The immunopathology of human schistosomiasis-III: immunoglobulin isotype profiles and response to praziquantel

Immunoglobulin (Ig) isotype (IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgD and IgE) levels were investigated, both pre- and post-treatment with praziquantel (PZQ), in 43 adults and children chronically infected with Schistosoma mansoni , by means of a two-site, isotype-specific immunoenzymometric assay. The patients were classified as responders (R) or non-responders (NR) on the basis of their circumoval precipitin test (COPT) results 12 months after treatment. In comparison with controls, pre-treatment R children showed significantly higher levels of IgG, IgG1, IgG4 (p<0.001) and IgE (p<0.01), and diminished IgG2 (p<0.05), while NR children showed significantly elevated levels only of IgE (p<0.05). Twelve months after therapy, R children maintained significantly lower levels of IgG2, but showed significantly decreased levels of IgG, IgG1, IgG4, and IgE, while the Ig isotype profile of NR children was unaltered. Adult R and NR showed similar isotype profiles before chemotherapy, with the exception of significantly elevated IgM levels in R. Twelve months after therapy, R adults showed significantly decreased levels of IgG, IgG1, and IgG4, while NR adults showed only diminshed IgG4 levels. These results reveal different Ig isotype profiles in untreated adults and children chronically infected with S. mansoni. The results further show that the pre-treatment Ig isotype profile may be significantly modified after an effective R to chemotherapy, accounted for by down regulation of the IgG1 isotype in association with negative seroconversion of the COPT in R patients. The COPT reaction has been associated with the highly specific egg glycoprotein antigen w1, which shows a significant reduction in reactivity six months after treatment. IgG1 may thus play a main role in the response against the w1 antigen

Development of Trypanosoma cruzi in vitro assays to identify compounds suitable for progression in Chagas’ disease drug discovery

Chagas' disease is responsible for significant mortality and morbidity in Latin America. Current treatments display variable efficacy and have adverse side effects, hence more effective, better tolerated drugs are needed. However, recent efforts have proved unsuccessful with failure of the ergosterol biosynthesis inhibitor posaconazole in phase II clinical trials despite promising in vitro and in vivo studies. The lack of translation between laboratory experiments and clinical outcome is a major issue for further drug discovery efforts. Our goal was to identify cell-based assays that could differentiate current nitro-aromatic drugs nifurtimox and benznidazole from posaconazole. Using a panel of T. cruzi strains including the six major lineages (TcI-VI), we found that strain PAH179 (TcV) was markedly less susceptible to posaconazole in vitro. Determination of parasite doubling and cycling times as well as EdU labelling experiments all indicate that this lack of sensitivity is due to the slow doubling and cycling time of strain PAH179. This is in accordance with ergosterol biosynthesis inhibition by posaconazole leading to critically low ergosterol levels only after multiple rounds of division, and is further supported by the lack of effect of posaconazole on the non-replicative trypomastigote form. A washout experiment with prolonged posaconazole treatment showed that, even for more rapidly replicating strains, this compound cannot clear all parasites, indicative of a heterogeneous parasite population in vitro and potentially the presence of quiescent parasites. Benznidazole in contrast was able to kill all parasites. The work presented here shows clear differentiation between the nitro-aromatic drugs and posaconazole in several assays, and suggests that in vitro there may be clinically relevant heterogeneity in the parasite population that can be revealed in long-term washout experiments. Based on these findings we have adjusted our in vitro screening cascade so that only the most promising compounds are progressed to in vivo experiments

Field evaluation of a new antibody-based diagnostic for Schistosoma haematobium and S. mansoni at the point-of-care in northeast Zimbabwe

