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Background/aims: Fetal rats with nitrofen-induced congenital diaphragmatic hernia (CDH) have lung and heart hypoplasia with reduced L/R ventricular width and aorto-pulmonary diameter ratios. Prenatal steroids induce biochemical maturity of the lung, improve its compliance and inhibit the muscular hyperthophy of arteries in CDH rats reducing the risk of pulmonary hypertension. The aim of this study is to test the hypothesis that prenatal dexamethasone could reverse also heart hypoplasia in rats with CDH. Methods: CDH was induced by giving i.g. nitrofen (100mg) to pregnant rats on gestational day 9.5. Dexamethasone (0.25 mg/kg) was subsequently given i.p. on days 19 and 20. The fetuses were recovered on day 21st and heart weight/body weight ratios, heart DNA and protein were measured in fresh specimens. Left-to-right ventricular diameter and aortic-to-pulmonary diameter ratios were measured after formalin fixation. Fetuses from mothers treated with dexamethasone alone served as controls. ANOVA was used for comparison between groups. Results: 50% of fetuses exposed to nitrofen had CDH and various cardiovascular malformations were found in 72 % of them. Heart weight/body weight ratios were similar in fetuses with CDH and controls (0.63 [+ or -] 0.09 vs 0.64 [+ or -] 0.07 %, n.s.) whereas heart DNA was increased (100.72 [+ or -] 29.26 vs 75.17 [+ or -] 24.03 mg/g, p [is less than] 0.05) and protein/DNA ratio was decreased (20.75 [+ or -] 6.82 vs 36.59 [+ or -] 7.15 mg/mg, p [is less than] 0.05) revealing that the heart mass was conserved, the number of myocardial cells was increased and cell size was smaller in CDH fetuses treated with dexamethasone in comparison with dexamethasone alone controls. In addition, the left-to-right ventricular diameter and the aortic-to-pulmonary diameter ratios were similar in CDH and control fetuses (1.09 [+ or -] 0.11 vs 1.16 [+ or -] 0.12 and 0.86 [+ or -] .0.23 vs 0.95 [+ or -] 0.22 respectively) suggesting that either left ventricular hypoplasia had been reversed or that the intrapulmonary flow conditions during late gestation were better after steroids. Conclusions: The hypoplasia of the heart in rats with CDH is reversed by preterm treatment with dexamethasone. These findings strongly support routine use of prenatal steroids in fetuses with CDH., Migliazza L MD, Xia H MD, Arnaiz A, Alvarez JI, Alfonso, LF MD, Valis A MD PhD, Diez-Pardo JA MD PhD and Tovar JA MD PhD; Hospital Universitario "La Paz". [...]

OBJECTIVE: There is substantial evidence supporting the role of interferon (IFN)-gamma-producing T helper (T(H)) 1 and interleukin (IL)-17-expressing T(H)17 lymphocytes in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). However, to date little is known about the potential cooperative interplay between these 2 cytokines. In the current study, we sought to evaluate the frequency of IFN-gamma-expressing T(H)17 lymphocytes in MS and EAE, and study their recruitment into the central nervous system (CNS). METHODS: Human T(H)17 lymphocytes were expanded in vitro from the blood of healthy controls and relapsing MS patients using IL-23. Immune cell migration to the CNS was assessed in vitro with primary cultures of human blood-brain barrier (BBB)-derived endothelial cells, and in vivo in EAE mice. RESULTS: We demonstrate that in response to IL-23, human memory lymphocytes expand into a T(H)17 phenotype, with a subpopulation of cells simultaneously expressing IFN-gamma and IL-17. We note that lymphocytes obtained from the blood of relapsing MS patients have an increased propensity to expand into IFN-gamma-producing T(H)17 cells and identify numerous T lymphocytes coexpressing IL-17 and IFN-gamma in brain tissue of MS patients. We also find lymphocytes expressing both the T(H)1- and the T(H)17-associated transcription factors RORgammat and T-bet, in situ and in vitro. We further provide in vitro and in vivo evidence that IFN-gamma(+) T(H)17 lymphocytes preferentially cross the human BBB and accumulate in the CNS of mice during the effector phase of EAE. INTERPRETATION: Our data underscore the involvement of IFN-gamma(+) T(H)17 lymphocytes in the pathology of MS and EAE and their preferential recruitment into the CNS during inflammatory events. Ann Neurol 2009;66:390-402. [ABSTRACT FROM AUTHOR]

A significant concern in our society is the potential impact on both health and the environment of air pollutants released during the incineration of waste. Therefore, it is crucial to conduct thorough control and monitoring measures. In this context, the objective of this research was to study the evolution of particulate matter (PM 2.5 ) and associated trace elements during the period before and after the installation of an Energy Recovery Plant (ERP). For that, a descriptive and temporal analysis of PM 2.5 concentration and composition were performed on two similar areas (impact/control) using the Before-After/Control-Impact (BACI) design and two periods (before from January 01, 2018 to February 06, 2020 and after from December 10, 2020 to September 30, 2022). Results showed a decrease in the levels of PM 2.5 and associated trace elements is observed in the impact zone (IZ) and in the control zone (CZ) throughout the study period. In the case of PM 2.5 , the most notable decrease occurred in the period of the start-up of the ERP, a period that coincides with the confinement and restrictions of COVID, with a subsequent increase in both zones, without reaching the levels observed in the period prior to the start-up of the ERP. Selenium is the only trace element that increases significantly in the IZ. In conclusion, a decrease is observed for all pollutants except selenium in both zones, although less pronounced in the IZ. Since selenium already showed an upward trend in the phase prior to the start of the ERP, it is necessary to investigate its evolution and find out the possible cause., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jesus Ibarluzea reports financial support was provided by Gipuzkoa Provincial Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages., (© 2023. Springer Nature Limited.)

