Vascular calcifications in homozygote familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (hmzFH) attributable to LDL receptor gene mutations have shown a remarkable increase in survival over the last 20 years. Early onset coronary heart disease (CHD) and calcific aortic valve stenosis are the major complications of this disorder. We now report extensive premature calcification of the aorta in patients with hmzFH. METHODS AND RESULTS: We examined 25 hmzFH patients from Canada; mean age was 32 years (range 5 to 54), and mean baseline cholesterol before treatment was 19+/-5 mmol/L (737+/-206 mg/dL). Aortic calcification was quantified using computed tomography (CT). An elevated mean calcium score was found in patients by age 20 and correlated with age (r(2)=0.53, P=0.001). One quarter (24%) of patients underwent aortic valve surgery. CONCLUSIONS: We document premature severe aortic calcifications in all adult hmzFH patients studied. These presented considerable surgical management challenges. Strategies to identify and monitor aortic calcification in hmzFH by noninvasive techniques are required, as are clinical trials to determine whether additional or more intensive therapies will prevent the progression of such calcifications. Whether vascular calcifications in hmzFH subjects are related to sustained increases in LDL-C levels or to other mechanisms, such as abnormal osteoblast activity, remains to be determined.

Rule change incidence on physiological characteristics of elite basketball players: a 10-year-period investigation.

OBJECTIVE: To evaluate, by examining data collected on professional basketball players during a 10-year period, the differences in aerobic capacity in function of the playing position and the impact on these parameters of the change in time regulation of 2000, which shortened the time allowed to attempt a field goal by 6 s and divided the duration of play in four quarters. METHODS: Twice a year between 1994 and 2004, professional basketball players (n = 68) were studied for anthropometric characteristics and were submitted to an incremental exercise test on a cycle ergometer. Statistical analyses were carried out to determine the interaction between the playing position and the effect of the change in time regulation on the physiological characteristics of the players. RESULTS: Anthropometric measurements were different in function of the playing position, the centres being taller and heavier than the forwards and the guards. Guards exhibited the highest Vo(2)max (54.0 (SE 1.6) ml/min/kg) and were the most affected by the change in time regulation of 2000 with a 19.5% increase. Significant main effects of "before" versus "after" rule changes were found for maximal and submaximal O(2) consumption, which were increased by 12.8% at ventilatory threshold, 7.3% at respiratory compensation point and 7.8% at Vo(2)max. CONCLUSION: While anthropometric characteristics remained constant during the last decade, the change in rule of 2000 may have contributed in modifying the physiological profile of basketball players, by generally increasing their level of fitness.

Interaction of lecithin:cholesterol acyltransferase (LCAT).alpha 2-macroglobulin complex with low density lipoprotein receptor-related protein (LRP). Evidence for an alpha 2-macroglobulin/LRP receptor-mediated system participating in LCAT clearance.

The reaction of lecithin:cholesterol acyltransferase (LCAT) with high density lipoproteins (HDL) is of critical importance in reverse cholesterol transport, but the structural and functional pathways involved in the regulation of LCAT have not been established. We present evidence for the direct binding of LCAT to alpha(2)-macroglobulin (alpha(2)M) in human plasma to form a complex 18.5 nm in diameter. Forty percent of plasma LCAT-HDL was associated with alpha(2)M; moreover, most of the LCAT in cerebrospinal fluid and in the medium of cultured human hepatoma cell line was associated with alpha(2)M. Purified recombinant human LCAT (rLCAT) labeled with (125)I bound to native and methylamine-activated alpha(2)M (alpha(2)M-MA) in vitro in a time- and concentration-dependent manner, and this binding did not depend on the presence of lipid. rLCAT bound to alpha(2)M-MA with greater affinity than to alpha(2)M. Furthermore, rLCAT did not activate alpha(2)M as phosphatidylcholine-specific phospholipase C does. Reconstituted HDL particles (LpA-I) inhibited the binding of rLCAT to alpha(2)M more efficiently than native HDL(3) did. LCAT associated with alpha(2)M was enzymatically inactive under both endogenous and exogenous assay conditions. Purified rLCAT alone did not bind to low density lipoprotein receptor-related protein (LRP) as lipoprotein lipase (LPL) does; however, when rLCAT was combined with alpha(2)M-MA to form a complex, binding, internalization, and degradation of rLCAT took place in LRP-expressing cells (LRP (+/+)) but not in cells deficient in LRP (LRP (-/-)). It is concluded that the binding of LCAT to alpha(2)M inhibits its enzymatic activity. Furthermore, the finding supports the possibility that the LRP receptor can act in vivo to mediate clearance of the LCAT-alpha(2)M complex and may significantly influence the bioavailability of LCAT.

