Seizure-induced alterations in cerebrovascular function in the neonate

Epileptiform seizures are most common during the neonatal period, affecting at least 0.3% of term neonates and more than 10% of preterm neonates. The adverse impact of neonatal seizures on the long-term neurological outcome has been well documented, but their cerebrovascular consequences are rarely emphasized. The cerebral blood flow is controlled by the interaction of the vascular and parenchymal cells forming the neurovascular unit via multiple mediator systems that have unique features in the newborn. Seizures drastically affect the neurovascular unit, resulting in (1) dramatic increases in brain metabolism and cerebral blood flow during the ictal period, (2) disruption of the blood-brain barrier, (3) an acute loss of cerebral pressure autoregulation, and (4) a delayed impairment of cerebrovascular reactivity to various stimuli. Furthermore, seizures frequently accompany and potentially aggravate a pre-existing cerebrovascular insult. This review summarizes the current knowledge on how seizures affecting various cells in the neurovascular unit result in the observed alterations in cerebrovascular function in the neonate.     

A novel anti-inflammatory function of human galectin-1: inhibition of hematopoietic progenitor cell mobilization

OBJECTIVE: The immunosuppressive and anti-inflammatory activity of mammalian galectin-1 (Gal-1) has been well established in experimental in vivo animal models and in vitro studies. Since the proliferation and migration of leukocytes represent a necessary and important step in response to the inflammatory insult, we have investigated whether Gal-1 affects the mobilization of hematopoietic progenitor cells (HPC) induced by cyclophosphamide (CY) and granulocyte colony-stimulating factor (G-CSF). METHODS: Bone marrow HPCs were mobilized with CY/G-CSF or CY/G-CSF plus human recombinant Gal-1 in BDF1 mice. Bone marrow (BM) and blood cells were taken at different time points and analyzed for their in vivo repopulating ability in lethally irradiated syngeneic animals. The number of myeloid progenitor cells in BM and blood samples was determined by colony-forming cell assay. Expression of surface markers (Sca-1, CD3epsilon, CD45R/B220, Ter-119, GR-1, and CD11b) on nucleated marrow cells was measured by flow cytometry. The lymphocytes, granulocytes, and monocytes in blood samples were counted after Giemsa staining. RESULTS: Gal-1 dramatically inhibited CY/G-CSF-induced HPC migration to the periphery as well as decreased peripheral neutrophilia and monocytosis in a dose- and time-dependent manner. In contrast, Gal-1 itself stimulated HPC expansion and accumulation within the BM. The presence of the lectin for inhibition of HPC mobilization was essential during the second half of the treatment. Moreover, Gal-1 inhbited transendothelial migration of BM-derived HPCs in response to SDF-1 in vitro. CONCLUSION: Gal-1 blocked BM progenitor cell migration induced by CY/G-CSF treatment, indicating a novel anti-inflammatory function of the lectin. We suggest that the inhibition of HPC mobilization occurs mainly via obstructing the transendothelial migration of BM-derived cells including primitive hematopoietic and committed myeloid progenitor cells and mature granulocytes and monocytes.     

Immunoactivation in preeclampsia: Vδ2+ and regulatory T cells during the inflammatory stage of disease

Recent data suggest a dominant role of the innate, rather than the adaptive immune system in pregnancy-related immunoregulation. γ/δ T cells, that comprise a minor subpopulation of human peripheral blood lymphocytes, represent a link between the innate and the acquired immune systems. However little is known about how they function in preeclampsia, which is suggested to be associated with a Th1 predominant immune response. The aim of our study was to investigate the presence and phenotype of Vδ2+ cells and of regulatory T cells in the pathogenesis of preeclampsia. Since Vδ2+ T cell function has been shown to be altered in patients with preeclampsia we investigated the expression of perforin, Fas and TIM-3 by Vδ2+ T cells and the possible role of activating and inhibitory NK cell receptors as well as of regulatory T cells. Vδ2+ T cells of preeclamptic patients demonstrated an increased perforin and IFNγ production, which could be explained by dysregulation of NK cell receptor expression. These Th1 polarized cells were less susceptible to apoptosis than Vδ2+ T cells from healthy pregnant women. Our data suggest that activated Vδ2+ T cells of preeclamptic women have an increased cytotoxic potential, which may be due to altered expression of NK cell inhibitory and activating receptors. In this study we report a series of observations, which taken together suggest the role of multiple pathways in generating an exaggerated systemic inflammatory response observed in the clinical stage of preeclampsia.     

The role of gamma/delta T cells in the feto-maternal relationship.

Polymorphic MHC is absent from the trophoblast, therefore, it resists NK as well as CTL-mediated lysis in vitro. Activated gamma / delta TCR positive cells are significantly enriched in the decidua as well as in peripheral blood of healthy pregnant women. Human peripheral gamma / delta lymphocytes preferentially express the V gamma 9/V delta 2 TCR, whereas those of the decidua use the V delta 1 chain. These subpopulations are functionally polarized, the former being Th1, the latter Th2. Potentially cytotoxic V delta 2+ lymphocytes recognize HLA-E on the trophoblast via the CD94/NKG2A receptor, which induces an inhibitory signal, thus potentially inhibiting Th1 type cytokine production.     

Further evidence for the functional role of nonsynaptic nicotinic acetylcholine receptors

The function of nicotinic acetylcholine receptors in the main central systems has been documented in the past decade. These studies focused mostly on the synaptic functions, although acetylcholine is released dominantly into the extrasynaptic space and the majority of nicotinic acetylcholine receptors on remote neurons are found on extrasynaptic membranes. Here, we show further evidence for the role of nonsynaptic nicotinic functions in the cognitive and the reward system. Dendrites of γ-amino-n-butyric acid (GABA)-containing interneurons of the hippocampus are densely equipped with nicotinic acetylcholine receptors. These cells play an important role in memory processing. We analysed the effects of nicotinic acetylcholine receptor stimulation on the Ca²⁺ dynamics of interneurons in different dendritic compartments. We also investigated the role of nicotinic receptors in the nucleus accumbens where nicotine stimulated vesicular dopamine release via activation of receptors located on varicosities. Nicotine produced comparable effects with 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) on dopamine release. These examples demonstrate that nonsynaptic nicotinic acetylcholine receptors can effectively influence activity pattern of neural networks in key structures of central systems.     

Age-related immune cell dynamics influence outcomes after allogeneic haematopoietic cell transplantation

An efficient immunological reconstitution construes the pillar for the success of allogeneic haematopoietic cell transplantation (HCT) in haematological disorders. Factors influencing post-transplant immune recovery have been largely investigated across multiple cohorts issuing heterogeneous results. Differences in outcomes in adult and paediatric populations suggest an age-related contribution to post-transplant immune reconstitution; however, it is unclear how recipient and donor age may affect the dynamics of single immune cells. Here, we retrospectively collected and analysed immunological data of 174 patients (58 children and 116 adults) consecutively transplanted for haematological disorders in our centre. We show that trajectories of specific immune cells were strictly dependent on recipient age and pretransplant virus exposure, with the strongest effect seen on T CD4+ and B-cell counterparts, while donor age and transplant platforms had a minimal impact. This mirrored different kinetics of immune reconstitution in adult and paediatric patients, with major divergences in immune cell composition in late post-transplant phases, featuring better survival, relapse-free survival and cumulative incidence of pathogen-specific infections in younger patients. Altogether, these findings underpin the importance of recipient age on post-transplant immune cell recovery and define the basic dynamics of the immune reconstitution in paediatric and adult populations as a benchmark for future studies.