Pro-inflammatory role of monocyte-derived CX3CR1int macrophages in Helicobacter hepaticus-induced colitis

Cells of the monocyte-macrophage lineage play important roles in the pathogenesis of inflammatory bowel diseases, but they are also present in the normal healthy intestine, where they are critical for maintaining homeostasis. It has been unclear whether the pro-inflammatory roles of intestinal macrophages reflect altered behaviour of the existing resident cells, or if they involve recruitment of a distinct cell type. Here we have explored these ideas using the model of colitis induced by Helicobacter hepaticus (Hh) in the context of neutralisation or deletion of interleukin 10 (IL-10). Granulocytes and monocytes made up most of the inflammatory myeloid infiltrates found in the colon of Hh-infected colitic mice, rising to a peak within 2 weeks of Hh inoculation, but taking several months to resolve completely. The inflammatory response was dependent on the combined presence of Hh and absence of IL-10, and was accompanied by increased production of inflammatory mediators such as IL-1β, TNFα, IL-6 and IL-23p19 by infiltrating myeloid cells, mostly relatively immature cells of the macrophage lineage that express intermediate levels of CX3CR1. In contrast, the population of mature CX3CR1hi macrophages did not expand as markedly during colitis, and these cells made little contribution to inflammatory mediator production. Taking into account their numerical dominance in the myeloid compartment, we conclude that newly recruited monocytes are the main source of pro-inflammatory mediators in colitis induced in the absence of IL-10 signalling, and that altered behaviour of mature macrophages is not a major component of this pathology

Economic analysis of a transesophageal echocardiography-guided approach to cardioversion of patients with atrial fibrillation The ACUTE economic data at eight weeks

AbstractObjectivesThe aim of this study was to compare the relative cost of a transesophageal echocardiography (TEE)-guided strategy versus conventional strategy for patients with atrial fibrillation (AF) >2 days duration undergoing electrical cardioversion over an eight-week period.BackgroundThe Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) trial found no difference in embolic rates between the two approaches. However, the TEE-guided strategy had a shorter time to cardioversion and a lower rate of composite bleeding. While similar clinical efficacy was concluded, the relative cost of these two strategies has not been explored.MethodsTwo economic approaches were employed in the ACUTE trial. The first approach was based on hospital charge data from complete hospital Universal Billing Code of 1992 forms, a detailed hospital charge questionnaire, or imputation. Regression analysis was used to investigate the added cost of adverse events. The second economic approach involved the development of an independent analytic model simulating treatment and actual ACUTE outcome costs as a validation of clinically derived data. Sensitivity analysis was performed on the analytic model to investigate the potential range in cost differences between the strategies.ResultsA total of 833 of the 1,222 patients were enrolled from 53 U.S. sites; TEE-guided (n = 420) and conventional (n = 413). At eight-week follow-up, total mean costs did not significantly differ between the two groups, respectively ($6,508 vs.$6,239; difference of $269; p = 0.50). Cumulative costs were 24% higher in the conventional group, primarily due to increased incidence of bleeding and hospital costs associated with bleeding. A separate analytic model showed that treatment costs were higher for the TEE-guided strategy, but outcome costs were higher for the conventional strategy. Sensitivity analysis of the analytic model illustrated that varying the incidence and cost of major bleeding and the cost of TEE had the greatest impact on cost differences between the two groups.ConclusionsIn patients with AF >2 days duration undergoing electrical cardioversion, the TEE-guided group showed little difference in patient costs compared with the conventional group. The TEE strategy had higher initial treatment costs but lower outcome-associated costs. Cumulative costs were 24% higher in the conventional group, primarily due to bleeding. The TEE-guided strategy is an economically feasible approach compared with the conventional strategy

Data to Action: Using Formative Research to Develop Intervention Programs to Increase Physical Activity in Adolescent Girls

Formative research is used to inform intervention development, but the processes of transmitting results to intervention planners and incorporating information into intervention designs are not well documented. The authors describe how formative research results from the Trial of Activity for Adolescent Girls (TAAG) were transferred to planners to guide intervention development. Methods included providing oral and written reports, prioritizing recommendations, and cross-checking recommendations with intervention objectives and implementation strategies. Formative work influenced the intervention in many ways. For example, results indicated that middle schools offered only coeducational physical education and health education classes, so the TAAG intervention was designed to be appropriate for both sexes, and intervention strategies were developed to directly address girls’ stated preferences (e.g., enjoyable activities, opportunity to socialize) and barriers (e.g., lack of skills, fear of injury) for physical activity. The challenges of using formative research for intervention development are discussed

Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis

Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (T 1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring T 17 and T 2 responses for clearance (bacterial and helminth infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell-mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use