Cellular cholesterol efflux is modulated by phospholipid-derived signaling molecules in familial HDL deficiency/Tangier disease fibroblasts.

Familial HDL deficiency (FHD) is the heterozygous form of Tangier disease (TD). Mutations of the ABCA1 gene cause FHD and TD. FHD/TD cells are unable to normally efflux cholesterol onto nascent HDL particles, which are rapidly catabolized. TD fibroblasts have an abnormal pattern of PLC and PLD activation following cell stimulation with HDL(3) or apolipoprotein A-I (apoA-I). We examined cellular cholesterol efflux in FHD and TD fibroblasts by phospholipid-derived-molecules, compared with that of normal cells. We used the PKC agonist 1,2-dioctanoylglycerol (DOG) and phorbol myristate acetate (PMA) to activate PKC, calphostin C, and GO 6976, as inhibitors of PKC; phosphatidic acid (PA), which is the product of PLD, and lysophosphatidic acid (LPA), phosphatidylcholine, sphingomyelin, and beta-cyclodextrin to investigate their potential effect in modulating cellular cholesterol efflux in [(3)H]cholesterol-labeled and cholesterol-loaded fibroblasts. Phosphatidylcholine, sphingomyelin, and beta-cyclodextrin promoted cholesterol efflux in an identical fashion in control, FHD, or TD fibroblasts. In a dose-dependent fashion, DOG (0-200 microM) increased apoA-I-mediated cellular cholesterol efflux by 40% in controls, 71% in FHD, and 242% in TD cells. PMA similarly increased cholesterol efflux to a maximum of 256% in controls, 182% in FHD, and 191% in TD cells. This effect was inhibited by calphostin C. PA (100 microM) also increased cholesterol efflux by 25% in control, 44% in FHD, and 100% in TD cells. Conversely, LPA reduced cholesterol efflux in a dose-dependent fashion in control and FHD cells (-50%, 200 microM) but not in TD cells, where efflux was increased by 140%. Propranolol (100 microM) significantly increased cholesterol efflux at 24 h in all three cell lines. n-Butanol partially decreased the DOG-mediated increase in cholesterol efflux. The inhibitory effect of calphostin C on DOG-stimulated cholesterol efflux could be partially overcome by propranolol, suggesting that PA is a downstream mediator of PKC-stimulated cholesterol efflux. We conclude that PLC and PLD activities are required for apoA-I-mediated cellular cholesterol efflux, and modulating cellular PA concentration can correct, at least partially, the cholesterol efflux defect in FHD and TD.

Conservation of RET proto-oncogene splicing variants and implications for RET isoform function.

