Of men and meals Beyer-Westendorf, J; Siegert, G
Journal of thrombosis and haemostasis,
June 2015, Letnik:
13, Številka:
6
Journal Article
Recenzirano
Rivaroxaban is increasingly used to treat patients with acute venous thromboembolism (VTE), a potentially life-threatening condition. Because absorption of rivaroxaban decreases from nearly 100% to ...66% under fasting conditions, it is recommended that VTE patients take rivaroxaban with a meal. However, this recommendation is based on preclinical pharmacokinetic (PK) studies in healthy volunteers. So far, no clinical evidence is available to support this recommendation. We describe a case of a compliant young patient who developed recurrent pulmonary embolism during rivaroxaban treatment. PK studies provided evidence that malabsorption of rivaroxaban 20 mg due to irregular intake of meals during shift work was the leading cause of recurrent pulmonary embolism. When the patient was instructed to take rivaroxaban with a regular meal, peak plasma concentrations increased from 115 to 318 ng mL(-1) (+ 176%). Consequently, the importance of taking rivaroxaban with food may have a greater clinical relevance than data from preclinical PK studies suggest.
Findings from five independent studies - with close to 350 patients with pheochromocytoma and more than 2,500 in whom the tumor was excluded - indicate that measurements of plasma free metanephrines ...provide an overall diagnostic sensitivity of 98% and specificity of 92%. The recommendation that initial testing for the tumor should always include measurements of either plasma or urinary fractionated metanephrines results from recognition of the high diagnostic sensitivity of measurements of plasma metanephrines. The few patients with pheochromocytoma in whom the test may not yield a positive result include those with very small tumors or microscopic disease and others with tumors that do not produce norepinephrine and epinephrine. Such patients are typically normotensive and do not exhibit symptoms of catecholamine excess. Additional measurements of methoxytyramine can be useful for detecting those tumors that produce only dopamine. Suboptimal diagnostic specificity and difficulties in distinguishing true- from false-positive elevations of plasma metanephrines remain challenges for diagnosis. Improvements in analytical technology (e.g., liquid chromatography with tandem mass spectrometry) and new strategies for follow-up testing provide possible solutions to these problems. The single most important remaining clinical care challenge is the development of effective cures for patients with malignant disease. Current treatments, none of which are truly satisfactory, include chemotherapy and radiopharmaceutical therapy with (131)I-labelled M-iodobenzylguanidine or radioactive somatostatin analogues. Improvements in treatment may in the future come from several fronts, but proof of efficacy ideally will require well-coordinated multicenter prospective trials in larger numbers of patients than in previous studies.
The tensile creep behavior of an oxide–oxide continuous fiber ceramic composite (CFCC) with ±45° fiber orientation was investigated at 1200
°C in laboratory air, in steam and in argon. The composite ...consists of a porous alumina matrix reinforced with laminated, woven mullite/alumina (Nextel™720) fibers, has no interface between the fiber and matrix, and relies on the porous-matrix for flaw tolerance. The tensile stress–strain behavior was investigated and the tensile properties measured at 1200
°C. The elastic modulus was 46
GPa and the ultimate tensile strength (UTS) was 55
MPa. Tensile creep behavior was examined for creep stresses in the 15–45
MPa range. Primary and secondary creep regimes were observed in all tests. Creep run-out (set to 100
h) was achieved in all test environments for creep stress levels ⩽35
MPa. At creep stresses >35
MPa, creep performance was best in laboratory air and worst in argon. The presence of either steam or argon accelerated creep rates and reduced creep life. Composite microstructure, as well as damage and failure mechanisms were investigated.
Subclinical inflammation was shown to be a strong predictor of cardiovascular events and was suggested to be a part of the metabolic syndrome (MS). The aim of the present study was to investigate the ...relationship of the inflammatory parametersmdash leukocyte count, C-reactive protein (CRP), and fibrinogen levelmdash to insulin resistance and insulin secretion, as well as to other components of the MS in a population at risk for diabetes. A total of 396 subjects (142 men and 254 women) were analyzed from the follow-up of the Risk Factors in Impaired Glucose tolerance (IGT) for Atherosclerosis and Diabetes (RIAD) study, who were at risk for type 2 diabetes, such as family history of diabetes, obesity, and/or hyper/dyslipoproteinemia. Subjects under lipid-lowering treatment or with acute infections were not eligible. A variety of risk factors within the MS were examined: lipids, glycemic parameters, coagulation, insulin fractions. and microalbuminuria. CRP was determined by a highly sensitive method, using an immunological agglutination test, and fibrinogen was measured by the method of Clauss. Insulin resistance was evaluated by the homeostasis model assessment (HOMA) and insulin secretion by HOMA and by insulin areas under curve in an oral glucose tolerance test (OGTT), insulin increment at 30 mnutes of OGTT, and insulin increment/glucose increment at 30 minutes of OGTT. By univariate analysis, fibrinogen level (
r = 0.180,
P lt .001), leukocyte count (
r = 0.162,
P = .001), and CRP (
r = 0.251,
P lt .001) were all highly significantly correlated to insulin resistance, but not to insulin secretion. A significant rise was found for the majority of the components of the MS in quartiles of the examined inflammatory parameters. In multivariate analysis of all analyzed metabolic parameters, including age, sex, physical activity, and smoking, body mass index (BMI) was found a strong independent determinant of all inflammatory markers examined. Thus, in a population at risk for type 2 diabetes we demonstrate that subclinical inflammation underlies the metabolic syndrome, through association to one of its primary anomaliesmdash insulin resistance, whereas no association was found to impaired insulin secretion.
