Ligands and receptors of the TNF superfamily are decreased in major depression and during early antidepressant therapy.

BACKGROUND: The up-regulation of pro-inflammatory agents, amongst them tumor necrosis factor (TNF), may represent low-grade inflammation in major depression. To further elucidate inflammatory mechanisms related to TNF in depression, the aim of the current study was to investigate the involvement of ligands and receptors of the TNF/TNF-receptor-superfamily yet un- or little explored in major depression. METHODS: Serum levels of ligands (TNF, TNF-related weak inducer of apoptosis [TWEAK], B-cell activating factor [BAFF], tumor necrosis factor superfamily member 14 [TNFSF14; LIGHT], A proliferation-inducing ligand [APRIL]) and receptor molecules (TNF receptor superfamily member 8 [TNFRSF8; sCD30], soluble TNF receptor type 1 [sTNFR1] and type 2 [sTNFR2]) of the TNF/TNF-receptor-superfamily were measured in 50 unmedicated patients suffering from major depression and 48 healthy controls and were reassessed in 37 of the depressed patients two weeks after the initiation of antidepressive treatment. RESULTS: In comparison to the healthy controls, the interrelated serum levels of TWEAK, BAFF, TNFSF8, sTNFR1 and sTNFR2 were reduced both in the unmedicated and medicated depressed patients. Serum levels of BAFF and TNF significantly increased during the initiation of antidepressive treatment. In the combined sample of unmedicated depressed and healthy controls, but not the separate groups, scores of the BDI-II inversely correlated with levels of TWEAK, BAFF, sTNFR1, sTNFR2 and TNFSF8. CONCLUSION: The current findings give evidence for a role of the TNF/TNF-receptor-superfamily in the pathophysiology of major depression that may involve reduced tissue regeneration and neurogenesis rather than an acceleration of pro-inflammatory pathways.

Biomimetic cofactors and methods for their recycling.

Nicotinamide cofactor biomimetics (NCBs) belong to a class of compounds that, as the name suggests, mimic the structures and functions of natural nicotinamide cofactors, namely nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate and their corresponding reduced forms. The first set of NCBs was discovered in the 1930s; these were initially used to study the chemical properties of this class of cofactors as well as understand nicotinamide binding of oxidoreductases. Since then, various NCBs, enzymes, and recycling systems have evolved and lately, new NCBs have been developed and used to run biocatalytic reactions.

Characterization of Biomimetic Cofactors According to Stability, Redox Potentials, and Enzymatic Conversion by NADH Oxidase from Lactobacillus pentosus.

Oxidoreductases are attractive biocatalysts that convert achiral substrates into products of higher value, but they are also for the most part dependent on nicotinamide cofactors. Recently, biomimetic nicotinamide derivatives have received attention as less costly alternatives to natural cofactors. However, recycling of biomimetics is still challenging because there are only limited opportunities. Here, we have characterized various biomimetic cofactors with regard to stability and redox potentials to find the best alternative to natural cofactors. Further, the cofactor spectrum of NADH oxidase from Lactobacillus pentosus (LpNox) could be expanded, and the enzymatic activity was also compared to activities with different small-molecule catalysts. As a result, we succeeded in identifying several strategies for regeneration of oxidized biomimetics.

Brain arousal regulation as response predictor for antidepressant therapy in major depression.

A tonically high level of brain arousal and its hyperstable regulation is supposed to be a pathogenic factor in major depression. Preclinical studies indicate that most antidepressants may counteract this dysregulation. Therefore, it was hypothesized that responders to antidepressants show a) a high level of EEG-vigilance (an indicator of brain arousal) and b) a more stable EEG-vigilance regulation than non-responders. In 65 unmedicated depressed patients 15-min resting-state EEGs were recorded off medication (baseline). In 57 patients an additional EEG was recorded 14 ± 1 days following onset of antidepressant treatment (T1). Response was defined as a ≥50% HAMD-17-improvement after 28 ± 1 days of treatment (T2), resulting in 29 responders and 36 non-responders. Brain arousal was assessed using the Vigilance Algorithm Leipzig (VIGALL 2.1). At baseline responders and non-responders differed in distribution of overall EEG-vigilance stages (F2,133 = 4.780, p = 0.009), with responders showing significantly more high vigilance stage A and less low vigilance stage B. The 15-minutes Time-course of EEG-vigilance did not differ significantly between groups. Exploratory analyses revealed that responders showed a stronger decline in EEG-vigilance levels from baseline to T1 than non-responders (F2,130 = 4.978, p = 0.005). Higher brain arousal level in responders to antidepressants supports the concept that dysregulation of brain arousal is a possible predictor of treatment response in affective disorders.

A water-forming NADH oxidase from Lactobacillus pentosus suitable for the regeneration of synthetic biomimetic cofactors.

