Projecting future transmission of malaria under climate change scenarios : challenges and research needs

There has been an intense debate about climatic impacts on the transmission of malaria. It is vitally important to accurately project future impacts of climate change on malaria to support effective policy–making and intervention activity concerning malaria control and prevention. This paper critically reviewed the published literature and examined both key findings and methodological issues in projecting future impacts of climate change on malaria transmission. A literature search was conducted using the electronic databases MEDLINE, Web of Science and PubMed. The projected impacts of climate change on malaria transmission were spatially heterogeneous and somewhat inconsistent. The variation in results may be explained by the interaction of climatic factors and malaria transmission cycles, variations in projection frameworks and uncertainties of future socioecological (including climate) changes. Current knowledge gaps are identified, future research directions are proposed and public health implications are assessed. Improving the understanding of the dynamic effects of climate on malaria transmission cycles, the advancement of modelling techniques and the incorporation of uncertainties in future socioecological changes are critical factors for projecting the impact of climate change on malaria transmission.

Staurosporine augments EGF-mediated EMT in PMC42-LA cells through actin depolymerisation, focal contact size reduction and Snail1 induction : a model for cross-modulation

Background A feature of epithelial to mesenchymal transition (EMT) relevant to tumour dissemination is the reorganization of actin cytoskeleton/focal contacts, influencing cellular ECM adherence and motility. This is coupled with the transcriptional repression of E-cadherin, often mediated by Snail1, Snail2 and Zeb1/δEF1. These genes, overexpressed in breast carcinomas, are known targets of growth factor-initiated pathways, however it is less clear how alterations in ECM attachment cross-modulate to regulate these pathways. EGF induces EMT in the breast cancer cell line PMC42-LA and the kinase inhibitor staurosporine (ST) induces EMT in embryonic neural epithelial cells, with F-actin de-bundling and disruption of cell-cell adhesion, via inhibition of aPKC. Methods PMC42-LA cells were treated for 72 h with 10 ng/ml EGF, 40 nM ST, or both, and assessed for expression of E-cadherin repressor genes (Snail1, Snail2, Zeb1/δEF1) and EMT-related genes by QRT-PCR, multiplex tandem PCR (MT-PCR) and immunofluorescence +/- cycloheximide. Actin and focal contacts (paxillin) were visualized by confocal microscopy. A public database of human breast cancers was assessed for expression of Snail1 and Snail2 in relation to outcome. Results When PMC42-LA were treated with EGF, Snail2 was the principal E-cadherin repressor induced. With ST or ST+EGF this shifted to Snail1, with more extreme EMT and Zeb1/δEF1 induction seen with ST+EGF. ST reduced stress fibres and focal contact size rapidly and independently of gene transcription. Gene expression analysis by MT-PCR indicated that ST repressed many genes which were induced by EGF (EGFR, CAV1, CTGF, CYR61, CD44, S100A4) and induced genes which alter the actin cytoskeleton (NLF1, NLF2, EPHB4). Examination of the public database of breast cancers revealed tumours exhibiting higher Snail1 expression have an increased risk of disease-recurrence. This was not seen for Snail2, and Zeb1/δEF1 showed a reverse correlation with lower expression values being predictive of increased risk. Conclusion ST in combination with EGF directed a greater EMT via actin depolymerisation and focal contact size reduction, resulting in a loosening of cell-ECM attachment along with Snail1-Zeb1/δEF1 induction. This appeared fundamentally different to the EGF-induced EMT, highlighting the multiple pathways which can regulate EMT. Our findings add support for a functional role for Snail1 in invasive breast cancer.

Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors

Background Breast carcinoma is accompanied by changes in the acellular and cellular components of the microenvironment, the latter typified by a switch from fibroblasts to myofibroblasts. Methods: We utilised conditioned media cultures, Western blot analysis and immunocytochemistry to investigate the differential effects of normal mammary fibroblasts (NMFs) and mammary cancer-associated fibroblasts (CAFs) on the phenotype and behaviour of PMC42-LA breast cancer cells. NMFs were obtained from a mammary gland at reduction mammoplasty, and CAFs from a mammary carcinoma after resection. Results We found greater expression of myofibroblastic markers in CAFs than in NMFs. Medium from both CAFs and NMFs induced novel expression of α-smooth muscle actin and cytokeratin-14 in PMC42-LA organoids. However, although conditioned media from NMFs resulted in distribution of vimentin-positive cells to the periphery of PMC42-LA organoids, this was not seen with CAF-conditioned medium. Upregulation of vimentin was accompanied by a mis-localization of E-cadherin, suggesting a loss of adhesive function. This was confirmed by visualizing the change in active β-catenin, localized to the cell junctions in control cells/ cells in NMF-conditioned medium, to inactive β-catenin, localized to nuclei and cytoplasm in cells in CAF-conditioned medium. Conclusion We found no significant difference between the influences of NMFs and CAFs on PMC42-LA cell proliferation, viability, or apoptosis; significantly, we demonstrated a role for CAFs, but not for NMFs, in increasing the migratory ability of PMC42-LA cells. By concentrating NMF-conditioned media, we demonstrated the presence of factor(s) that induce epithelial-mesenchymal transition in NMF-conditioned media that are present at higher levels in CAF-conditioned media. Our in vitro results are consistent with observations in vivo showing that alterations in stroma influence the phenotype and behaviour of surrounding cells and provide evidence for a role for CAFs in stimulating cancer progression via an epithelial-mesenchymal transition. These findings have implications for our understanding of the roles of signalling between epithelial and stromal cells in the development and progression of mammary carcinoma.

Assessing the property market impact of stigma removal : high voltage overhead transmission lines removal in Wellington, NZ

This thesis advances the understanding of the impact of stigma on property values. A case study in Wellington, New Zealand, enabled hedonic modelling and an empirical analysis to determine the impact of the stigma from the high voltage transmission line structure and how long the stigma remained after removal. The results reveal a substantial difference between the discount applied to individual properties while the structure is in place, as compared to the overall increase in neighbourhood value once the structure, which created the stigma, is removed.

The making of control : an ethnomethodology of choosing management accounting systems [La fabrique du controle : une ethnomethodologie du choix des outils de gestion]

This paper sets out to contribute to the literature on the design and the implementation of management control systems. To this end, we question what is discussed when a management control system is to be chosen and on what decision-making eventually rests. This study rests upon an ethnomethodology of the Salvation Army’s French branch. Operating in the dual capacity of a researcher and a counsellor to management, between 2000 and 2007, we have unrestricted access to internal data revealing the backstage of management control: discussions and interactions surrounding the choosing of control devices. We contribute to understanding the arising of a need for control, the steps and process followed to decide upon a management control system, and controls in nonprofits. [Cet article vise à contribuer à la littérature sur la mise en place des systèmes de contrôle de gestion. À cette fin, nous questionnons ce qui est discuté lors du choix d’un système de contrôle et sur quoi repose in fine la décision. Cet article est fondé sur une approche ethnométhodologique de l’Armée du Salut en France permise par notre double qualité de chercheurs mais également de conseiller auprès de la direction de l’organisation entre 2000 et 2007. Un accès illimité à des données internes nous permet ainsi de mettre en lumière les aspects méconnus et invisibles du contrôle de gestion : les discussions et interactions entourant le choix d’outils. Nous contribuons à la compréhension de l’émergence du besoin de contrôle, des étapes et du processus de choix d’outils et enfin du contrôle de gestion dans une organisation à but non lucratif.]

From democracy in America to a la francaise accountability. Grasping the sociopolitical origins of accountability [De la démocratie en Amérique du Nord à l’accountability à la française]

Whilst native French speakers oftentimes collapse accountability to account giving, this paper outlines the shape of an accountability ala française. Reading Tocqueville’s (1835) work highlights that accountability as practiced in Anglo-Saxonc countries has been an offspring of American democracy. An accountability a la française would be characterised by conformance to a set or universal values, the submission of minorities to choices made by the majority, a means obligation as well as the rejection of transparency. [Alors que le francophone réduit généralement l’accountability à la reddition de comptes, cet article esquisse les contours d’une véritable accountability à la française. La lecture de Tocqueville (1835) révèle que l’accountability pratiquée dans les pays anglo-saxons trouve ses origines dans les fondements de la démocratie américaine. En France, l’accountability serait caractérisée par le respect d’un ensemble de valeurs universelles, l’adhésion des minorités aux choix majoritaires, l’absence de discriminations, une obligation de moyens et un rejet de la transparence.]

