Patients who were deficient also had significantly more CD209+ DC

Patients who were deficient also had significantly more CD209+ DCs than those who were insufficient (P = 0·003). Furthermore, those who were VD3-insufficient or -deficient also had significantly higher circulating levels of CD1c+ DCs compared to healthy controls (P = 0·0003 and P < 0·0001, respectively). As shown in Fig. 3d, a strong inverse correlation exists between circulating

CD86+ DCs and VD3 status (R2 = 0·8501, P < 0·0001). VD3 also correlated inversely with PBMC expression Selleckchem BYL719 of CD209+ (Fig. 3e) (R2 = 0·7977, P < 0·0001), CD1c (Fig. 3f) (R2 = 0·8404, P < 0·0001) and CD1a (R2 = 0·9197, P < 0·0001, data not shown). Of the nine CRSwNP patients with CD209+ measurement, five had negative allergy testing, three had positive allergy testing and one was untested. Further evaluation determined that there were no significant differences between circulating CD209+ DCs levels in atopic versus non-atopic CRSwNP individuals (data not shown, P = 0·88). This would suggest that while atopic status may contribute to elevated numbers of DCs, such as in AFRS, there are mechanisms such as VD3 deficiency that result in an altered immune profile independent of atopy. While the Alectinib supplier CRSsNP cohort was overall VD3-sufficient, a correlation

analysis was conducted between VD3 and CD68+. As expected, there was no association between VD3 and circulating numbers of CD68+ cells (data not shown; R2 = 0·08, P = 0·72). Similarly, there was no correlation between VD3 plasma levels and circulation CD14+ monocyte levels among any of the cohorts (data not shown; R2 = 0·015, P = 0·71). Next we assessed plasma levels of macrophage and DC regulatory products, GM-CSF and PGE2. Figure 4a,b demonstrates that compared Decitabine research buy to control, GM-CSF and PGE2 were increased in CRSsNP (P = 0·02 and P = 0·0011, respectively), CRSwNP (P < 0·0001 and P = 0·0004, respectively) and AFRS (P = 0·0067 and P = 0·0057, respectively). Levels of GM-CSF were also significantly higher in CRSwNP and AFRS compared to CRSsNP (P = 0·03 and P = 0·01, respectively) and levels of PGE2 were significantly higher

in AFRS compared to CRSsNP (P = 0·005). There was no statistically significant difference between CRSsNP and CRSwNP plasma PGE2 levels (P = 0·08). Similar to the DCs/VD3 correlation, VD3 correlated inversely with GM-CSF (R2 = 0·7039, P = 0·0012) (Fig. 4c) and PGE2 (Fig. 4d) (R2 = 0·7401, P = 0·0081). These results demonstrate that VD3 deficiency is associated with elevated levels of circulating DCs and DC regulatory products in CRSwNP and AFRS. VD3 has long been known as a regulator of bone health due to its ability to stimulate calcium absorption. Therefore we measured the severity of bone erosion on preoperative CT scans in patients with varying levels of VD3. As shown in Fig. 5a, the average CT bone remodelling score in patients with insufficient levels (<32 ng/ml) of serum VD3 was significantly greater than in patients with adequate (≥32 ng/ml) VD3 (P = 0·016) levels.

Noteworthy, interruption of LPS treatment, or a single LPS admini

Noteworthy, interruption of LPS treatment, or a single LPS administration, in female NOD mice led to diabetes occurrence within a time window strikingly similar to the

delay observed upon adoptive transfer (Fig. 1C, D). Together, these data strongly this website suggested that a subset of cells present in LPS-treated donors actively controlled diabetogenic cell potential in the NOD/SCID recipients. To directly assess the contribution of Treg to the prevention of diabetes mediated by LPS we performed adoptive transfer of splenocytes depleted of these cells (Fig. 6B). While Treg are best identified by expression of Foxp3, this nuclear marker does not allow negative purification of live cells. However, most Treg are enriched in the subset of lymphocytes expressing the surface marker CD25 [51], and most CD25+ T cells

