Teicoplanin pharmacokinetics during albumin dialysis.

Teicoplanin (TP) pharmacokinetics was assessed in a critically ill patient during albumin dialysis (AD), which was performed with the molecular adsorbent recirculating system. After a 1200-mg loading dose (24 mg/kg), doses of 1200 and 1000 mg (20 mg/kg) on day 2 and 3, respectively, were administered during two cycles of AD. The mean TP peak and trough concentrations amounted to 99.3 and 21.4 µg/mL, respectively, during AD. A mean half-life of 5.5 h, an apparent volume of distribution of 0.302 L/kg, and a mean total TP clearance of 39 mL/h/kg were calculated. Ninety minutes after the start of AD, the extracorporeal clearance was 3560 mL/h. Within 8 h of AD therapy, the serum concentrations decreased by about 75%. Despite a considerable elimination of TP by AD, therapeutic serum levels could be maintained during the entire treatment by administration of high doses and close monitoring of TP serum concentrations.

Chronic antiepileptic monotherapy, bone metabolism, and body composition in non-institutionalized children.

AIM: The aim of this study was to determine the influence of chronic monotherapy with antiepileptic drugs (AEDs) on vitamin D levels, bone metabolism, and body composition. METHOD: Eighty-five children (38 males, 47 females; mean age 12 y 5 mo, SD 3 y 4 mo) were treated with valproate and 40 children (28 males, 12 females; mean age 11 y 10 mo, SD 3 y) were treated with other AEDs (lamotrigine, sulthiame, or oxcarbazepine), comprising the non-valproate group. Forty-one healthy children (29 males 12 females; mean age 12 y 1 mo, SD 3 y 5 mo) served as a comparison group. Height, weight, body impedance analysis, 25-hydroxyvitamin D, calcium, phosphate, two bone resorption markers (receptor activator of nuclear factor kappaB ligand [RANKL] and tartrate-resistant acid phosphatase 5b [TRAP5b]), osteoprotegerin, and leptin were measured. RESULTS: No child was vitamin D deficient as defined by a 25-hydroxyvitamin D (25OHD) level of less than 25 nmol/l (<10 ng/ml). Leptin, body fat, weight standard deviation score (SDS), and body mass index (BMI) SDS were all significantly higher (each p<0.001) in valproate-treated children than in the non-valproate group, as were calcium (p=0.027) and RANKL (p=0.007) concentrations. Similarly, leptin was significantly higher in the valproate group than in control participants (p<0.001), as were body fat (p=0.023), weight SDS (p=0.046), BMI SDS (p=0.047), calcium (p<0.001), and RANKL (p<0.001), whereas TRAP5b concentrations were significantly lower in the valproate-treated group (p=0.002). Furthermore, calcium and RANKL levels were significantly higher in the non-valproate group than in comparison participants (p<0.001 and p=0.016 respectively). INTERPRETATION: Non-enzyme-inducing or minimal enzyme-inducing AED monotherapy does not cause vitamin D deficiency in otherwise healthy children with epilepsy. Valproate therapy is associated with increases in weight, body fat, and leptin concentration, as well as with a bone metabolic profile that resembles slightly increased parathyroid hormone action.

Pulmonary epithelial lining fluid concentrations after use of systemic amphotericin B lipid formulations.

Amphotericin B (AMB) concentrations were determined in pulmonary epithelial lining fluid (ELF) of 44 critically ill patients, who were receiving treatment with liposomal AMB (LAMB) (n = 11), AMB colloidal dispersion (ABCD) (n = 28), or AMB lipid complex (ABLC) (n = 5). Mean AMB levels (+/- standard errors of the means) in ELF amounted to 1.60 +/- 0.58, 0.38 +/- 0.07, and 1.29 +/- 0.71 microg/ml in LAMB-, ABCD-, and ABLC-treated patients, respectively (differences are not significant).

The vasopressin and copeptin response in patients with vasodilatory shock after cardiac surgery: a prospective, controlled study.