This research examines the levels and trends of pollutants, specifically 17 congeners of PCDD/Fs and 12 dl-PCBs, in the air measured in the province of Gipuzkoa (Basque Country, Spain). The study used PCDD/Fs, dl-PCB, and the sum of dioxin-like compounds as separate response variables. A total of 113 air samples were collected and analyzed using the method described in the European Standard (EN-1948:2006) from two industrial areas. The results were analyzed using non-parametric test to assess the variability of these pollutants based on different factors (year, season and day of the week) and General Linear Models to assess the weight of each factor. The study found that the toxic equivalents (TEQs) for PCDD/Fs were 12.29 fg TEQm -3 and for dl-PCBs were 1.63 fg TEQm -3 , which were in a similar range or lower than those observed in other national and international studies in industrial areas. The results showed temporal variations, with higher levels of PCDD/Fs in autumn-winter than in spring-summer and higher levels of PCDD/Fs and dl-PCBs during weekdays than on weekends. The industrial area where the energy recovery plant (ERP) will be located had higher levels of air pollutants due to the presence of two PCDD/Fs emitting industries nearby, as indicated by the Spanish Registry of Polluting Emission Sources. Both industrial areas showed similar profiles of PCDD/Fs and dl-PCBs, with the PCDD/F profiles dominated by OCDD, 1,2,3,4,6,7,8-HpCDD, and 1,2,3,4,6,7,8-HpCDF in terms of concentrations and 1,2,3,7,8-PeCDD, 2,3,4,7,8-PeCDF, and 2,3,7,8-TCDD in terms of TEQs. The dl-PCB profiles were dominated by PCB 118, PCB 105, and PCB 77 in terms of concentrations and PCB 126 in terms of TEQs. The findings of this study can serve as an indicator of the potential impact of ERP on the health of the resident population and the environment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jesus Ibarluzea reports financial support was provided by Gipuzkoa Provincial Council., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Many studies have shown the capacity of soil humic substances (HS) to improve plant growth in natural ecosystems. This effect involves the activation of different processes within the plant at different coordinated molecular, biochemical, and physiological levels. However, the first event triggered by plant root-HS interaction remains unclear. Some studies suggest the hypothesis that the interaction of HS with root exudates involves relevant modification of the molecular conformation of humic self-assembled aggregates, including disaggregation, which might be directly involved in the activation of root responses. To investigate this hypothesis, we have prepared two humic acids. A natural humic acid (HA) and a transformed humic acid obtained from the treatment of HA with fungal laccase (HA enz). We have tested the capacity of the two humic acids to affect plant growth (cucumber and Arabidopsis) and complex Cu. Laccase-treatment did not change the molecular size but increased hydrophobicity, molecular compactness and stability, and rigidity of HA enz. Laccase-treatment avoided the ability of HA to promote shoot- and root-growth in cucumber and Arabidopsis. However, it does not modify Cu complexation features. There is no molecular disaggregation upon the interaction of HA and HA enz with plant roots. The results indicate that the interaction with plant roots induced in both HA and laccase-treated HA (HA enz), changes in their structural features that showed higher compactness and rigidity. These events might result from the interaction of HA and HA enz with specific root exudates that can promote intermolecular crosslinking. In summary, the results indicate that the weakly bond stabilized aggregated conformation (supramolecular-like) of HA plays a crucial role in its ability to promote root and shoot growth. The results also indicate the presence of two main types of HS in the rhizosphere corresponding to those non-interacting with plant roots (forming aggregated molecular assemblies) and those produced after interacting with plant root exudates (forming stable macromolecules)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aranaz, de Hita, Olaetxea, Urrutia, Fuentes, Baigorri, Garnica, Movila, Zamarreño, Erro, Baquero, Gonzalez-Gaitano, Alvarez and Garcia-Mina.)

Mice modeling the hemizygous deletion of chromosome 22q11.2 (22qMc) have been utilized to address various clinical phenotypes associated with the disease, including cardiac malformations, altered neural circuitry, and behavioral deficits. Yet, the status of the T cell compartment, an important clinical concern among 22q11.2 deletion syndrome (22qDS) patients, has not been addressed. While infancy and early childhood in 22qDS are associated with deficient T cell numbers and thymic hypoplasia, which can be severe in a small subset of patients, studies suggest normalization of the T cell counts by adulthood. We found that adult 22qMc do not exhibit thymic hypoplasia or altered thymic T cell development. Our findings that immune cell counts and inflammatory T cell activation are unaffected in 22qMc lend support to the hypothesis that human 22qDS immunodeficiencies are secondary to thymic hypoplasia, rather than intrinsic effects due to the deletion. Furthermore, the 22q11.2 deletion does not impact the differentiation capacity of T cells, nor their activity and response during inflammatory activation. Thus, 22qMc reflects the T cell compartment in adult 22qDS patients, and our findings suggest that 22qMc may serve as a novel model to address experimental and translational aspects of immunity in 22qDS., (© 2022 Wiley-VCH GmbH.)