BACKGROUND: Rapid diagnostic tests (RDTs) for use at the point-of-care (POC) are likely to become increasingly useful as large-scale control programmes for schistosomiasis get underway. Given the low sensitivity of the reference standard egg count methods in detecting light infections, more sensitive tests will be required to monitor efforts aimed at eliminating schistosomiasis as advocated by the World Health Assembly Resolution 65.21 passed in 2012. METHODS: A recently developed RDT incorporating Schistosoma mansoni cercarial transformation fluid (SmCTF) for detection of anti-schistosome antibodies in human blood was here evaluated in children (mean age: 7.65 years; age range: 1-12 years) carrying light S. mansoni and S. haematobium infections in a schistosome-endemic area of Zimbabwe by comparison to standard parasitological techniques (i.e. the Kato-Katz faecal smear and urine filtration). Enzyme-linked immunosorbent assays (ELISAs) incorporating S. haematobium antigen preparations were also employed for additional comparison. RESULTS: The sensitivity of the SmCTF-RDT compared to standard parasitological methods was 100% while the specificity was 39.5%. It was found that the sera from RDT “false-positive” children showed significantly higher antibody titres in IgM-cercarial antigen preparation (CAP) and IgM-soluble egg antigen (SEA) ELISA assays than children identified by parasitology as “true-negatives”. CONCLUSIONS: Although further evaluations are necessary using more accurate reference standard tests, these results indicate that the RDT could be a useful tool for the rapid prevalence-mapping of both S. mansoni and S. haematobium in schistosome-endemic areas. It is affordable, user-friendly and allows for diagnosis of both schistosome species at the POC

2 nd Brazilian Consensus on Chagas Disease, 2015

Abstract Chagas disease is a neglected chronic condition with a high burden of morbidity and mortality. It has considerable psychological, social, and economic impacts. The disease represents a significant public health issue in Brazil, with different regional patterns. This document presents the evidence that resulted in the Brazilian Consensus on Chagas Disease. The objective was to review and standardize strategies for diagnosis, treatment, prevention, and control of Chagas disease in the country, based on the available scientific evidence. The consensus is based on the articulation and strategic contribution of renowned Brazilian experts with knowledge and experience on various aspects of the disease. It is the result of a close collaboration between the Brazilian Society of Tropical Medicine and the Ministry of Health. It is hoped that this document will strengthen the development of integrated actions against Chagas disease in the country, focusing on epidemiology, management, comprehensive care (including families and communities), communication, information, education, and research

World Health Organization Estimates of the Global and Regional Disease Burden of 11 Foodborne Parasitic Diseases, 2010: A Data Synthesis

We would like to acknowledge the assistance of the WHO Secretariat over the life of the FERG initiative, particularly Amy Cawthorne, Tim Corrigan, Tanja Kuchenmüller, Yuki Minato, Kurt Straif and Claudia Stein. We acknowledge the Institute for Health Metrics and Evaluation (Seattle, WA, USA) for providing data on the global burden of selected diseases.In this data synthesis, Paul Robert Torgerson and colleagues estimate the global and regional disease burden of 11 foodborne parasitic diseases.Yeshttp://www.plosmedicine.org/static/editorial#pee

Changing perspectives on the internationalization of R&D and innovation by multinational enterprises: a review of the literature

Internationalization of R&D and innovation by Multinational Enterprises (MNEs) has undergone a gradual and comprehensive change in perspective over the past 50 years. From sporadic works in the late 1950s and in the 1960s, it became a systematically analysed topic in the 1970s, starting with pioneering reports and “foundation texts”. Our review unfolds the theoretical and empirical evolution of the literature from dyadic interpretations of centralization versus decentralization of R&D by MNEs to more comprehensive frameworks, wherein established MNEs from Advanced Economies still play a pivotal role, but new players and places also emerge in the global generation and diffusion of knowledge. Hence views of R&D internationalization increasingly rely on concepts, ideas and methods from IB and other related disciplines such as industrial organization, international economics and economic geography. Two main findings are highlighted. First, scholarly research pays an increasing attention to the network-like characteristics of international R&D activities. Second, different streams of literature have emphasized the role of location- specific factors in R&D internationalization. The increasing emphasis on these aspects has created new research opportunities in some key areas, including inter alia: cross-border knowledge sourcing strategies, changes in the geography of R&D and innovation, and the international fragmentation of production and R&D activities