[Management of thyroid dysfunction by primary care physicians of the Province of Quebec: a transversal study]. / Etude transversale sur l'approche thérapeutique des patients avec troubles thyroïdiens par les omnipraticiens du Québec.

OBJECTIVES: This study aims to evaluate clinical practice of primary care physicians regarding common thyroid disorders. MATERIALS AND METHODS: A sample of 210 primary care physicians was randomly selected in three Quebec's administrative regions. Four clinical vignettes (V1 to V4) were presented by mail: two cases of subclinical hypothyroidism (women of 25 years - V1 - and 70 - V2 - years of age) for which physicians had to choose to either treat or not with thyroid replacement and two cases of hyperthyroidism (women of 30 - V3 - and 66 - V4- years of age) for which they had to choose a course of action (observation, treatment or referral to a specialist). V1 and V2 where followed by four sub-questions presenting supportive elements that could influence the decision to treat (presence of antithyroid antibodies, accumulation of symptoms, LDL cholesterol and thyreostimulin levels). RESULTS: The overall response rate was 22%. Forty-two percent of respondents would have treated V1 outright and 49% would have treated V2. The therapeutic approach in the face of these two vignettes, independently of the presence or absence of supportive clinical or biochemical elements, did not vary according to geographic practice area. However, one region was significantly more conservative for V4. The number of years in practice or assistance to continuous medical education activities did not affect management of vignettes. CONCLUSION: This study outlines the importance of clinical practice guidelines and tools to facilitate their application in clinical management of thyroid disorders.

Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits.

Fasting plasma total homocysteine (tHcy) concentration was measured in 380 men and 204 women selected for health on the basis of clinical history, physical examination, and normal results of a biochemical profile. We sought to define tHcy reference values in healthy individuals and to determine relations between tHcy and plasma folic acid, vitamin B-12, and pyridoxal phosphate (vitamin B-6) concentrations. Men had significantly higher plasma tHcy than women (9.7 +/- 4.9 compared with 7.6 +/- 4.1 mumol/L, x +/- SD) and lower folate concentrations (8.6 +/- 5.2 compared with 9.8 +/- 6.6 nmol/L, P < 0.05). Significant correlations were found between tHcy and uric acid, creatinine, albumin, folate, and vitamin B-12 concentrations. There was no correlation with age, body mass index, blood pressure, glucose, and total and lipoprotein lipids. When divided in quartiles of vitamin concentrations, subjects with the lowest vitamin B-12 and folate values had significantly higher tHcy concentrations than those in the other three quartiles. Interestingly, after exclusion of subjects in the lowest quartiles of folate and vitamin B-12 concentration, correlations between tHcy and vitamin concentrations were no longer observed, except for vitamin B-12 in men. Stepwise-multiple-regression analyses showed that the sex-specific influence of biological variables on tHcy concentrations was twice as important in healthy women than in healthy men. This study emphasizes the significance of sex-associated differences in the biology of homocysteine and underlines the importance of considering these in the determination of threshold values.

Cyclic fluctuations in human serum lipid and apolipoprotein levels during the normal menstrual cycle: comparison with changes occurring during oral contraceptive therapy.

The influence of menstrual cycle phases and hormonal contraception on serum lipid and apolipoprotein (apo) levels was investigated in a group of normally menstruating young women. The study period covered a normal menstrual cycle (pretherapy), the fourth cycle of treatment with a triphasic oral contraceptive (OC) preparation, and the cycle immediately following interruption of therapy (cycle 5, posttherapy). Cycle phases were defined on the basis of serum hormone levels and basal body temperature determinations. Significant differences in cholesterol (free and esterified) levels were observed during the menstrual phase of both the normal menstrual cycle (lower) and the OC cycle (higher), when compared with the other phases. Triglycerides, which were higher under OCs, fluctuated similarly throughout the two cycles, but phase differences did not reach statistical significance. Apo AI and apo B were both higher under OCs, and apo B followed a trend similar to cholesterol during the two cycles. During the first month after discontinuation of OCs, cholesterol levels returned progressively to baseline values, while triglycerides were only partially decreased. We conclude that cyclic fluctuations in lipid levels do occur under the influence of both endogenous and exogenous sex hormones.

