Reproducibility of individualized coronary heart disease risk calculations in patients with diabetes mellitus.

AIMS: To determine prospectively, the reproducibility of individualized coronary heart disease (CHD) risk estimations in a high-risk (diabetic) population. METHODS: One hundred and three patients attending a hospital diabetes clinic who were in the primary prevention category for CHD had measurements of cholesterol, HDL-cholesterol and systolic blood pressure (SBP) performed in one of 13 general practices and then 2 weeks later in the hospital clinic. The data were combined with age, sex, smoking history and diabetic status data to produce a 10-year CHD risk estimate for each occasion using the Framingham algorithm. RESULTS: The coefficients of variation for cholesterol, HDL and SBP were 6.0%, 9.4% and 7.0%, respectively. When classified by treatment thresholds of 15% and 30% 10-year CHD risk, 88% of patients were classified in the same category on both occasions. Kappa values for the 15% and 30% risk thresholds were 0.71 and 0.82. This indicates good interobserver agreement for the estimation of CHD risk. The use of a single BP rather than the mean of two, resulted in seven of 206 estimations of CHD risk performed in 103 patients crossing a risk threshold, with 6/7 being placed in a higher risk category. CONCLUSIONS: Estimation of CHD risk on a single occasion is sufficient to make robust treatment decisions based on risk thresholds. Use of a single BP measurement rather than the mean of two overestimates the risk category in around 3% of cases.

Comparative accuracy of cardiovascular risk prediction methods in patients with diabetes mellitus.

OBJECTIVE: To compare the accuracy of cardiovascular risk prediction methods based on equations derived from the Framingham Heart Study in a cohort of patients with diabetes mellitus. RESEARCH DESIGN AND METHODS: Risk factor data was collected prospectively from 906 patients with diabetes mellitus. Absolute cardiovascular risks were calculated using the Framingham equation, and estimated with the currently available Framingham-based risk tables and charts. The sensitivity, specificity, positive and negative predictive values of the tables and charts to assess cardiovascular risk were assessed using calculation of risk from the full Framingham equation as the reference method. RESULTS: In all, 146 subjects (16.1%) had calculated 10-year coronary heart disease (CHD) risks > or = 30%, and 585 (64.6%) had risks > or = 15%. For identification of those at 10-year CHD risk > or = 30%, the original Sheffield tables had a sensitivity of 43% (95% confidence intervals (CI) 19.9-61.7%) and specificity of 94% (CI 90.8-96.7%). Modifications of the Sheffield tables improve sensitivity (95% CI 93.9-97%) but reduce specificity (90% CI 85.6-95.7%). The Joint British Guidelines' charts have a moderate sensitivity (69.5% CI 51.8-81.9%) and high specificity (99.7% CI 98.9-100%). For identification of individuals at a 10-year CHD risk > or = 27%, the Framingham categorical tables had a sensitivity of 95% (CI 91.6-97.8%), but a specificity of only 83% (95% CI 79.1-85.5%). CONCLUSIONS: The Joint British charts appear to have the best performance in a cohort of patients with diabetes mellitus, however, calculation of CHD/CVD (cardiovascular disease) risks with personal or laboratory computers using the full Framingham equation remains the most accurate way to assess cardiovascular risk in a primary prevention setting.

The leukemogenic transcription factor E2a-Pbx1 induces expression of the putative N-myc and p53 target gene NDRG1 in Ba/F3 cells.

The chimeric transcription factor E2a-Pbx1 is expressed as a result of the 1;19 chromosomal translocation in some 5% of cases of pediatric acute lymphoblastic leukemia. We investigated the biological and transcriptional consequences of forced expression of E2a-Pbx1 in the interleukin-3 (IL-3) dependent, bone marrow-derived cell line Ba/F3. We show that forced expression of E2a-Pbx1 induces apoptosis in Ba/F3 cells without apparent effects on cell cycle progression. This pro-apoptotic effect is enhanced on cytokine deprivation. Furthermore, using cDNA representational difference analysis (RDA), we show that these cellular effects are associated with marked induction of the gene NDRG1, which was previously identified as a target of transcriptional repression by N-myc and induction by the tumor suppressor protein p53. We identify a portion of the NDRG1 promoter capable of mediating transcriptional induction by E2a-Pbx1 and show that NDRG1 is also induced on simple IL-3 deprivation of BaF3 cells. Although we show that E2a-Pbx1 induction of NDRG1 is not impaired as a result of targeting p53 using HPV E6, and therefore does not appear to be p53-dependent, our results overall are consistent with the notion that induction of NDRG1 by E2a-Pbx1 may represent part of an apoptotic or cytostatic cellular response to oncogene activation.