OBJECTIVE: To evaluate arginine vasopressin (AVP) and copeptin plasma concentrations in patients with vasodilatory shock after cardiac surgery. DESIGN: Prospective, controlled, clinical study. SETTING: Surgical intensive care unit and cardiac surgery ward in a tertiary university teaching hospital. PATIENTS AND PARTICIPANTS: Thirty-three critically ill patients with vasodilatory shock after cardiac surgery and ten control patients undergoing uncomplicated aorto-coronary bypass surgery. MEASUREMENTS AND RESULTS: Hemodynamic, laboratory and clinical data were recorded daily in all patients during the first 7 days after cardiac surgery. At the same time, points blood was withdrawn to determine plasma concentrations of AVP (radioimmunoassay) and copeptin (immunoluminometric assy). Standard tests, a mixed effects model and regression analyses were used for statistical analysis. The course of AVP was significantly different between groups (P < 0.001). While AVP concentrations were lower in the study group on the first postoperative day, they were higher than that in the control group from postoperative day 3 on. There was no difference in the postoperative AVP response between study patients with or without chronic angiotensin-converting enzyme inhibitor therapy. Except during continuous veno-venous hemofiltration, AVP and copeptin correlated significantly with each other (P < 0.001; r = 0.749). CONCLUSIONS: The AVP response to cardiac surgery is significantly different between patients with vasodilatory shock and patients undergoing uncomplicated aorto-coronary bypass surgery. Although no causative relationship between AVP concentrations and cardiovascular instability can be drawn from these results, our data support the hypothesis that inadequately low AVP plasma levels contribute to the failure to restore vascular tone in vasodilatory shock after cardiac surgery.

Lack of association of soluble CD40 ligand with the presence of acute myocardial infarction or ischemic stroke in the emergency department.

BACKGROUND: Soluble CD40 ligand (sCD40L) has been proposed as a new risk marker for cardiovascular diseases; however, its possible role as a diagnostic marker in the emergency department (ED) has not yet been investigated. METHODS: We investigated sCD40L for the diagnosis of acute myocardial infarction or ischemic stroke in 1089 consecutive patients (525 males, 564 females; age, 17-98 years; median, 56 years) in an ED treating mainly adults with medical or neurologic emergencies. We used a research assay from Roche Diagnostics to measure sCD40L in heparinized plasma prepared from routinely drawn blood samples. RESULTS: Intraassay and interassay CVs in our laboratory ranged from 1.6%-4.2% and from 4.4%-4.9%, respectively. A multiple linear regression analysis revealed sCD40L concentration to be significantly associated with C-reactive protein concentration (P = 0.012) and platelet count (P < 0.001). In addition, a subgroup analysis revealed a significant association between smoking and sCD40L concentration (P = 0.006). All other tested variables, including discharge diagnosis, age, sex, and other laboratory variables, showed no significant associations. CONCLUSIONS: In adults presenting to the ED, sCD40L is not useful as a diagnostic marker for acute cardiac, cerebrovascular ischemic, or thromboembolic events.

Blood coagulation activation and fibrinolysis during a downhill marathon run.

Prolonged physical exercise is associated with multiple changes in blood hemostasis. Eccentric muscle activation induces microtrauma of skeletal muscles, inducing an inflammatory response. Since there is a link between inflammation and coagulation we speculated that downhill running strongly activates the coagulation system. Thirteen volunteers participated in the Tyrolean Speed Marathon (42,195 m downhill race, 795 m vertical distance). Venous blood was collected 3 days (T1) and 3 h (T2) before the run, within 30 min after finishing (T3) and 1 day thereafter (T4). We measured the following key parameters: creatine kinase, myoglobin, thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen, plasminogen-activator-inhibitor-1 antigen and thrombelastography with ROTEM [intrinsic pathway (InTEM) clotting time, clot formation time, maximum clot firmness, alpha angle]. Thrombin generation was evaluated by the Thrombin Dynamic Test and the Technothrombin TGA test. Creatine kinase and myoglobin were elevated at T3 and further increased at T4. Thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen and plasminogen-activator-inhibitor-1 antigen were significantly increased at T3. ROTEM analysis exhibited a shortening of InTEM clotting time and clot formation time after the marathon, and an increase in InTEM maximum clot firmness and alpha angle. Changes in TGA were indicative for thrombin generation after the marathon. We demonstrated that a downhill marathon induces an activation of coagulation, as measured by specific parameters for coagulation, ROTEM and thrombin generation assays. These changes were paralleled by an activation of fibrinolysis indicating a preserved hemostatic balance.

B-type natriuretic peptide (BNP) is more sensitive to rapid hemodynamic changes in acute heart failure than N-terminal proBNP.

