CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis

Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.Fil: Blanco-Pérez, Frank. Paul-ehrlich-institut;Fil: Kato, Yoichiro. Tokyo Women's Medical University;Fil: Gonzalez-Menendez, Irene. Universitätsklinikum Tübingen Medizinische Fakultät;Fil: Laiño, Jonathan Emiliano. Paul-ehrlich-institut;Fil: Ohbayashi, Masaharu. Toyohashi Sozo University;Fil: Burggraf, Manja. Paul-ehrlich-institut;Fil: Krause, Maren. Paul-ehrlich-institut;Fil: Kirberg, Jörg. Paul-ehrlich-institut;Fil: Iwakura, Yoichiro. Tokyo University Of Science;Fil: Martella, Manuela. Universitätsklinikum Tübingen Medizinische Fakultät;Fil: Quintanilla-Martinez, Leticia. Universitätsklinikum Tübingen Medizinische Fakultät;Fil: Shibata, Noriyuki. Tokyo Women's Medical University;Fil: Vieths, Stefan. Paul-ehrlich-institut;Fil: Scheurer, Stephan. Paul-ehrlich-institut;Fil: Toda, Masako. Paul-ehrlich-institut; . Tohoku University

Mitochondrial DNA haplogroups associated with MRI-detected structural damage in early knee osteoarthritis

[Abstract] Objective: Magnetic resonance imaging (MRI)-detected structural features are associated with increased risk of radiographic osteoarthritis (ROA). Specific mitochondrial DNA (mtDNA) haplogroups have been associated with incident ROA. Our objective was to compare the presence of MRI-detected structural features across mtDNA haplogroups among knees that developed incident ROA. Design: Knees from the Osteoarthritis Initiative (OAI) that developed incident ROA during 48 months follow-up were identified from Caucasian participants. mtDNA haplogroups were assigned based on a single base extension assay. MRIs were obtained annually between baseline and 4-year follow-up and scored using the MRI Osteoarthritis Knee Score (MOAKS). The association between mtDNA haplogroups and MRI-detected structural features was estimated using log-binomial regression. Participants who carried haplogroup H served as the reference group. Results: The sample included 255 participants contributing 277 knees that developed ROA. Haplogroups included H (116, 45%), J (17, 7%), T (26, 10%), Uk (61, 24%), and the remaining less common haplogroups ("others") (35, 14%). Knees of participants with haplogroup J had significantly lower risk of medium/large bone marrow lesions (BMLs) in the medial compartment [3.2%, relative risks (RR) = 0.17; 95%CI: 0.05, 0.64; P = 0.009] compared to knees of participants who carried haplogroup H [16.3%], as did knees from participants within the "others" group [2.8%, RR = 0.20; 95%CI: 0.08, 0.55; P = 0.002], over the 4 year follow-up period. Conclusions: mtDNA haplogroup J was associated with lower risk of BMLs in the medial compartment among knees that developed ROA. Our results offer a potential hypothesis to explain the mechanism underlying the previously reported protective association between haplogroup J and ROA.National Institute of Health; NIH HHSN2682010000 21CNational Institute of Health; NIH AR06660

Mast cells partly contribute to allergic enteritis development: Findings in two different mast cell-deficient mice