are Foxp3+ (Fig. S5). To efficiently reduce the number of Treg in the splenocyte preparations, we depleted CD25-expressing cells by mAb and complement treatment (Fig. S8A). Noteworthy, we showed above that the total frequency of CD25-expressing cells is similar in LPS-treated and healthy mice (Fig. 4), guaranteeing that depletion would be of similar efficiency in each experimental group. Depletion of CD25+ cells in splenocytes isolated from healthy donors prior to adoptive transfer did not accelerate the already rapid onset of diabetes. This finding is consistent with the reported progressive lost of Treg suppressive function in ageing NOD [4–7]. In contrast, Apoptosis inhibitor CD25+ cell depletion in splenocytes isolated from LPS-protected

animals prior to adoptive transfer dramatically precipitated diabetes in the recipient mice, as 50% of the animals were sick by 6.5 weeks after transfer (Fig. 6B). Remarkably, in this experimental group, progression of diabetes was indistinguishable from that of recipients HAS1 of total or CD25− cells prepared from healthy donors, indicating that protection in the donors was dominant and that the protective cells were readily depleted in these experiments. Similar results were obtained with donor and recipient males (Fig. S7B). We conclude that CD25+ Treg cells mediated the delay in diabetes onset in NOD/SCID female recipients of splenocytes isolated from LPS-protected animals. In turn, this result suggests that LPS treatment prevented CD25+ cell loss of regulatory function previously observed in ageing NOD mice [4–7]. In the present work we investigated the cellular mechanism at the basis of LPS-mediated prevention of spontaneous T1D in NOD mice and demonstrate a dominant regulation mediated by enhanced CD25+ Treg. The originality and power of our study rely in the comparative analysis of two modes of disease protection. Profiting from the incomplete penetrance of diabetes in NOD animals raised in SPF condition, we analysed untreated old but disease-free females and males in comparison with gender- and age-matched LPS-treated animals.

Infants younger than 12 months with a positive serology in whom a

Infants younger than 12 months with a positive serology in whom a urine or blood PCR test could not be performed were excluded from the study, since it was not possible to ascertain their HCMV infection status. Detection of anti-HCMV antibodies was carried out by the clinical laboratory using standard diagnostic tests. Detection of HCMV genome was performed by using Q-CMV Real Time Complete

Kit (Nanogen Advanced Diagnostics, Torino, Italy), a nucleic acid amplification assay based on TaqMan®-MGB (Minor Groove Binder) technology for detection and quantification of CMV DNA. The amplification reaction targets the gene region that encodes the Major Immediate Early Antigen (MIEA) of HCMV as well as a region of the human beta globin gene, FK506 order which is amplified simultaneously Venetoclax with the target sequence to verify successful DNA isolation in order to exclude false-negative results. Anti-NKG2C was from R&D Systems (Minneapolis, MN). Anti-NKG2A (clone Z199, kindly provided by Dr. A. Moretta, University of Genova), anti-LILRB1 (clone HP-F1), anti-CD161 (clone HP-3G10), and the anti-Myc (clone 9E10) negative control, were directly produced in our

laboratory. Indirect immunofluorescence staining with these reagents was carried out with a phycoerythrin (PE)-labeled F(ab′)2 rabbit anti-mouse Ig (Dako, Glostrup, Denmark). Anti-CD3-peridin-chlorophyll-protein (PerCP) and anti-CD56-allophycocyanin were from BD Biosciences (San Diego, CA); anti-CD45-allophycocyanin-Cy7 was from BioLegend (San Diego, CA). The expression of NKG2C, NKG2A, LILRB1, and CD161 by NK and T cells was analyzed by multicolor flow cytometry in fresh peripheral blood samples, obtained by venous

