Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing and Potentially Promotes Neoplasia

© 2015 Smout et al. Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated with wound healing and cancer pathways. Given the notable but seemingly paradoxical properties of liver fluke granulin in promoting not only wound healing but also a carcinogenic microenvironment, Ov-GRN-1 likely holds marked potential as a therapeutic wound-healing agent and as a vaccine against an infection-induced cancer of major public health significance in the developing world

Burden and modifications in life from the perspective of caregivers for patients after stroke

OBJECTIVE: to analyze the impact that caring has on a member of the family caring for a patient after a cerebrovascular accident, correlating life modifications and mental suffering with the perceived burden. METHOD: a cross-sectional, quantitative study, undertaken in January-April 2010 in Fortaleza, Ceará, Brazil. RESULT: 61 individuals were investigated, monitored by three hospitals' Home Care Program. Data collection was through interviews for identifying life changes, and through the application of three scales for investigating perceived burden, mental state and mental suffering. Respectively these were the Caregiver Burden Scale (CBS), the Mini-Mental State Examination (MMSE) and the Self Reported Questionnaire (SRQ). The majority of the carers were female, married, and the children of the stroke patients. The average age was 48.2 years (±12.4). The most-cited life modifications referred to the daily routine, to leisure activities, and to exhaustion or tiredness. Regarding burden, the dimensions of General tension, Isolation and Disappointment stood out. It was ascertained that overload was more severe when the carer presented more symptoms of psychological distress, in the absence of a secondary carer, and when the principal carers reported perceiving changes in their bodies and health. CONCLUSION: an association between burden and the carer's mental state was not observed. Understanding the care, through analysis of the burden and of the knowledge of the biopsychosocial situation will provide support for the nurse's work in reducing the overload for family caregivers.OBJETIVO: analizar el impacto del cuidar para el cuidador familiar de paciente después de accidente vascular cerebral, correlacionando modificaciones de vida y sufrimiento psíquico con la sobrecarga percibida. MÉTODO: estudio transversal, cuantitativo, realizado de enero a abril de 2010, en Fortaleza, Ceará, Brasil. RESULTADO: se investigaron 61 individuos, acompañados por el Programa de Servicio Domiciliar de tres hospitales. La colecta de los datos ocurrió mediante entrevista para identificar modificaciones de vida, y con la aplicación de tres escalas para investigar la sobrecarga percibida, estado mental y sufrimiento psíquico. Son ellas, respectivamente: Caregiver Burden Scale (CBS), Mini Examen del Estado Mental (MEEM) y Self Reported Questionnaire (SRQ). Los cuidadores, en su mayoría, eran del sexo femenino, casados (as) e hijo (as) de los pacientes después del AVC. Edad Media de 48,2 años (±12,4). Las modificaciones de vida más citadas fueron referentes a la rutina diaria, a las actividades de ocio y agotamiento o cansancio. En cuanto a la sobrecarga, se destacaron las dimensiones Tensión general, Aislamiento y Decepción. Se verificó mayor sobrecarga cuanto más síntomas de sufrimiento psíquico el cuidador presentase, en la ausencia de cuidador secundario y cuando los cuidadores principales relataron percibir modificación en el cuerpo y en la salud. CONCLUSIÓN: no fue observada asociación de la sobrecarga con el estado mental del cuidador. Entender la coyuntura del cuidado, mediante análisis del recargo de trabajo, y del conocimiento de la situación biopsicosocial, suministrará subsidios para la actuación del enfermero para reducir la carga generada para los cuidadores familiares.OBJETIVO: analisar o impacto do cuidar para o cuidador familiar de paciente após acidente vascular cerebral (AVC), correlacionando modificações de vida e sofrimento psíquico com a sobrecarga percebida. MÉTODO: estudo transversal, quantitativo, realizado de janeiro a abril de 2010, em Fortaleza, Ceará, Brasil. RESULTADO: investigaram-se 61 indivíduos, acompanhados pelo Programa de Atendimento Domiciliar (PAD), de três hospitais. A coleta dos dados ocorreu mediante entrevista para identificar modificações de vida, e com a aplicação de três escalas para investigar sobrecarga percebida, estado mental e sofrimento psíquico. São elas, respectivamente: Caregiver Burden Scale (CBS), Miniexame do Estado Mental (MEEM) e Self Reported Questionnaire (SRQ). Os cuidadores, na sua maioria, eram do sexo feminino, casados(as) e filho(as) dos pacientes após AVC. A média de idade era de 48,2 anos (±12,4). As modificações de vida mais citadas foram referentes à rotina diária, às atividades de lazer e esgotamento ou cansaço. Quanto à sobrecarga, destacaram-se as dimensões tensão geral, isolamento e decepção. Verificou-se maior sobrecarga quanto mais sintomas de sofrimento psíquico o cuidador apresentasse, na ausência de cuidador secundário e quando os cuidadores principais relataram perceber modificação no corpo e na saúde. CONCLUSÃO: não foi observada associação da sobrecarga com o estado mental do cuidador. Entender a conjuntura do cuidado, mediante análise da sobrecarga de trabalho, e do conhecimento da situação biopsicossocial fornecerá subsídios para a atuação do enfermeiro para reduzir a carga gerada para os cuidadores familiares

Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4 (+) T cell responses

IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28−/− mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28−/loxCre+/−+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28−/− mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28−/loxCre+/− mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28−/− mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5+ TFH cell population. Furthermore, total number of CD4+ T cells and B220+ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28−/− mice and tamoxifen treated CD28−/loxCre+/− mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4+ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28−/loxCre+/− mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection

Treatment of mice with S4B6 IL-2 complex prevents lethal toxoplasmosis via IL-12- and IL-18-dependent interferon-gamma production by non-CD4 immune cells.

