Cytochrome P450 2C9 *2 and *3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus.

Sulfonylurea hypoglycemics are mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme. The CYP2C9*2 and *3 polymorphisms encode proteins with less enzymatic activity and are correlated with elevated serum levels of sulfonylurea, as demonstrated in healthy volunteers. In this study, the effect of these variants is described for patients with diabetes mellitus treated with sulfonylurea. Associations between CYP2C9 polymorphisms, prescribed doses of sulfonylurea, and change in glucose levels after the start of sulfonylurea therapy were assessed in all patients with incident diabetes mellitus starting on sulfonylurea therapy in the Rotterdam Study, a population-based cohort study of 7,983 elderly people. In CYP2C9*3 allele carriers using tolbutamide, the prescribed dose was lower compared to patients with the wild-type CYP2C9 genotype. No differences in the prescribed dose were found in tolbutamide users with the CYP2C9*1/*2 or CYP2C9*2/*2 genotype compared to wild-type patients or in patients using other sulfonylurea. In CYP2C9*3 allele carriers, the mean decrease in fasting serum glucose levels after the start of tolbutamide therapy was larger than in patients with the wild-type genotype, although not statistically significant. Patients with diabetes mellitus who are carriers of a CYP2C9*3 allele require lower doses of tolbutamide to regulate their serum glucose levels compared to patients with the wild-type genotype.

A critical appraisal of non-invasive diagnosis and exclusion of deep vein thrombosis and pulmonary embolism in outpatients with suspected deep vein thrombosis or pulmonary embolism: how many tests do we need?

The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism of less than 1% during 3 month follow-up. Compression ultrasonography (CUS) has a negative predictive value (NPV) of 97% to 98% indicating the need of repeated CUS testing. Serial CUS testing is safe but you have to repeat 100 CUS to find 1 or 2 CUS positive for deep vein thrombosis (DVT), which is not cost-effective indicating the need to improve the diagnostic work-up of DVT by the use of clinical score assessment and D-dimer testing. The combination of a less sensitive D-dimer test (SimpliRed) and low clinical score does not, whereas the combination of a sensitive D-dimer test (ELISA VIDAS or Tinaquant) and low clinical score does safely exclude DVT without the need of CUS. The combination of a first negative CUS and a negative less sensitive D-dimer test (SimpliRed) or a sensitive ELISA D-dimer at a higher cut off level of 1,000 ng/ml safely excludes DVT with a NPV of > 99% without the need to repeated CUS in about 60%. The sequential use of a sensitive D-dimer and clinical score assessment will safely reduce the need for CUS testing by 40% to 60%. Large prospective outcome studies demonstrate that one negative examination with complete duplex color ultrasonography (CCUS) of the proximal and distal veins of the affected leg with suspected DVT is safe to withhold anticoagulant treatment with a NPV of 99.5%. This indicates that CCUS is equal or superior to serial CUS or the combined use of clinical score, D-dimer testing and CUS. Pulmonary angiography is the gold standard for segmental pulmonary embolism (PE) but not for subsegmental PE. A normal perfusion lung scan and a normal rapid ELISA VIDAS D-dimer test safely exclude PE. Helical spiral CT detects all clinically relevant PE and a large number of alternative diagnoses in symptomatic patients with a non-diagnostic ventilation perfusion scan (VP-scan) or a high probability VP-scan. Single-slice helical CT as the primary diagnostic test in patients with suspected PE in 5 retrospective studies and in 3 prospective management studies indicate that the NPV of a normal helical spiral CT, a negative CUS of the legs together with a low or intermediate pretest clinical probability is 99%. Helical spiral CT can replace both the VP-scan and pulmonary angiography to safely rule in and out PE. The combination of clinical assessment, a rapid ELISA VIDAS D-dimer followed by CUS will reduce the need for helical spiral CT by 40% to 50%.

Diagnosis of deep vein thrombosis: how many tests do we need?

The requirement for a safe diagnostic strategy should be based on an overall post-test incidence of venous thromboembolism (VTE) of less than 1% during 3 month follow-up. Compression ultrasonography (CUS) has a negative predictive value (NPV) of 97 to 98% indicating a post-CUS incidence of deep vein thrombosis (DVT) of 2 to 3%. A post-CUS DVT incidence of 3% implicates that 90 to 120 DVTs per 1 million inhabitants will be overlooked each year indicating the need to improve the diagnostic work-up of DVT as much as possible. The qualitative D-dimer test (SimpliRed) has a sensitivity of 82 to 89% and a negative predictive value of 94 to 95% indicating a 5 to 6% post-test incidence of DVT, which is not sensitive enough for venous thrombosis exclusion. The post-test DVT incidence could be reduced from 3.2% to 0.6% in one study and from 11% to 2% in another study by the combination of a normal CUS and low clinical score and from 4.5% to 1.6% by the combination of low clinical score and a negative SimpliRed test in one study. The combination of a negative CUS and a negative SimpliRed test reduced the post-test incidence of DVT from 2.6% to < 1% or even < 1% in two management studies without the need of a repeated CUS on the basis of which anticoagulant therapy can safely be withheld. The rapid quantitative turbidimetric D-dimer assay (Tinaquant) has a sensitivity and a negative predictive value (NPV) of 97.7% with a 2.3% post-test incidence of DVT. The combination of a normal Tinaquant D-Dimer test result plus a low to moderate clinical score reduces the post-test incidence of DVT from 2.3 to 0.6% without the need of CUS testing in 29% of patients with suspected DVT. The rapid ELISA VIDAS D-dimer assay has a sensitivity and NPV of 98.6 and 99.5% in two management studies for the exclusion of DVT irrespective of clinical score. The combination of a normal ELISA VIDAS D-Dimer test with clinical score assessment will reduce the post-test DVT incidence of less than 0.5% and the need for CUS testing by 40 to 50%. It is concluded that the sequential use of a rapid quantitative D-dimer test, clinical score and CUS appears to be safe and the most cost-effective diagnostic work-up of DVT.