puncture in EDTA tubes. Whole blood Astemizole samples were pretreated with human aggregated Ig (30 μg/mL) to block Fc receptors, incubated with individual NKR-specific mAbs, washed and further incubated with a PE-tagged F(ab′)2 rabbit anti-mouse Ig. Washed samples were incubated with anti-CD3-PerCP, anti-CD56-allophycocyanin, and anti-CD45-allophycocyanin-Cy7. Erythrocytes were lysed using BD PharmLyse lysing buffer (BD Biosciences). Samples were analyzed in a BD LSR II flow cytometer (BD Biosciences, San Jose, CA). BD FACSDiva software (BD Biosciences) was used for data analysis and calculation of the MFI values. Results from hemograms, obtained in parallel to the samples used for immunophenotypic analysis, were used to calculate the absolute numbers of NK and T-cell populations.

01) Conclusion: Our studies confirmed the role of Gd-IgA1-IgG IC

01). Conclusion: Our studies confirmed the role of Gd-IgA1-IgG IC in the pathogenesis of IgAN and induction of proteinuria and hematuria.

Furthermore, the Gd-IgA1-IgG IC may bind to glomerular endothelial cells and induce release of pathogenic cytokines and chemokines. SUZUKI HITOSHI1, SUZUKI YUSUKE1, MAKITA YUKO1, YANAGAWA HIROYUKI1, JULIAN BRUCE A2,3, NOVAK JAN3, TOMINO YASUHIKO1 1Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine; 2Departments of Medicine, this website University of Alabama at Birmingham; 3Departments of Microbiology, University of Alabama at Birmingham Introduction: IgA1 in circulating immune complexes and mesangial deposits of patients with IgA nephropathy (IgAN) is aberrantly glycosylated, galactose-deficient in O-glycans (Gd-IgA1), and is bound to anti-glycan IgG/IgA autoantibodies. However, the origin of cells producing Gd-IgA1 and the autoantibodies is not certain. Upper respiratory tract infections and tonsillitis are frequently associated with clinical presentation and exacerbation of IgAN, suggesting a link with disease pathogenesis. In some patients, tonsillectomy and glucocorticoids (TSP) may slow disease progression MK-1775 price in early clinical stages. Therefore, we assessed whether

tonsillar cells produce Gd-IgA1 or anti-glycan autoantibodies. Methods: Tonsillar

cells obtained from 29 patients with IgAN were cultured 72 hours. Gd-IgA1 and anti-glycan IgG secreted by these cells were measured by ELISA. Proteinuria and hematuria, and serum levels of Gd-IgA1, Gd-IgA1-specific IgG and IgA, and IgG-IgA immune complexes (IC) were measured before and Ribose-5-phosphate isomerase after TSP. Results: Proteinuria and hematuria improved after TSP (P < 0.05). Eighteen of 29 patients had proteinuria less 0.3 g/g and 5 red blood cells/HPF after TSP (Remission group). Eleven patients did not clinically improve (non-Remission group). Serum levels of Gd-IgA1, Gd-IgA1-specific autoantibodies, and IgG-IgA IC decreased during glucocorticoid therapy after tonsillectomy (P < 0.01). The rates of decrease in the levels of Gd-IgA1, Gd-IgA1-specific antibodies and IgG-IgA IC were greater in the Remission group (P < 0.01). Tonsillar cells from Remission group produced more Gd-IgA1 and anti-glycan IgG than those from non-Remission group (P < 0.01). Conclusion: Tonsillar cells may contribute to the circulating Gd-IgA1 and anti-glycan IgG in patients with IgAN. These biomarkers may be useful for guiding therapy of IgAN. YAMADA KOSHI1,2, HUANG ZHI-QIANG1, RASKA MILAN1,3, REILY COLIN R.1, SUZUKI HITOSHI1,2, MOLDOVEANU ZINA1, KIRYLUK KRZYSZTOF4, SUZUKI YUSUKE2, TOMINO YASUHIKO2, GHARAVI ALI G.4, WILLEY CHRISTOPHER D.1, JULIAN BRUCE A.

