Barrier mechanisms in neonatal stroke.

Clinical data continue to reveal that the incidence of perinatal stroke is high, similar to that in the elderly. Perinatal stroke leads to significant morbidity and severe long-term neurological and cognitive deficits, including cerebral palsy. Experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. Cerebral vasculature undergoes substantial structural and functional changes during early postnatal brain development. Thus, the state of the vasculature could affect susceptibility of the neonatal brain to cerebral ischemia. In this review, we discuss some of the most recent findings regarding the neurovascular responses of the immature brain to focal arterial stroke in relation to neuroinflammation. We also discuss a possible role of the neonatal blood-CSF barrier in modulating inflammation and the long-term effects of early neurovascular integrity after neonatal stroke on angiogenesis and neurogenesis

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014 and SysInflame, grant 01ZX1306A), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. I.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Evaluation of therapeutically useful transport routes across the blood-brain barrier using synthetic and natural carrier systems

Die Blut-Hirnschranke (BHS) ist ein Netzwerk aus Blutgefäßen, die von Endothelzellen (BCEC) ausgekleidet werden. Tight junction (TJ) Proteine verbinden die BCEC und verhindern den Übertritt von toxischen Verbindungen ins Gehirn, erschweren aber die Behandlung von neurodegenerativen Erkrankungen. Für das Gehirn wichtige Stoffe werden über endogene Transportwege befördert. Wichtige Transportrouten für Medikamente über die BHS wurden untersucht. SR-BI als Rezeptor für HDL an der apikalen Seite der BCEC erleichtert den HDL-vermittelten Vitamin E-Transport in vitro und in vivo. ApoA-I ist ein hochaffiner Ligand für SR-BI. Zunächst wurden Nanopartikel (NP) mit verbesserten Permeabilitätseigenschaften hergestellt. Solche als Proticles bezeichnete NP bestanden aus Protamin und Oligonukleotiden. Die Aufnahme- und Transcytoseeigenschaften von ApoA-I-gecoateten Proticles in einem BHS-Modell wurden untersucht. Das Coating mit ApoA-I zeigte eine verbesserte Transzytose sowie eine verstärkte Aufnahme durch beide Zelltypen. ApoA-I-gecoatete und reine Proticles zeigten eine unterschiedliche zelluläre Verteilung. Weiters wurde vasoaktives intestinales Peptid (VIP) in eine Matrix aus Proticles eingebettet, um das Peptid vor enzymatischer Degradierung zu schützen. Die Bindungseffizienz von VIP an Proticles wurde untersucht sowie die anti-inflammatorischen Eigenschaften von reinem VIP und VIPproticles in humanen und Mausmikrogliazellen. Maus BV2-Zellen wurden durch LPS effizienter stimuliert als humane C13NJ Zellen. VIPproticles zeigten zum Teil einen besseren Effekt als freies VIP in beiden Zelltypen. Schließlich wurde Afamin als Vitamin E-Transporter untersucht. Afamin transportierte??TocH über die BHS und erleichterte dessen Aufnahme durch Astrozyten. Neben endogener Synthese und Sekretion wird Afamin auch in isolierten Maus- und Schweinekapillaren exprimiert und ist in der humanen postmortem und Schweine-Zerebrovaskulatur, sowie in Maushirnen vorhanden.Drug delivery to the brain is restricted due to the low permeability of the blood-brain barrier (BBB) that is lined by brain capillary endothelial cells (BCEC). The BCEC are closely connected by tight junctions (TJs). Here therapeutically useful transport routes for drugs across the BBB were investigated. Scavenger receptor SR-BI as the prime receptor for HDL is expressed at the apical side of primary porcine(p) BCEC and facilitates uptake of HDL-associated Vitamin E across BCEC in vitro and in vivo. ApoA-I as the major apolipoprotein of HDL is a high affinity ligand of SR-BI. Uptake and transcytosis properties of apoA-I-coated protamine-oligonucleotide nanoparticles (NP), termed proticles, were investigated in an in vitro model of the BBB. Coating of proticles with apoA-I resulted in significantly enhanced transcytosis and improved uptake rates by both cell types. Uncoated and apoA-I-coated proticles showed different cellular localization. In addition, vasoactive intestinal peptide (VIP) was encapsulated into a matrix of proticles to protect this peptide against rapid enzymatic degradation. Binding efficiency of VIP to proticles showed up to 80% binding. Effects of VIP and VIP proticles on inflammatory gene expression in mouse (BV2) and human (C13NJ) microglial cell lines were investigated. These experiments revealed higher sensitivity of BV2 microglia towards LPS, and anti-inflammatory effects of VIP and proticle-associated VIP were more pronounced in those cells. In addition, afamin contributes to ?TocH transport across the BBB. Exogenously added afamin was transported across BCEC Transwell cultures and ?TocH transport to astrocytoma cells was facilitated by afamin. pBCEC also synthesize afamin endogenously and afamin was detected by immunohistochemistry in porcine, human postmortem, and mouse brain. Afamin mRNA expression in isolated brain capillaries suggests that afamin is a new family member of transport proteins for ?TocH homeostasis at the BBB in vivo.Ingrid KratzerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheGraz, Univ., Diss., 2009OeBB(VLID)20748

