A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension.

Patients with severe hypertension (>180/110 mm Hg) require large blood pressure (BP) reductions to reach recommended treatment goals (<140/90 mm Hg) and usually require combination therapy to do so. This 8-week, multicenter, randomized, double-blind, parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension (mean sitting diastolic blood pressure (msDBP)>or=105 mm Hg and <120 mm Hg). In all, 183 patients were randomized (2:1) to aliskiren 150 mg (n=125) or lisinopril 20 mg (n=58) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren-based treatment (ALI) was similar to lisinopril-based treatment (LIS) with respect to the proportion of patients reporting an adverse event (AE; ALI 32.8%; LIS 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; LIS 3.4%). The most frequently reported AEs in both groups were headache, nasopharyngitis and dizziness. At end point, ALI showed similar mean reductions from baseline to LIS in msDBP (ALI -18.5 mm Hg vs LIS -20.1 mm Hg; mean treatment difference 1.7 mm Hg (95% confidence interval (CI) -1.0, 4.4)) and mean sitting systolic blood pressure (ALI -20.0 mm Hg vs LIS -22.3 mm Hg; mean treatment difference 2.8 mm Hg (95% CI -1.7, 7.4)). Responder rates (msDBP<90 mm Hg and/or reduction from baseline>or=10 mm Hg) were 81.5% with ALI and 87.9% with LIS. Approximately half of patients required the addition of HCTZ to achieve BP control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to LIS alone, or in combination with HCTZ, in patients with severe hypertension.

[Reports of transfusion incidents: experiences from the first year of hemovigilance in the region of the former ZWN (South West Netherlands) blood bank in Rotterdam]. / Meldingen over transfusie-incidenten: ervaringen in het eerste jaar van hemovigilantie in de regio van de voormalige Bloedbank ZWN Rotterdam.

OBJECTIVE: Itemize blood transfusion incidents in the South-West Netherlands region (about 3.5 million inhabitants), where a regional reporting system for transfusion incidents was introduced in January 2001. DESIGN: Prospective, descriptive. METHOD: In the period 1 January 2001-31 December 2001, 22 hospitals voluntarily reported transfusion incidents in patients to the blood bank. All incidents were anonymously recorded in a standardised report and registered in 14 categories. RESULTS: A total of 119 transfusion incidents were reported and categorised as: incorrect blood component transfused (n = 8), mild fever 1-2 degrees C (n = 14), non-haemolytic fever > 2 degrees C (n = 36), acute haemolytic transfusion reactions (n = 3). delayed haemolytic transfusion reactions (n = 18), allergic reactions (n = 11), bacterial contamination (n = 3), transfusion-related acute lung injury (n = 1), near accidents (n = 6) and product recalls (n = 19). There were no reports in the categories anaphylactic shock, post-transfusion purpura, transfusion-acquired viral infection, and transfusion-related graft versus host disease. In the same year of haemovigilance, the blood bank issued a total of 158,000 blood products. A complication rate of 1:700 blood products was calculated. It is estimated that 53% of all incidents were reported. CONCLUSION: Despite all of the safety measures taken, severe adverse events still occurred. A well-run system for haemovigilance can contribute to the knowledge of transfusion incidents. The safety and quality of blood transfusions can be improved if this knowledge is incorporated into ongoing education about blood transfusions and in the prevention and treatment of transfusion reactions.

Rapid ELISA assay for plasma D-dimer in the diagnosis of segmental and subsegmental pulmonary embolism. A comparison with pulmonary angiography.

STUDY OBJECTIVE: To assess the accuracy of a rapid ELISA D-dimer assay for the exclusion of pulmonary embolism (PE) in patients suspected of PE, using pulmonary angiography alone as reference method rather than a diagnostic strategy including lung scintigraphy and leg vein ultrasonography. METHODS: In 342 patients who were examined by pulmonary angiography to diagnose or exclude PE, the accuracy of the quantitative rapid VIDAS D-dimer test for the exclusion of PE was evaluated retrospectively. D-dimer levels were assayed in frozen samples collected during the diagnostic work-up at the time of pulmonary angiography while on treatment with unfractionated heparin for 1-2 days. RESULTS: Mean plasma D-dimer concentrations were increased in patients with angiographic evidence of PE (P <0.0001). The sensitivity of D-dimer for segmental PE was 98%, its accuracy in excluding segmental PE was 99%, higher than the respective figures for subsegmental PE (76% and 94%; P <0.01, both). For both forms of PE combined the sensitivity was 90% and the negative predictive value 94%. DISCUSSION: The sensitivity and negative predictive values reported here, are low compared with previous studies using the same rapid ELISA D-dimer assay. This probably reflects an overlooking of mild cases of subsegmental PE in previous studies, although a reduction of D-dimer levels by the heparin pretreatment may have contributed to part of the discrepancy. Prospective studies are needed to clarify this issue.