The RET proto-oncogene encodes a receptor tyrosine kinase required for development of the kidney and neural crest-derived cell types. Alternative splicing of the 3' exons of human RET results in three protein isoforms with distinct C-termini: RET9, RET51, and RET43. These RET isoforms show differential binding to downstream adapter molecules, suggesting they may have distinct signaling functions. We have characterized Ret 3' sequences in mouse and investigated alternative splicing of this region. We found that the organization of Ret 3' sequences is very similar to human RET. The mouse locus also has alternatively spliced C-terminal coding regions, and the sequences corresponding to RET9 and RET51 are highly conserved in both position and sequence with the human locus. Further, we compared the predicted C-terminal amino acids of RET9 and RET51 in seven vertebrate species, and found that they are well conserved. We have identified sequence encoding a putative ret43 isoform in mouse, however the predicted amino acid sequence showed low homology to human RET43. Our data suggest that RET isoforms are evolutionarily highly conserved over a broad range of species, which may indicate that each isoform has a distinct role in normal RET function.

Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.

We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.

Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations.

BACKGROUND: High density lipoproteins (HDL) are complex lipoprotein particles involved in reverse cholesterol (C) transport and are negatively associated with the risk for coronary artery disease (CAD). We have described a disorder of familial HDL deficiency (FHD) due to abnormal cellular cholesterol efflux. In the present study, we investigated cellular cholesterol efflux on skin fibroblast from 15 probands with moderate to severe hypoalphalipoproteinemia, including one subject with Tangier disease (TD). We performed family studies on eight of these probands (269 individuals) with familial hypoalphalipoproteinemia (defined as a HDL-C <5th%, and with no known cause of HDL deficiency). We have previously shown that four of our FHD patients and patients with TD have mutations at the ABC1 gene, demonstrating that FHD is a heterozygous form of TD. METHODS: On each subject, we carried out detailed biochemical analysis and determined apoA-I-mediated cellular cholesterol efflux using 3H-cholesterol labeled skin fibroblasts from study subjects compared with controls. TD has also been associated with abnormal cellular cholesterol efflux. Cell fusion experiments with polyethylene glycol (PEG) were carried out with fibroblasts from a subject with TD and one with FHD in order to determine whether the Tangier cells can complement the FHD defect. In all subjects with a reduced cellular cholesterol efflux, exons of the ABCA1 gene were sequenced. RESULTS: Familial forms of HDL deficiency, defined as HDL-C levels <5th percentile, are a heterogeneous group of lipoprotein disorders. A reduced cellular cholesterol efflux has been identified in eight subjects from seven kindred (7/14 or 50% of probands tested), being reduced by a mean 59% of controls (range 49-63%). In four of these subjects, a mutation at the ABCA1 gene locus was identified. In three other subjects an efflux defect was idenfified but no critical mutation at the ABCA1 gene locus has been identified. In the remaining subjects, (7/14), no efflux defect was identified. Complementation studies reveal that the FHD defect is not corrected by Tangier cells, confirming that FHD and TD represent a spectrum of the same genetic defect. CONCLUSION: Familial hypoalphalipoproteinemia syndromes are phenotypically heterogeneous; one form is associated with abnormal cellular cholesterol efflux caused by heterozygous mutations at the ABCA1 gene, that defines familial HDL Deficiency while homozygous mutations or compound heterozygocity causes TD. Other forms are primary hypoalphalipoproteinemia of unknown cause, while the remaining cases are associated with hypertriglyceridemia with or without elevated apoB levels. We conclude that a cellular cholesterol defect is a relatively frequent cause of familial HDL deficiency and that a mutation at the ABCA1 gene can be identified in half of these patients.

Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux.