They also found that mice lacking either NLRP3 or the ASC compone

They also found that mice lacking either NLRP3 or the ASC component of the inflammasome were protected against tetrachloride- or thioactamide-induced liver damage 40. Imaeda and co-workers found that IL-1β synthesis in the liver is dependent on TLR9- and NLRP3-mediated pathways 41. They used acetaminophen-induced liver injury and various mouse gene

knockouts to demonstrate that DNA released by the damaged hepatocytes activates the TLR9 pathway to produce pro-IL-1 and IL-18, and that NLRP3 inflammasome components (NLRP3, ASC or caspase-1) are required to produce the mature cytokines. Knockout mice lacking either TLR9 or one of the NLRP3 inflammasome components show reduced synthesis of IL-1β and IL-18, and subsequent reduced mortality and liver injury after acetaminophen treatment. The authors also found that liver injury could be significantly Fulvestrant mouse reduced if the animals were treated with aspirin before or concordantly with acetaminophen. The beneficial effect of aspirin in this case was found to be mainly due to its ability to downregulate pro-IL-1β and pro-IL-18 transcription. These studies confirm that, apart from the direct cytotoxic effects of, for example, acetaminophen, IL-1β- and IL-18-mediated innate immune responses play a significant role in causing liver damage. These cytokines are, therefore, logical targets to be considered when deciding how to best treat acute and chronic liver

damage in the future. The main reservation regarding the potential success of this approach is the reported finding that, under certain circumstances, NLRP3/ASC/caspase-1 complex activation may directly lead to cell death rather than IL-1β production 42; this mechanism may also Compound Library concentration have contributed to liver damage in the experimental animals. Rheumatoid arthritis (RA) was the first major disease in which IL-1 blockade was tested. Anakinra was well tolerated in patients

with active RA, and moderately effective when used as monotherapy, or in combination with methotrexate 43, 44. However, a systematic review, published in 2009, concluded that the through utility of anakinra for the treatment of RA is likely to be limited; only modest improvements have been reported, compared with other biological medications, such as anti-TNF therapy 45. It seems plausible therefore that unlike TNF and IL-6, IL-1β is not pivotal in the hierarchy of cytokines orchestrating the marked immunological perturbations in autoimmune conditions such as RA. Anti-IL-1β therapy has had a major impact on the treatment of a number of autoinflammatory diseases, particularly the HPF, although it would appear be less effective in treatment of autoimmune disease. However, increasing knowledge of the function of the NLRP3 inflammasome in other complex disorders is suggesting that a niche will also be found for this approach in a subset of these disorders. G. Cook is supported by Yorkshire Cancer Research, S. Savic by the NIHR-Leeds Musculoskeletal Biomedical Research Unit (LMBRU), M.

33 Smad3 plays an essential

role in TGF-β1-induced EMT 34

33 Smad3 plays an essential

role in TGF-β1-induced EMT.34 Evidence of renal EMT has been obtained by numerous independent studies in different animal models of chronic renal disease and also in human kidney biopsies.35–38 The inverse correlation between increasing numbers of tubular epithelial cells undergoing EMT and decline of excretory renal function suggests a pathological role of EMT in the progression of renal fibrosis.39,40 The observation that reversal of EMT improved renal function and decreased mortality in a mouse model with nephrotoxic serum nephritis further confirmed the importance of EMT in the progression of chronic renal disease.34 Advanced glycation end-product (AGE)-induced EMT has been implicated in the pathogenesis of DN.41 TGF-β1, AGE, high glucose,42 angiotensin II43 and oxidative stress44 are also key EMT inducers, shown to be involved in the development and progression of diabetic renal AZD8055 price fibrosis. Endothelium is a simple squamous epithelium, a specialized type of epithelial tissue. Romidepsin supplier Thus, EndoMT can be considered to be a specific form of EMT. EndoMT is an essential mechanism in cardiac development.45 During heart valve formation, a subset of EC overlying the future valve site delaminate, differentiate into mesenchymal cells and migrate into the cardiac jelly to form cardiac cushions, a process

referred to as endothelial-mesenchymal transition.46 Disruption of Notch signalling results in failure of EndoMT, revealing an essential role for notch in the control of endocardial cushion EndoMT.47,48 Evidence that wnt/β-catenin signalling was restricted to a subset of mesenchymal cells in endocardial cushions in the developing mouse heart49 and that antagonism of wnt/β-catenin signalling in zebrafish embryos inhibited cardiac cushion EndoMT suggested wnt/β-catenin signalling may activate expression of genes crucial for EndoMT.49β-catenin also acts as a structural link between actin and Vascular Endothelial Cadherin