Multicenter evaluation of the Elecsys CA 125 II assay.

The technical performance and clinical usefulness of the newly developed Elecsys CA 125 II assay (Boehringer Mannheim) was evaluated in a multicenter study. Imprecision studies were carried out using control sera and human pool sera with CA 125 concentrations from 11 to 1026 U/ml. Within-run CVs between 0.7 to 4.8% (median 1.7%) and between-day CVs between 2.4 to 10.9% (median 5.7%) were found. Method comparison studies with Enzymun-Test CA 125 II carried out in four laboratories yielded slopes between 0.94 to 1.07 and intercepts < 3 U/ml. A good comparability of the Elecsys CA 125 II assay was also found with one MEIA and the Centocor" IRMA. For a second MEIA and a second IRMA the slopes were 1.23 and 1.42, and the corresponding correlation coefficients were 0.987 and 0.977, respectively. The Elecys CA 125 II concentrations are clearly related to the tumor stage of ovarian carcinoma patients. The maximum of diagnostic efficiency of ovarian carcinoma patients compared with patients of benign gynecological diseases is reached at 150 U/ml with a specificity of 93% and a sensitivity of 69%. Follow-up studies of ovarian carcinoma patients reflect the status of the disease and the effect of various therapeutic applications. The technical and clinical evaluation of the Elecsys CA 125 II assay show a superior analytical performance with a broad measuring range up to 5000 U/ml and a short measuring time of 18 minutes.

Analytical and clinical evaluation of an electrochemiluminescence immunoassay for the determination of CA 125.

The CA 125 II assay on the Elecsys(R) 2010 analyzer was evaluated in an international multicenter trial. Imprecision studies yielded within-run CVs of 0.8-3.3% and between-day CVs of 2.4-10.9%; CVs for total imprecision in the manufacturer's laboratory were 2.4-7.8%. The linear range of the assay extended to at least 4500 kilounits/L (three decades). Interference from triglycerides (10.3 mmol/L), bilirubin (850 micromol/L), hemoglobin (1.1 mmol/L), anticoagulants (plasma), and several widely used drugs was undetectable. Method comparisons with five other CA 125 II assays showed good correlation but differences in standardization. A 95th percentile cutoff value of 35 kilounits/L was calculated from values measured in 593 apparently healthy (pre- and postmenopausal) women. In 95% of patients with benign gynecological diseases CA 125 was 190 kilounits/L. A comparison of CA 125 values obtained with the Elecsys test and with other common CA 125 tests in monitored patients being treated for ovarian cancer showed identical patterns. In conclusion, the Elecsys CA 125 II assay is linear over a broad range, yields precise and accurate results, is free from interferences, and compares well with other assays.

Precision of the magnesium determination in mononuclear blood cells and erythrocytes.

OBJECTIVE: Establishing the analytical variation and reproducibility of the intracellular magnesium (Mg) assay in mononuclear blood cells (MBC) and erythrocytes (RBC). DESIGN AND METHODS: We assessed the analytical variation of the several determination steps, and the reproducibility for the complete intracellular Mg-assay (combination of preanalytical, analytical, and biological variation). The influence of platelets was determined by comparing Mg concentrations obtained from heparinized blood and defibrinated blood. RESULTS: Coefficients of variation of the several determination steps used in the MBC- and RBC-assay were < or = 5.4%. The overall analytical variation was 5.0-6.8%, and reproducibility of the complete Mg-assay 11.6-14.0%. Mg measurements in MBC (expressed as fmol/cell) obtained from heparinized blood showed significantly higher values than those obtained from defibrinated blood. CONCLUSION: This is the first study to describe in detail reproducibility data for the individual steps in the overall procedure to measure intracellular magnesium. It is shown that results obtained in daily practice should be interpreted with care. Moreover, the removal of platelets is essential in the determination of Mg in MBC.

Magnesium fractions in serum of healthy individuals and CAPD patients, measured by an ion-selective electrode and ultrafiltration.

OBJECTIVES: Validation and comparison of a magnesium ion-selective electrode (ISE) with a cation-exchange resin technique, followed by determination of all magnesium fractions in serum of healthy volunteers and continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN AND METHODS: The analytical aspect has been studied by measuring the influence of complexing agents on the fraction ionized magnesium (friMg2+). A theoretical approximation of friMg2+, based on mass equilibria and complexation constants, was calculated and compared with the measurements. RESULTS: ISE measurements showed good agreement with theory. Reference values of the ionized, protein-bound, and complexed magnesium fractions were (mean +/- SD) 0.65 +/- 0.04, 0.27 +/- 0.04, and 0.08 +/- 0.03, respectively. Fractions obtained in the CAPD group were 0.62 +/- 0.04, 0.22 +/- 0.05, and 0.16 +/- 0.05, respectively, and differed significantly from the values of the reference population. CONCLUSIONS: All known serum magnesium parameters can be established by a combination of ultrafiltration, atomic absorption spectrometry, and ISE measurements. Unknown complexing compounds most probably account for the increased fraction of complexed magnesium in the serum of CAPD patients.