Abstract Background There are currently no reliable biomarkers for malignant pheochromocytomas and paragangliomas (PPGLs). This study examined whether measurements of catecholamines and their ...metabolites might offer utility for this purpose. Methods Subjects included 365 patients with PPGLs, including 105 with metastases, and a reference population of 846 without the tumour. Eighteen catecholamine-related analytes were examined in relation to tumour location, size and mutations of succinate dehydrogenase subunit B ( SDHB ). Results Receiver-operating characteristic curves indicated that plasma methoxytyramine, the O-methylated metabolite of dopamine, provided the most accurate biomarker for discriminating patients with and without metastases. Plasma methoxytyramine was 4.7-fold higher in patients with than without metastases, a difference independent of tumour burden and the associated 1.6- to 1.8-fold higher concentrations of norepinephrine and normetanephrine. Increased plasma methoxytyramine was associated with SDHB mutations and extra-adrenal disease, but was also present in patients with metastases without SDHB mutations or those with metastases secondary to adrenal tumours. High risk of malignancy associated with SDHB mutations reflected large size and extra-adrenal locations of tumours, both independent predictors of metastatic disease. A plasma methoxytyramine above 0.2 nmol/L or a tumour diameter above 5 cm indicated increased likelihood of metastatic spread, particularly when associated with an extra-adrenal location. Conclusion Plasma methoxytyramine is a novel biomarker for metastatic PPGLs that together with SDHB mutation status, tumour size and location provide useful information to assess the likelihood of malignancy and manage affected patients.
Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in ...paediatric patients with congenital bleeding disorders. Forty‐one patients consisting of children with von Willebrand’s disease (VWD, n = 26) and platelet function defects (PFD, n = 15) received DDAVP intravenously at a dosage of 0.3 μg/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen‐binding activity (VWF:CB) and PFA 100® closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two‐ to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non‐responder, the CT shortened within 240 min after DDAVP. Two non‐responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.
To examine carotid intimal-medial thickness (IMT) and its determinants in newly detected type 2 diabetic subjects, classified according to the new criteria of the American Diabetes Association, in ...comparison with age- and sex-matched control subjects with normal glucose tolerance.
This study was case-controlled, with matched pairs for 71 newly diagnosed type 2 diabetic individuals. Subjects aged 40-70 years were recruited from a risk population for diabetes seen in the Risk Factors in IGT for Atherosclerosis and Diabetes (RIAD) Study. Standard risk factors, 75-g oral glucose tolerance test with real insulin, proinsulin, and C-peptide, and ultrasound measurement of the IMT of the common carotid artery were performed.
The diabetic subjects, both men and women, displayed carotid intimal-medial thickening, even in the subgroup with fasting plasma glucose between 7.0 and 7.8 mmol/l. HbA1c was significantly increased in the diabetic patients (6.33 vs. 5.48%). Insulin, proinsulin, and C-peptide were also significantly higher. Among the coronary risk factors, triglycerides and plasminogen activator inhibitor were significantly increased. After age and sex adjustment. IMT in the diabetic group was correlated to triglycerides and the total-to-HDL cholesterol ratio. In the total group, IMT was significantly correlated to blood pressure, 2-h glucose in oral glucose tolerance testing, triglycerides, albuminuria, and the total-to-HDL cholesterol ratio, and inversely correlated to HDL cholesterol. No independent determinant of IMT was found in the diabetic group by multivariate analysis.
Newly detected type 2 diabetic patients exhibit a higher degree of early atherosclerosis than normal glucose-tolerant subjects matched for age and sex. Our data suggest that hyperglycemia, together with a clustering of risk factors, and in particular dyslipidemia, may cause intimal-medial thickening in the early phases of diabetes.
