Evaluation of peripheral serotonin content and α2-adrenergic receptor function as potential markers for life-long recurrent depressive disorder by using methodological improvements.

OBJECTIVE: We aimed to evaluate the role and the relations between peripheral platelet serotonin content, blood plasma serotonin concentration and the function of platelet α2-adrenergic receptors (α2-AR) as potential state or trait biomarkers for recurrent depressive disorder (RDD). METHODS: 26 drug-free patients with life-long RDD and 31 healthy controls were included in the study. Several methodological improvements in blood collection and platelet isolation were implemented following the present standards in Haematology and Light transmission aggregometry. RESULTS: Our results have shown lower platelet serotonin content, higher plasma serotonin concentration and desensitization of platelet α2-AR in patients with RDD. The variables were found heterogeneous and mainly influenced by the clinical characteristics of the current episode. High amplitude of the α2-AR correlated with severe anxious symptoms and high platelet serotonin content (as well as low plasma serotonin levels) were associated with psychotic symptoms. CONCLUSIONS: The evaluated peripheral markers reflect only state (but not trait) abnormalities in patients with current severe episode of RDD. The observed peripheral α2-AR and serotonin abnormalities are mutually not related and they are probably triggered by different mechanisms.

Peripheral glutamate and TNF-α levels in patients with intracerebral hemorrhage: Their prognostic values and interactions toward the formation of the edemal volume.

OBJECTIVE: We aimed to evaluate the prognostic values, contribution and interactions of the peripheral blood plasma glutamate and tumor-necrosis factor-α (TNF-α) levels toward the formation of the perifocal edema in patients with intracerebral hemorrhage (ICH). METHODS: Fifty patients with ICH and fifty healthy controls were included in the study. The peripheral markers were detected by high-sensitivity ELISA. RESULTS: A highly significant differences in plasma glutamate and TNF-α levels with good separation of their values was detected between patients and healthy controls. The two variables correlated with the severity of the symptoms and the initial volume of the ICH at admission. Both peripheral glutamate and TNF-α levels at admission were estimated as significant predictors for the formation of the perifocal edema five days after ICH; nevertheless, it was shown that they independently contribute to the development of the edema, without effects of interaction and regardless the localization of the ICH. CONCLUSIONS: Our results support the idea for the significance of glutamate and TNF-α as peripheral markers for excitotoxicity and inflammation in ICH patients. The developed multiple regression model for prediction of the development of the edema could be beneficial in decision making between conservative treatment and surgical intervention in the clinical practice.

Inflammatory and oxidative stress markers in intracerebral hemorrhage: Relevance as prognostic markers for quantification of the edema volume.

We aimed to analyze the inflammatory and oxidative stress (OS) markers after intracerebral hemorrhage (ICH) and their temporal changes, interaction effects, and prognostic values as biomarkers for the prediction of the edema volume. Our prospective, longitudinal study included a cohort group of 73 conservatively treated patients with ICH, without hematoma expansion or intraventricular bleeding, which were initialized with the same treatment and provided with the same in-hospital care during the disease course. Study procedures included multilevel comprehensive analyses of clinical and neuroimaging data, aligned with the exploration of 19 inflammatory and five OS markers. White blood cells (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophilia, and lymphopenia peaked 3 days post-ICH, and they showed much stronger correlations with clinical and neuroimaging variables, when compared to the admission values. An intricate interplay among inflammatory (WBC, CRP, neutrophils, neutrophil-to-lymphocyte ratio [NLR], interleukin (IL)-6, and IL-10) and OS mechanisms (catalase activity and advanced oxidation protein products [AOPP]) was detected operating 3-days post-ICH, being assessed as relevant for prediction of the edema. The overall results suggested complex pathology of formation of post-ICH edema, via: (A) Not additive, but statistically significant synergistic interactions between CRP-ESR, neutrophils-CRP, and neutrophils-IL-6 as drivers for the edema formation; (B) Significant antagonistic effect of high protein oxidation on the CRP-edema dependence, suggesting a mechanism of potential OS-CRP negative feedback loop and redox inactivation of CRP. The final multiple regression model separated the third-day variables NLR, CRP × AOPP, and WBC, as significant prognostic biomarkers for the prediction of the edema volume, with NLR being associated with the highest effect size. Our developed mathematical equation with 3D modeling for prediction and quantification of the edema volume might be beneficial for taking timely adequate strategies for prevention of delayed neurological deteriorations.

Prediction of in-hospital mortality after acute upper gastrointestinal bleeding: cross-validation of several risk scoring systems.

OBJECTIVE: We aimed to identify the clinical, biochemical, and endoscopic features associated with in-hospital mortality after acute upper gastrointestinal bleeding (AUGIB), focusing on cross-validation of the Glasgow-Blatchford score (GBS), full Rockall score (RS), and Cedars-Sinai Medical Center Predictive Index (CSMCPI) scoring systems. METHODS: Our prospective cross-sectional study included 156 patients with AUGIB. Several statistical approaches were used to assess the predictive accuracy of the scoring systems. RESULTS: All three scoring systems were able to accurately predict in-hospital mortality (area under the receiver operating characteristic curve [AUC] > 0.9); however, the multiple logistic model separated the presence of hemodynamic instability (state of shock) and the CSMCPI as the only significant predictive risk factors. In compliance with the overall results, the CSMCPI was consistently found to be superior to the other two systems (highest AUC, highest sensitivity and specificity, highest positive and negative predictive values, highest positive likelihood ratio, lowest negative likelihood ratio, and 1-unit increase in CSMCPI associated with 6.3 times higher odds of mortality), outperforming the GBS and full RS. CONCLUSIONS: We suggest consideration of the CSMCPI as a readily available and reliable tool for accurately predicting in-hospital mortality after AUGIB, thus providing an essential backbone in clinical decision-making.