PIP: Total and free cholesterol, triglycerides, and apolipoproteins apo-A1 and B were determined at precise phases of a pre-therapy menstrual cycle, the 4th cycle on a triphasic oral contraceptive, and in the 1st post-therapy menstrual cycle in 18 women. The triphasic pill contained 5 mcg ethinyl estradiol and 180, 215 and 250 mcg norgestimate for 7 days each (ORF 10131 Triphasic, Ortho Pharmaceuticals, Raritan, NJ). Total cholesterol and triglycerides were measured enzymatically by autoanalyzer (Abbott Bichromatic Analyzer 100), free cholesterol by commercial kit (Boehringer-Mannheim, Mannhein, Germany), and apolipoproteins by electroimmunoassay (Hydragel Apo A1/B, Sebia, Issy- les-Moulineaux, France), with strict quality control using commercial standards. Sera were sampled in 4 phases: Days 3, 4 or 5 of menses, in the follicular phase during rising or peak estradiol levels, at ovulation at peak or highest LH level, and in luteal phase at peak progesterone level. In pill cycles, sera were sampled during each week. Total cholesterol was significantly lower in the menstrual phase, rose on average 9.2% in follicular phase (range -6.8% to +34.4%, in 13 of 18 women), and declined only slightly in luteal phase. Free and esterified cholesterol showed a similar pattern. Triglycerides similarly were lowest in menstrual phase, but were not significantly higher during menstrual cycles. In oral contraceptive cycles, total cholesterol fell an average of 10.7% in the 1st week, and remained at that level until the next pill-free interval or upon discontinuation, when cholesterol rose 11.2%. After discontinuation of the pill, all women resumed normal ovulatory cycles and showed stepwise normalization of cholesterol. Apo-A1 was significantly higher in pill cycles and pill-free intervals than in normal menstrual cycles (p0.001 at all 4 sample points); apo-B was also significantly higher in all samples form pill cycles (p0.05-0.001). There was no correlation between cholesterol levels and any of the hormone levels measured, estradiol, progesterone, LH or FSH.

Influence of a triphasic oral contraceptive preparation on plasma lipids and lipoproteins.

The influence of a triphasic oral contraceptive preparation on plasma lipid, lipoprotein, and apolipoprotein levels was studied in 20 women during 12 treatment cycles. Multiple blood samples representing all phases of the therapeutic cycle as well as posttherapy were obtained. Total and low-density lipoprotein (LDL) cholesterol fluctuated transiently in the earlier part of the study but after 9 and 12 cycles of therapy did not differ from baseline. Cyclic elevations in total cholesterol corresponding to changes in LDL cholesterol were noted twice. Total high-density lipoprotein (HDL) cholesterol remained remarkably stable over the entire study while HDL2 cholesterol decreased and HDL3 cholesterol increased. Triglycerides (total and lipoprotein fractions) increased during treatment and fell to baseline levels within one posttreatment cycle. Very low-density lipoprotein (VLDL) cholesterol was also elevated during the study. Apolipoprotein (apo) AI, apo AII, and apo B rose under therapy, the latter increase producing a lowered LDL cholesterol/apo B ratio. Apolipoprotein E showed a temporary decrease early in the study but otherwise remained unchanged.

Identification of the patient at risk in the physician's office and drug management of dyslipoproteinemia.

The wealth of convincing evidence favouring the major role of lipids in atherosclerosis and the benefit of lipid lowering therapy for its prevention now sets the stage for more practical questions: "Whom to treat? When to treat? How to treat?". Although each patient must be considered individually, there are general rules and specific guidelines that should be underlined. An isolated finding of abnormal lipid levels should by no means be a systematic starting point for initiating treatment. In a step by step approach, guidelines for individual risk assessment, systematic search for specific clinical clues and pertinence of complementary investigative measures are given. In addition to ensuring a correct diagnosis, these recommendations will orient the physician's decision with respect to the necessity of initiating treatment and, if warranted, the choice of an optimal treatment algorithm. Therapeutic modalities are discussed both in general and specific terms, focusing mostly on pharmacologic agents. Clinical indications, mechanisms of action, adverse effects and expected efficacy are seen for each drug or family of drugs, including those with a promising future. In summary, 10 easy rules of thumb are provided to ensure adequate diagnosis and management of hyperlipidemia.