Allergic enteritis (AE) is a gastrointestinal form of food allergy. The presence of mast cells and granulocytes has been detected in the inflamed tissues in AE. In this study, we aimed to elucidate the role of mast cells in AE development using two mast cell-deficient mouse strains: KIT(W-sh/W-sh) bearing the W-sash (W(sh)) inversion mutation and Cpa3Cre/+, which lack mast cells due to Cre-mediated mast cell eradication, were used in an AE experimental model. The development of clinical symptoms (e.g. drop in body temperature and weight loss) were abolished in both strains, whereas inflammatory levels of AE (e.g. villous atrophy, edema, and granulocyte accumulation) were reduced mainly in KITW-sh/W-sh mice. FACS analysis of the KITW-sh/W-sh intestinal lamina propria, showed a reduction in the eosinophil (CD45+CD11b+SiglecF+cells) and neutrophil (CD45+CD11b+SiglecF−Ly6G+ cells) accumulation. Cpa3Cre/+ mice showed reduced eosinophil (CD45+CD11b+SiglecF+cells) accumulation, but neutrophil (CD45+CD11b+SiglecF−Ly6G+ cells) accumulation was retained at AE sites. The concentrations of CC chemokine ligand 1 (CCL1), a known CC chemokine receptor 8 ligand leading to eosinophil recruitment, was reduced in intestinal homogenates of both mast cell-deficient mouse strains. These results suggest that mast cells play a role in AE development in part by expressing CCL1 and contributing to eosinophil accumulation at AE. This study offers implications for establishing AE treatments that target infiltrating leucocytes in AE tissues.Fil: Blanco Pérez, Frank. No especifíca;Fil: Gonzalez Menendez, Irene. No especifíca;Fil: Stassen, Michael. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Kato, Yoichiro. Tokyo Women's Medical University; JapónFil: Laiño, Jonathan Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; ArgentinaFil: Kirberg, Jörg. No especifíca;Fil: Krause, Maren. No especifíca;Fil: Martella, Manuela. No especifíca;Fil: Shibata, Noriyuki. Tokyo Women's Medical University; JapónFil: Quintanilla-Martinez, Leticia. No especifíca;Fil: Feyerabend, Thorsten B.. No especifíca;Fil: Rodewald, Hans Reimer. No especifíca;Fil: Galli, Stephen J.. University of Stanford; Estados UnidosFil: Vieths, Stefan. No especifíca;Fil: Scheurer, Stephan. No especifíca;Fil: Toda, Masako. No especifíca

High incidence of PTSD diagnosis and trauma-related symptoms in a trauma exposed bipolar I and II sample

Post-traumatic stress disorder (PTSD) is an established comorbidity in Bipolar Disorder (BD), but little is known about the characteristics of psychological trauma beyond a PTSD diagnosis and differences in trauma symptoms between BD-I and BD-II. (1) To present characteristics of a trauma-exposed BD sample; (2) to investigate prevalence and trauma symptom profile across BD-I and BD-II; (3) to assess the impact of a lifetime PTSD diagnosis vs. a history of trauma on BD course; and (4) to research the impacts of sexual and physical abuse. This multi-center study comprised 79 adult participants with BD with a history of psychological trauma and reports baseline data from a trial registered in Clinical Trials (; ref: NCT02634372). Clinical variables were gathered through clinical interview, validated scales and a review of case notes. The majority (80.8%) of our sample had experienced a relevant stressful life event prior to onset of BD, over half of our sample 51.9% had a lifetime diagnosis of PTSD according to the Clinician Administered PTSD scale. The mean Impact of Event Scale-Revised scores indicated high levels of trauma-related distress across the sample, including clinical symptoms in the PTSD group and subsyndromal symptoms in the non-PTSD group. Levels of dissociation were not higher than normative values for BD. A PTSD diagnosis (vs. a history of trauma) was associated with psychotic symptoms [2(1) = 5.404, p = 0.02] but not with other indicators of BD clinical severity. There was no significant difference between BD-I and BD-II in terms of lifetime PTSD diagnosis or trauma symptom profile. Sexual abuse significantly predicted rapid cycling [2(1) = 4.15, p = 0.042], while physical abuse was not significantly associated with any clinical indicator of severity. Trauma load in BD is marked with a lack of difference in trauma profile between BD-I and BD-II. Although PTSD and sexual abuse may have a negative impact on BD course, in many indicators of BD severity there is no significant difference between PTSD and subsyndromal trauma symptoms. Our results support further research to clarify the role of subsyndromic PTSD symptoms, and highlight the importance of screening for trauma in BD patients

High incidence of PTSD diagnosis and trauma-related symptoms in a trauma exposed bipolar I and II sample