Comparative accuracy of cardiovascular risk prediction methods in primary care patients.

OBJECTIVE: To compare the relative accuracy of cardiovascular disease risk prediction methods based on equations derived from the Framingham heart study. DESIGN: Risk factor data were collected prospectively from subjects being evaluated by their primary care physicians for prevention of cardiovascular disease. Projected cardiovascular risks were calculated for each patient with the Framingham equations, and also estimated from the risk tables and charts based on the same equations. SETTING: 12 primary care practices (46 doctors) in Birmingham. PATIENTS: 691 subjects aged 30-70 years. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of the Framingham based risk tables and charts for treatment thresholds based on projected cardiovascular disease or coronary heart disease risk. RESULTS: 59 subjects (8.5%) had projected 10 year coronary heart disease risks >/= 30%, and 291 (42.1%) had risks >/= 15%. At equivalent projected risk levels (10 year coronary heart disease >/= 30% and five year cardiovascular disease >/= 20%), the original Sheffield tables and those from New Zealand have the same sensitivities (40.0%, 95% confidence interval (CI) 26.6% to 57.8% v 41.2%, 95% CI 28.7% to 57. 3%) and specificities (98.6%, 95% CI 97.2% to 99.3% v 99.7%, 95% CI 98.8% to 100%). Modifications to the Sheffield tables improve sensitivity (91.4%, 95% CI 81.3% to 96.9%) but reduce specificity (95.8%, 95% CI 93.9% to 97.3%). The revised joint British recommendations' charts have high specificity (98.7%, 95% CI 97.5% to 99.5%) and good sensitivity (84.7%, 95% CI 71.0% to 93.0%). CONCLUSIONS: The revised joint British recommendations charts appear to have the best combination of sensitivity and specificity for use in primary care patients.

Laboratory-based calculation of coronary heart disease risk in a hospital diabetic clinic.

AIMS: To develop an estimation of risk of coronary heart disease (CHD) based on the Framingham equation for use in a diabetes clinic, given concerns about the accuracy of the Sheffield risk tables in this setting. METHODS: A computer program using the Framingham equation based on patients' age, sex, systolic blood pressure, smoking history, presence of diabetes and left ventricular hypertrophy was applied to requests for lipid screening of patients attending the diabetes clinics of Birmingham Heartlands Hospital. The calculated risks for the population were compared with those estimated from the Sheffield tables. RESULTS: Of 1060 patients with diabetes mellitus, 215 (20%) had an annual CHD risk > or =3%, which is considered to be the threshold at which lipid-lowering drugs are cost-effective. Only 24 of these 215 patients (11%) were correctly identified by the Sheffield tables, which we conclude have an unacceptably low sensitivity in diabetes mellitus. CONCLUSIONS: A laboratory-based CHD risk calculation system is a practical alternative to the Sheffield system and may have a greater sensitivity in the diabetic clinic.

A novel fully automated method for the measurement of sulphoconjugated catecholamines in urine using the Gilson ASTED-XL sample preparation system and high-performance liquid chromatography.

Dopamine is produced in the kidney where it causes sodium excretion. Dopamine sulphate is deconjugated in vivo, and may be a physiological reservoir for this active renal dopamine. To investigate the role of dopamine and dopamine sulphate in sodium homeostasis we have developed a fully automated HPLC assay for free, total and sulphoconjugated dopamine. Using the Gilson ASTED-XL sample preparation unit, with temperature controlled racks, urinary free and total dopamine are measured pre-and post-incubation with arylsulphatase. Dopamine sulphate is calculated from the difference between free and total measurements. Acidified 24 h urines are processed automatically. Free dopamine assay follows buffering to pH 7.0, addition of internal standard, addition of EDTA to stabilize free catecholamines at neutral pH, and incubation at 37 degrees C for 30 min. This mixture is trace enriched on a HEMA-SB TEC prior to ion-paired HPLC with amperometric detection. To measure total dopamine the entire process is automatically repeated with addition of arylsulphatase (400 mU/mL urine) at the beginning of the 37 degrees C incubation. The working range of the assay is up to 7 micromol/L total dopamine. Within-and between-run imprecision for dopamine sulphate is less than 3 and 7% respectively. Median dopamine sulphate excretion in 12 normotensive subjects was 4.3 micromol/24 h.