Inflammation is a biological process that dynamically alters the surrounding microenvironment, including participating immune cells. As a well-protected organ surrounded by specialized barriers and with immune privilege properties, the central nervous system (CNS) tightly regulates immune responses. Yet in neuroinflammatory conditions, pathogenic immunity can disrupt CNS structure and function. T cells in particular play a key role in promoting and restricting neuroinflammatory responses, while the inflamed CNS microenvironment can influence and reshape T cell function and identity. Still, the contraction of aberrant T cell responses within the CNS is not well understood. Using autoimmunity as a model, here we address the contribution of CD4 T helper (Th) cell subsets in promoting neuropathology and disease. To address the mechanisms antagonizing neuroinflammation, we focus on the control of the immune response by regulatory T cells (Tregs) and describe the counteracting processes that preserve their identity under inflammatory challenges. Finally, given the influence of the local microenvironment on immune regulation, we address how CNS-intrinsic signals reshape T cell function to mitigate abnormal immune T cell responses., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Objectives: In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor-like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS., Methods: Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP., Results: Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP + B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP + immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS., Discussion: Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Global inactivation of IκB kinase (IKK)-α results in defective lymph node (LN) formation and B cell maturation, and loss of IKK-α-dependent noncanonical NF-κB signaling in stromal organizer and hematopoietic cells is thought to underlie these distinct defects. We previously demonstrated that this pathway is also activated in vascular endothelial cells (ECs). To determine the physiologic function of EC-intrinsic IKK-α, we crossed Ikkα F/F mice with Tie2-cre or Cdh5-cre mice to ablate IKK-α in ECs. Notably, the compound defects of global IKK-α inactivation were recapitulated in Ikkα Tie2 and Ikkα Cdh5 mice, as both lacked all LNs and mature follicular and marginal zone B cell numbers were markedly reduced. However, as Tie2-cre and Cdh5-cre are expressed in all ECs, including blood forming hemogenic ECs, IKK-α was also absent in hematopoietic cells (HC). To determine if loss of HC-intrinsic IKK-α affected LN development, we generated Ikkα Vav mice lacking IKK-α in only the hematopoietic compartment. While mature B cell numbers were significantly reduced in Ikkα Vav mice, LN formation was intact. As lymphatic vessels also arise during development from blood ECs, we generated Ikkα Lyve1 mice lacking IKK-α in lymphatic ECs (LECs) to determine if IKK-α in lymphatic vessels impacts LN development. Strikingly, while mature B cell numbers were normal, LNs were completely absent in Ikkα Lyve1 mice. Thus, our findings reveal that IKK-α in distinct EC-derived compartments is uniquely required to promote B cell homeostasis and LN development, and we establish that LEC-intrinsic IKK-α is absolutely essential for LN formation., Competing Interests: The authors declare no competing interest.

The concerted actions of the CNS and the immune system are essential to coordinating the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model, in which the hedgehog signalling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress the pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signalling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signalling regulates the pathogenic profile of CD4 T cells by limiting their production of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor and interferon-γ and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signalling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation, as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS and propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Multiple sclerosis (MS) is an idiopathic demyelinating disease in which meningeal inflammation correlates with accelerated disease progression. The study of meningeal inflammation in MS has been limited because of constrained access to MS brain/spinal cord specimens and the lack of experimental models recapitulating progressive MS. Unlike induced models, a spontaneously occurring model would offer a unique opportunity to understand MS immunopathogenesis and provide a compelling framework for translational research. We propose granulomatous meningoencephalomyelitis (GME) as a natural model to study neuropathological aspects of MS. GME is an idiopathic, progressive neuroinflammatory disease of young dogs with a female bias. In the GME cases examined in this study, the meninges displayed focal and disseminated leptomeningeal enhancement on magnetic resonance imaging, which correlated with heavy leptomeningeal lymphocytic infiltration. These leptomeningeal infiltrates resembled tertiary lymphoid organs containing large B cell clusters that included few proliferating Ki67 + cells, plasma cells, follicular dendritic/reticular cells, and germinal center B cell-like cells. These B cell collections were confined in a specialized network of collagen fibers associated with the expression of the lympho-organogenic chemokines CXCL13 and CCL21. Although neuroparenchymal perivascular infiltrates contained B cells, they lacked the immune signature of aggregates in the meningeal compartment. Finally, meningeal B cell accumulation correlated significantly with cortical demyelination reflecting neuropathological similarities to MS. Hence, during chronic neuroinflammation, the meningeal microenvironment sustains B cell accumulation that is accompanied by underlying neuroparenchymal injury, indicating GME as a novel, naturally occurring model to study compartmentalized neuroinflammation and the associated pathology thought to contribute to progressive MS., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia. As the blood-brain barrier is the immunological interface between the brain and the periphery, we investigated whether this vascular phenotype is intrinsically compromised in the most common genetic risk factor for schizophrenia, the 22q11.2 deletion syndrome (22qDS). Blood-brain barrier like endothelium differentiated from human 22qDS+schizophrenia-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 was upregulated in 22qDS+schizophrenia-induced blood-brain barrier and in 22qDS mice, indicating compromise of the blood-brain barrier immune privilege. This immune imbalance resulted in increased migration/activation of leucocytes crossing the 22qDS+schizophrenia blood-brain barrier. We also found heightened astrocyte activation in murine 22qDS, suggesting that the blood-brain barrier promotes astrocyte-mediated neuroinflammation. Finally, we substantiated these findings in post-mortem 22qDS brain tissue. Overall, the barrier-promoting and immune privilege properties of the 22qDS blood-brain barrier are compromised, and this might increase the risk for neuropsychiatric disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Antigen (Ag)-specific tolerance induction by intravenous (i. v.) injection of high-dose auto-Ags has been explored for therapy of autoimmune diseases, including multiple sclerosis (MS). It is thought that the advantage of such Ag-specific therapy over non-specific immunomodulatory treatments would be selective suppression of a pathogenic immune response without impairing systemic immunity, thus avoiding adverse effects of immunosuppression. Auto-Ag i.v. tolerance induction has been extensively studied in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and limited clinical trials demonstrated that it is safe and beneficial to a subset of MS patients. Nonetheless, the mechanisms of i.v. tolerance induction are incompletely understood, hampering the development of better approaches and their clinical application. Here, we describe a pathway whereby auto-Ag i.v. injected into mice with ongoing clinical EAE induces interferon-gamma (IFN-γ) secretion by auto-Ag-specific CD4 + T cells, triggering interleukin (IL)-27 production by conventional dendritic cells type 1 (cDC1). IL-27 then, via signal transducer and activator of transcription 3 activation, induces programmed death ligand 1 (PD-L1) expression by monocyte-derived dendritic cells (moDCs) in the central nervous system of mice with EAE. PD-L1 interaction with programmed cell death protein 1 on pathogenic CD4 + T cells leads to their apoptosis/anergy, resulting in disease amelioration. These findings identify a key role of the IFN-γ/IL-27/PD-L1 axis, involving T cells/cDC1/moDCs in the induction of i.v. tolerance., (Copyright © 2020 Casella, Rasouli, Thome, Descamps, Vattikonda, Ishikawa, Boehm, Hwang, Zhang, Xiao, Park, Zhang, Alvarez, Rostami and Ciric.)

