246 research outputs found
Whipworm and roundworm infections
Trichuriasis and ascariasis are neglected tropical diseases caused by the gastrointestinal dwelling nematodes Trichuris trichiura (a whipworm) and Ascaris lumbricoides (a roundworm), respectively. Both parasites are staggeringly prevalent, particularly in tropical and subtropical areas, and are associated with substantial morbidity. Infection is initiated by ingestion of infective eggs, which hatch in the intestine. Thereafter, T. trichiura larvae moult within intestinal epithelial cells, with adult worms embedded in a partially intracellular niche in the large intestine, whereas A. lumbricoides larvae penetrate the gut mucosa and migrate through the liver and lungs before returning to the lumen of the small intestine, where adult worms dwell. Both species elicit type 2 anti-parasite immunity. Diagnosis is typically based on clinical presentation (gastrointestinal symptoms and inflammation) and the detection of eggs or parasite DNA in the faeces. Prevention and treatment strategies rely on periodic mass drug administration (generally with albendazole or mebendazole) to at-risk populations and improvements in water, sanitation and hygiene. The effectiveness of drug treatment is very high for A. lumbricoides infections, whereas cure rates for T. trichiura infections are low. Novel anthelminthic drugs are needed, together with vaccine development and tools for diagnosis and assessment of parasite control in the field
Joint IARC/NCI International Cancer Seminar Series Report: Expert consensus on future directions for ovarian carcinoma research
Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches, and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization, and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic, and prognostic research on ovarian carcinoma
Functional Impairment of Human Myeloid Dendritic Cells during Schistosoma haematobium Infection
Chronic Schistosoma infection is often characterized by a state of T cell hyporesponsiveness of the host. Suppression of dendritic cell (DC) function could be one of the mechanisms underlying this phenomenon, since Schistosoma antigens are potent modulators of dendritic cell function in vitro. Yet, it remains to be established whether DC function is modulated during chronic human Schistosoma infection in vivo. To address this question, the effect of Schistosoma haematobium infection on the function of human blood DC was evaluated. We found that plasmacytoid (pDC) and myeloid DC (mDC) from infected subjects were present at lower frequencies in peripheral blood and that mDC displayed lower expression levels of HLA-DR compared to those from uninfected individuals. Furthermore, mDC from infected subjects, but not pDC, were found to have a reduced capacity to respond to TLR ligands, as determined by MAPK signaling, cytokine production and expression of maturation markers. Moreover, the T cell activating capacity of TLR-matured mDC from infected subjects was lower, likely as a result of reduced HLA-DR expression. Collectively these data show that S. haematobium infection is associated with functional impairment of human DC function in vivo and provide new insights into the underlying mechanisms of T cell hyporesponsiveness during chronic schistosomiasis
Induction of CD4+CD25+FOXP3+ Regulatory T Cells during Human Hookworm Infection Modulates Antigen-Mediated Lymphocyte Proliferation
Hookworm infection is considered one of the most important poverty-promoting neglected tropical diseases, infecting 576 to 740 million people worldwide, especially in the tropics and subtropics. These blood-feeding nematodes have a remarkable ability to downmodulate the host immune response, protecting themselves from elimination and minimizing severe host pathology. While several mechanisms may be involved in the immunomodulation by parasitic infection, experimental evidences have pointed toward the possible involvement of regulatory T cells (Tregs) in downregulating effector T-cell responses upon chronic infection. However, the role of Tregs cells in human hookworm infection is still poorly understood and has not been addressed yet. In the current study we observed an augmentation of circulating CD4+CD25+FOXP3+ regulatory T cells in hookworm-infected individuals compared with healthy non-infected donors. We have also demonstrated that infected individuals present higher levels of circulating Treg cells expressing CTLA-4, GITR, IL-10, TGF-β and IL-17. Moreover, we showed that hookworm crude antigen stimulation reduces the number of CD4+CD25+FOXP3+ T regulatory cells co-expressing IL-17 in infected individuals. Finally, PBMCs from infected individuals pulsed with excreted/secreted products or hookworm crude antigens presented an impaired cellular proliferation, which was partially augmented by the depletion of Treg cells. Our results suggest that Treg cells may play an important role in hookworm-induced immunosuppression, contributing to the longevity of hookworm survival in infected people
Expression of CD11c Is Associated with Unconventional Activated T Cell Subsets with High Migratory Potential
Ajudes rebudes: Marie Curie Career Integration Grant; Dexeus Foundation for Women's Health Research; i Contratos Ramón y CajalCD11c is an α integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from naïve mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including γδ T cells and invariant natural killer T (iNKT) cells. However, in women, only γδ T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)-γ secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential
Filarial Lymphedema Is Characterized by Antigen- Specific Th1 and Th17 Proinflammatory Responses and a Lack of Regulatory T Cells
Background: Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema,
hydrocele, and elephantiasis in a subset of infected patients.