A non-isotopic method for estimating 11 beta hydroxysteroid dehydrogenase activity in vivo.

11 beta-hydroxysteroid dehydrogenase (11 beta HSD) has both dehydrogenase (11 beta DH) and reductase (11 beta R) activities, which catalyse the interconversion of cortisol and cortisone, and prednisolone and prednisone. This enzyme confers specificity on the mineralocorticoid receptor by local oxidation of cortisol to cortisone. Using radiolabelled cortisol 11 beta HSD activity has been shown to be lower in some cases of essential hypertension. This study investigated a novel approach to estimating 11 beta HSD activity in vivo. Plasma steroid kinetics were investigated following oral hydrocortisone (a substrate for 11 beta DH) and prednisone (a substrate for 11 beta R) in five normotensive volunteers after dexamethasone suppression of endogenous steroid production. This approach was evaluated by inducing partial deficiency of 11 beta HSD in the volunteers who took liquorice (to inhibit 11 beta DH) and then carbenoxolone (to inhibit both 11 beta DH and 11 beta R). The ratio of cortisol to prednisolone (formed from prednisone) provided a measure of the activity of both 11 beta DH and 11 beta R. At 75 min after the steroid bolus the ratio increased from 1.1 (0.6-1.3) (median, range) under control conditions to 1.2 (0.8-1.7) after liquorice (P = 0.01, n = 5), and 2.0 (1.3-5.9) after carbenoxolone (P = 0.02, n = 5). It may therefore be applied to the measurement of 11 beta HSD activity in vivo in large numbers of hypertensive patients without the use of radioisotopes.

Uses and misuses of serum hCG--a clinical audit.

A 24-hour laboratory-based service was established in the City Hospital, Birmingham, England, in 1987 for semi-quantitative serum human chorionic gonadotrophin (hCG) assay and specific clinical criteria for requests were agreed. However, a 309% increase in workload between 1988 and 1992 prompted a detailed clinical audit of this service. During a representative month only 35% of 142 requests conformed to the agreed criteria. Those for routine diagnosis of pregnancy, threatened miscarriage, and 'abdominal pain screen' comprised 49% of total requests and seemed inappropriate. No pregnancy was diagnosed by 'abdominal pain screen'. Adhering to agreed clinical criteria, therefore, would not jeopardise patient care and could halve the cost of the service. As a result of this audit the established criteria for serum hCG estimation were reinforced and re-issued to all relevant clinical teams. Additionally, to improve delivery of service and reduce costs a semi-quantitative urine hCG assay was introduced in the Accident and Emergency Department for use by approved staff. Records in this department showed no increase in hCG requests during the six months after the service change, compared with those in the preceding half year. However, theoretical cost savings of 5173 pounds per annum were eroded by an estimated 10% because 208 (26%) tests were unaccounted for. The reasons for this apparent 'wastage' are unclear, and highlight the difficulty in auditing a biochemical test performed outside the laboratory.

Lead poisoning from Asian traditional remedies in the West Midlands--report of a series of five cases.

1. Traditional remedies are an unusual, but recognised cause of lead poisoning. Only two cases have previously been reported in this country. 2. We report a series of five cases of lead poisoning due to traditional remedies in the West Midlands. All developed typical clinical features. 3. Blood lead and zinc protoporphyrin (ZPP) concentrations were elevated 2-10 times the upper limit of normal. The remedies contained up to 60% lead by weight. One also contained traces of mercury, another arsenic, and a third aluminium and tin. 4. Confirmation of the medicines as the cause of the poisoning was made in one patient by measurement of lead isotopic ratios. 5. The present morbidity from traditional remedies may be far greater than is realised, and will continue until such time as the supply of harmful preparations can be effectively limited. There needs to be increased awareness of their dangers amongst doctors and the communities at risk. This will best be achieved by appropriately targeted education.