This paper presents the experimental procedure to develop air lime-based injection grouts, including polymeric superplasticizers, a water repellent agent and pozzolanic agents as additives. Our research focuses on the development of grouts to improve various characteristics simultaneously by combining different additions and admixtures. Aiming to improve the injectability of the grouts, in this study, different polymeric superplasticizers were added, namely polycarboxylated-ether derivative (PCE), polynaphthalene sulfonate (PNS) and condensate of melamine-formaldehyde sulfonate (SMFC). As a water-repellent agent, sodium oleate was used to reduce the water absorption. The enhancement of the strength and setting time was intended by using microsilica and metakaolin as pozzolanic mineral additions. Compatibility between the different admixtures and action mechanism of the different polymers were studied by means of zeta potential and adsorption isotherms measurements. Diverse grout mixtures were produced and investigated by assessing their injectability, fluidity, stability, compressive strength, hydrophobicity and durability. This research led to several suitable mixtures produced by using more than one component, to enhance efficiency and to provide better performance of grouts. According to the results, the grout composed of air lime, metakaolin, sodium oleate and PCE was found to be the most effective composition, improving the mechanical strength, injectability and hydrophobicity.

The presence of B lymphocyte-associated oligoclonal immunoglobulins in the cerebrospinal fluid is a classic hallmark of multiple sclerosis (MS). The clinical efficacy of anti-CD20 therapies supports a major role for B lymphocytes in MS development. Although activated oligoclonal populations of pathogenic B lymphocytes are able to traffic between the peripheral circulation and the central nervous system (CNS) in patients with MS, molecular players involved in this migration have not yet been elucidated. In this study, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) identifies subsets of proinflammatory B lymphocytes and drives their transmigration across different CNS barriers in mouse and human. We also showcased that blocking ALCAM alleviated disease severity in animals affected by a B cell-dependent form of experimental autoimmune encephalomyelitis. Last, we determined that the proportion of ALCAM + B lymphocytes was increased in the peripheral blood and within brain lesions of patients with MS. Our findings indicate that restricting access to the CNS by targeting ALCAM on pathogenic B lymphocytes might represent a promising strategy for the development of next-generation B lymphocyte-targeting therapies for the treatment of MS., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A new range of grouts prepared by air lime and metakaolin (MK) as a pozzolanic admixture has been obtained by using as dispersing agents two polymers, namely poly-naphthalene sulfonate (PNS) and lignosulfonate (LS), with the aim of improving the fluidity of the fresh grouts. Fluidity and setting times of the grouts were assessed. Differences in the molecular architecture and in the anionic charge density explained the different adsorption of the polymers and the different performance. The higher anionic charge of PNS and its linear shape explained its better adsorption and effectiveness. The pozzolanic reaction was favoured in grouts with PNS, achieving the highest values of compressive strength (4.8 MPa after 182 curing days). The addition of PNS on lime grouts slightly decreased the frost resistance of the grouts (from 24 freeze-thaw cycles for the polymer-free samples to 19 or 20 cycles with 0.5 or 1 wt % of PNS). After the magnesium sulphate attack, grouts were altered by decalcification of hydrated phases and by formation of hexahydrite and gypsum. A protective role of portlandite against magnesium sulphate attack was clearly identified. Accordingly, the polymer LS, which preserves a significant amount of Ca(OH)₂, could be an alternative for the obtaining of grouts requiring high sulphate attack resistance.

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS) 1-3 . Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood 4,5 . Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14 + cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.

Rasmussen's encephalitis (RE) is a chronic inflammatory brain disorder that causes frequent seizures and unilateral hemispheric atrophy with progressive neurological deficits. Hemispherectomy remains the only treatment that leads to seizure freedom for this refractory epileptic syndrome. The absence of an animal model of disease has been a major obstacle hampering the development of effective therapies. Here, we describe an experimental mouse model that shares several clinical and pathological features with the human disease. Immunodeficient mice injected with peripheral blood mononuclear cells from RE patients and monitored by video electroencephalography developed severe seizures of cortical origin and showed intense astrogliosis and accumulation of human IFN-γ- and granzyme B-expressing T lymphocytes in the brain compared with mice injected with immune cells from control subjects. We also provide evidence for the efficacy of α4 integrin blockade, an approved therapy for the treatment of multiple sclerosis and Crohn's disease, in reducing inflammatory markers associated with RE in the CNS. This model holds promise as a valuable tool for understanding the pathology of RE and for developing patient-tailored experimental therapeutics.