Dyslipidemias and the primary prevention of cardiovascular disease: analysis of the FAMUS primary care register.

BACKGROUND: Primary prevention of cardiovascular disease with a pharmacological approach to dyslipidemias is controversial. Little is known about the clinical management by general practitioners in this area. OBJECTIVES: To evaluate the patterns of treatment of patients in primary prevention who were entered in the FAmily Medicine, Université de Sherbrooke (FAMUS) register and to calculate the probability of their receiving a hypolipidemic agent according to the presence of various risk profiles. PATIENTS AND METHODS: Descriptive study based on the FAMUS prospective primary care register. Data from patients in primary prevention (those who had not sustained a cardiovascular event) were extracted and analyzed. MAIN RESULTS: Of the 52,505 patients in the register, 48, 190 were identified as being in primary prevention. Of these, 22,250 (46.2%) had a complete lipid profile on record, and 2300 had received a prescription for a hypolipidemic agent (4.8%). Patients under pharmacological treatment had significantly higher lipid values. The adjusted relative risk of being treated with a hypolipidemic agent was 1.3 for smokers, 1.3 for diabetic patients, 2.0 for those with a positive family history of premature cardiovascular disease, 2.2 for hypertensives and 3.3 for men over 45 years of age or women over 55 years, compared with patients who were not taking lipid-lowering medications. The number of risk factors was even more strongly associated with the probability of being treated. CONCLUSION: Overall, few patients in primary prevention in the register were treated with a pharmacological agent. The presence of associated risk factors in this study was an important predictor for treatment, suggesting that patients in primary prevention are being evaluated globally as a function of all of their risk factors, not just their lipid and lipoprotein levels. Further attention, nonetheless, needs to be directed to the segment of the population with multiple risk factors whose lipoprotein profile is unknown or who are not being treated to guideline target levels.

Antiplatelet and lipid-lowering therapies for the secondary prevention of cardiovascular disease: are we doing enough?

OBJECTIVE: To evaluate whether current recommendations with respect to the treatment of dyslipidemias and the use of antiplatelet agents are being applied in the secondary prevention of cardiovascular disease in primary care settings. DESIGN: Descriptive study based on data from the FAMUS (FAmily Medicine, Université de Sherbrooke) primary care register. SETTING AND PARTICIPANTS: Two-hundred and thirty-three physicians participating in the FAMUS project contributed information from nonpregnant patients over 20 years of age consulting for a periodic health examination between 1992 and 1996. INTERVENTIONS: Data from patients in secondary prevention (those with or having had angina, a previous myocardial infarction, bypass surgery, coronary angioplasty or peripheral vascular disease) were extracted and analyzed. MAIN RESULTS: Of the 52,505 patients in the register, 4315 (8%) were identified as being in secondary prevention. Overall, 53% were noted as receiving an antiplatelet agent while 4% were taking warfarin therapy. Only 64% (2780) had a complete lipid profile on record while 38% were being treated with a hypolipidemic agent. In the treated group, only 30% had a low density lipoprotein cholesterol level below 3.0 mmol/L compared with 22% in the untreated group. CONCLUSIONS: A large number of patients identified as being in secondary prevention were not screened for dyslipidemias, and, of those who were, the majority were undertreated according to current recommendations. Antiplatelet agents were more widely prescribed but potentially underused.

Informatics methodologies for evaluation research in the practice setting.

A continuing challenge in health informatics and health evaluation is to enable access to the practice of health care so that the determinants of successful care and good health outcomes can be measured, evaluated and analysed. Furthermore the results of the analysis should be available to the health care practitioner or to the patient as might be appropriate, so that he or she can use this information for continual improvement of practice and optimisation of outcomes. In this paper we review two experiences, one in primary care, the FAMUS project, and the other in hospital care, the Autocontrol project. Each project demonstrates an informatics approach for evaluation research in the clinical setting and indicates ways in which useful information can be obtained which with appropriate feed-back and education can be used towards the achievement of better health. Emphasis is given to data collection methods compatible with practice and to high quality information feedback, particularly in the team context, to enable the formulation of strategies for practice improvement.

