Exogenous hydrogen sulfide produces hemodynamic effects by triggering central neuroregulatory mechanisms

Recently, it was found that hydrogen sulfide (H2S) may serve as an important transmitter in peripheral organs as well as in the brain. The aim of the present study was to evaluate the possible function of H2S in the brain regulation of the circulatory system. Experiments were performed on conscious, male, Wistar-Kyoto rats. Mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously under baseline conditions and during infusions into the lateral cerebral ventricle (LCV) of the experimental animals. In control series LCV infusion of vehicle (Krebs-Henseleit bicarbonate-buffer) did not cause significant changes in MABP or HR. LCV infusion of H2S donor (NaHS) at the rate of 400 n/h resulted in an increase in MABP, whereas infusions at the rate of 100 n/h and 200 n/h failed to change MABP. On the other hand LCV infusion of H2S donor at the rate of 200 n/h caused a significant increase in HR while infusion at the rate of 400 n/h produced an increase in HR, which was smaller than this observed during infusion at the rate of 200 n/h. H2S donor administered at the rate of 100 n/h failed to affect HR. In conclusion, the present study demonstrates that exogenous hydrogen sulfide changes hemodynamic parameters by centrally mediated mechanisms. The hemodynamic effect seems to be dependent on H2S concentration in cerebrospinal fluid. It appears that the hypertensive response may occur at a concentration, which does not exceed twice the physiological level.     

The poxvirus vectors MVA and NYVAC as gene delivery systems for vaccination against infectious diseases and cancer

Recombinants based on poxviruses have been used extensively as gene delivery systems to study many biological functions of foreign genes and as vaccines against many pathogens, particularly in the veterinary field. Based on safety record, efficient expression and ability to trigger specific immune responses, two of the most promising poxvirus vectors for human use are the attenuated modified vaccinia virus Ankara (MVA) and the Copenhagen derived NYVAC strains. Because of the scientific and clinical interest in these two vectors, here we review their biological characteristics, with emphasis on virus-host cell interactions, viral immunomodulators, gene expression profiling, virus distribution in animals, and application as vaccines against different pathogens and tumors.     

Evolution of hepatitis C virus hypervariable region 1 in chronically infected children

Hepatitis C virus (HCV) quasispecies diversification plays an essential role in the establishment of chronic infections. Our earlier analysis of HCV population structure in children subjected to interferon-ribavirin treatment demonstrated that viral quasispecies is homogenous in patients who failed to respond to the therapy and heterogeneous in sustained responders. We also showed that certain variants of HCV hypervariable region 1 (HVR1) are conserved in non-responders. To better elucidate the pathways of HCV evolution, here we examined the changes of HVR1 in viral populations isolated from sera of eight treatment-naive pediatric patients. We found that HCV evolution in untreated chronically infected children occurs according to two pathways and results in the formation of either genetically homogenous or variable quasispecies. Variable populations are prone to quasispecies shifts. In contrast, homogenous populations are composed of closely related variants that undergo only minor changes. In addition, we observed that a phenomenon of inter-quasispecies conservation of HVR1 is associated with some of the homogenous HCV populations. The collected data suggest that there exist HVR1 variants with superior fitness, capable of persisting in different hosts.     

The kinetics and apoptotic profile of circulating endothelial cells in autologous hematopoietic stem cell transplantation in patients with lymphoproliferative disorders