Modeling prognostic factors for poor neurological outcome in conservatively treated patients with intracerebral hemorrhage: A focus on TNF-α.

OBJECTIVE: Prognostic models for Intracerebral hemorrhage (ICH), mainly based on clinical evaluation, have remained inherently confounded by subjective scoring assessments and limited accuracy. In this study, we aimed at assessing the risk for poor outcome after ICH based on peripheral biochemical markers (TNF-α, glutamate and glucose) and radiological variables (both at admission and five days after patient's care), for modeling purposes of prognostication. PATIENTS AND METHODS: The defined initial variables of fifty non-comatose conservatively treated ICH patients without severe complications during the hospitalization process (as intraventricular bleeding, or hematoma expansion) were aligned with the evaluated parameters during re-evaluation (3 months later). A comprehensive statistical approach has been applied by using different modeling strategies for prediction of their functional status and outcome. RESULTS: Higher blood plasma glutamate, TNF-α and initial ICH volume at admission, as well as higher volumes of ICH and perihematomal edema after five days of care were significantly more likely associated with the poor outcome. Nevertheless, in all of the constructed models, TNF-α was estimated as the only significant predictive risk factor, thus outperforming the capacity of the initial ICH volume and the radiological variables after 5 days, both in terms of prognostication of the functional status and the 3-month neurological outcome. The constructed canonical variable that has fairly marked off the different outcomes was also mainly weighed by the admission TNF-α levels. For the first time, we have carefully developed probability functions for the neurological outcome as a response to the admission TNF-α levels; TNF-α levels >110.35 pg/mL were assessed as an optimal cutoff point fairly identifying patients who will fall into the group with poor outcome. CONCLUSIONS: TNF-α based models and admission TNF-α screening might be appropriate as a key component that assists more objective prognostication and management of patient's care in clinical decision making, as rapid initial diagnosis and concentrated management are crucial for secondary prevention of further devastating neurological impairments after ICH.

SSRI-reduced platelet reactivity in non-responding patients with life-long Recurrent Depressive Disorder: Detection and involved mechanisms.

INTRODUCTION: Adverse effects with bleeding disorders are often associated with the administration of SSRI in depression, although the exact mechanisms remain contradicting. This study is aimed at detecting and exploring the mechanisms of SSRI-induced changes in platelet reactivity in non-responding patients with Recurrent Depressive Disorder (RDD) and life-long exposure to antidepressants. MATERIALS AND METHODS: Thirty-one patients and thirty-one healthy controls were included in the study. A comprehensive approach which includes evaluation of peripheral markers and microscopic analyses of platelet morphology changes has been used. RESULTS: RDD SSRI patients have shown blunted aggregatory responses towards collagen and epinephrine. Evident differences in the microscopic evaluation of platelet morphology were observed between the groups, with inherent absence of micro-aggregates and platelet shape changes within the patients; after quantification, the sensitivity and specificity of this method were assessed as high. The abnormalities were found in association with lower platelet serotonin content and high fluctuations of free plasma serotonin levels. Changes in the levels of CRP, fibrinogen and nitric oxide were not observed. Macroplatelets were also detected within RDD SSRI patients via increased MPV, PDW and P-LCR, which were associated with discoid shape and without procoagulant activity. CONCLUSIONS: The microscopic evaluation might be useful as a simple method for detection of SSRI-reduced platelet function for research purposes or systematic correlations with other biochemical parameters. The mechanisms involved in SSRI-reduced platelet function in non-responding RDD patients are complex, including combined effects of lower platelet serotonin content, high fluctuations in plasma serotonin concentration and abnormal α-AR function.

Validation of the ELISA Method for Quantitative Detection of TNF-α in Patients with Intracerebral Hemorrhage.

AIM: We aimed to investigate the sensitivity, reproducibility and validity of the commercial ELISA kits for quantitative detection of TNF-α and their potential application for screening purposes in patients with ICH. METHODS: Analysis of six independent standard series, evaluation of the deviation of the TNF-α concentration in patients with ICH, standard addition and visual analysis of whole UV-Vis spectra were carefully performed. RESULTS: Low standard deviations of the absorbance were detected for every standard, as well as in the samples of healthy controls and patients with ICH. The standard addition series have also confirmed high sensitivity and reproducibility of the assay, with a congruent shift of the standard curves with the concentration of TNF-α for the added plasma. The visual analyses of the gained spectra have revealed the absence of any matrix effects from the addition of the human plasma in the reconstituted standards. CONCLUSION: The commercial ELISA kits can be used in the clinical practice for screening purposes of the plasma TNF-α levels in patients with ICH.