Rising use of nanoparticles in manufacturing as well as in commercial products bring issues related to environmental release and human exposure. A large amount of TiO 2 nanoparticles will eventually reach wastewater treatment plants. Low pressure membrane filtration has been suggested as a feasible treatment of water streams. This study investigated first at laboratory scale the influence of: i) membrane material, ii) pore size and iii) water chemistry on nTiO 2 removal. TiO 2 retention was governed by the cake layer formation mechanism and significant retention of nanoparticles was observed even for filters having considerably larger pores than nTiO 2 . PVDF showed a great potential for nTiO 2 rejection. Additionally, filtration pilot plant experiments were carried out using PVDF membranes (0.03 and 0.4μm pore size). The release of nTiO 2 in the pilot scale filtration system was always above the instrumental detection limit (>1.5μg/L) and in most cases below 100μg/L regardless of the pore size and applied conditions. The nTiO 2 membrane breakthrough predominantly occurred in the first few minutes after backwashes and ceased when the cake layer was formed. Ultrafiltration and microfiltration were comparable with rejection of nTiO 2 above 95% at similar permeate flow rates. Nevertheless, ultrafiltration is more promising than microfiltration because it allowed longer operation times between backwash cycles., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mortars with two different binders (Portland cement (PC) and high alumina cement (HAC)) were modified upon the bulk incorporation of nano-structured photocatalytic additives (bare TiO₂, and TiO₂ doped with either iron (Fe-TiO₂) or vanadium (V-TiO₂)). Plastic and hardened state properties of these mortars were assessed in order to study the influence of these nano-additives. Water demand was increased, slightly by bare TiO₂ and Fe-TiO₂, and strongly by V-TiO₂, in agreement with the reduction of the particle size and the tendency to agglomerate. Isothermal calorimetry showed that hydration of the cementitious matrices was accelerated due to additional nucleation sites offered by the nano-additives. TiO₂ and doped TiO₂ did not show pozzolanic reactivity in the binding systems. Changes in the pore size distribution, mainly the filler effect of the nano-additives, accounted for the increase in compressive strengths measured for HAC mortars. A complex microstructure was seen in calcium aluminate cement mortars, strongly dependent on the curing conditions. Fe-TiO₂ was found to be homogeneously distributed whereas the tendency of V-TiO₂ to agglomerate was evidenced by elemental distribution maps. Water absorption capacity was not affected by the nano-additive incorporation in HAC mortars, which is a favourable feature for the application of these mortars., Competing Interests: The authors declare no conflict of interest.

Laquinimod is currently being tested as a therapeutic drug in multiple sclerosis. However, its exact mechanism of action is still under investigation. Tracking of fluorescently-tagged encephalitogenic T cells during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, revealed that laquinimod significantly reduces the invasion of pathogenic effector T cells into the CNS tissue. T-cell activation, differentiation and amplification within secondary lymphoid organs after immunization with myelin antigen, their migratory capacity and re-activation within the nervous tissue were either only mildly affected or remained unchanged. Instead, laquinimod directly impacted the functionality of the CNS vasculature. The expression of tight junction proteins p120 and ZO-1 in human brain endothelial cells was up-regulated upon laquinimod treatment, resulting in a significant increase in the transendothelial electrical resistance of confluent monolayers of brain endothelial cells. Similarly, expression of the adhesion molecule activated leukocyte cell adhesion molecule (ALCAM) and inflammatory chemokines CCL2 and IP-10 was suppressed, leading to a significant reduction in the migration of memory T H 1 and T H 17 lymphocytes across the blood brain barrier (BBB). Our data indicate that laquinimod exerts its therapeutic effects by tightening the BBB and limiting parenchymal invasion of effector T cells, thereby reducing CNS damage., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The endothelium provides a strong barrier separating circulating blood from tissue. It also provides a significant challenge for immune cells in the bloodstream to access potential sites of infection. To mount an effective immune response, leukocytes traverse the endothelial layer in a process known as transendothelial migration. Decades of work have allowed dissection of the mechanisms through which immune cells gain access into peripheral tissues, and subsequently to inflammatory foci. However, an often under-appreciated or potentially ignored question is whether transmigrated leukocytes can leave these inflammatory sites, and perhaps even return across the endothelium and re-enter circulation. Although evidence has existed to support "reverse" transendothelial migration for a number of years, it is only recently that mechanisms associated with this process have been described. Here we review the evidence that supports both reverse transendothelial migration and reverse interstitial migration within tissues, with particular emphasis on some of the more recent studies that finally hint at potential mechanisms. Additionally, we postulate the biological significance of retrograde migration, and whether it serves as an additional mechanism to limit pathology, or provides a basis for the dissemination of systemic inflammation.

SEE WINGER AND ZAMVIL DOI101093/BRAIN/AWW121 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The innate immune system plays a central role in the chronic central nervous system inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments. The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells. Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis. This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program. Treatment results in an attenuated inflammatory milieu in the central nervous system, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood-brain barrier and less neurodegeneration. These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central nervous system inflammation., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.