[The ambulatory care of the acute myocardial infarction in Quebec: description, classification and typology]. / Les soins ambulatoires de l'infarctus aigu du myocarde au Québec : description, classification et typologie.

OBJECTIVE: Description of ambulatory care of AMI, in Quebec population. DESIGN: A retrospective cohort study was designed to classify and propose a typology of ambulatory care. METHODS: The studied population was included in all 25 years and older inpatients residing in Quebec, whose admission were from January to December 2000. The principal variables were: the number of medical visits, the type of consulted physicians and the place of consultation. The secondary variables were: age, sex and the presence of a revascularization. RESULTS: A typology of ambulatory care was created from principal variables. Men, younger patients and receiving a revascularization in the index hospitalization were cared for by a specialist.

Eruptive and tubero-eruptive xanthomas of the skin arising on sites of prior injury. Two case reports.

Eruptive and tubero-eruptive xanthomas arising at the site of previous minor skin injury are described in two patients with type IV and type III hyperlipidemia, respectively. In one case, the lesions appeared following a cat scratch, while in the second, massive bee stinging preceded the appearance of a constellation of xanthomas.

Family history and the risk of coronary heart disease: comparing predictive models.

Family history is commonly used when evaluating coronary heart disease (CHD) risk yet it is usually treated as a simple binary variable according to the occurrence or non-occurrence of disease. This definition however fails to consider the potential components of a family history which may in fact exert different degrees of influence on the overall risk profile. The purpose of this paper is to compare different predictive models for CHD which incorporate family history as either a binary variable or different types of family risk indices in terms of their predictive ability. Models for estimating CHD risk were constructed based on usual risk factors and different family history variables. This construction was accomplished using logistic regression and RECursive Partition and AMalgamation (RECPAM) trees. Our analyses demonstrate the importance of using more sophisticated definitions of family history variables compared to a simple binary approach since this leads to a significant improvement in the predictive ability of CHD risk models.

Apolipoprotein E polymorphism association with lipoprotein profile in endogenous hypertriglyceridemia and familial hypercholesterolemia.

Apolipoprotein (apo) E polymorphism was among the first-reported genetic polymorphisms that explained part of the normal variation in plasma cholesterol concentrations in humans. The aim of this study was to assess the influence of allelic variation at the apo E gene locus on the plasma lipoprotein profile in hyperlipidemia. The lipoprotein levels of hyperlipidemic subjects of the major apo E phenotypes (E3/2, E3/3, and E4/3) were compared. One hundred eighty-two subjects with endogenous hypertriglyceridemia and 98 subjects with familial hypercholesterolemia due to a 10-kb deletion in their low density lipoprotein (LDL) receptor genes were compared with 424 normolipidemic controls from the same environmental background. LDL concentrations were lower in the E3/2 subset than in the E3/3 or E4/3 subset in the control, hypertriglyceridemic, and familial hypercholesterolemic groups. In absolute values, the magnitude of the effect was greatest in the familial hypercholesterolemic group. However, the direction and percentage change were identical in the presence or absence of the LDL receptor defect, indicating that the apo E phenotype effect is independent of LDL receptor status. Triglyceride and very low density lipoprotein (VLDL) cholesterol concentrations were higher in E3/2 than in E3/3 or E4/3 hypertriglyceridemic subjects, but this difference was not found in the familial hypercholesterolemic or control group. Thus, there seems to be a specific interaction between apo E isoforms and VLDL metabolism in hypertriglyceridemia; allelic variation at the apo E gene locus seems to be associated with specific alterations in the plasma lipoprotein profile of subjects with well-defined types of hyperlipidemia.

Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health.

Five-hundred seventy-five white-collar workers (374 men; 99% Caucasians) aged 20-59 years were selected on the basis of their being healthy and clinically free from cardiovascular risk factors (except smoking and family history). We have observed a higher relative frequency of the epsilon 3 allele in this population, as is true of populations with a low prevalence of coronary heart disease. Each of the 11 plasma lipid and lipoprotein traits studied was adjusted for age, weight, height, body mass index, plasma glucose, and uric acid in men and women separately. The influence of each of the three common apo E alleles on each adjusted trait was evaluated by use of the average excess statistic. We established that in a population selected for health, the epsilon 2 allele is associated with lower plasma levels of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B associated with LDL cholesterol in both men and women. Conversely, the epsilon 4 allele is associated with higher levels of these traits in women only. In contrast to the findings in populations not selected for health, the presence of the epsilon 2 allele in our subjects tended to be associated with lower and the epsilon 4 allele with higher plasma triglyceride levels. Finally and of particular note, the influence of the apolipoprotein E polymorphism on plasma measures of LDL metabolism is different in men and women. Specifically, the influence of the epsilon 4 allele is of greater magnitude in women. A part of this gender difference in allele effects on LDL metabolism in women is associated with the use of oral contraceptives and postmenopausal hormone replacement therapy.