The cell-free biocatalytic production of fine chemicals by oxidoreductases has continuously grown over the past years. Since especially dehydrogenases depend on the stoichiometric use of nicotinamide pyridine cofactors, an integrated efficient recycling system is crucial to allow process operation under economic conditions. Lately, the variety of cofactors for biocatalysis was broadened by the utilization of totally synthetic and cheap biomimetics. Though, to date the regeneration has been limited to chemical or electrochemical methods. Here, we report an enzymatic recycling by the flavoprotein NADH-oxidase from Lactobacillus pentosus (LpNox). Since this enzyme has not been described before, we first characterized it in regard to its optimal reaction parameters. We found that the heterologously overexpressed enzyme only contained 13% FAD. In vitro loading of the enzyme with FAD, resulted in a higher specific activity towards its natural cofactor NADH as well as different nicotinamide derived biomimetics. Apart from the enzymatic recycling, which gives water as a by-product by transferring four electrons onto oxygen, unbound FAD can also catalyze the oxidation of biomimetic cofactors. Here a two electron process takes place yielding H2O2 instead. The enzymatic and chemical recycling was compared in regard to reaction kinetics for the natural and biomimetic cofactors. With LpNox and FAD, two recycling strategies for biomimetic cofactors are described with either water or hydrogen peroxide as by-product.

Dynamics of melanin-concentrating hormone (MCH) serum levels in major depressive disorder during antidepressant treatment.

BACKGROUND: In preclinical studies, the hypothalamic polypeptide melanin-concentrating hormone (MCH) has been shown to be involved in depression-like behavior and modulations of MCH and MCH-receptors were proposed as potential new antidepressant drug targets. METHODS: For the first time, MCH serum levels were explored in 30 patients with major depressive disorder (MDD) prior to (T1) and after 2 (T2) and 4 weeks (T3) of antidepressant treatment and in 30 age- and sex-matched healthy controls by applying a fluorescence immunoassay. RESULTS: Levels of MCH did not differ significantly between un-medicated patients (444.11±174.63pg/mL SD) and controls (450.68±210.03pg/mL SD). In MDD patients, MCH levels significantly decreased from T1 to T3 (F=4.663; p=0.013). Post-hoc analyses showed that these changes were limited to patients treated with mirtazapine but not escitalopram and female but not male patients. MCH-levels showed high correlations from T1 to T3 (r≥0.964, p<0.001) and were found to correlate significantly with parameters of sleep within the controls. LIMITATIONS: Small sample size. No follow-up measures were performed within the control group. CONCLUSIONS: Our findings suggest peripheral MCH-levels not to be altered in depression but possibly reflecting depression-related state properties that can be modulated by sleep, medication and sex.

Computer simulation of cardiac cryoablation: comparison with in vivo data.

Simulation of cardiac cryoablation by the finite element method can contribute to optimizing ablation results and understanding the effects of modifications prior to time-consuming and expensive experiments. In this work an intervention scenario using a 9 Fr 8 mm tip applicator applied to ventricular tissue was simulated using the effective heat capacity model based on Pennes' bioheat equation. Using experimentally obtained refrigerant flow rates and temperature profiles recorded by a thermocouple located at the tip of the applicator the cooling performance of the refrigerant was estimated and integrated by time and temperature dependent boundary conditions based on distinct phases of a freeze-thaw cycle. Our simulations exhibited a mean difference of approximately 6°C at the applicator tip compared to temperature profiles obtained during in vivo experiments. The presented model is a useful tool for simulation and validation of new developments in clinical cardiac cryoablation.

Prediction of countershock success: a comparison of autoregressive and fast fourier transformed spectral estimators.

OBJECTIVES: Spectral analysis of the ventricular fibrillation (VF) ECG has been used for predicting countershock success, where the Fast Fourier Transformation (FFT) is the standard spectral estimator. Autoregressive (AR) spectral estimation should compute the spectrum with less computation time. This study compares the predictive power and computational performance of features obtained by the FFT and AR methods. METHODS: In an animal model of VF cardiac arrest, 41 shocks were delivered in 25 swine. For feature parameter analysis, 2.5 s signal intervals directly before the shock and directly before the hands-off interval were used, respectively. Invasive recordings of the arterial pressure were used for assessing the outcome of each shock. For a proof of concept, a micro-controller program was implemented. RESULTS: Calculating the area under the receiver operating characteristic (ROC) curve (AUC), the results of the AR-based features called spectral pole power (SPP) and spectral pole power with dominant frequency (DF) weighing (SPPDF) yield better outcome prediction results (85%; 89%) than common parameters based on FFT calculation method (centroid frequency (CF), amplitude spectrum area (AMSA)) (72%; 78%) during hands-off interval. Moreover, the predictive power of the feature parameters during ongoing CPR was not invalidated by closed-chest compressions. The calculation time of the AR-based parameters was nearly 2.5 times faster than the FFT-based features. CONCLUSION: Summing up, AR spectral estimators are an attractive option compared to FFT due to the reduced computational speed and the better outcome prediction. This might be of benefit when implementing AR prediction features on the microprocessor of a semi-automatic defibrillator.