Growing evidence supports a role for IL-1 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), but how it impacts neuroinflammation is poorly understood. We show that susceptibility to EAE requires activation of IL-1R1 on radiation-resistant cells via IL-1β secreted by bone marrow-derived cells. Neutrophils and monocyte-derived macrophages (MDMs) are the main source of IL-1β and produce this cytokine as a result of their transmigration across the inflamed blood-spinal cord barrier. IL-1R1 expression in the spinal cord is found in endothelial cells (ECs) of the pial venous plexus. Accordingly, leukocyte infiltration at EAE onset is restricted to IL-1R1(+) subpial and subarachnoid vessels. In response to IL-1β, primary cultures of central nervous system ECs produce GM-CSF, G-CSF, IL-6, Cxcl1, and Cxcl2. Initiation of EAE or subdural injection of IL-1β induces a similar cytokine/chemokine signature in spinal cord vessels. Furthermore, the transfer of Gr1(+) cells on the spinal cord is sufficient to induce illness in EAE-resistant IL-1β knockout (KO) mice. Notably, transfer of Gr1(+) cells isolated from C57BL/6 mice induce massive recruitment of recipient myeloid cells compared with cells from IL-1β KO donors, and this recruitment translates into more severe paralysis. These findings suggest that an IL-1β-dependent paracrine loop between infiltrated neutrophils/MDMs and ECs drives neuroinflammation., (© 2016 Levesque et al.)

The blood-brain barrier (BBB) is comprised of unique endothelial cells (ECs) that regulate the delicate central nervous system (CNS) microenvironment. During development, vasculature sprouts from the perivascular neural plexus and penetrates the CNS parenchyma. Recent studies indicate that these nascent vessels rely on radial glia (RG)-secreted factors for guidance and barrier induction. This early association also sustains astrocyte development, allowing for a tight interaction between these mature glia and ECs. The astrocyte-EC interface is crucial to BBB function and is substantially modified during pathology. Understanding the relationship between astrocytes and ECs lays the groundwork for advancing protective therapies that target neuroinflammatory disorders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Dyslipidemias have been shown to bear a close association with an increased risk of cardiovascular diseases, atherosclerosis in particular. As efforts are being made to find alternative therapies and ways to prevent disease, there is a corresponding rise in public interest in food and/or active food components that contribute to an improved lipid profile and, thus, to better health. Besides supplying the basic nutrients necessary for well-being, some foods add further physiologic benefits. In fact, specific foods and bioactive components could be beneficial in controlling dyslipidemias. From a review of the literature on foods and bioactive compounds, their recommended quantities, and expected effects, we found that the following nutrients and food components could positively impact the lipid profile: monounsaturated and polyunsaturated fatty acids, soluble fiber, vegetable proteins, phytosterols, and polyphenols. Therefore, incorporating these components into the regular diets of individuals is justified, because they contribute additional positive effects. This suggests that they also be recommended in clinical practice., (© 2015 American Society for Nutrition.)

Leukocyte transmigration into the central nervous system promotes multiple sclerosis pathogenesis, yet ambiguity remains regarding the mechanisms controlling the migration of distinct immune cell subsets. Using in vitro, ex vivo and postmortem human materials, we identified a significant upregulation of junctional adhesion molecule-like expression at the blood-brain barrier, monocytes, and CD8 T cells of multiple sclerosis patients. We also detected junctional adhesion molecule-like(+) trans-migratory cups when monocytes/CD8 T cells adhered to the blood-brain barrier, however, their migratory capacity was significantly compromised when junctional adhesion molecule-like was blocked. These findings highlight a novel role for junctional adhesion molecule-like in leukocyte transmigration and its potential as a promising therapeutic target.

Phosphate coating hazardous wastes originated from the automotive industry were efficiently encapsulated by an acid-base reaction between phosphates present in the sludge and calcium aluminate cement, yielding very inert and stable monolithic blocks of amorphous calcium phosphate (ACP). Two different compositions of industrial sludge were characterized and loaded in ratios ranging from 10 to 50 wt.%. Setting times and compressive strengths were recorded to establish the feasibility of this method to achieve a good handling and a safe landfilling of these samples. Short solidification periods were found and leaching tests showed an excellent retention for toxic metals (Zn, Ni, Cu, Cr and Mn) and for organic matter. Retentions over 99.9% for Zn and Mn were observed even for loadings as high as 50 wt.% of the wastes. The formation of ACP phase of low porosity and high stability accounted for the effective immobilization of the hazardous components of the wastes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Although Tc17 lymphocytes are enriched in the central nervous system (CNS) of multiple sclerosis (MS) subjects and of experimental autoimmune encephalomyelitis (EAE) animals, limited information is available about their recruitment into the CNS and their role in neuroinflammation. Identification of adhesion molecules used by autoaggressive CD8(+) T lymphocytes to enter the CNS would allow further characterization of this pathogenic subset and could provide new therapeutic targets in MS. We propose that melanoma cell adhesion molecule (MCAM) is a surface marker and adhesion molecule used by pathogenic CD8(+) T lymphocytes to access the CNS., Methods: Frequency, phenotype, and function of MCAM(+) CD8(+) T lymphocytes was characterized using a combination of ex vivo, in vitro, in situ, and in vivo approaches in humans and mice, including healthy controls, MS subjects, and EAE animals., Results: Herein, we report that MCAM is expressed by human effector CD8(+) T lymphocytes and it is strikingly upregulated during MS relapses. We further demonstrate that MCAM(+) CD8(+) T lymphocytes express more interleukin 17, interferon γ, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor than MCAM(-) lymphocytes, and exhibit an enhanced killing capacity toward oligodendrocytes. MCAM blockade restricts the transmigration of CD8(+) T lymphocytes across human blood-brain barrier endothelial cells in vitro, and blocking or depleting MCAM in vivo reduces chronic neurological deficits in active, transfer, and spontaneous progressive EAE models., Interpretation: Our data demonstrate that MCAM identifies encephalitogenic CD8(+) T lymphocytes, suggesting that MCAM could represent a biomarker of MS disease activity and a valid target for the treatment of neuroinflammatory conditions., (© 2015 American Neurological Association.)