BACKGROUND: We examined whether B-type natriuretic peptide (BNP) and its precursor fragment, N-terminal proBNP (NT-proBNP), can serve as non-invasive markers of hemodynamic response to treatment in acute heart failure in a prospective observational study. METHODS: 29 unselected, consecutive patients (mean age: 61.6, 39-83 years; 25 males, 4 females) in urgent need for positive inotropic support and invasive hemodynamic monitoring by a Swan-Ganz catheter. Positive hemodynamic response to treatment was defined as > or =25% decrease in pulmonary artery occlusion pressure after 24 h. Hemodynamics were recorded simultaneously with blood sampling for BNP and NT-proBNP testing before and 24 h after initiation of inotropic support. BNP (Bayer Diagnostics) and NT-proBNP (Roche Diagnostics) were measured by commercial immunoassays. RESULTS: Both markers were markedly elevated. However, there were no close correlations (r<0.43, p<0.05) of BNP or NT-proBNP with hemodynamic parameters at baseline or 24 h thereafter. Only BNP showed a significant (p=0.023) decrease compared to baseline values in hemodynamic responders. The area under receiver operating characteristics curve for relative changes of BNP for the prediction of hemodynamic response was 0.76. CONCLUSIONS: Our preliminary results indicate that BNP is more sensitive to acute hemodynamic changes than NT-proBNP. This study also highlights limitations of both markers as surrogates of hemodynamics in critically ill acute heart failure patients.

Cognitive deterioration in Alzheimer's disease is accompanied by increase of plasma neopterin.

The pro-inflammatory reaction of the immune system is a feature of healthy aging and might influence the progression of Alzheimer's disease (AD). Neopterin is a pteridine derivative, released from macrophages upon stimulation with pro-inflammatory cytokine interferon-gamma. Forty-three probable AD patients were investigated at baseline and follow up (14.5+/-0.5 months; mean+/-s.e.m.). We assessed the clinical progression by the Consortium to Establish a Registry for Alzheimer's disease (CERAD) battery and compared cognitive changes to serum concentrations of neopterin, C-reactive protein (CRP) and antibody to cytomegalovirus (CMV). The mean neopterin concentrations increased significantly from 9.8+/-1.0 to 13.6+/-2.1 nM (p=0.04). In contrast, mean CRP concentrations at baseline was 0.46+/-0.1 and non-significantly decreased to 0.28+/-0.04 mg/dl. Of AD patients 70% were CMV IgG-seropositive at baseline and CMV-antibody concentrations correlated with levels of neopterin (Spearman r=0.386, p=0.016). CERAD scores did not correlate with any of immune parameters at baseline. At follow up, the increase of neopterin correlated significantly with the decrease in the total CERAD and MMSE scores, according to the clinical progression (r=-0.353, p<0.05 and r=-0.401, p<0.01, respectively). Subdividing the sample with respect to baseline MMSE scores, neopterin concentrations significantly increased only in the group of MMSE<20. In the multiple testing covariated for age, gender, Apolipoprotein E-epsilon4 allele, time difference between both measurements, neopterin remained significantly associated with cognitive decline. In summary, neopterin concentrations correlated with cognitive decline in AD patients, which might be due to high CMV seropositivity in that population.

Sex- and age-specific reference curves for serum markers of bone turnover in healthy children from 2 months to 18 years.

INTRODUCTION: This study aimed to establish sex- and age-specific reference curves enabling the calculation of z-scores and to examine correlations between bone markers and anthropometric data. METHODS: Morning blood samples were obtained from 572 healthy children and adolescents (300 boys) aged 2 months to 18 yr. Height, weight, and pubertal stage were recorded. Serum osteocalcin (OC), bone-specific alkaline phosphatase (BALP), type-1 collagen degradation markers [carboxyterminal telopeptide region of type I collagen (ICTP), carboxyterminal telopeptide alpha1 chain of type I collagen (CTX)], and tartrate-resistant acid phosphatase (TRAP5b) were measured. Cross-sectional centile charts were created for the 3rd, 50th, and 97th centiles. RESULTS: Apart from TRAP5b, all bone markers were nonnormally distributed, requiring logarithmic (BALP, OC, ICTP) or square root (CTX) transformation. Back-transformed centile curves for age and sex are presented for practical use. All bone markers varied with age and pubertal stage (P < 0.001). Significant correlations were found between sd score (SDS) for bone formation markers BALP and OC (r = 0.13; P = 0.004), SDS for collagen degradation markers ICTP and CTX (r = 0.14; P = 0.002), and SDS for the phosphatases (r = 0.34, P < 0.001). Height and weight SDS correlated weakly with some bone marker SDS, particularly with lnBALP SDS (r = 0.20 and 0.24, respectively; both P < 0.001). CONCLUSION: This study provides reference curves for OC, BALP, CTX, ICTP, and TRAP5b in healthy children. Taller and heavier individuals for age had greater bone marker concentrations, likely reflecting greater growth velocity. SDS for markers of bone formation, collagen degradation, and phosphatases were each independently correlated, suggesting they derive from the same biological processes. The possibility of calculating SDS will facilitate monitoring of antiresorptive therapy or disease progression in children with metabolic bone disease.