In various diseases n-3 fatty acids exert anti-inflammatory properties. These effects seem to be related to the uptake and incorporation of eicosapentaenoic acid (EPA) into the cellular substrate ...pool after dietary intake of EPA, which is contained in fish oils (FO). In the state of inflammation EPA is released to compete with arachidonic acid (AA) for metabolism at the cyclo-oxygenase and the 5-lipoxygenase level. The metabolites of EPA have less inflammatory and chemotactic potency than the substances derived from AA. In addition to positive effects, early studies pointed towards prolonged bleeding times after dietary intake of n-3 fatty acids. This study was undertaken to address the issue of potential coagulation disturbances associated with postoperative parenteral FO administration. This was a prospective, randomised, double blinded clinical trial, carried out in two operative intensive care units (13 and 16 beds) in a university hospital. Forty-four patients undergoing elective major abdominal surgery participated in the trial. Patients were randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO, Lipovenoess 10% PLR; 1.0 g/kgBW per day; n = 20) for five days or with a combination of FO and SO (FO, Omegaven; 0.2 g/kgBW per day plus SO, Lipovenoes 10% PLR; 0.8 g/kgBW per day, n = 24), respectively. Blood samples were taken preoperatively (day -1), prior to (day 1) during (days 2-5) and after TPN (day 6). The coagulation parameters thromboplastin time (Quick), activated partial thromboplastin time (aPTT), fibrinogen and antithrombin III were measured. To differentially assess activation levels of extrinsic and intrinsic coagulation pathway, factors VIIa and XIIa were quantified. Moreover platelet function was determined by resonance thrombography. Baseline values of coagulation and platelet function were comparable in both groups, but coagulation activity dropped after surgery. Over the observation period of 6 days, however, physiological levels were regained. No clinically significant differences were observed between the SO- and SO + FO- group. These findings suggest that infusion of fish oil in doses up to 0.2 g/kgBW per day is safe regarding coagulation and platelet function.
The Quick test and activated partial thromboplastin time (aPTT) are so-called global assays used to characterize different steps in plasmatic hemostasis. They reflect hemostasis in its classical ...differentiation into extrinsic and intrinsic pathways. However, they do not cover physiological aspects of cell-based hemostasis. Results are not necessarily congruent with a specific clinical situation and do not replace a complete medical history. Patients suffering from hemophilia A or B, for example, have normal Quick test results. Severe factor XII deficiency reveals an extreme aPTT prolongation without a significant bleeding tendency. In Lupus patients, aPTT is also prolonged with clinically a rather increased thrombotic risk. Fibrinogen as a substrate of coagulation discloses pathological results in both global tests in case of considerable reduction. In case of positive bleeding history and a normal global assay, disorders in platelets, von Willebrand factor and factor XIII must be considered. Reduced Quick test results may be expected in factor VII, II, V, or X deficiency. Disorders of liver synthesis of coagulation factors as well as vitamin K deficiency will be indicated by the Quick test rather than by aPTT. The most frequent hereditary reasons for a prolonged aPTT are hemophilia A and B as well as von Willebrand disease. In case of an acquired bleeding tendency, the diagnostic strategy must include autoantibodies. The sensitivity of the aPTT reagent varies widely. Low-molecular weight heparin and pentasaccharides do not influence the test. Oral direct inhibitors may reveal pathological results in a reagent-dependent manner.
We analysed the relationship between fasting plasma glucose, carotid intima media thickness and some atherosclerosis risk factors in 307 non-diabetic individuals. Male (n = 120) and female subjects ...(n = 187) with a familial history of Type II diabetes mellitus and/or obesity and hyperlipoproteinaemia were examined in the age group 40-70 years. Plasma triglycerides, total and high-density-lipoprotein cholesterol, plasminogen activator inhibitor were measured by conventional methods. Specific insulin, pro-insulin and C-peptide were measured by specific enzyme immunoassay. Intima media thickness increased in quintiles for fasting plasma glucose in men, but not in women. There was a rise of triglycerides, body mass index, waist to hip ratio, plasminogen activator inhibitor, true insulin, proinsulin, C-peptide and a decrease of high-density-lipoprotein cholesterol in quintiles for fasting plasma glucose. Fasting plasma glucose was found to be significantly positively correlated to intima media thickness, body mass index, waist to hip ratio, haemoglobin A1c, insulin, C-peptide, triglycerides, plasminogen activator inhibitor and significantly negatively correlated to high density lipoprotein cholesterol. However, the correlation of fasting plasma glucose to intima media thickness was no longer significant after adjustment for age and sex. After adjustment for age and sex intima media thickness was significantly correlated to body mass index, total cholesterol, triglycerides, albuminuria and inversely correlated to high-density-lipoprotein cholesterol. In multivariate analysis age, male sex, high-density-lipoprotein cholesterol and total cholesterol were significant determinants of intima media thickness. Our data suggest that a weak association exists between fasting plasma glucose and intima media thickness, which may be mediated by a clustering of risk factors in the upper range of non-diabetic fasting plasma glucose level with a central role for dyslipidaemia.
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