In neoplastic disorders, endothelial cells take part in tumor progression and also influence the recovery of hematopoiesis after high-dose chemotherapy. Measurements of circulating endothelial cells (CEC), their subsets and kinetics were taken in patients with lymphoid malignancies (37 multiple myeloma, ten lymphoma) during autologous hematopoietic stem cell transplantation (HSCT). CEC were evaluated by four-color flow cytometry at different time points. Additionally levels of angiopoietins 1 and 2 were evaluated by ELISA assay. The baseline number of CECs and their subsets in patients were higher than in the control group. The median CEC number dropped significantly after transplantation (from 9.5/μL to 6.2/μL, p?<?0.001). Apoptosis of CECs 24 h after chemotherapy was enhanced in comparison to baseline values (median apoptotic CEC number 4.15/μL vs 3.1/μL; p?<?0,001). The time for neutrophil engraftment was shorter for patients with a low apoptotic CEC count at baseline as compared to those with a high apoptotic CEC count (median time to engraftment 13 vs. 16 days respectively, p?=?0.04). We observed an adverse correlation of progenitor CEC numbers measured 1 h after transplantation with the time to neutrophil engraftment (r?=??0.49, p?=?0.008). We also found a negative correlation between the number of CECs originating from microvessels measured 1 h after transplantation, and the time to neutrophil engraftment (r?=??0.39, p?=?0.04). Baseline angiopoietins 1 and 2 concentration did not influence the post-transplant regeneration time. CEC numbers significantly change during autologous HSCT. Our results suggest that progenitor CECs and CECs derived from microvessels both take part in successful engraftment.     

Pseudomonas aeruginosa biofilm is a potent inducer of phagocyte hyperinflammation

Objective

Pseudomonas aeruginosa effectively facilitate resistance to phagocyte killing by biofilm formation. However, the cross talk between biofilm components and phagocytes is still unclear. We hypothesize that a biofilm provides a concentrated extracellular source of LPS, DNA and exopolysaccharides (EPS), which polarize neighbouring phagocytes into an adverse hyperinflammatory state of activation.

Methods

We measured the release of a panel of mediators produced in vitro by murine neutrophils and macrophages exposed to various biofilm components of P. aeruginosa cultures.

Results

We found that conditioned media from a high biofilm-producing strain of P. aeruginosa, PAR5, accumulated high concentrations of extracellular bacterial LPS, DNA and EPS by 72 h. These conditioned media induced phagocytes to release a hyperinflammatory pattern of mediators, with enhanced levels of TNF-α, IL-6, IL12p40, PGE₂ and NO. Moreover, the phagocytes also upregulated COX-2 and iNOS with no influence on the expression of arginase-1.

Conclusions

Phagocytes exposed to biofilm microenvironment, called by us biofilm-associated neutrophils/macrophages (BANs/BAMs), display secretory properties similar to that of N1/M1-type phagocytes. These results suggest that in vivo high concentrations of LPS and DNA, trapped in biofilm by EPS, might convert infiltrating phagocytes into cells responsible for tissue injury without direct contact with bacteria and phagocytosis.

     

Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium

The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.     

Insomnia symptoms influence CPAP compliance

Purpose

The aim of this study is to determine parameters which influence 6-month compliance of continuous positive airway pressure therapy (CPAP) in patients with obstructive sleep apnea syndrome (OSAS).

Methods

This prospective study investigated 73 patients (24 females) with OSAS and medical indication for CPAP therapy: age 55.1?±?11.5 years, body mass index (BMI) 30.8?±?5.0 kg/m2, Apnea–Hypopnea Index (AHI) 39.2?±?26.7/h, Oxygen Desaturation Index (ODI) 33.2?±?25.4/h, minimum O₂ saturation 78.9?±?7.6%. The influence of baseline parameters (demographic and polysomnographic data, sleeping medication intakes, BMI, psychometrics [Epworth Sleepiness Scale, Regensburg Insomnia Scale, Vigilance test and Beck Depression Inventory]) on 6-month compliance was evaluated with a correlation and a linear regression analysis.

Results

The baseline value of the Regensburg Insomnia Scale (RIS) predicts 6-month CPAP compliance (r?=??0.376, R ²?=?0.14, p?<?0.001), although no other baseline parameter correlates. Patients with a compliance of <4 h/night show higher RIS scores, i.e., more insomnia symptoms (17.6?±?8.8) compared to those with ≥4 h/night (12.6?±?6.9; p?<?0.05).

Conclusions

Insomnia symptoms prior to the beginning of CPAP treatment show a negative influence on CPAP compliance. Further studies should clarify, if a treatment of insomnia symptoms leads to a benefit in compliance.