Stage-dependent association of BDNF and TGF-ß1 with lung function in stable COPD.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is characterised by complex inflammatory, neuronal and fibrotic changes. Brain-derived Neurotrophic Factor (BDNF) is a key regulator of neuronal plasticity, whereas Transforming Growth Factor-ß1 (TGF-ß1) plays a crucial role in tissue repair and emphysema pathogenesis. Both mediators are stored in platelets and released from platelets in inflammatory conditions and during serum preparation. In patients with asthma, it was previously shown that elevated serum BDNF concentrations correlate with disease severity, whereas TGF-ß1 concentrations were normal. METHODS: In the present study, 63 patients with stable COPD (spirometric GOLD stages 2-4) and 17 age- and comorbidity-matched controls were studied. Lung function, smoking history, medication, platelet concentrations in peripheral blood and serum concentrations of BDNF, TGF-ß1 and Serotonin (5-HT) were assessed in all participants. RESULTS: Serum levels of both BDNF and TGF-ß1 (but not concentrations of platelets in peripheral blood) were significantly elevated in all stages of COPD as compared to controls. Highest BDNF concentrations were found in spirometric GOLD stage 3, whereas highest TGF-ß1 serum levels were found in spirometric GOLD stage 4. There were specific, stage-dependent correlations of these mediators with lung function parameters of the patients. CONCLUSIONS: Taken together, we show that, in contrast to asthma, COPD is characterised by elevated concentrations of both BDNF and TGF-ß1 in serum. The stage-dependent association with lung function supports the hypothesis that these platelet mediators may play a role in the pathogenesis of COPD.

Intracardiac injection of erythropoietin induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model.

Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes beneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO injection and EPO-mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac injection. Compared to myocardial infarction control group (MIC), EPO significantly improved left ventricular function (n =11-14, P < 0.05) and decreased right ventricular wall stress (n = 8, P < 0.05) assessed by pressure-volume loops after 6 weeks. MI-EPO hearts exhibited smaller infarction size (20.1 +/- 1.1% versus 27.8 +/- 1.2%; n = 6-8, P < 0.001) and greater capillary density (338.5 +/- 14.7 versus 259.8 +/- 9.2 vessels per mm2; n = 6-8, P < 0.001) than MIC hearts. Direct EPO injection reduced post-MI myocardial apoptosis by approximately 41% (0.27 +/- 0.03% versus 0.42 +/- 0.03%; n = 6, P= 0.005). The chemoattractant SDF-1 was up-regulated significantly assessed by quantitative realtime PCR and immunohistology. c-Kit(+) and CD34(+) stem cells were significantly more numerous in MI-EPO than in MIC at 24 hrs in peripheral blood (n = 7, P < 0.05) and 48 hrs in the infarcted hearts (n = 6, P < 0.001). Further, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in MI-EPO hearts (n = 7, P < 0.05). Intracardiac EPO injection restores myocardial functions following MI, which may attribute to the improved early recruitment of c-Kit(+) and CD34(+) stem cells via the enhanced expression of chemoattractant SDF-1.

Platelet and plasma BDNF in lower respiratory tract infections of the adult.

Enhanced bronchial responsiveness during and following lower respiratory tract infections is a major clinical problem, but its pathogenesis is poorly understood. Brain-derived neurotrophic factor (BDNF), which can be released by platelets and leukocytes, has been identified as a mediator of bronchial hyperresponsiveness. It is unknown whether the release of BDNF is altered during lower respiratory tract infections of the adult. In this clinical pilot study, 16 patients (35-80 years old) with the diagnosis of an acute bacterial lower respiratory tract infection and elevated serum concentrations of c-reactive protein (>100 microg/ml) and procalcitonin (>0.1 ng/ml) were examined on admission to the hospital and 1 week after antibiotic treatment. Sixteen age- and sex-matched controls were examined in the same time period. BDNF concentrations in serum and platelets, but not in plasma, were markedly reduced in patients on the day of admission (median <25% of the controls). Analysis of the platelet marker serotonin (5-HT) suggested that the decrease of platelet BDNF is part of a non-specific release of platelet-derived mediators in this condition. Clinical improvement was accompanied by a restoration of serum and platelet BDNF concentrations which returned to control levels after 1 week of treatment. Cell culture experiments revealed that bacterial lipopolysaccharide (LPS) enhanced the release of BDNF by peripheral blood mononuclear cells of the patients at both time points. In conclusion, these data suggest that lower respiratory tract infections might be associated with an augmented release of BDNF by platelets and mononuclear cells.

Maternal nerve growth factor serum levels in the perinatal period.

Neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are potent modulators of neuronal and immune function, and have been implicated recently in diseases associated with pregnancy. In contrast to serum BDNF, which is reportedly suppressed in the perinatal period, regulation of NGF in the perinatal period is unknown. In this study, serum NGF concentrations were measured in 40 pregnant (follow-up: 30th and 37th week of gestation, 1 week and 8 weeks after childbirth) and 40 non-pregnant women. Maternal NGF serum levels did not differ significantly from controls (median: 7.6 pg NGF/ml serum) neither before nor after childbirth, although there was a trend towards increased NGF concentrations at the 37th week of gestation (median: 12.5 pg NGF/ml serum) and 1 week after childbirth (median: 11.6 pg NGF/ml serum). There was no association of maternal NGF with 17beta-estradiol, progesterone, dehydroepiandrosterone sulfate (DHEAS) and cortisol concentrations in maternal serum, or maternal depression, as measured by the Edinburgh Postnatal Depression Scale (EPDS). In the non-pregnant control group, NGF serum concentrations were negatively correlated with the number of days since the first day of the menstrual cycle (r=-0.32, p<0.05). In conclusion, NGF is not altered during normal pregnancy on a systemic level. In addition, NGF displays a different regulation compared with BDNF during the menstrual cycle.

Maternal serum concentrations of BDNF and depression in the perinatal period.

There is accumulating evidence that a deficiency in brain-derived neurotrophic factor (BDNF) plays a critical role in the pathophysiology of depression. This is in line with the postulate that low BDNF levels in serum are associated with depression. However, the regulation of maternal BDNF serum levels in the perinatal period, and its relationship to maternal depression is unknown. In this study, serum BDNF concentrations were measured in 40 pregnant (follow-up: 30th and 37th week of gestation, 1 week and 8 weeks after childbirth) and 40 non-pregnant women (20-40 years old). The Edinburgh Postnatal Depression Scale (EPDS) was assessed in all subjects at all time points. Maternal serum levels of BDNF were markedly decreased, both before and after childbirth (median: <30% of non-pregnant controls). BDNF correlated with decreased Serotonin (5-HT) levels in serum (r>0.6 and p<0.001 at all time points). In contrast, there was no association with altered estrogen, progesterone, dehydroepiandrosterone or cortisol concentrations in serum. There were significantly higher cortisol levels in cases of maternal depression (EPDS scores>9 points) than in cases without depression. There was a trend to a decrease of BDNF and 5-HT levels in cases of maternal depression (as compared to cases without depression), but this was not significant. In conclusion, we demonstrate that women display markedly decreased BDNF serum levels before and after childbirth. This phenomenon might reflect an increased risk for the development of mood disorders in the perinatal period. However, the individual serum concentration of BDNF alone did not predict maternal depression in our study.

The impact of age, weight and gender on BDNF levels in human platelets and plasma.

Brain-derived neurotrophic factor (BDNF) is a key mediator of neuronal plasticity in the adult. BDNF is known to be stored in human platelets and to circulate in plasma, but the regulation and function of BDNF in peripheral blood is still poorly understood. In this prospective study, we have examined 140 healthy, non-allergic adults (20-60 years old) to elucidate the impact of age and physical parameters on BDNF levels in human platelets and plasma. There was a wide concentration range of BDNF in serum (median: 22.6 ng/ml), platelets (median: 92.7 pg/10(6) platelets) and plasma (median: 92.5 pg/ml). BDNF levels in plasma decreased significantly with increasing age or weight, whereas platelet levels did not. When matched for weight, there were no significant gender differences regarding BDNF plasma levels. However, women displayed significantly lower platelet BDNF levels than men. In addition, platelet BDNF levels changed during the menstrual cycle. In conclusion, we demonstrate that parameters such as age or gender have a specific impact on stored and circulating BDNF levels in peripheral blood.

Brain-derived neurotrophic factor in platelets and airflow limitation in asthma.

Brain-derived neurotrophic factor (BDNF), a key mediator of neuronal plasticity, contributes to airway obstruction and hyperresponsiveness in a model of allergic asthma. BDNF is stored in human platelets and circulates in human plasma, but the significance of BDNF in this compartment is poorly understood. We investigated the relationship between platelet and plasma BDNF levels and pulmonary function in a cohort of 26 adult patients with recently diagnosed allergic asthma. BDNF levels in serum, platelets, and plasma were significantly increased in participants with asthma, as compared with 26 age- and sex-matched control subjects. In steroid-naive patients, but not in patients using inhaled corticosteroids, enhanced platelet BDNF levels correlated with parameters of airway obstruction and airway hyperresponsiveness to histamine. Experiments with activated peripheral blood mononuclear cells revealed that corticosteroids such as fluticasone effectively suppress BDNF secretion. In conclusion, we demonstrate that enhanced platelet BDNF is associated with airflow limitation and airway hyperresponsiveness in asthma. In addition, we provide evidence that corticosteroids suppress BDNF production by activated immune cells.

Multicentre performance evaluation of the E170 module for modular analytics.