High tissue factor concentration in the omentum, a possible cause of its hemostatic properties.

The hemostatic properties of the pedicled omentoplasty turned out to be helpful in difficult hemorrhages in extensive surgery. As suggested by others, a high concentration of tissue factor (TF) in the omentum could be responsible for this favourable property. The authors investigated the nature of that property in 11 patients who underwent laparotomy. In omentum and striated muscle (controls) the TF-concentrations in both tissues were estimated by the ELISA method. A significant difference between TF-concentration in omentum and striated muscle could be demonstrated.

Current sample handling methods for measurement of platinum-DNA adducts in leucocytes in man lead to discrepant results in DNA adduct levels and DNA repair.

DNA adduct levels were measured with atomic spectroscopy in white blood cells (WBCs) from patients with solid tumours who were treated with six weekly courses of cisplatin. In 21 patients (I) the WBCs were collected after thawing frozen whole-blood samples according to a previously described method. In 32 other patients (II) WBCs were collected immediately after blood sample collection. The two methods for WBC collection were also compared in vitro. The maximal DNA adduct levels in vivo after the first course were in I 2.48 +/- 1.14 and in II 1.28 +/- 0.40 pg of platinum per microgram of DNA (P < 0.0001). The DNA 'repair' in the first course (DNA adduct level at the end of the infusion minus the level 15 h post infusion) was in I 40% +/- 29% and in II 18% +/- 29% (P = 0.009). These differences were consistent in all measured courses. In vitro, the DNA adduct levels in the freshly prepared WBCs were significantly lower at 0, 1 and 4, but not 24 h, after start of the incubation with cisplatin than in the WBCs collected after freezing and thawing the blood sample. The same experiment with carboplatin in vitro also resulted in significantly lower adducts in freshly isolated WBCs. The higher DNA adduct levels and DNA 'repair' in I are caused by remaining unbound cisplatin in the sample tubes, which can form DNA adducts ex vivo. The same results in vivo can be anticipated when carboplatin is used.

Pharmacokinetic-dynamic relationship of cisplatin in vitro: simulation of an i.v. bolus and 3 h and 20 h infusion.

The profiles of an i.v. bolus and 3 h and 20 h infusion of cisplatin (CDDP) were simulated in vitro by using a culture of the IGROV1 human ovarian cancer cell line. Disappearance of pharmacologically active unbound CDDP was accomplished by adding human albumin to the medium. Total and unbound CDDP and CDDP-DNA adduct levels were quantitated by atomic absorption spectroscopy (AAS), and tumour cell survival was measured by the clonogenic assay. The design of the experiment resulted in non-significant differences in the magnitude of the area under the concentration-time curve (AUC) of unbound CDDP between the three dose-input functions (AUC i.v. bolus, 6.34 +/- 0.36; 3 h infusion, 6.35 +/- 0.59; and 20 h infusion, 6.76 +/- 0.40 micrograms h ml-1). Also, the differences between the area under the CDDP-DNA adduct-time curves (AUA) of the three dose-input functions were not significant. The initial rate of decline of the CDDP-DNA adduct-time curve was significantly higher for the i.v. bolus and 3 h infusion than for the 20 h infusion. There was a log-linear relationship between the AUC of unbound CDDP and cell survival. These relationships were not significantly different between the three dose-input functions. Variation in the rate of input of CDDP leads to differences in the shape of the AUC and AUA without significant effects on cell survival.

Analytical evaluation of Kone Microlyte determination of ionized magnesium.

We performed an analytical evaluation of a commercially available instrument for determining ionized magnesium through use of a neutral carrier, liquid-membrane-based ion-selective electrode. Reproducibility (CV 2-4%), linearity (0.30-2.50 mmol/L), lower limit of detection (0.30 mmol/L), and absence of interference from Ca2+ indicate adequate performance for measuring ionized magnesium in plasma or serum samples in the normal to high-concentration range. Sodium in excess of 150 mmol/L caused a negative bias, which can be explained by ionic strength-induced changes in activity coefficients. The use of heparin as an anticoagulant must be restricted to concentrations < 15 units/mL because of the binding of magnesium to heparin. The mean +/- SD concentration of ionized magnesium and its fraction of total magnesium in 76 healthy volunteers were 0.56 +/- 0.05 mmol/L and 0.65 +/- 0.04, respectively.

Clinical evaluation of a pancreatic lipase mass concentration assay.