BACKGROUND: A low concentration of HDL cholesterol is the most common lipoprotein abnormality in patients with premature atherosclerosis. We have shown that Tangier disease, a rare and severe form of HDL deficiency characterised by a biochemical defect in cellular cholesterol efflux, is caused by mutations in the ATP-binding-cassette (ABC1) gene. This gene codes for the cholesterol-efflux regulatory protein (CERP). We investigated the presence of mutations in this gene in patients with familial HDL deficiency. METHODS: Three French-Canadian families and one Dutch family with familial HDL deficiency were studied. Fibroblasts from the proband of each family were defective in cellular cholesterol efflux. Genomic DNA of each proband was used for mutation detection with primers flanking each exon of the ABC1 gene, and for sequencing of the entire coding region of the gene. PCR and restriction-fragment length polymorphism assays specific to each mutation were used to investigate segregation of the mutation in each family, and to test for absence of the mutation in DNA from normal controls. FINDINGS: A different mutation was detected in ABC1 in each family studied. Each mutation either created a stop codon predicted to result in truncation of CERP, or altered a conserved aminoacid residue. Each mutation segregated with low concentrations of HDL-cholesterol in the family, and was not observed in more than 500 control chromosomes tested. INTERPRETATION: These data show that mutations in ABC1 are the major cause of familial HDL deficiency associated with defective cholesterol efflux, and that CERP has an essential role in the formation of HDL. Our findings highlight the potential of modulation of ABC1 as a new route for increasing HDL concentrations.

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.

Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).

Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency.

Familial high density lipoprotein (HDL) deficiency (FHD) is a genetic lipoprotein disorder characterized by a severe decrease in the plasma HDL cholesterol (-C) level (less than the fifth percentile). Unlike Tangier disease, FHD is transmitted as an autosomal dominant trait. FHD subjects have none of the clinical manifestations of Tangier disease (lymphoid tissue infiltration with cholesteryl esters and/or neurological manifestations). Plasmas from FHD subjects contain pre-beta-migrating HDLs but are deficient in alpha-migrating HDLs. We hypothesized that a reduced HDL-C level in FHD is due to abnormal transport of cellular cholesterol to the plasma membrane, resulting in reduced cholesterol efflux onto nascent HDL particles, leading to lipid-depleted HDL particles that are rapidly catabolized. Cellular cholesterol metabolism was investigated in skin fibroblasts from FHD and control subjects. HDL3- and apolipoprotein (apo) A-I-mediated cellular cholesterol and phosphatidylcholine efflux was examined by labeling cells with [3H]cholesterol and [3H]choline, respectively, during growth and cholesterol loading during growth arrest. FHD cells displayed an approximately 25% reduction in HDL3-mediated cellular cholesterol efflux and an approximately 50% to 80% reduction in apoA-I-mediated cholesterol and phosphatidylcholine efflux compared with normal cells. Cellular cholesterol ester levels were decreased when cholesterol-labeled cells were incubated with HDL3 in normal cells, but cholesterol ester mobilization was significantly reduced in FHD cells. HDL3 binding to fibroblasts and the possible role of the HDL binding protein/vigilin in FHD were also investigated. No differences were observed in 125I-HDL3 binding to LDL-loaded cells between FHD and control cells. HDL binding protein/vigilin mRNA levels and its protein expression were constitutively expressed in FHD cells and could be modulated ( approximately 2-fold increase) by elevated cellular cholesterol in normal cells. In conclusion, FHD is characterized by reduced HDL3- and apoA-I-mediated cellular cholesterol efflux. It is not associated with abnormal cellular HDL3 binding or a defect in a putative HDL binding protein.

Angiotensin converting enzyme insertion/deletion polymorphism in French Canadian subjects with premature coronary artery disease.

The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been postulated to be associated with CAD in some populations of European descent. As part of a study investigating metabolic and genetic factors in subjects with premature coronary artery disease (CAD), we examined the I/D polymorphism of the ACE gene in 134 subjects with premature CAD (105 men and 29 women, mean age 49 +/- 6 years) and 116 control subjects selected for health (71 men, 45 women; mean age 39 +/- 7 years). Both patients and controls were of French Canadian descent. As expected, significant differences were found between cases and controls with respect to age, plasma lipoprotein cholesterol, presence of smoking, diabetes and high blood pressure after correction for age. Multivariate analysis confirms the importance of age, HDL-C levels, smoking and apo B levels as determinants of CAD. Allele frequencies of the I and D polymorphism were 43.1% and 57.9% in controls, and 48.5% and 51.5% in CAD cases (chi 2 = 0.622, p = 0.430). No significant association between the I/D polymorphism and conventional cardiovascular risk factors, including plasma levels of lipids, lipoprotein cholesterol, diabetes or smoking, was found in cases or controls. Furthermore, the presence of the I/D polymorphism did not correlate with a history of hypertension or a family history of premature CAD in CAD patients. We conclude that, in our selected population, the I/D polymorphism of the ACE gene is not associated with CAD, conventional risk factors, or a family history of CAD. Although our sample size does not allow sufficient power to ascertain that the ACE I/D polymorphism is not associated with CAD, we do not recommend the routine measurement of the ACE polymorphism in our population to determine cardiovascular risk.