Blood-brain barrier function is driven by the influence of astrocyte-secreted factors. During neuroinflammatory responses the blood-brain barrier is compromised resulting in central nervous system damage and exacerbated pathology. Here, we identified endothelial netrin 1 induction as a vascular response to astrocyte-derived sonic hedgehog that promotes autocrine barrier properties during homeostasis and increases with inflammation. Netrin 1 supports blood-brain barrier integrity by upregulating endothelial junctional protein expression, while netrin 1 knockout mice display disorganized tight junction protein expression and barrier breakdown. Upon inflammatory conditions, blood-brain barrier endothelial cells significantly upregulated netrin 1 levels in vitro and in situ, which prevented junctional breach and endothelial cell activation. Finally, netrin 1 treatment during experimental autoimmune encephalomyelitis significantly reduced blood-brain barrier disruption and decreased clinical and pathological indices of disease severity. Our results demonstrate that netrin 1 is an important regulator of blood-brain barrier maintenance that protects the central nervous system against inflammatory conditions such as multiple sclerosis and experimental autoimmune encephalomyelitis., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Early changes in the normal appearing white matter of multiple sclerosis (MS) patients precede the appearance of gadolinium-enhancing lesions. Although these findings suggest blood-brain barrier (BBB) breakdown as an important feature in MS pathogenesis, limited information is available on the BBB alterations during lesion genesis. Here, we perform a longitudinal characterization of the vascular, neuropathological and immunological changes before lesion formation in mice developing spontaneous relapsing-remitting experimental autoimmune encephalomyelitis (sRR-EAE). We found a significant upregulation of Th1 and Th17 cytokines in the periphery of sRR-EAE mice before any evident neuropathology. In the CNS, BBB and astroglial activations were the first pathological changes occurring after 45days of age and were followed by immune cell infiltration by day 50. These pathological alterations subsequently led to perivascular demyelination and disease onset. In MS, (p)reactive lesions mirrored the changes seen in early sRR-EAE by displaying considerable BBB disruption, perivascular astrogliosis, redistribution of junctional proteins and increased expression of endothelial cell adhesion molecules. Our findings suggest that BBB breach occurs before significant immune cell infiltration and demyelination. In addition, peripheral immune activation during sRR-EAE precedes CNS pathology, suggesting that outside in signaling mechanisms play a role in the development of neuroinflammatory lesions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The current investigation sought to explore the nature of the secondary metabolites in the algae, Laurencia pacifica., Results: This report details the first isolation of the sesquiterpenes isoaplysin (1), isolaurenisol (2), debromoisolaurinterol (3), debromoaplysinol (4), laur-11-en-10-ol (5), 10α-hydroxyldebromoepiaplysin (6), and the previously unknown 10-bromo-3,7,11,11-tetramethylspiro[5.5]undeca-1,7-dien-3-ol (7) from the algae, Laurencia pacifica. Isoaplysin (1) and debromoaplysinol (4) showed promising levels of growth inhibition against a panel cancer-derived cell lines of colon (HT29), glioblastoma (U87, SJ-G2), breast (MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (Du145), neuroblastoma (BE2-C), pancreas (MIA), murine glioblastoma (SMA) origin with average GI50 values of 23 and 14 μM., Conclusions: Isoaplysin (1) and debromoaplysinol (4) were up to fourfold more potent in cancer-derived cell populations than in non-tumor-derived normal cells (MCF10A). These analogues are promising candidates for anticancer drug development. Graphical Abstract ᅟ.

Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.

Disruption of the blood-brain and blood-spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP(+) myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP(+) cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Background: The laparoscopic approach for colorectal pathologies is becoming more widely used, and surgeons have had to learn how to perform this new technique. The purpose of this work is to study the indicators of the learning curve for laparoscopic colectomy in a community hospital and to find when the group begins to improve., Methodology: From January 1 2005 to December 31 2012, 313 consecutive laparoscopic colorectal surgeries were performed (105 rectal and 208 colonic) by at least 60% of the same surgical team (6 members) in each operation. We evaluate the learning curve by moving averages and cumulative sums (CUSUM) for different variables related to the surgery outcomes., Results: Moving average curves for postoperative stay, fasting, and second step analgesia show a stabilizing trend toward improvement as we get more experience. However, intensive care unit stay, number of lymph nodes achieved, and operating time did not show a clear decreasing tendency. CUSUM curves of conversion, specimens<12 lymph nodes, and complications all show a clear turning point marked on all the charts around the procedure 60, accumulating a positive trend toward improvement. The CUSUM curve of the "learning variable" shows this improvement point at procedure 70., Conclusions: The laparoscopic colectomy learning curve accelerates with a collective team involvement in each procedure. The CUSUM and moving average curves are useful for initial and ongoing monitoring of new surgical procedures. The markers of the learning curve evidenced in our study are the conversion rate, postoperative surgical morbidity, and the number of patients with a lymph node count<12. WHAT IS NEW IN THIS PAPER?: The significance of this study is the evaluation of the learning curve, in laparoscopic colorectal surgery, of a surgical team in a community hospital, using moving average and CUSUM curves. This study demonstrated that the number of patients needed to achieve skilful practice decreased when there is collective team involvement in each procedure.