Biomarker discovery in breast cancer serum using 2-D differential gel electrophoresis/ MALDI-TOF/TOF and data validation by routine clinical assays.

In the present study, we used 2-D differential gel electrophoresis (2-D DIGE) and MS to screen biomarker candidates in serum samples obtained from 39 patients with breast cancer and 35 controls. First, we pooled the serum samples matched with age and menopausal status. Then, we depleted the two most abundant proteins albumin and IgG by immunoaffinity chromatography under partly denaturing conditions in order to enrich low-abundance proteins and proteins with low molecular weight. Concentrated and desalted samples were labeled with three different CyDyes including one internal standard, pooled from all the samples, and separated with 2-D DIGE in triplicate experiments. Biological variations of the protein expression level were analyzed with DeCyder software and evaluated for reproducibility and statistical significance. The profile of differentially expressed protein spots between patients and controls revealed proapolipoprotein A-I, transferrin, and hemoglobin as up-regulated and three spots, apolipoprotein A-I, apolipoprotein C-III, and haptoglobin alpha2 as down-regulated in patients. Finally, routine clinical immunochemical reactions were used to validate selected candidate biomarkers by quantitative determination of specific proteins in all individual serum samples. The serum level of transferrin correlated well with the 2-D-DIGE results. However, the serum levels of apolipoprotein A-I and haptoglobin could not be detected with the clinical routine diagnostic tests. This demonstrated an advantage 2-D DIGE still has over other techniques. 2-D DIGE can distinguish between isoforms of proteins, where the overall immunochemical quantification does fail due to a lack of isoform-special antibodies.

Natriuretic peptides as markers of mild forms of left ventricular dysfunction: effects of assays on diagnostic performance of markers.

BACKGROUND: We compared the performance of different natriuretic peptides to diagnose mild forms of left ventricular dysfunction (LVD) and investigated the influence of measuring B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) with different assays on the diagnostic performance of these markers. METHODS: We measured BNP (Triage BNP), NT-proBNP (Biomedica), and N-terminal pro-A-type natriuretic peptide (NT-proANP; Biomedica) in 130 consecutive patients (age range, 28-83 years) with clinically suspected mild LVD. In patients with sufficient sample volume, we measured BNP and NT-proBNP with additional assays (Shionoria and Roche, respectively). RESULTS: For identifying patients with mild systolic LVD, BNP and NT-proBNP were the best markers, with mean (95% confidence interval) areas under the curves (AUC) of 0.78 (0.63-0.89) and 0.75 (0.58-0.87), respectively. However, the diagnostic performance of NT-proANP [AUC, 0.64 (0.48-0.77)] was significantly worse than that of BNP (P = 0.014). Both BNP assays (Triage and Shionoria) and both NT-proBNP assays (Biomedica and Roche) performed equally well for the diagnosis of systolic LVD despite the poor agreement between NT-proBNP assays. In patients with isolated diastolic LVD, the diagnostic performance of the Triage BNP [AUC, 0.70 (0.56-0.81)] was significantly better (P = 0.006) than that of Biomedica NT-proBNP [0.49 (0.34-0.65)]. Furthermore, the performance of the Biomedica NT-proBNP assay was significantly worse (P = 0.03) than that of the Roche NT-proBNP assay for diagnosis of isolated diastolic LVD. CONCLUSIONS: The performance of BNP for the diagnosis of systolic or diastolic LVD is not affected by the assay used, whereas the performance of NT-proBNP for the diagnosis of isolated diastolic LVD is assay dependent.