Toxoplasmic encephalitis is an AIDS-defining condition. The decline of IFN-γ-producing CD4+ T cells in AIDS is a major contributing factor in reactivation of quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important to characterize CD4-independent mechanisms that constrain acute T. gondii infection. We investigated the in vivo regulation of IFN-γ production by CD8+ T cells, DN T cells and NK cells in response to acute T. gondii infection. Our data show that processing of IFN-γ by these non-CD4 cells is dependent on both IL-12 and IL-18 and the secretion of bioactive IL-18 in response to T. gondii requires the sensing of viable parasites by multiple redundant inflammasome sensors in multiple hematopoietic cell types. Importantly, our results show that expansion of CD8+ T cells, DN T cells and NK cell by S4B6 IL-2 complex pre-treatment increases survival rates of mice infected with T. gondii and this is dependent on IL-12, IL-18 and IFN-γ. Increased survival is accompanied by reduced pathology but is independent of expansion of TReg cells or parasite burden. This provides evidence for a protective role of IL2C-mediated expansion of non-CD4 cells and may represent a promising lead to adjunct therapy for acute toxoplasmosis

Universites de Paris 6 Paris 7 - CNRS (UMR 7599)

We study the path properties for the #--pinning wetting model in (1 + 1)-- dimension. In other terms, we consider a random walk model with fairly general continuous increments conditioned to stay in the upper half plane and with a #--measure reward for touching zero, that is the boundary of the forbidden region. It is well known that such a model displays a localization/delocalization transition, according to the size of the reward. Our focus is on getting a precise pathwise description of the system, in both the delocalized phase, that includes the critical case, and in the localized one. From this we extract the (Brownian) scaling limits of the model

Head-to-head comparison of diagnostic scores for acute heart failure in the emergency department: results from the PARADISE cohort

International audienceBREST and PREDICA scores have recently emerged for the diagnosis of acute heart failure (AHF) in the emergency department (ED). This study aimed to perform a head-to-head comparison in a large contemporary cohort. BREST and PREDICA scores were calculated from, respectively, 11 and 8 routine clinical variables recorded in the ED in 1386 patients from the PArADIsE cohort. The diagnostic performance of the scores for adjudicated AHF diagnosis was assessed by the area under the ROC curve (AUC). Acute HF diagnosis was adjudicated according to the European Society of Cardiology criteria and BNP levels. A BREST score ≤ 3 or PREDICA score ≤ 1 was associated with low probabilities of AHF (5.7% and 2.6%, respectively). Conversely, a BREST score ≥ 9 or PREDICA score ≥ 5 was associated with a high risk of AHF diagnosis (77.3% and 66.9%, respectively) although more than half of the population was within the "gray zone" (4-8 and 2-4 for the BREST and PREDICA scores, respectively). Diagnostic performances of both scores were good (AUC 79.1%, [66.1-82.1] for the BREST score and 82.4%, [79.8-85.0] for the PREDICA score). PREDICA score had significantly higher diagnostic performance than BREST score (increase in AUC 3.3 [0.8-5.8], p = 0.009). Our study emphasizes the good diagnostic performance of both BREST and PREDICA scores, albeit with a significantly higher diagnostic performance of the PREDICA score. Yet, more than half of the population was classified within the "gray zone" by these scores; additional diagnostic tools are needed to ascertain AHF diagnosis in the ED in a majority of patients

IL-4Ralpha-associated antigen processing by B cells promotes immunity in Nippostrongylus brasiliensis infection.

In this study, B cell function in protective T(H)2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Ralpha and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Ralpha(-)/(-) mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Ralpha expressing B cells into naive BALB/c mice, but not IL-4Ralpha or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4(+) T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88(-)/(-) B cells. These data suggest TLR dependent antigen processing by IL-4Ralpha-responsive B cells producing IL-13 contribute significantly to CD4(+) T cell-mediated protective immunity against N. brasiliensis infection

Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease

Antibody trapping: A novel mechanism of parasite immune evasion by the trematode Echinostoma caproni

Helminth infections are among the most prevalent neglected tropical diseases, causing an enormous impact in global health and the socioeconomic growth of developing countries. In this context, the study of helminth biology, with emphasis on host-parasite interactions, appears as a promising approach for developing new tools to prevent and control these infections.The role that antibody responses have on helminth infections is still not well understood. To go in depth into this issue, work on the intestinal helminth Echinostoma caproni (Trematoda: Echinostomatidae) has been undertaken. Adult parasites were recovered from infected mice and cultured in vitro. Double indirect immunofluorescence at increasing culture times was done to show that in vivo-bound surface antibodies become trapped within a layer of excretory/secretory products that covers the parasite. Entrapped antibodies are then degraded by parasite-derived proteases, since protease inhibitors prevent for antibody loss in culture. Electron microscopy and immunogold-labelling of secreted proteins provide evidence that this mechanism is consistent with tegument dynamics and ultrastructure, hence it is feasible to occur in vivo. Secretory vesicles discharge their content to the outside and released products are deposited over the parasite surface enabling antibody trapping.At the site of infection, both parasite secretion and antibody binding occur simultaneously and constantly. The continuous entrapment of bound antibodies with newly secreted products may serve to minimize the deleterious effects of the antibody-mediated attack. This mechanism of immune evasion may aid to understand the limited effect that antibody responses have in helminth infections, and may contribute to the basis for vaccine development against these highly prevalent diseases