No clear effect of diabetes education on glycaemic control for Turkish type 2 diabetes patients: a controlled experiment in general practice.

BACKGROUND: In Turkish immigrant diabetics, problems with communication and cultural differences may hinder delivery of diabetes care. METHODS: In a prospective controlled study, the effect of an ethnic-specific diabetes education programme on glycaemic control and cardiovascular risk factors in Turkish type 2 diabetes patients was assessed, by comparing Turkish diabetics who were offered the education programme with Turkish diabetics offered routine care only (control group). From 16 general practices (31 GPs) in Rotterdam, 104 Turkish type 2 diabetes patients were recruited, 85 of whom could be assessed at one-year follow-up. Glycaemic control, lipid concentrations, blood pressure and body mass index were measured. RESULTS: Compared with the control group, mean HbA(1C) in the intervention group decreased by 0.3% (95% CI -0.8 to 0.2). A significant decrease in HbA(1C) was observed in women with HbA(1C) >7% at baseline (-0.9%; 95% CI -1.73 to -0.09) but not in the other subgroups studied. serum lipid concentrations, blood pressure and body mass index remained unchanged in the intervention group. CONCLUSION: Ethnic-specific diabetes education by Turkish female educators has no obvious beneficial effect on glycaemic control or cardiovascular risk profile. More focus on specific patient selection and gender equality between educators/patients may prove worthwhile.

Prostate specific antigen testing and digital rectal examination before and during a randomized trial of screening for prostate cancer: European randomized study of screening for prostate cancer, Rotterdam.

PURPOSE: Worldwide 2 large-scale randomized screening trials for prostate cancer have been initiated. Determining prostate specific antigen (PSA) involves a simple test that may influence the outcome of these trials if frequently done in the control arm or before study enrollment. We quantified PSA and digital rectal examination before and during the screening trial in Rotterdam, The Netherlands and in the general population. MATERIALS AND METHODS: Trial participants were administered study intake questionnaires on tests done before study participation. Data on PSA from the regional general practice laboratory were correlated with participant data. Various sources were used to quantify PSA tests and digital rectal examinations in the general population. RESULTS: Of men 55 to 74 years old 45% underwent digital rectal examination at 1 time and 13% reported that PSA was tested before trial participation. Each rate increased with age. No statistically significant effect of former PSA testing or digital rectal examination on the cancer detection rate was identified. The rate of PSA determination after initial screening and/or randomization in the control arm was 2-fold that in the screening arm (76 versus 33/1,000 person-years). PSA determination initially decreased in the screening arm but increased rapidly after some time. The number of PSA determinations in the general population was estimated to be 45/1,000 person-years at ages 55 to 69 years. CONCLUSIONS: PSA testing was moderate in the control arm but if different men undergo this test each year, the contamination rate may become rather high. In the final analysis of mortality PSA testing should be considered.

Lack of effect of omeprazole in oral acenocoumarol anticoagulant therapy.

BACKGROUND: Omeprazole is eliminated almost completely by hepatic metabolism within the cytochrome P-450 system and might inhibit the oxidative metabolism of other drugs. This is particularly relevant for compounds with a narrow therapeutic range, such as acenocoumarol. In this study we evaluated the effect of omeprazole use in patients receiving continuous acenocoumarol therapy. METHODS: One thousand and fifty-seven patients receiving long-term oral acenocoumarol combined with omeprazole were selected retrospectively. In 118 of these patients omeprazole was considered the only factor of possible influence on anticoagulant therapy. The control group consisted of 299 age- and sex-matched patients taking acenocoumarol without interfering medication. Dose adjustment of acenocoumarol on starting omeprazole therapy was indicated by clinically relevant changes in coagulation time. RESULTS: No adaptation of the anticoagulant dose was necessary in 74 of 118 omeprazole patients (62.7%), compared with 169 of 299 controls (56.5%). A higher dose was necessary in 30 of 118 omeprazole patients (25.4%), compared with 84 of 299 controls (28.0%). In 14 of 118 omeprazole patients (11.9%) a lowering of the anticoagulant dose was required, compared with 46 of 299 controls (15.4%). CONCLUSIONS: We found no evidence of any interaction between omeprazole and acenocoumarol. It seems likely that omeprazole can be administered safely to patients treated with acenocoumarol.

Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study)

A deficiency of protein C (PC), antithrombin, or protein S is strongly associated with deep-vein thrombosis in selected patients and their families. However, the strength of the association with venous thrombosis in the general population is unknown. This study was a population-based, patient-control study of 474 consecutive outpatients, aged less than 70 years, with a first, objectively diagnosed, episode of venous thrombosis and without an underlying malignant disease, and 474 healthy controls who matched for age and sex. Relative risks were estimated as matched odds ratios. Based on a single measurement, there were 22 (4.6%) patients with a PC deficiency (PC activity, less than 0.67 U/mL or PC antigen, less than 0.33 U/mL when using coumarins). Among the controls, the frequency was 1.5% (seven subjects). Thus, there is a threefold increase in risk of thrombosis in subjects with PC levels below 0.67 or 0.33 U/mL [matched odds ratio, 3.1; 95% confidence interval (CI), 1.4 to 7.0]. When a PC deficiency was based on two repeated measurements, the relative risk for thrombosis increased to 3.8 (95% CI, 1.3 to 10); when it was based on DNA-confirmation, the relative risk increased further to 6.5 (95% CI, 1.8 to 24). In addition, there was a gradient in thrombosis risk, according to PC levels. The results for antithrombin are similar to those for PC, although less pronounced (relative risk, 2.2; 95% CI, 1.0 to 4.7). We could not find an association between reduced total protein S (relative risk, 0.7; 95% CI, 0.3 to 1.8) or free protein S levels (relative risk, 1.6; 95% CI, 0.6 to 4.0) and thrombosis risk. Although not very frequent, PC and antithrombin deficiency are clearly associated with an increase in thrombosis risk.

Comparative study between two prophylactic antibiotic regimens of cefamandole during coronary artery bypass surgery.

In two groups of patients undergoing coronary artery bypass grafting (CABG), two different regimens of antibiotic prophylaxis with cefamandole nafate were compared. In Group 1, 30 mg per kilogram of body weight was administered intravenously during induction of anesthesia. In Group 2, a second dose of 15 mg/kg was administered intravenously shortly before cannulation. Serum and tissue levels in the right atrium, the pericardium, and the sternum were determined using high-pressure liquid chromatography. The results showed that in Group 2 the serum levels were significantly higher from 48 minutes onward after induction and remained at an acceptable level during CABG. The tissue levels in the sternum and pericardium were also significantly higher in Group 2 compared with Group 1. It is concluded that a second dose of cefamandole (15 mg/kg) shortly before the beginning of cardiopulmonary bypass is recommended, particularly for high-risk patients.

The effect of age, weight-related parameters and hormonal contraceptives on andrological assays.

Serum levels of dehydroepiandrosterone-sulfate (DHEA-S), testosterone (T), sex hormone binding globulin (SHBG), T/SHBG ratio and the calculated free T were evaluated in healthy female blood donors. The influence of age and weight-related parameters were studied together with the effects of 9 different oral contraceptives. A gradual decrease with age of DHEA-S, T, T/SHBG and free T levels were observed. The Quetelet index showed a significant negative correlation with the androgen levels except for the T/SHBG ratio. In the females using contraceptives, DHEA-S levels were only significantly decreased in the group using Depo-provera. Most contraceptive users had slightly lowered T levels. Marvelon and Ministat induced an increase in the SHBG levels. Androstenedione (A) levels were studied for some of the contraceptives (Ministat, Marvelon, Lyndiol, Depoprovera); levels were found to be significantly lower than in normal premenopausal women. A highly significant correlation was demonstrated between DHEA-S and the T, T/SHBG and free T levels in the serum of 106 normal women.

Variant expression of lactate dehydrogenase complexes, interfering with isoenzyme analysis.

Three patients with an elevated serum LD activity and unusual, but quite different LD isoenzyme patterns, were studied. It was shown by immunofixation procedures, that complexes between LD isoenzymes and immunoglobulins of the IgG-kappa, IgA-kappa and IgG-lambda class, respectively, caused the observed isoenzyme patterns. From mixing experiments it appeared that the immunoglobulins were specific for either the H-subunit only or an antigenic determinant expressed by a combination of H- and M-subunits in the LD isoenzymes. The observed complexes could be dissociated, in vitro, with NAD+ in two patients, while in the third patient the complex was resistant to NAD+ addition. No common denominator was found with respect to clinical diagnosis. Auto-immune disorders or infection with hepatitis B virus were not involved.

Addition of polyethylene glycol 6000 improves the sensitivity of the protein A plaque assay for detection of human immunoglobulin secreting cells.

A technical modification of the protein A plaque assay is described in which the addition of polyethylene glycol 6000 results in increased sensitivity in detection of human immunoglobulin secreting cells. Optimal conditions for use of this modification are described which result in improved detection and visualisation of haemolytic zones and have, with continued use, been shown to improve the reproducibility and reliability of this assay.