Metabolic factors clustering, lipoprotein cholesterol, apolipoprotein B, lipoprotein (a) and apolipoprotein E phenotypes in premature coronary artery disease in French Canadians.

Plasma lipoprotein cholesterol abnormalities, diabetes, hypertension and smoking have all been identified as independent predictors of cardiovascular events. Clustering of multiple risk factors suggests a common metabolic link among high blood pressure, insulin resistance, plasma lipoprotein abnormalities and obesity. New guidelines for the management of dyslipidemias target patients with established coronary artery disease (CAD), and high risk patients with multiple risk factors and severe genetic lipoprotein disorders, such as familial hypercholesterolemia. To determine the prevalence of lipoprotein, apolipoprotein and metabolic disorders in premature CAD, 243 men and 61 women with premature CAD (occurring before age 60 years) and 203 age- and sex-matched controls (152 men, 61 women) were studied. After correcting for beta-blocker use (40% of men and 54% of women), hypertension and diabetes were seen more frequently in CAD patients than in controls. In men and women, cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) were significantly higher, and high density lipoprotein (HDL) cholesterol was lower, in CAD patients than in controls. By stratifying patients according to LDL cholesterol: HDL cholesterol ratio (5 or less, or greater than 5) and by triglyceride levels (less than 2.3 mmol/L, or 2.3 mmol/L or greater), significantly more men and women with CAD were found to have an elevated LDL cholesterol:HDL cholesterol ratio and elevated triglycerides (13.8% versus 1.9%, men and women combined, CAD versus controls, P < 0.0001). A metabolic factor index was devised, assigning a score of 1 each for presence of hypertension, lipoprotein abnormalities, diabetes or fasting blood glucose above 7.0 mmol/L, and a body mass index of 27 or greater. The prevalence of a metabolic factor index of 3 or more was 29.2% in CAD men versus 6.7% in controls (P < 0.0001) and 38.3% in CAD women versus 11.7% in controls (P < 0.01). Familial hypercholesterolemia was seen in fewer than 5% of patients with premature CAD and type III dyslipoproteinemia in one of 343 CAD patients. The distribution of apolipoprotein E phenotypes was the same in CAD patients and controls. Multivariate analysis revealed that in men, HDL cholesterol, lipoprotein (a) levels and smoking were the best predictors of risk. In men, plasma levels of LDL cholesterol, triglycerides or body mass index did not enter the model at the P < 0.05 level. In women, low HDL cholesterol, lipoprotein (a), the presence of diabetes, smoking and apolipoprotein B levels were all predictors of risk (P < 0.05). However, the clustering of risk factors may be the best predictor of risk. In this selected population, HDL and lipoprotein (a) are the best metabolic markers of premature CAD; metabolic factor clustering is common in patients with premature CAD.

[Profile of biostatistics utilization in three medical reviews. Implications for medical education]. / Profil d'utilisation des biostatistiques dans trois revues médicales. Implications pour la formation des médecins.