Myoepithelial molecular markers in human breast carcinoma PMC42-LA cells are induced by extracellular matrix and stromal cells

The microenvironment plays a key role in the cellular differentiation of the two main cell lineages of the human breast, luminal epithelial, and myoepithelial. It is not clear, however, how the components of the microenvironment control the development of these cell lineages. To investigate how lineage development is regulated by 3-D culture and microenvironment components, we used the PMC42-LA human breast carcinoma cell line, which possesses stem cell characteristics. When cultured on a two-dimensional glass substrate, PMC42-LA cells formed a monolayer and expressed predominantly luminal epithelial markers, including cytokeratins 8, 18, and 19; E-cadherin; and sialomucin. The key myoepithelial-specific proteins α-smooth muscle actin and cytokeratin 14 were not expressed. When cultured within Engelbreth-Holm- Swarm sarcoma-derived basement membrane matrix (EHS matrix), PMC42-LA cells formed organoids in which the expression of luminal markers was reduced and the expression of other myoepithelial-specific markers (cytokeratin 17 and P-cadherin) was promoted. The presence of primary human mammary gland fibroblasts within the EHS matrix induced expression of the key myoepithelial-specific markers, α-smooth muscle actin and cytokeratin 14. Immortalized human skin fibroblasts were less effective in inducing expression of these key myoepithelial-specific markers. Confocal dual-labeling showed that individual cells expressed luminal or myoepithelial proteins, but not both. Conditioned medium from the mammary fibroblasts was equally effective in inducing myoepithelial marker expression. The results indicate that the myoepithelial lineage is promoted by the extracellular matrix, in conjunction with products secreted by breast-specific fibroblasts. Our results demonstrate a key role for the breast microenvironment in the regulation of breast lineage development.

Programa Piloto de Diseño Promoción y Desarrollo de Productos con Alto Valor Agregado en la Empresa Peruana

Este proyecto se desarrollo por iniciativa de las autoras y con el apoyo de un grupo interdisciplinario, con el interés común de desarrollar una investigación académica cuyo resultado sea de utilidad para el desarrollo del sector productivo artesanal Peruano. El proceso de investigación nace a partir de una observación de campo acerca de la problemática del producto artesanal Peruana y enfocada en los aspectos comerciales, de diseño y producción. Esta observación se centro en Cajamarca (por ser el departamento menos intervenido por otras investigaciones en este tema) en la zona de Aylambo y Cruz Blanca, en los talleres artesanales que desarrollan productos cerámicos. A partir de un análisis de tipo FODA de los productos y de su contexto de desarrollo, encontramos que los artesanos que trabajan con los empresarios exportadores, requieren un tipo de capacitación que les permita desarrollar su trabajo mediante un proceso orientado a cumplir con exigencias técnicas y de diseño para el desarrollo de productos validos como oferta exportable. Como punto de partida se recurrió a las instituciones no gubernamentales y del gobierno, que promueven el sector artesanal Peruano (Prompex, Adex, Proyecto PARA, IMPART) para conocer su opinión respecto a los mercados objetivos de este sector, y para adoptar como parte del proyecto, lo vigente respecto a las políticas y planes de comercialización. Para entender la contraparte comercial de este sector artesanal recurrimos a empresas privadas exportadoras con muchos años de experiencia, para ello contamos con la colaboración de empresas como Allpa, Manos Amigas, Novica. A partir de la observación de campo preliminar y de la información recogida de los expertos consultados, se realizo un diagnostico de la situación productiva en este sector. En base a la definición del problema, se establecieron las estrategias y metodologías para el diseño de la investigación, siendo parte de estas estrategias, la realización de un taller de desarrollo de productos en Cajamarca. Las estrategias tuvieron como enfoque principal la definición de metodologías de trabajo, cuya aplicación sea posible en el marco del contexto económico, político y cultural en el que se desarrolla este sector en la realidad inmediata del país. El proyecto culmina con la presentación de una propuesta que mas allá de abarcar únicamente lo metodológico en el área del diseño, presenta también ‘modelos’ de trabajo entre los diferentes actores que intervienen en el sector, de manera que a través de estrategias colaborativas se pueda potenciar el crecimiento del sector y beneficiar el desarrollo del artesano.