(VE-cadherin) to form the cell–cell adherens junction necessary for polarity of EC.50 Bone morphogenetic proteins 2 and 4 (BMP-2 and 4), TGF-β2 and TGF-β3 are required for initiation Methamphetamine and completion of EndoMT.46 The role of TGF-β and BMP signalling pathways in endocardial cushion EndoMT has been thoroughly studied.51,52 Recent studies have demonstrated that EndoMT contributes to the development of tissue fibrosis. Zeisberg et al.53 used Tie1Cre; R26RstoplacZ mice to track cells of endothelial origin, and placed aortic bands on the hearts of mice to induce cardiac fibrosis. They showed that EC undergo EndoMT during cardiac fibrosis and contribute to the total pool of cardiac fibroblasts. In addition, they showed that TGF-β1 induced EndoMT, whereas BMP7 abrogated EndoMT, preserved the endothelial phenotype and reversed or prevented TGF-β1-induced EndoMT and cardiac fibrosis.

[2] In some areas of the sheep placenta, called placentomes, ther

[2] In some areas of the sheep placenta, called placentomes, there is aggressive interdigitation between trophoblast villi on the fetal side (cotyledon) and the

uterus on the maternal side (caruncle), and at points the epithelia form a common syncytium allowing for more efficiency of gas and nutrient exchange. Pigs have a similar but more diffuse placental structure than sheep with less aggressive interdigitation.[2, 17] The human/primate uterus is a single muscular organ different structurally from the two-horned uterus of rodents (for mice see Margaret J Cook’s LY294002 datasheet book at, pigs,[18] rabbits,[16] or sheep.[19] While the electro-mechanics of the human/primate uterus may be fundamentally different from that seen in other species,[20, 21] the uteri of rodents,[22] rabbits[23] sheep,[24] and pigs[18] respond to oxytocin, suggesting a common expression

of the receptor, and most have been used to study the mechanisms underlying uterine contractility in vitro. In addition to hormones such as estrogen (discussed elsewhere), progesterone is a key hormone of pregnancy that appears to be differentially regulated in humans and animals.[25] The particulars of the responsiveness to this hormone and its interaction with estrogen in successful pregnancy remain learn more a topic of intense investigation. In humans, the corpus luteum is the major site of progesterone expression with help from chorionic

gonadotropin released by the early conceptus.[26] Blockade of progesterone during this time causes pregnancy loss.[26] Major production of progesterone switches to the placenta by 5–6 weeks’ gestation. Maternal serum levels of progesterone raise post-conceptionally and continue to elevate beyond parturition.[25, 27] However, progesterone has been given with variable success to treat women with recurrent miscarriage[28] and antiprogesterone given late in pregnancy can cause cervical ripening and delivery in some women[29] suggesting a complex biology. Human fetal membranes can produce[30] TCL and metabolize progesterone,[31] and locally produced progesterone metabolites may be important in uterine quiescence and activation.[32] The human uterus can produce an inhibitory progesterone receptor which increases before parturition.[33] Finally, progesterone receptor regulation at multiple levels in the cytoplasm and the nucleus may regulate functional progesterone activity leading to parturition.[34] Progesterone’s regulation during pregnancy in related non-human primates is similar to human pregnancy in several respects including dependence on early production of progesterone by the corpus luteum[35] that early pregnancy can be interrupted by antiprogestins[36] and that there is not systemic withdrawal before parturition.