Background: Post-traumatic stress disorder (PTSD) is an established comorbidity in Bipolar Disorder (BD), but little is known about the characteristics of psychological trauma beyond a PTSD diagnosis and differences in trauma symptoms between BD-I and BD-II. Objective: (1) To present characteristics of a trauma-exposed BD sample; (2) to investigate prevalence and trauma symptom profile across BD-I and BD-II; (3) to assess the impact of a lifetime PTSD diagnosis vs. a history of trauma on BD course; and (4) to research the impacts of sexual and physical abuse. Methods: This multi-center study comprised 79 adult participants with BD with a history of psychological trauma and reports baseline data from a trial registered in Clinical Trials (https://clinicaltrials.gov; ref: NCT02634372). Clinical variables were gathered through clinical interview, validated scales and a review of case notes. Results: The majority (80.8%) of our sample had experienced a relevant stressful life event prior to onset of BD, over half of our sample 51.9% had a lifetime diagnosis of PTSD according to the Clinician Administered PTSD scale. The mean Impact of Event Scale-Revised scores indicated high levels of trauma-related distress across the sample, including clinical symptoms in the PTSD group and subsyndromal symptoms in the non-PTSD group. Levels of dissociation were not higher than normative values for BD. A PTSD diagnosis (vs. a history of trauma) was associated with psychotic symptoms [2(1) = 5.404, p = 0.02] but not with other indicators of BD clinical severity. There was no significant difference between BD-I and BD-II in terms of lifetime PTSD diagnosis or trauma symptom profile. Sexual abuse significantly predicted rapid cycling [2(1) = 4.15, p = 0.042], while physical abuse was not significantly associated with any clinical indicator of severity. Conclusion: Trauma load in BD is marked with a lack of difference in trauma profile between BD-I and BD-II. Although PTSD and sexual abuse may have a negative impact on BD course, in many indicators of BD severity there is no significant difference between PTSD and subsyndromal trauma symptoms. Our results support further research to clarify the role of subsyndromic PTSD symptoms, and highlight the importance of screening for trauma in BD patients

Cultivos y sabores de nuestra América

El presente libro es una creación conjunta de la Red Latinoamericana ProHuerta creada en el marco del Convenio JICA MREyC INTA MDS para la ejecución del Curso “Autoproducción de alimentos, seguridad alimentaria y desarrollo local” con el objetivo de compartir y promover el modelo ProHuerta en distintos países de América Latina, Caribe y ahora África. El desafío que nos propusimos como red fue recopilar cultivos y recetas populares que formen parte de nuestra cultura culinaria de los distintos países de nuestra américa grande y ponerlos en manos de las nuevas generaciones. El resultado es un libro con las técnicas de cultivo de 13 especies que rescatan recetas y usos ancestrales en las voces de las mujeres y hombres que integran y conforman nuestra américa "para que en la gente del maíz siga caminando sin morir sobre la tierra"ProHuertaFil: Abdo, Guadalupe Del Carmen. Instituto Nacional de Tecnología Agropecuaria (INTA). ProHuerta; ArgentinaFil: Morales Mata, Adolfo. Ministerio de Agricultura y Ganadería; Costa RicaFil: Villota, Guadalupe. Instituto Nacional de Investigaciones Agropecuarias (INIAP). ConQuito; EcuadorFil: Blanco Beteta, Francisco José. Instituto de Desarrollo Rural; NicaraguaFil: Vigil, Carlos. Ministerio de la Presidencia, Despacho de la Primera Dama; PanamáFil: Saavedra, Fanny. Ministerio de la Presidencia, Despacho de la Primera Dama; PanamáFil: Núñez de Olmedo, Teresa Concepción. Ministerio de Agricultura y Ganadería; ParaguayFil: Castellanos, Aurelia. Asociación Cubana de Producción Animal; CubaFil: Figueroa, Vilda. Asociación Cubana de Producción Animal; CubaFil: Pujols, Ramón. Secretaría de Estado de Agricultura; República DominicanaFil: Membreño, Jonathan. Secretaría de Estado de Agricultura; República DominicanaFil: Naut, Laura. Secretaría de Estado de Agricultura; República DominicanaFil: Rodríguez, Angel. Secretaría de Estado de Agricultura; República DominicanaFil: Figuereo, Leonardo. Secretaría de Estado de Agricultura; República DominicanaFil: Pérez Aquino, Frank. Secretaría de Estado de Agricultura; República Dominican