Cardiovascular disease. Physician attitudes toward prevention and treatment.

OBJECTIVE: Survey of physician attitudes toward practising cardiovascular disease prevention. DESIGN: Questionnaire administered via telecommunication from 1992 through 1994. SETTING: The FAMUS (Family Medicine, University of Sherbrooke) project, between 1992 and 1996, used weekly telecommunication to collect data from 200 general practitioners throughout the province of Quebec on cardiovascular disease risk factors and their treatment. PARTICIPANTS: Of 200 physicians contributing to the FAMUS project, 156 completed questionnaires (response rate 78%). MAIN OUTCOME MEASURES: Variations in attitudes to prevention policy and risk factor interventions. RESULTS: Survey results revealed physicians knew important risk factors for cardiovascular disease but differed in attitudes toward efficacy of treatment. Intervention to control cholesterol was thought to be very effective by 21.2% (95% confidence interval [CI] 21.2 +/- 6.4) and without effect by 10.3% (95% CI 10.3 +/- 4.8). Intervention to improve dietary habits was considered ineffective by 48.1% (95% CI 48.1 +/- 7.8). Confidence in managing risk factors varied; most respondents described themselves as only moderately skilled. A few practitioners (30.1%; 95% CI 30.1 +/- 7.2) acknowledged practice guidelines as an important source of information on which to base preventive interventions. Only 14.7% (95% CI 14.7 +/- 5.6) of those surveyed included remuneration as contributing to their implementation of prevention activities in practice. CONCLUSIONS: Variations in physician attitudes could influence risk factor intervention. Interventions to change lifestyle are associated with uncertainty about patient compliance, efficacy of treatment, and ability to effect lifestyle changes.

Sources of variation in plasma lipid and lipoprotein traits in a sample selected for health.

Substantial variation in plasma lipid, lipoprotein, and apolipoprotein B levels was found in a sample of healthy white collar workers aged 23-59 years (144 women, 371 men) devoid of most clinically identifiable manifestations of cardiovascular disease or major biochemical anomalies and for whom data were gathered in Montreal, Canada, in 1987. The nature of this variability was examined for each gender by means of a stepwise linear regression analysis using indices of biologic variation and behavioral traits. In women, age, height, and weight together accounted for approximately 10% and uric acid for another 7-10% of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B level variation. In men, age alone accounted for 13-16% of the total variation in these traits while uric acid contributed only 3%. The additional contribution of behavioral traits was found to be at least double that associated with the indices of biologic variation for measures of very low density lipoprotein (VLDL) and high density lipoprotein (HDL) cholesterol in women and HDL cholesterol in men. After taking all of the above into account, genetic variation determined by the three common apo E alleles explained an additional 6% of LDL cholesterol variation in women and 3.5% in men. These results emphasize the range of variability in lipid, lipoprotein, and apolipoprotein values in healthy individuals as well as important gender differences in the contribution of biologic, behavioral, and genetic factors in this variability.

Impact of age and body size on inter-individual variation in measures of lipid metabolism: influence of gender and apolipoprotein E genotype.

This study was undertaken in 1695 adult subjects (870 women and 825 men) in order to further document the complexity of the influence of the apolipoprotein (apo) E genotypes on the mean levels and intragenotypic variability of seven measures of lipid metabolism. In addition, the statistical relationships between variability in these traits and variation in age, body mass index (BMI) and waist-to-hip ratio (WHR) were assessed. The contribution of variation in age and body size to inter-individual variation was found to be dependent on context, defined by gender and apo E genotype. Our findings are consistent with the reality that it is neither genes nor environments, but their interactions that are responsible for the variation in risk of cardiovascular disease.

