively. These differences remained statistically significant after adjustment for the various risk factors as well as in sub-analysis restricted to the patients with LDL-cholesterol between 240 and 300 mg dL-1 (range with similar distribution in the two groups). When classified according to the severity of their mutations, FH individuals with null LDL receptor allele tended to have thicker carotid IMT than FH individuals carrying the LDL receptor-defective allele. CONCLUSION: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, the presence of a genetically ascertained FH is associated with a higher degree of atherosclerosis. This suggests that molecular genetic identification of FH may be helpful to evaluate better the coronary heart disease risk in these patients.

The use of Achilles tendon ultrasonography for the diagnosis of familial hypercholesterolemia.

Differentiating FH from other causes of hypercholesterolemia has important clinical and therapeutic implications but is often not possible by standard clinical criteria. As accumulation of cholesterol in tendon is generally considered as pathognomonic of FH, we evaluated the sensitivity and specificity of clinical and ultrasonographic tendon characteristics using the data of 127 genetically ascertained FH and 160 controls with various lipid profiles. Upon clinical examination, none of the controls and 29% of FH individuals (17% FH women and 38% FH men) presented with xanthomata in Achilles tendons, but no female and only 6% of male FH patients also showed xanthomata in the extensor tendon of the hand. Amongst all possible quantitative parameters (thickness, breadth, section and roundness) of Achilles tendon (AT) measured by ultrasonography, the thickness presented the best receiver operating curves. AT thickness above 5.8 mm was the most useful threshold for diagnosis of FH, procuring sensitivity of 75% and specificity of 85%. Analysis of variation of AT thickness with age and sex indicated that this clinical criterion performed better in females older than 45 and in males under 45. In patients carrying the APOB-R3500Q mutation, AT-thickness appeared significantly less important compared with those carrying LDLR mutations. In conclusion, this study recommends identification of possible FH individuals amongst hypercholesterolemic patients using a criteria of AT-thickness over 5.8 mm eventually associated with a specific genetic test for APOB-R3500Q mutation.

Sequencing of the coding exons of the LRP1 and LDLR genes on individual DNA samples reveals novel mutations in both genes.

Five coding polymorphisms in de LRP1 gene, i.e. A217V, A775P, D2080N, D2632E and G4379S were discovered by sequencing its 89 exons in three test-groups of 22 healthy individuals, 29 Alzheimer patients and 18 individuals with different clinical and molecularly uncharacterized lipid metabolism problems. No genetic defect was evident in the LRP1 gene of any of the Alzheimer's disease (AD) patients, further excluding LRP1 as a major genetic problem in AD. Lipoprotein receptor related protein (LRP) A217V (exon 6) was clearly present in all groups as a polymorphism, while D2632E was observed only once in a healthy volunteer. On the other hand, LRP1 alleles A775P, D2080N, and G4379 were encountered only in patients with FH or with undefined problems of lipid metabolism. This finding forced one to also analyze the LDL receptor (LDLR) gene, for which a method was devised to sequence the entire region comprising LDLR exons 2-18. The resulting sequence contig of 33567 nucleotides yielded finally an exact physical map that corrects published and listed LDLR gene maps in many positions. In addition, next to known mutations in LDLR that cause FH, four novel LDLR defects were defined, i.e. del e7-10, exon 9 mutation N407T, a 20 bp insertion in exon 4, and a double mutation C292W/K290R in exon 6. No evidence for pathology connected to the LRP1 'mutations' was obtained by subsequent screening for the five LRP1 variants in larger groups of 110 FH patients and 118 patients with molecularly undefined, clinical problems of cholesterol and/or lipid metabolism. In three individuals with a mutant LDLR gene a variant LRP1 allele was also present, but without direct, obvious clinical compound effects, indicating that the variant LRP1 alleles must, for the present, be considered polymorphisms.

Familial hypercholesterolaemia in a Belgian community.

Familial hypercholesterolaemia (FH) is a genetic disease in which low-density lipoproteins are defectively removed from plasma as a result of mutations that impair the function either of the LDL receptor or of the apolipoprotein B. The consequences are an elevated concentration of LDL-cholesterol and the early occurrence of cardiovascular diseases. Although FH is well understood, it remains a diagnostic challenge for the clinician. Differentiating FH from other causes of hypercholesterolaemia has, however, important clinical and therapeutic implications: FH being associated with early and severe cardiovascular risk, the plasma LDL-cholesterol must be lowered as drastically and as early as possible; because FH is a dominantly inherited disorder, family members need to be screened and counseled. Prevalence, morbidity and genetic characterization of FH have never been explored in our country. Through our experience of large-scale screening of LDL-receptor and Apo B amongst suspected individuals, we are beginning to understand the molecular spectrum of FH in Belgium. Furthermore, using the large collection of clinical data accumulated amongst patients with genetically ascertained FH, we have attempted to establish specific and sensible diagnostic criteria useful and feasible in routine medical practice.

LDL oxidation: therapeutic perspectives.

The peroxidation step of lipid transormation is considered to be essential in the pathogenesis of atherosclerosis. Although data concerning the mechanisms by which lipid peroxidation occurs in vivo are scarce, several lines of evidence suggest that some endogenous and exogenous compounds with antioxidant activity could have some beneficial effects in the prevention of atherosclerosis. Ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) act as the most important hydrophilic and lipophilic antioxidants, respectively in vivo. Accordingly, animal and human studies suggest that these compounds may have some preventive effect against the development of clinical coronary heart disease. Many plant phenols and flavonoids may be important dietary antioxidants and it has been speculated that these compounds in red wine or in the Mediterranean diet could explain the 'French paradox'. Several studies show that antioxidants such as probucol and butylated hydroxytoluene can inhibit development of atherosclerotic lesions in Watanabe and cholesterol-fed rabbits. Some drugs such as beta-blockers, calcium antagonists, hypolipodemic drugs,...appear to have at least in vitro antioxidant effects but the clinical relevance of these properties remains unkonwn. Moreover, some interventions aimed to decrease the LDL-oxidative susceptibility have not been shown to attenuate atherogenesis when cholesterol levels remain markedly elevated.

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), a common autosomal dominant disorder. The LDLR database is a computerized tool that has been developed to provide tools to analyse the numerous mutations that have been identified in the LDLR gene. The second version of the LDLR database contains 140 new entries and the software has been modified to accommodate four new routines. The analysis of the updated data (350 mutations) gives the following informations: (i) 63% of the mutations are missense, and only 20% occur in CpG dinucleotides; (ii) although the mutations are widely distributed throughout the gene, there is an excess of mutations in exons 4 and 9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of mutations located within the ligand-binding domain shows that 74% of the mutations in this domain affect a conserved amino-acid, and that they are mostly confined in the C-terminal region of the repeats. Conversely, the same analysis in the EGF-like domain shows that 64% of the mutations in this domain affect a non-conserved amino-acid, and, that they are mostly confined in the N-terminal half of the repeats. The database is now accessible on the World Wide Web at http://www.umd.necker.fr