A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands : challenges for malaria diagnostics in an elimination setting

Background Many countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting. Methods During the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared. Results A total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections. Conclusion Asymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.

Interrupting malaria transmission: quantifying the impact of interventions in regions of low to moderate transmission

Malaria has been eliminated from over 40 countries with an additional 39 currently planning for, or committed to, elimination. Information on the likely impact of available interventions, and the required time, is urgently needed to help plan resource allocation. Mathematical modelling has been used to investigate the impact of various interventions; the strength of the conclusions is boosted when several models with differing formulation produce similar data. Here we predict by using an individual-based stochastic simulation model of seasonal Plasmodium falciparum transmission that transmission can be interrupted and parasite reintroductions controlled in villages of 1,000 individuals where the entomological inoculation rate is <7 infectious bites per person per year using chemotherapy and bed net strategies. Above this transmission intensity bed nets and symptomatic treatment alone were not sufficient to interrupt transmission and control the importation of malaria for at least 150 days. Our model results suggest that 1) stochastic events impact the likelihood of successfully interrupting transmission with large variability in the times required, 2) the relative reduction in morbidity caused by the interventions were age-group specific, changing over time, and 3) the post-intervention changes in morbidity were larger than the corresponding impact on transmission. These results generally agree with the conclusions from previously published models. However the model also predicted changes in parasite population structure as a result of improved treatment of symptomatic individuals; the survival probability of introduced parasites reduced leading to an increase in the prevalence of sub-patent infections in semi-immune individuals. This novel finding requires further investigation in the field because, if confirmed, such a change would have a negative impact on attempts to eliminate the disease from areas of moderate transmission.

Spatial analysis of risk factors for transmission of the Barmah forest virus in Queensland, Australia

Barmah Forest virus (BFV) disease is the second most common mosquito-borne disease in Australia but few data are available on the risk factors. We assessed the impact of spatial climatic, socioeconomic and ecological factors on the transmission of BFV disease in Queensland, Australia, using spatial regression. All our analyses indicate that spatial lag models provide a superior fit to the data compared to spatial error and ordinary least square models. The residuals of the spatial lag models were found to be uncorrelated, indicating that the models adequately account for spatial and temporal autocorrelation. Our results revealed that minimum temperature, distance from coast and low tide were negatively and rainfall was positively associated with BFV disease in coastal areas, whereas minimum temperature and high tide were negatively and rainfall was positively associated with BFV disease (all P-value.

The hereditary transmission of the glutathione transferase hGSTT1-1 conjugator phenotype in a large family

The polymorphism of human glutathione transferase hGSTT1-1 is expressed in three phenotypes. Experimentally, individuals can be classified as non-conjugators, low conjugators and 'high' conjugators depending on the enzyme activity in blood towards methylene chloride using a gas chromatographic assay. Non-conjugators do not have a functional hGSTT1 gene; however, little is known about the molecular basis of the three conjugator phenotypes. The higher hGSTT1-1 activity in high conjugators may be the result of enzyme induction or be genetically determined. Twenty-nine members of a large family, including three generations were phenotyped and genotyped with respect to hGSTT1-1. The hGSTT1-1 enzyme activity of high conjugators was twice as high as that of low conjugators. The distribution of hGSTT1-1 phenotypes strongly indicates a Mendelian intermediary inheritance, in which a gene-dosage effect results in a doubled enzyme expression in the presence of two functional alleles. The Mendelian intermediary inheritance is further supported by the findings of a semiquantitative polymerase chain reaction method designed to distinguish the three genotypes of hGSTT1 for rapid screening of large study groups.