OBJECTIVE: To identify the most commonly used biostatistical concepts and tests in three journals read by family physicians. DESIGN: Descriptive study of the biostatistical content of 12 issues of the Canadian Medical Association Journal (CMAJ), Canadian Family Physician (CFP), and the New England Journal of Medicine (NEJM). MAIN OUTCOME MEASURES: Frequency of citations of concepts and tests, and Spearman's correlation coefficients comparing the biostatistical profiles of the three journals. RESULTS: Biostatistical content of NEJM was diverse (on average, 39 concepts and 21 tests per issue). In CFP, we found 10 concepts and four tests per issue. In CMAJ, there were, on average, nine concepts and five tests per issue. CONCLUSIONS: The journals' profiles (order of importance of concepts and tests) were fairly similar.

Lack of association of the apolipoprotein A-I-C-III-A-IV gene XmnI and SstI polymorphisms and of the lipoprotein lipase gene mutations in familial combined hyperlipoproteinemia in French Canadian subjects.

Familial combined hyperlipoproteinemia (FCH) is a common familial lipoprotein disorder characterized by elevated plasma cholesterol and triglyceride levels with segregation in first-degree relatives. Most affected subjects with FCH have elevated plasma levels of apolipoprotein (apo) B. The disorder results from oversecretion of hepatic apoB-containing lipoprotein particles. The genetic defect(s) are unknown. Previous work has suggested that genetic polymorphisms of the apoA-I gene and functional abnormalities of the lipoprotein lipase (LPL) gene are associated with FCH. We investigated the XmnI and SstI restriction fragment length polymorphisms (RFLP) of the apoA-I gene in FCH subjects of French Canadian descent. We also investigated three common functional mutations of the lipoprotein lipase (LPL) gene (LPLGly188Glu, LPLPro207Leu, and LPLAsp250Asn) in French Canadians that account for approximately 97% of cases of complete LPL deficiency in the province of Québec, Canada. We identified and characterized 54 FCH probands in lipid clinics and examined at least one first-degree relative. There were 37 men and 17 women (mean age 48 +/- 9 and 58 +/- 8 years, respectively). None of the probands had diabetes mellitus; mean plasma glucose was 5.5 mmol/L. High blood pressure was diagnosed in 32% of men and 29% of women. The body mass index (weight (kg)/height(m2)) was elevated in probands (27 +/- 4 for men and 26 +/- 4 for women). Mean plasma levels of cholesterol (C) was 7.6 +/- 1.5 mmol/L, triglycerides 3.5 +/- 1.6 mmol/L, LDL-C 4.9 +/- 1.2 mmol/L, HDL-C 1.0 +/- 0.3 mmol/L, and apoB 1.83 +/- 0.67 g/L in the probands. Allele frequency of the rare alleles of the XmnI and SstI RFLP was not significantly different from a healthy reference group. In several families studied, the XmnI and SstI RFLP did not unequivocally segregate with the FCH phenotype. There was no significant effect of the presence or absence of the XmnI or SstI RFLP's on plasma lipids, lipoprotein cholesterol or apoB levels. Only one FCH proband was found to have a mutation of the LPL gene (Gly188Glu), and this did not segregate with the FCH phenotype in the family. We conclude that in our highly selected group of FCH subjects of French Canadian descent, the XmnI and SstI RFLPs of the apoA-I gene and common functional mutations of the LPL gene resulting in complete LPL deficiency are not associated with FCH.

Fasting hyperinsulinism, insulin resistance syndrome, and coronary artery disease in men and women.