Proceedings from the Turner Resource Network symposium: The crossroads of health care research and health care delivery

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural “Turner Resource Network (TRN) Symposium” brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: 1. inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; 2. investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant 1R13HD079209-01)March of Dimes Birth Defects FoundationAmerican Heart AssociationNational Institutes of Health (U.S.) Office of Women's HealthLeaping Butterfly MinistryTurner Syndrome Society of the United State

A 3D cellular context for the macromolecular world

We report the outcomes of the discussion initiated at the workshop entitled A 3D Cellular Context for the Macromolecular World and propose how data from emerging three-dimensional (3D) cellular imaging techniques—such as electron tomography, 3D scanning electron microscopy and soft X-ray tomography—should be archived, curated, validated and disseminated, to enable their interpretation and reuse by the biomedical community

A programme theory for liaison mental health services in England

Background: Mechanisms by which liaison mental health services (LMHS) may bring about improved patient and organisational outcomes are poorly understood. A small number of logic models have been developed, but they fail to capture the complexity of clinical practice. Method: We synthesised data from a variety of sources including a large national survey, 73 in-depth interviews with acute and liaison staff working in hospitals with different types of liaison mental health services, and relevant local, national and international literature. We generated logic models for two common performance indicators used to assess organisational outcomes for LMHS: response times in the emergency department and hospital length of stay for people with mental health problems. Results: We identified 8 areas of complexity that influence performance, and 6 trade-offs which drove the models in different directions depending upon the balance of the trade-off. The logic models we developed could only be captured by consideration of more than one pass through the system, the complexity in which they operated, and the trade-offs that occurred. Conclusions: Our findings are important for commissioners of liaison services. Reliance on simple target setting may result in services that are unbalanced and not patient-centred. Targets need to be reviewed on a regular basis, together with other data that reflect the wider impact of the service, and any external changes in the system that affect the performance of LMHS, which are beyond their control

"A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

<p>Abstract</p> <p>Background</p> <p>The study of breast cancer metastasis depends on the use of established breast cancer cell lines that do not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was developed using primary breast tumor-initiating cells isolated from patient core biopsies that would more accurately reflect human breast cancer metastasis.</p> <p>Methods</p> <p>Tumorspheres were isolated under serum-free culture conditions from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity <it>in vivo</it>. Tumors and metastatic lesions were analyzed by hematoxylin and eosin (H+E) staining and immunohistochemistry (IHC).</p> <p>Results</p> <p>Tumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen receptor α (ERα)/progesterone receptor (PR)/Her2/neu status or tumor grade. Each tumorsphere was estimated to contain 50-100 cells. Transplantation of 50 tumorspheres (1-5 × 10³cells) in combination with Matrigel into the mammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months post-injection. Tumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and injection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases were detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear β catenin and fibronectin but were negative for ERα and vimentin. In lung and liver metastases, variable redistribution of E-cadherin and β catenin to the membrane of tumor cells was observed. ERα was re-expressed in lung metastatic cells in two of five samples.</p> <p>Conclusions</p> <p>Tumorspheres isolated under defined culture conditions from patient core biopsies were tumorigenic when transplanted into the mammary fat pad of NUDE mice, and metastasized to multiple mouse organs. Micrometastases in mouse organs demonstrated a dormancy period prior to outgrowth of macrometastases. The development of macrometastases with organ-specific phenotypic distinctions provides a superior model for the investigation of organ-specific effects on metastatic cancer cell survival and growth.</p

Geometagenomics illuminates the impact of agriculture on the distribution and prevalence of plant viruses at the ecosystem scale

Disease emergence events regularly result from human activities such as agriculture, which frequently brings large populations of genetically uniform hosts into contact with potential pathogens. Although viruses cause nearly 50% of emerging plant diseases, there is little systematic information about virus distribution across agro-ecological interfaces and large gaps in understanding of virus diversity in nature. Here we applied a novel landscape-scale geometagenomics approach to examine relationships between agricultural land use and distributions of plantassociated viruses in two Mediterranean-climate biodiversity hotspots (Western Cape region of South Africa and Rhône river delta region of France). In total, we analysed 1725 geo-referenced plant samples collected over two years from 4.5 × 4.5 km2 grids spanning farmlands and adjacent uncultivated vegetation. We found substantial virus prevalence (25.8–35.7%) in all ecosystems, but prevalence and identified family-level virus diversity were greatest in cultivated areas, with some virus families displaying strong agricultural associations. Our survey revealed 94 previously unknown virus species, primarily from uncultivated plants. This is the first effort to systematically evaluate plant-associated viromes across broad agro-ecological interfaces. Our findings indicate that agriculture substantially influences plant virus distributions and highlight the extent of current ignorance about the diversity and roles of viruses in nature