The murine thymus originates from the third pharyngeal pouch at d

The murine thymus originates from the third pharyngeal pouch at day E9.5 of embryonic development PF-01367338 molecular weight and is solely derived from the endoderm [7]. Specification of the thymus involves the sequential upregulation of important transcription factors (Hoxa3, Pax-9, Pax-1, Eya1, Rae2, chordin, and BMP; (reviewed in [8]) eventually leading to the expression of the thymic-specific

transcription factor Foxn1 [9, 10]. From E11.5 onwards, the first precursor T cells migrate into the thymic anlage and noncanonical NF-κB signaling becomes important for full differentiation of the medullary microenvironment, culminating in the upregulation of auto-immune regulator (Aire) [11-13] that enables medullary TECs to express self-antigens [2, 3]. In the adult thymus cross-talk remains important, as the process of differentiation but also maintenance of medullary TECs, via ligation of RANK and CD40 by ligands expressed on thymocytes [11, 12, 14]. Mature cortical and medullary TEC originate from a common thymic epithelial

progenitor cell (TEPC) [15, 16]. Although full differentiation of mature TECs from a clonal precursor population has been demonstrated, the precise phenotypical characterization of that precursor as well as its genotype are still lacking, making it difficult to identify this TEC in the adult KU 57788 thymus. Despite this, expression of placenta-expressed transcript 1 (Plet-1) does identify a subset of TEPCs with the ability to generate differentiated progeny. Especially, fetal Plet-1+ TECs are able to give rise to a functional thymus when transplanted under the kidney capsule [17-19]. However, although present on TECs in the adult thymus, Plet-1+ cells seem to lose their precursor potential after E15 of embryonic development [20]. So far, no exclusive marker for TEPCs has been identified in the adult thymus. Still, the regenerative

capacity of the involuted thymi has been revealed in different murine models (reviewed in [21]), suggesting the presence of an adult TEPC population. Leucine-rich repeat-containing G protein-coupled receptor (Lgr)5 is a marker for stem cells in the adult intestine of mice [22]. Single Lgr5+ cells from adult murine intestine were able to expand and form a new crypt/villus structure second in-vitro [23, 24]. Although Lgr5+ cells in the crypt are a transient state of the BMI+ stem cells, they still give rise to epithelial cell subsets of the intestine [25, 26]. Lgr5 together with Lgr4 responds to the wingless type (Wnt) agonist R-spondin, together these receptors fine-tune Wnt signaling [27, 28]. Mice with a targeted deletion of Lgr5 die immediately after birth due to fusion of the tongue with the floor of the oral cavity [29]. In addition, Lgr5-deficient embryos tend to have premature paneth cell differentiation in the small intestine [30]. Lgr5+ transcripts have been reported in the E13.

Irrespective of the exact mechanism, the targeting of TIR adaptor

Irrespective of the exact mechanism, the targeting of TIR adaptor proteins may represent PF-02341066 solubility dmso a further mechanism underlying the inhibitory effects of

viral Pellino on TLR signalling. Viruses have evolved a wide range of immunoevasive strategies, including the targeting of key innate immune signalling pathways. Vaccinia virus A52R has been shown to inhibit TLR-mediated activation of NF-κB by disrupting signalling complexes containing TRAF6 and IRAK2 28. Furthermore, in a manner similar to the actions of viral Pellino on IRAK-1, MCMV M45 was found to bind RIP1, blocking its ubiquitination and thereby activation of NF-κB by TNF-α and TLR3 signalling 29. Here, we reveal the immunoevasive