A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy

Co-located wind and wave energy farms: Uniformly distributed arrays

publisher: Elsevier articletitle: Co-located wind and wave energy farms: Uniformly distributed arrays journaltitle: Energy articlelink: http://dx.doi.org/10.1016/j.energy.2016.07.069 content_type: article copyright: © 2016 Elsevier Ltd. All rights reserved

Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis

Seasonality of the particle number concentration and size distribution : a global analysis retrieved from the network of Global Atmosphere Watch (GAW) near-surface observatories

Aerosol particles are a complex component of the atmospheric system which influence climate directly by interacting with solar radiation, and indirectly by contributing to cloud formation. The variety of their sources, as well as the multiple transformations they may undergo during their transport (including wet and dry deposition), result in significant spatial and temporal variability of their properties. Documenting this variability is essential to provide a proper representation of aerosols and cloud condensation nuclei (CCN) in climate models. Using measurements conducted in 2016 or 2017 at 62 ground-based stations around the world, this study provides the most up-to-date picture of the spatial distribution of particle number concentration (N-tot) and number size distribution (PNSD, from 39 sites). A sensitivity study was first performed to assess the impact of data availability on N-tot's annual and seasonal statistics, as well as on the analysis of its diel cycle. Thresholds of 50% and 60% were set at the seasonal and annual scale, respectively, for the study of the corresponding statistics, and a slightly higher coverage (75 %) was required to document the diel cycle. Although some observations are common to a majority of sites, the variety of environments characterizing these stations made it possible to highlight contrasting findings, which, among other factors, seem to be significantly related to the level of anthropogenic influence. The concentrations measured at polar sites are the lowest (similar to 10(2) cm(-3)) and show a clear seasonality, which is also visible in the shape of the PNSD, while diel cycles are in general less evident, due notably to the absence of a regular day-night cycle in some seasons. In contrast, the concentrations characteristic of urban environments are the highest (similar to 10(3)-10(4) cm(-3)) and do not show pronounced seasonal variations, whereas diel cycles tend to be very regular over the year at these stations. The remaining sites, including mountain and non-urban continental and coastal stations, do not exhibit as obvious common behaviour as polar and urban sites and display, on average, intermediate N-tot (similar to 10(2)-10(3) cm(-3)). Particle concentrations measured at mountain sites, however, are generally lower compared to nearby lowland sites, and tend to exhibit somewhat more pronounced seasonal variations as a likely result of the strong impact of the atmospheric boundary layer (ABL) influence in connection with the topography of the sites. ABL dynamics also likely contribute to the diel cycle of N-tot observed at these stations. Based on available PNSD measurements, CCN-sized particles (considered here as either >50 nm or >100 nm) can represent from a few percent to almost all of N-tot, corresponding to seasonal medians on the order of similar to 10 to 1000 cm(-3), with seasonal patterns and a hierarchy of the site types broadly similar to those observed for N-tot. Overall, this work illustrates the importance of in situ measurements, in particular for the study of aerosol physical properties, and thus strongly supports the development of a broad global network of near surface observatories to increase and homogenize the spatial coverage of the measurements, and guarantee as well data availability and quality. The results of this study also provide a valuable, freely available and easy to use support for model comparison and validation, with the ultimate goal of contributing to improvement of the representation of aerosol-cloud interactions in models, and, therefore, of the evaluation of the impact of aerosol particles on climate.Peer reviewe