[Treatment patterns of hypertension in 1996. Data from the Quebec Family Practice, University of Sherbrooke registry]. / Habitudes de traitement de l'hypertension en 1996. Données du registre québécois FAMUS.

OBJECTIVE: To describe the treatment of hypertension, alone or in combination with associated conditions, by a group of general practitioners in the FAMUS network and to compare these treatment patterns to the recommendations of the Canadian Hypertension Society Consensus. DESIGN: Descriptive study based on data collected by 233 physicians in the FAMUS provincial register on hypertensive patients treated in 1996. PARTICIPANTS: Developed between 1992 and 1996, the register contains 52,505 patients, 9,094 of whom have high blood pressure. These patients consulted their general practitioners for a complete examination. The data concern the risk factors for cardiovascular disease and include the list of medications prescribed. MAIN OUTCOME MEASURES: Evaluation of the proportions in which various classes of medications were prescribed, and the most common combinations in relation to the presence or absence of associated conditions. RESULTS: Of the 4,049 hypertensive patients seen in 1996, 50.2% were treated with one medication; 32.9% were treated with more than one medication; and 16.9% received no antihypertensive medication. The most frequently prescribed medications were calcium channel blockers (26.1%), followed by diuretics (25.3%), angiotensin-converting enzyme inhibitors (24.3%), and beta-blockers (20.0%). Other agents made up the remaining 4.3% of prescriptions. The proportions were similar for patients without complications who received one medication. CONCLUSIONS: Results of this study suggest that the new molecules are widely used and that treatment patterns differ from the recommendations of the Canadian Hypertension Society Consensus, particularly in the absence of associated conditions.

Characterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects.

We have found a novel apoE5 mutation, using isoelectric focusing (IEF), in two apparently unrelated French-Canadian subjects. Co-dominant inheritance was demonstrated in the family of the first proband, a healthy male subject. The presence of the apoE5 form was not associated with lipid abnormalities or cardiovascular disease in this family. The second proband was a hyperlipidemic female patient suffering from angina, with no informative relatives available for study. In both individuals, monoclonal antibody studies demonstrated that the mutation was associated with the loss of two overlapping epitopes at the amino terminus of the protein. Cysteamine treatment of the very low density lipoproteins indicated that the mutant apoE contained only one cysteine residue, suggesting that apoE3 was the parental form. Two-dimensional electrophoresis suggested that the mutated protein had a slightly lower molecular weight (by 1-2 kDa). However, DNA sequencing of the third exon of the apoE gene in both probands revealed a single G to A substitution at the 48th nucleotide, changing the amino acid at position 13 from glutamic acid to lysine. These results were confirmed by oligo melting experiments with allele-specific probes in relatives of the probands. The study of this apoE variant should provide additional insight into the structure-function relationship of apoE.

Patterns of association between genetic variability in apolipoprotein (apo) B, apo AI-CIII-AIV, and cholesterol ester transfer protein gene regions and quantitative variation in lipid and lipoprotein traits: influence of gender and exogenous hormones.

Patterns of RFLP association were studied, to identify gene regions influencing quantitative variation in lipid and lipoprotein traits (coronary artery disease [CAD] risk factors or metabolically related traits). Subjects (118 female and 229 male; age 20-59 years) were selected for health. Multiple RFLPs were used to sample variability in regions around genes for apolipoprotein (apo) B (restriction enzymes HincII, PvuII, EcoRI, and XbaI), apo AI-CIII-AIV (BamHI, XmnI, TaqI, PstI, SstI, and PvuII) and cholesterol ester transfer protein (TaqI). Separate analyses were done by gender. The sample was truncated at mean +/- 4 SD, to remove extreme outliers. There was no significant gender difference in RFLP genotype frequency distribution. After trait-level adjustment to maximize removal of concomitant variability, analysis of variance was used to estimate the percentage trait phenotypic variance explained by measured variability in the gene regions studied. Fewer gene regions were involved in men, with less influence on quantitative trait variation than in women, in whom hormone use affected association patterns. Gender differences imply that pooling genders or adjusting data for gender effects removes genetic information and should be avoided. The association patterns show that variability around the candidate genes modulates trait levels: the genes are contributors to the genetics of CAD risk variables in a healthy sample.