Methods and Findings: To elucidate the role of CD4+ T cell subsets in the development of lymphatic pathology, we
examined specific sets of cytokines in individuals with filarial lymphedema in response to parasite antigen (BmA) and
compared them with responses from asymptomatic infected individuals. We also examined expression patterns of Toll-like
receptors (TLR1–10) and Nod-like receptors (Nod1, Nod2, and NALP3) in response to BmA. BmA induced significantly higher
production of Th1-type cytokines—IFN-c and TNF-a—in patients with lymphedema compared with asymptomatic
individuals. Notably, expression of the Th17 family of cytokines—IL-17A, IL-17F, IL-21, and IL-23—was also significantly
upregulated by BmA stimulation in lymphedema patients. In contrast, expression of Foxp3, GITR, TGFb, and CTLA-4, known
to be expressed by regulatory T cells, was significantly impaired in patients with lymphedema. BmA also induced
significantly higher expression of TLR2, 4, 7, and 9 as well Nod1 and 2 mRNA in patients with lymphedema compared with
asymptomatic controls.
Conclusion: Our findings implicate increased Th1/Th17 responses and decreased regulatory T cells as well as regulation of
Toll- and Nod-like receptors in pathogenesis of filarial lymphedema
Cochlin, Intraocular Pressure Regulation and Mechanosensing
Fluid shear modulates many biological properties. How shear mechanosensing occurs in the extracellular matrix (ECM) and is transduced into cytoskeletal change remains unknown. Cochlin is an ECM protein of unknown function. Our investigation using a comprehensive spectrum of cutting-edge techniques has resulted in following major findings: (1) over-expression and down-regulation of cochlin increase and decrease intraocular pressure (IOP), respectively. The overexpression was achieved in DBA/2J-Gpnmb+/SjJ using lentiviral vectors, down-regulation was achieved in glaucomatous DBA/2J mice using targeted disruption (cochlin-null mice) and also using lentiviral vector mediated shRNA against cochlin coding region; (2) reintroduction of cochlin in cochlin-null mice increases IOP; (3) injection of exogenous cochlin also increased IOP; (4) increasing perfusion rates increased cochlin multimerization, which reduced the rate of cochlin proteolysis by trypsin and proteinase K; The cochlin multimerization in response to shear stress suggests its potential mechanosensing. Taken together with previous studies, we show cochlin is involved in regulation of intraocular pressure in DBA/2J potentially through mechanosensing of the shear stress
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Free breakfasts in schools: design and conduct of a cluster randomised controlled trial of the Primary School Free Breakfast Initiative in Wales [ISRCTN18336527]
Background: School-based breakfast provision is increasingly being seen as a means of improving educational performance and dietary behaviour amongst children. Furthermore, recognition is growing that breakfast provision offers potential as a means of addressing social inequalities in these outcomes. At present however, the evidence base on the effectiveness of breakfast provision in bringing about these improvements is limited.
Methods/Design: This paper describes the research design of a large scale evaluation of the effectiveness of the Welsh Assembly Government's Primary School Free Breakfast Initiative. A cluster randomised trial, with school as the unit of randomisation was used for the outcome evaluation, with a nested qualitative process evaluation. Quantitative outcome measures included dietary habits, attitudes, cognitive function, classroom behaviour, and school attendance. The study recruited 111 primary schools in Wales, of which 56 were randomly assigned to control condition and 55 to intervention. Participants were Year 5 and 6 students (aged 9–11 years) in these schools. Data were collected for all 111 schools at each of three time points: baseline, 4 month and 12 month follow-up. This was achieved through a repeated cross-sectional survey of approximately 4350 students on each of these occasions. Of those students in Year 5 at baseline, 1975 provided data at one or both of the follow-ups, forming a nested cohort. The evaluation also included a nested process evaluation, using questionnaires, semi-structured interviews and case studies with students, school staff, and local authority scheme coordinators as key informants.
Discussion: An overview of the methods used for the evaluation is presented, providing an example of the feasibility of conducting robust evaluations of policy initiatives using a randomised trial design with nested process evaluation. Details are provided of response rates and the flow of participants. Reflection is offered on methodological issues encountered at various stages through the course of the study, focusing upon issues associated with conducting a randomised trial of a government policy initiative, and with conducting research in school settings.
Trial registration: Current Controlled Trials ISRCTN1833652
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