A large segment of the population gradually develops insulin resistance, and the related metabolic syndrome is one of the most frequent causes of atherosclerosis. Searching for a practical indicator of insulin resistance, we studied the correlations between fasting serum insulin level, the general manifestations of insulin resistance syndrome, and various aspects of coronary artery disease in 797 men and 322 women. After we classified patients according to the quartiles of serum insulin level, we noted in the top quartile the presence of practically all manifestations of insulin resistance syndrome in persons of both sexes (e.g., increased waist/hip ratio, body mass index, glucose, uric acid, triglycerides, apolipoprotein B and decreased high-density lipoprotein cholesterol levels as well as apolipoprotein A-I/B ratios, and so forth). We also noted a higher prevalence of hypertension, diabetes mellitus, and type IV hyperlipidemia. Significantly more women in the fourth than in the first quartile had angiographically documented significant stenosis of the coronary arteries (p = 0.0016, odds ratio 2.9, 95% confidence interval 1.5 to 5.6) and previous myocardial infarction (p = 0.0297, odds ratio 2.1, 95% confidence interval 1.1 to 4.1). Men in both the first and the fourth quartile had a more disturbed lipid profile and a higher prevalence of significant stenoses of coronary arteries and/or previous myocardial infarction than women; there was a tendency toward a lower prevalence of alcohol consumption (p = 0.0503), a higher prevalence of gout (p = 0.0634), and previous myocardial infarction (p = 0.0791) in men in the fourth than in the first quartile.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe familial HDL deficiency in French-Canadian kindreds. Clinical, biochemical, and molecular characterization.

A decreased level of HDL cholesterol (HDL-C) is the most common lipoprotein abnormality seen in people with premature coronary artery disease (CAD). In many cases, HDL-C reduction in patients with CAD may be the result of increased apo B-containing lipoprotein production by the liver with secondary hypoalphalipoproteinemia. Primary hypoalphalipoproteinemia is seen in approximately 4% of people with CAD. We report findings in four subjects with severe familial HDL deficiency (HDL-C << 5th percentile for age and sex; 0.08 to 0.38 mmol/L) in three French-Canadian kindreds with autosomal codominant inheritance. By inclusion criteria, all four subjects had normal fasting triglycerides and none were diabetic. HDL particle size by gradient gel electrophoresis revealed small HDL particles (estimated Stokes' diameter, 8.14 to 8.30 nm). Apo AI analysis by polyacrylamide gel electrophoresis and use of isoelectrofocusing gels in affected subjects revealed normal molecular weight (28.3 kD) and normal isoelectrofocusing point but a relative increase in proapoliprotein AI, with near-normal levels of proapolipoprotein AI in plasma, suggesting normal secretion of apo AI. Quantitative Southern blot analysis of the apo AI-CIII-AIV gene cluster reveals no gene rearrangements or allele deletion. Haplotypes of the apo AI gene, determined by use of the restriction enzymes Pst I, Xmn I, and Sst I and of the apo AII gene by use of the enzyme Msp I, did not reveal segregation of the low HDL-C trait with either the apo AI or the AII gene. Sequence analysis of the promoter region of the apo AI gene reveals heterozygosity for guanine-to-adenine substitution at position 76 in two kindreds with no evidence of segregation with the low HDL trait. None of the patients had mutations of the lipoprotein lipase gene common in subjects of French-Canadian descent. Haplotype analysis of the lipoprotein lipase gene did not show segregation with the low HDL trait. Plasma lecithin: cholesterol acyltransferase (LCAT) activity was found to be within normal levels in affected subjects and in nonaffected first-degree relatives. None of the affected subjects had clinical manifestations of Tangier disease. Two of the four cases examined, both men, had severe CAD and had undergone revascularization procedures. The third is a younger brother of one of these probands and the fourth is a 30-year-old woman, and both were free of clinical CAD. However, in none of the families did the low HDL trait unequivocally cosegregate with CAD.(ABSTRACT TRUNCATED AT 400 WORDS)

The place of ferritin among risk factors associated with coronary artery disease.