properties of a poxviral Pellino homolog. This identifies the ability of an entomopoxvirus protein find more to combat insect immunity. The ability of viral Pellino to also interfere with TLR signalling highlights the amazing conservation across the evolutionary divide of Toll and TLR signalling. An increased understanding of the mechanistic basis to the regulatory effects of viral Pellino may also provide a greater appreciation of the precise role of mammalian Pellinos in IL-1/TLR signalling. Viral Pellino was initially discovered based on the sequence identity with members of the mammalian Pellino family. However, the sequence identity was quite low and given that the X-ray structure of part of the Pellino2 protein had been recently resolved, we employed homology modelling to evaluate if the limited sequence identity has the potential to translate into shared structural properties. An intriguing picture emerges in which viral Pellino shares some of the structural characteristics of mammalian proteins but differs in other respects. Like some of EGFR inhibitor its mammalian counterparts, it has a cytoplasmic localisation. This is hardly surprising since bioinformatic analysis failed to predict any

transmembrane domain or nuclear localisation sequences. Mammalian Pellinos possess two distinct domains; a N-terminal FHA domain that facilitates binding to phosphorylated IRAK-1 18 and a C-terminal RING-like domain that catalyses polyubiquitination of IRAK-1. Viral Pellino lacks the latter but appears to have the potential to form a FHA domain based on two sets of findings. First, homology modelling in conjunction with molecular dynamics indicates the potential for viral Pellino to form a stable 11-stranded β-sandwich that is characteristic of a canonical FHA domain. Second, viral Pellino shows conservation of the four signature amino acid residues in FHA domain-containing proteins that mediate direct binding to phosphorylated threonine residues on partner proteins.

The morphology was consistent with involvement by a low-grade B-c

The morphology was consistent with involvement by a low-grade B-cell lymphoma. Immunohistochemical findings showed BGB324 CD20+, CD10–, CD5–, TdT–, EBV–encoded RNA in situ– and IgM–. The above findings were consistent with involvement by a non-dural extranodal marginal zone B-cell lymphoma (MZBCL) primary to the brain

and spinal cord. This is a case report of a CNS MZBCL of mucosa-associated lymphoid tissue type involving the brain and spinal cord parenchyma. “
“Abnormalities of the brain microvasculature in Alzheimer’s disease have led to the vascular hypothesis of the disease, which predicts that vascular changes precede neuronal dysfunction and degeneration. To determine the spectrum of endothelial injury in the elderly and its relation to Alzheimer-type neuropathology we investigated DNA damage in a population-based sample derived from the Medical Research Council Cognitive Function and Ageing Study. We examined endothelial damage in frontal and temporal cortex (n = 97) using immunohistochemistry for γH2AX and DNA–protein kinase (DNA-PKcs). To determine the effects of endothelial DNA damage at the earliest stages of Alzheimer’s pathology we further focused our analysis on cases classified as Braak 0–II and examined endothelial senescence using histochemistry for β-galactosidase and the expression of genes related to DNA damage and

senescence using quantitative polymerase chain reaction (qPCR). We demonstrated large variation in endothelial DNA damage which was not associated with Alzheimer’s neuropathology. Endothelial DNA-PKcs RVX-208 correlated with neuronal and glial DNA-PKcs counts.

Focusing our further analysis on Braak 0–II cases, qPCR analysis demonstrated a trend to increased TP53 (P = 0.064) in cases with high compared with low endothelial DNA damage which was supported by immunohistochemical analysis of p53. Endothelial β-galactosidase expression was associated with increased neuronal (P = 0.033) and glial (P = 0.038), but not endothelial DNA-PKcs expression. Damage to brain endothelial cells occurs early in relation to, or independently of, Alzheimer pathology, and parallels that in neurones and glia. Endothelial DNA damage and senescence are a brain ageing process that may contribute to dysfunction of the neurovascular unit in some elderly individuals. “
“C-J. Xu, L. Xu, L-D. Huang, Y. Li, P-P. Yu, Q. Hang, X-M. Xu and P-H. Lu (2011) Neuropathology and Applied Neurobiology37, 135–155 Combined NgR vaccination and neural stem cell transplantation promote functional recovery after spinal cord injury in adult rats Aims: After spinal cord injury (SCI), there are many adverse factors at the lesion site such as glial scar, myelin-derived inhibitors, cell loss and deficiency of neurotrophins that impair axonal regeneration.