The molecular anatomy and functions of the choroid plexus in healthy and diseased brain

International audienceThe choroid plexus (CP) is located in the ventricular system of the brain (one in each ventricle), and the CP epithelial cells form an important barrier between the blood and the cerebrospinal fluid (CSF). Their main function comprises CSF secretion, maintenance of brain homeostasis, signalling, and forming a neuroprotective barrier against harmful external and internal compounds. The CPs mature early and demonstrate expressional changes of barrier-specific genes and proteins related to location and developmental stage of the CP. Important proteins for the barrier function include tight junction proteins, numerous transporters and enzymes. Natural senescence leads to structural changes in the CP cells and reduced or loss of function, while further loss of CP function and changes in immune status may be relevant in neurodegenerative diseases such as Alzheimer's disease and Multiple Sclerosis. Neuroprotective genes expressed at CPs may be unexplored targets for new therapies for neurodegenerative diseases

Barrier mechanisms in neonatal stroke.

Clinical data continue to reveal that the incidence of perinatal stroke is high, similar to that in the elderly. Perinatal stroke leads to significant morbidity and severe long-term neurological and cognitive deficits, including cerebral palsy. Experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. Cerebral vasculature undergoes substantial structural and functional changes during early postnatal brain development. Thus, the state of the vasculature could affect susceptibility of the neonatal brain to cerebral ischemia. In this review, we discuss some of the most recent findings regarding the neurovascular responses of the immature brain to focal arterial stroke in relation to neuroinflammation. We also discuss a possible role of the neonatal blood-CSF barrier in modulating inflammation and the long-term effects of early neurovascular integrity after neonatal stroke on angiogenesis and neurogenesis

Exchange interactions and critical temperature of bulk and thin films of MnSi: A density functional theory study

Recent theoretical work [H. Wu et al., Phys. Rev. Lett. 92, 237202 (2004); M. Hortamani et al., Phys. Rev. B 74, 205305 (2006); M. Hortamani, Ph.D. thesis, Freie Universität, Berlin, 2006] predicted ferromagnetism at zero temperature in thin MnSi films of B2-type crystal structure on Si(100). The relevance of this finding for finite-temperature experiments needs to be clarified by further investigations, since bulk MnSi is a weak ferromagnet with an experimentally measured Curie temperature of only Tc=30 K, and Tc is generally expected to be lower in thin films than in bulk materials. Here, we estimate Tc of such MnSi films using a multiple-sublattice Heisenberg model with first- and second-nearest-neighbor interactions determined from density functional theory calculations for various collinear spin configurations. The Curie temperature is calculated either in the mean-field approximation (MFA) or in the random-phase approximation (RPA). In the latter case we find a weak logarithmic dependence of Tc on the magnetic anisotropy parameter, which was calculated to be 0.4 meV for this system. In stark contrast to the above mentioned rule, large Curie temperatures of above 200 K for a monolayer (ML) MnSi film and above 300 K for a two ML MnSi film with B2-type structure on Si(100) are obtained within the RPA, and even higher values in MFA. Complementary calculations of MnSi bulk structures and thin unsupported MnSi films are performed in order to analyze these findings. We find that bulk MnSi in the cubic B2 structure is paramagnetic, in contrast to MnSi in the B20 ground-state structure in agreement with the Stoner criterion. In a tetragonally distorted B2 structure, the Mn atoms gradually develop a spin magnetic moment, passing through a low-spin and a high-spin state. However, the ferromagnetism of the MnSi/Si (100) films cannot be explained by tetragonal distortions alone, since the distorted B2 bulk structure is found to order antiferromagnetically. Comparison of the calculations of supported and unsupported films suggests that the reduced coordination of Mn atoms near surfaces and interfaces is crucial for the ferromagnetic ground state of the films. The coordination number of the Mn atoms in B2-type MnSi films on Si(100) constitutes a borderline case, where the spin magnetic moments of Mn are still large despite their sixfold coordination to Si, but the sp-d hybridization with Si states gives rise to a sizable ferromagnetic coupling of the Mn spins. We conclude that the Curie temperatures predicted from the Heisenberg Hamiltonian make thin MnSi films an interesting subject for further experimental investigation of spintronics materials