BACKGROUND: Prospective studies of East Finnish men demonstrated an increased risk of myocardial infarction in association with elevated serum ferritin levels (> or = 200 micrograms/l). The present study was designed to explore whether serum ferritin concentrations are related to angiographically determined coronary artery disease or to a past history of myocardial infarction. METHODS: We studied 225 men and 74 women, most of them of French-Canadian origin, undergoing elective coronary arteriography, and classified them according to the presence, absence, and severity of angiographic findings. A history of myocardial infarction was defined as clinical and electrocardiographic and/or enzymatic evidence of a myocardial infarction occurring more than 12 weeks previously or akinesia of the left ventricle. Serum ferritin was measured with the Baxter Stratus II immunoassay system. RESULTS: There were no significant differences in ferritin levels between patients with > or = 50% diameter stenosis (195 men, 48 women) and those with intact or minimally affected arteries (31 men, 26 women) either in men or in women. There was no correlation between the quartiles of serum ferritin and the severity of coronary artery disease. There were no differences in ferritin levels in patients with (95 men, 25 women) or without (71 men, 43 women) a history of myocardial infarction. However, serum lipid levels were significantly related to all the above conditions. CONCLUSION: In a French-Canadian population, serum ferritin levels, unlike serum lipids, were not related to the presence or severity of angiographically determined coronary artery disease, nor to a history of myocardial infarction.

Relation of coronary artery disease in women < 60 years of age to the combined elevation of serum lipoprotein (a) and total cholesterol to high-density cholesterol ratio.

After age 40 years, coronary artery disease (CAD) is the leading cause of death in both women and men, yet in women the factors associated with, or leading to, CAD have been less extensively studied. This study examined the strength of association of a number of risk factors to CAD in groups of women < 60 years of age with (n = 108) and without (n = 66) angiographically documented significant narrowing of coronary arteries. In univariate analyses, there were significant differences between control subjects and patients with regard to age (49 +/- 6 vs 52 +/- 7 years) and total lipids and apolipoproteins measured. The relative frequency of cigarette smoking and diabetes was higher and that of estrogen replacement therapy lower in patients with CAD than in control subjects. In multivariate analysis the following factors were independently associated with CAD (adjusted odds ratios and 95% confidence intervals): total cholesterol to high-density lipoprotein (HDL) cholesterol (1.91; 1.56 to 2.34); lipoprotein (a) (10.66; 3.51 to 32.35); estrogen replacement (0.24; 0.11 to 0.54); age (1.12; 1.04 to 1.18); and smoking (1.50; 0.98 to 2.29). The nonadjusted odds ratio of CAD, based on combined tercile values of lipoprotein (a) serum level and total cholesterol to HDL cholesterol ratio, was very low (0.15; 0.06 to 0.36) when both values were within the first tercile, but very high (16.63; 3.54 to 78.07) when both were in the third tercile.(ABSTRACT TRUNCATED AT 250 WORDS)

[How effective is the teaching of critical analysis of scientific publications? Review of studies and their methodological quality]. / L'enseignement de l'analyse critique des publications scientifiques médicales est-il efficace? Révision des études et de leur qualité méthodologique.

OBJECTIVE: To evaluate studies assessing the effectiveness of teaching critical appraisal of the literature to medical students. DATA SOURCES: French and English articles published between 1980 and 1990 indexed on MEDLINE or FAMLI as well as articles identified from the bibliographies. STUDY SELECTION: Studies were evaluated if the subjects were undergraduate or postgraduate medical students and if the teaching intervention was aimed at improving one or more of the following areas: knowledge in clinical epidemiology and biostatistics, reading habits and ability to critically appraise a scientific article. DATA EXTRACTION: The methodologic quality of the articles was assessed by three evaluators, who used a modified version of Poynard's checklist to assign a score. Articles with a score of 60% or more were considered satisfactory. The reliability of the checklist was evaluated by means of the kappa (kappa) coefficient and a coefficient of intraclass correlation. DATA SYNTHESIS: For the three evaluators the mean kappa coefficient was 0.33 and the coefficient of intraclass correlation 0.70. Five of the 10 studies had an overall score of 60% or higher. The quality of the individual sections of the articles varied: purpose of the study 85%, description of the population 58%, methods 44%, analysis of results 50%, and conclusions 90%. CONCLUSIONS: The effectiveness of teaching critical appraisal of the literature remains uncertain. More rigorous methods are needed in research in this area.