Spatial-temporal filter effect in a computer model study of ventricular fibrillation.

Prediction of countershock success from ventricular fibrillation (VF) ECG is a major challenge in critical care medicine. Recent findings indicate that stable, high frequency mother rotors are one possible mechanism maintaining VF. A computer model study was performed to investigate how epicardiac sources are reflected in the ECG. In the cardiac tissues of two computer models - a model with cubic geometry and a simplified torso model with a left ventricle - a mother rotor was induced by increasing the potassium rectifier current. On the epicardium, the dominant frequency (DF) map revealed a constant DF of 23 Hz (cubic model) and 24.4 Hz (torso model) in the region of the mother rotor, respectively. A sharp drop of frequency (3-18 Hz in the cubic model and 12.4-18 Hz in the torso model) occurred in the surrounding epicardial tissue of chaotic fibrillatory conduction. While no organized pattern was observable on the body surface of the cubic model, the mother rotor frequency can be identified in the anterior surface of the torso model because of the chosen position of the mother rotor in the ventricle (shortest distance to the body surface). Nevertheless, the DFs were damped on the body surfaces of both models (4.6-8.5 Hz in the cubic model and 14.4-16.4 Hz in the torso model). Thus, it was shown in this computer model study that wave propagation transforms the spatial low pass filtering of the thorax into a temporal low pass. In contrast to the resistive-capacitive low pass filter formed by the tissue, this spatial-temporal low pass filter becomes effective at low frequencies (tens of Hertz). This effect damps the high frequency components arising from the heart and it hampers a direct observation of rapid, organized sources of VF in the ECGs, when in an emergency case an artifact-free recording is not possible.

Mother rotor anchoring in branching tissue with heterogeneous membrane properties.

Abstract Current understanding of atrial fibrillation is based on the co-existence of multiple re-entrant waves propagating randomly throughout the tissue. However, recent experimental results indicate that in many cases one or a small number of periodic, high-frequency re-entrant sources (mother rotors) can drive the arrhythmia. Owing to the high activation rate, mother rotors seem to be located in regions of shortened action potential duration. In this study a computer model of cardiac propagation was applied to investigate mechanisms leading to the formation and maintenance of such mother rotors. For this purpose, a region of short action potential duration was generated by varying the acetylcholine concentration across the tissue. A mother rotor initiated in the center of this region drifts away, and the activation terminates. If an additional heterogeneity such as a bundle is included into the model, a further drift mechanism directed to the bundle is observed and the rotor can be stabilized. Therefore, bundle insertions may play an important role in the maintenance of mother rotors. The influence of the driving rotor on the activation pattern was studied in a three-dimensional model of rectangular shape and a monolayer model of anatomically correct atrial geometry.

Frequency distribution effects of anchored mother rotors--a computer model study.

Recent findings indicate that major organized centers (mother rotors) can maintain ventricular fibrillation (VF). In computer models the mother rotors can be induced by local shortening of the action potential duration (APD) in the cardiac tissue. Because of the fact that these rotors tend to drift away towards regions with longer APD, an additional heterogeneity (e.g. bundle) has to be included in the model for stabilizing the activation. Thus, the rotor anchors on this bundle and yields to interesting frequency distribution effects. In the dominant frequency (DF) map of a simplified computer model of the left ventricle it can be observed that the anchoring site of the rotor produces a slightly lower DF than in the surrounding cardiac tissue. That means that due to the load effect of the bundle the frequency is decreased. Furthermore the meandering of the mother rotor around this anchor site is reflected in the spectra of signals taken randomly in the organized region. These effects are both detected with two different independent spectral estimators with different resolutions.

On computing dominant frequency from bipolar intracardiac electrograms.

Dominant frequency (DF) computed from action potentials is a key parameter for investigating atrial fibrillation in animal studies and computer models. A recent clinical trial reported consistent results computing DF from 30 Hz to 400 Hz bandpass filtered bipolar electrograms in humans. The DF (< 15 Hz and, thus, filtered out) was recovered by rectifying the signal, while the theoretical background of this approach was left uncommented. It is the focus of this paper to provide this background by a Fourier analysis. We demonstrate that it is mainly the timing of the narrow deflections (local activation at the catheter tip) which contribute to the DF peak in the frequency spectrum. Due to the typical signal morphology pronounced harmonic peaks occur in the spectrum. This is a disadvantage when computing the regularity index (RI) as a parameter for local organization and signal quality. It is demonstrated for synthetical and patient data that at low DF the RI is far below the optimal value one even for high underlying organization and good signal quality. The insight obtained promotes the development of better measures for organization. The finding that mainly timing of activation contributes to DF might promote the development of powerful realtime signal processing tools for computing DF.