Polyphosphate-modified calcium aluminate cement matrices were prepared by using aqueous solutions polluted with toxic metals as mixing water to obtain waste-containing solid blocks with improved management and disposal. Synthetically contaminated waters containing either Pb or Cu or Zn were incorporated into phosphoaluminate cement mortars and the effects of the metal's presence on setting time and mechanical performance were assessed. Sorption and leaching tests were also executed and both retention and release patterns were investigated. For all three metals, high uptake capacities as well as percentages of retention larger than 99.9% were measured. Both Pb and Cu were seen to be largely compatible with this cementitious matrix, rendering the obtained blocks suitable for landfilling or for building purposes. However, Zn spoilt the compressive strength values because of its reaction with hydrogen phosphate anions, hindering the development of the binding matrix., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Health studies and more specifically epidemiological studies require an extended analysis of the physical and chemical characteristics of the environment in which are held. The aim of this study is to evaluate the concentration of six Polycyclic Aromatic Hydrocarbons (PAHs) in PM2.5 fraction of air in a peri-urban environment in the province of Gipuzkoa (Basque Country, Spain) where residential areas are surrounded by industrial activity. The six studied PAH are as follows: Fluoranthene, Benzo(b)fluoranthene, Benzo(k)fluoranthene, (Benzo(a)pyrene, Indene(123-cd)pyrene and Benzo(ghi)perylene. Our six-year study shows a decrease in PAH concentrations between 2006 and 2011, especially since 2008 due to the fall in industrial activity and related traffic. Overall, 801 data were obtained. Total PAH concentration ranged between 0.3 and 8.29ngm(-3) and Benzo(a)pyrene (BaP) from 0.05 to 0.88ngm(-3). The mean value for BaP in PM2.5 was 0.15ngm(-3) and the target value established by European legislation in PM10 was only exceeded in occasional days. Contribution percentages of each PAH in the monitoring sites were very similar, indicating common sources. The results of this study suggest that emission from industry play an important role although we also have to consider the contribution of traffic. PAH seasonal variations are similar as those reported in many previous studies. BaP and PAH concentration values in our region of study were in the range of other Spanish cities., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The Blood Brain Barrier (BBB) is a specialized vascular structure tightly regulating central nervous system (CNS) homeostasis. Endothelial cells are the central component of the BBB and control of their barrier phenotype resides on astrocytes and pericytes. Interactions between these cells and the endothelium promote and maintain many of the physiological and metabolic characteristics that are unique to the BBB. In this review we describe recent findings related to the involvement of astroglial cells, including radial glial cells, in the induction of barrier properties during embryogenesis and adulthood. In addition, we describe changes that occur in astrocytes and endothelial cells during injury and inflammation with a particular emphasis on alterations of the BBB phenotype., (Copyright © 2013 Wiley Periodicals, Inc.)

The ability of calcium aluminate cement (CAC) to encapsulate toxic metals (Pb, Zn and Cu) was assessed under two curing conditions. Changes in the consistency and in the setting time were found upon the addition of the nitrates of the target metals. Both Pb and Cu caused a delay in CAC hydration, while Zn accelerated the stiffening of the mortar. Compressive strengths of the metal-doped mortars, when initially cured at 60 °C/100% RH, were comparable with that of the free-metal mortar. Three different pore size distribution patterns were identified and related to the compounds identified by XRD and SEM. Sorbent capacities of CAC for the toxic metals were excellent: a total uptake was achieved for up to 3 wt.% loading of the three metals. In this way, CAC mortars were perfectly able to encapsulate the toxic metals, allowing the use of CAC for waste management as proved by the leaching tests., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Blood vessel-specific fluorescent transgenic mice are excellent tools to study the development of the vasculature and angiogenic processes. There is growing interest in the biological processes relevant to endothelial cells but limited tools exist to selectively evaluate subcellular functions of this cell type in vivo. Here, we report a novel transgenic animal model that expresses mitochondrially targeted enhanced green fluorescent protein (EGFP) via the Hb9 promoter, a homeobox transcription factor with limited known involvement in the vasculature. Random integration of the transgene, containing the entire mouse Hb9 promoter, was found to be expressed in a variety of vascularised tissues. Further inspection revealed that Mito-EGFP localizes to the endothelial cells (ECs) of a subset of microvascular blood vessels, especially in the central nervous system (CNS), heart, spleen, thymus, lymph nodes and skin. We demonstrate the utility of this novel transgenic mouse, named Endo-MitoEGFP, in the detection, imaging, and isolation of microvascular ECs and evaluation of EC mitochondrial function isolated from adult animals. These transgenic mice will be useful to studies of ECs in development, physiology, and pathology.

The brain is in many ways an immunologically and pharmacologically privileged site. The blood-brain barrier (BBB) of the cerebrovascular endothelium and its participation in the complex structure of the neurovascular unit (NVU) restrict access of immune cells and immune mediators to the central nervous system (CNS). In pathologic conditions, very well-organized immunologic responses can develop within the CNS, raising important questions about the real nature and the intrinsic and extrinsic regulation of this immune privilege. We assess the interactions of immune cells and immune mediators with the BBB and NVU in neurologic disease, cerebrovascular disease, and intracerebral tumors. The goals of this review are to outline key scientific advances and the status of the science central to both the neuroinflammation and CNS barriers fields, and highlight the opportunities and priorities in advancing brain barriers research in the context of the larger immunology and neuroscience disciplines. This review article was developed from reports presented at the 2011 Annual Blood-Brain Barrier Consortium Meeting.