The E170 module was evaluated at 13 sites in an international multicentre study. The objective of the study was to assess the analytical performance of 49 analytes, and to collect feedback on the system's reliability and practicability. The typical, within-run coefficients of variation (CVs) for most of the quantitative assays ranged between 1 and 2% while a range of 2-4% was achieved with the infectious disease methods. Total precision CVs were found to be within the manufacturer's expected performance ranges, demonstrating good concordance of the system's measuring channels and a high reproducibility during the 2-4-week trial period. The functional sensitivity of 11 selected assays met the clinical requirements (e.g., thyreotroponin (TSH) 0.008 mU/l, troponin T 0.02 microg/l, total prostate-specific antigen (PSA) 0.03 microg/l). The E170 showed no drift during an 8-hour period and no relevant reagent carryover. Accuracy was confirmed by ring trial experiments and method comparisons vs. Elecsys 2010. The reliability and practicability of the system's hardware and software met with, or even exceeded, the evaluator's requirements. Workflow studies showed that E170 can cover the combined workload of various routine analysers in a variety of laboratory environment. Throughput and sample processing time requirements were achieved while personnel 'hands-on-time' could be reduced.

Multicenter analytical performance evaluation of the Elecsys proBNP assay.

The purpose of this multicenter study was to evaluate the technical performance of the automated Elecsys proBNP (brain natriuretic peptide) assay, which is indicated as an aid in the diagnosis of individuals suspected of having congestive heart failure. The Elecsys proBNP assay is an electrochemiluminescent immunoassay employing two polyclonal NT-proBNP-specific antibodies in a sandwich test format. The study was performed on the three Elecsys analyzers (E 1010, E 2010, and E 170) at eight different sites world-wide. Within- and total precision were < or = 3%, with total precision slightly higher on the Elecsys E 170 instrument with multiple modules. Reproducibility among sites and platforms was < 5%. Precision at particularly low NT-proBNP concentrations was assessed down to approximately 25 pg/ml with CVs of 12.6% at 29.2 pg/ml and 9.6% at 38.5 pg/ml for the Elecsys 1010/2010 and E 170, respectively. Linearity was evaluated up to 25,000 pg/ml with a sample-based non-linear response observed with recoveries of < 90% for proBNP concentrations < 10,000 pg/ml. Slopes ranged between 0.92 and 1.02 and intercepts from -5.3 to 10.4 pg/ml (r > or = 0.998) among the three types of analyzers. Slopes were 4.95 and 4.53 in comparison to the Biosite Triage and Shionogi BNP assays. There was no assay interference, and no effect of barrier gels, tube composition, or freeze-thaw. NT-proBNP concentrations in EDTA plasma were up to 10% lower than in serum or heparinized plasma and the analyte was stable at 4 degrees C for up to 72 hours (the maximum time tested). There was no circadian rhythm in normal subjects or congestive heart failure patients and there was no effect of drawing position. In summary, the Elecsys proBNP assay exhibits good technical performance and is suitable for use in routine clinical laboratories to aid in the diagnosis of congestive heart failure.

Evaluation of a fully automated procalcitonin chemiluminescence immunoassay.

We evaluated a new fully automated microparticle immunoassay for procalcitonin (LIAISON BRAHMS PCT) in comparison with a previously established manual chemiluminescence assay from the same manufacturer (LUMItest PCT, BRAHMS AG). Procalcitonin (PCT) is an early and rather specific marker of systemic bacterial infection. In addition, the efficacy of antibiotic therapy can be monitored by sequential analysis of PCT values. This is why rapid and accurate determinations of PCT are urgently required by intensive care units. The aim of this study was to evaluate in a clinical set-up a new fully automated rapid PCT test. Analytical results are compared with results obtained by a previously introduced quantitative manual test. Intra-assay coefficients of variation (CV) were found in the range of 0.94 to 7.1% at concentrations between 0.46 and 97.2 microg/l. Over a time period of 27 days the inter-assay CV was found below 4.0% at concentrations of 1.93 and 14.29 microg/l and 9.9% at 0.40 microg/l. The functional sensitivity at a CV level of 20% was determined as 0.2 microg/l. Linearity could be demonstrated in a concentration range from 0 to 445 microg/l. When serum and plasma with EDTA, citrate or heparin anti-coagulation were analyzed in parallel, no systematic bias was found. A method comparison by regression analysis showed PCT values determined by both tests in very good agreement (r = 0.99). PCT concentrations in apparently healthy subjects (n =101) were below 0.58 microg/l in line with previously published results. Patients with sepsis (n = 43) or with infectious adult respiratory distress syndrome (ARDS) (n = 28) showed median values of 22.2 and 18.9 microg/l, respectively. In a clinical set-up the LIAISON Brahms PCT assay provided rapid and accurate PCT results supporting the early detection of severe sepsis, the differentiation between systemic bacterial infection and other inflammatory diseases, and the monitoring of antibiotic therapy in septic patients. The results of the new LIAISON BRAHMS PCT assay show an excellent concordance with the LUMItest PCT. The clinical information derived from the measurements is well comparable to the results obtained with the LUMItest PCT, too.