An immunoactivation assay for determining pancreatic lipase mass concentration was clinically evaluated and compared with results obtained by measuring total amylase and pancreatic amylase activity. A group of 30 patients with pancreatitis was compared with a control group of 32 patients in which this disease was suspected but excluded. Both lipase mass concentration and pancreatic amylase activity exhibit good sensitivity (0.93 each) and specificity (0.94 and 0.97, respectively) at cutoff concentrations of 200 micrograms/L and 200 U/L, respectively. The median increase in lipase mass concentration (37.1 times the upper limit of the reference interval) in the pancreatitis group was higher than that for either total amylase or pancreatic amylase activity (5.94 and 14.5 times, respectively) but showed a similar time to peak value. We conclude that the lipase assay is the method of choice for diagnosing pancreatitis.

Improved method for the determination of serotonin in plasma by high-performance liquid chromatography using on-line sample pre-treatment.

An improved method for the determination of serotonin in platelet-rich plasma (PRP) and platelet-poor plasma (PPP), by reversed-phase high-performance liquid chromatography with electrochemical detection and direct plasma injection, is described. The chromatographic system comprises a strong cation-exchange pre-column and a C18 analytical column. The method is selective, rapid, simple and sensitive, and offers good reproducibility and recovery. Reference values for serotonin concentrations in healthy adults (n = 10) are 31 nM for PPP and 6 nmol per 10(9) platelets for PRP. The conditions used for the preparation of PRP and PPP may influence the serotonin concentration in PRP.

Improved method for the determination of the cortisol production rate using high-performance liquid chromatography and liquid scintillation counting.

Two new methods for the determination of the cortisol production rate using reversed-phase high-performance liquid chromatography are described. One uses ultraviolet detection at 205 nm, the other on-line post-column derivatization with benzamidine, followed by fluorimetric detection. The specific activity of tetrahydrocortisol and tetrahydrocortisone in urine from patients who had received tritium-labelled cortisol was determined by the indicated methods, followed by fraction collection and liquid scintillation counting. The post-column reaction detection procedure was superior to ultraviolet detection, both in selectivity and analysis time. Intra- and inter-assay variance of the post-column reaction detection procedure were 3.7 and 4.7%, respectively. A good correlation (r = 0.99) was obtained between values determined by this procedure and by a thin-layer chromatographic procedure.

Non-specific binding of the fluorescent beta-adrenergic receptor probe alprenolol-NBD.

The fluorescent beta-adrenergic receptor probe alprenolol-NBD was found to exhibit a high affinity (Kd 3.2 nM) and a low capacity (10 fmol/mg protein) for the beta 2-adrenergic receptor on living Chang liver cells but also a high affinity (Kd 320 nM) for non-beta-adrenergic receptor binding sites with a very high capacity (28,000 fmol/mg protein). Calculations are presented which make clear that less than 3% of the binding of alprenolol-NBD during visualization experiments is beta-adrenergic receptor related. Furthermore, it is shown that besides the downregulation of beta-adrenergic receptors during incubation with isoproterenol, the high-affinity non-beta-receptor binding sites are also deminishing during incubation with isoproterenol. Based on our findings it is concluded that the results of Henis et al. who claimed the visualization of the beta-adrenergic receptor population on Chang liver cells by alprenolol-NBD must be interpreted as an almost completely non-specific fluorescence.

Patterns of anomalous pulmonary venous drainage.

All of our cases of abnormal pulmonary venous connections collected to the middle of 1965 and verified at surgery or autopsy have been reviewed by means of diagrams and tabulations, using a specially devised code to facilitate the survey. The material consisted of 52 autopsy cases (half of them obtained after surgery) and the cases of 72 patients who survived operation. The postmortem group was much younger than the surgical group and differed also from the latter by showing male preponderance as well as relatively many instances of total abnormal pulmonary venous connection and frequently associated cardiac anomalies. Partial anomalous connection of right pulmonary veins was 10 times more frequent than that of the left pulmonary veins. This was caused by (1) the frequent drainage of some of the right pulmonary veins into the junctional area between right atrium and superior vena cava in the presence of normal left pulmonary veins, and (2) the complete absence of isolated left pulmonary venous connection to the right atrium. Abnormal connection of solitary pulmonary veins was always effected to the most proximal venous structure among the four possible ones which are derived from the main embryonic channels (superior vena cava and inferior vena cava on the right side, and left superior vena cava and coronary sinus on the left side). Common pulmonary veins from one lung also drained in accordance with this proximity rule, if this may be taken to apply also to the drainage of right pulmonary veins into the right atrium. The one exception in our material was the drainage of all right pulmonary veins into the portal venous system. Total abnormal pulmonary venous connection may be found with all structures mentioned, but most frequently with the left superior vena cava, or coronary sinus, or both, usually by way of a common pulmonary vein. In a few cases however, drainage into different sites, all of them abnormal, did occur. Then again the proximity rule seemed to apply. A tentative embryological explanation is given for the patterns described.