Baseline spatial distribution of malaria prior to an elimination programme in Vanuatu

BACKGROUND: The Ministry of Health in the Republic of Vanuatu has implemented a malaria elimination programme in Tafea Province, the most southern and eastern limit of malaria transmission in the South West Pacific. Tafea Province is comprised of five islands with malaria elimination achieved on one of these islands (Aneityum) in 1998. The current study aimed to establish the baseline distribution of malaria on the most malarious of the province's islands, Tanna Island, to guide the implementation of elimination activities. METHODS: A parasitological survey was conducted in Tafea Province in 2008. On Tanna Island there were 4,716 participants from 220 villages, geo-referenced using a global position system. Spatial autocorrelation in observed prevalence values was assessed using a semivariogram. Backwards step-wise regression analysis was conducted to determine the inclusion of environmental and climatic variables into a prediction model. The Bayesian geostatistical logistic regression model was used to predict malaria risk, and associated uncertainty across the island. RESULTS: Overall, prevalence on Tanna was 1.0% for Plasmodium falciparum (accounting for 32% of infections) and 2.2% for Plasmodium vivax (accounting for 68% of infections). Regression analysis showed significant association with elevation and distance to coastline for P. vivax and P. falciparum, but no significant association with NDVI or TIR. Colinearity was observed between elevation and distance to coastline with the later variable included in the final Bayesian geostatistical model for P. vivax and the former included in the final model for P. falciparum. Model validation statistics revealed that the final Bayesian geostatistical model had good predictive ability. CONCLUSION: Malaria in Tanna Island, Vanuatu, has a focal and predominantly coastal distribution. As Vanuatu refines its elimination strategy, malaria risk maps represent an invaluable resource in the strategic planning of all levels of malaria interventions for the island

The emergence of insecticide resistance in central Mozambique and potential threat to the successful indoor residual spraying malaria control programme.

BACKGROUND: Malaria vector control by indoor residual spraying was reinitiated in 2006 with DDT in Zambézia province, Mozambique. In 2007, these efforts were strengthened by the President's Malaria Initiative. This manuscript reports on the monitoring and evaluation of this programme as carried out by the Malaria Decision Support Project. METHODS: Mosquitoes were captured daily through a series of 114 window exit traps located at 19 sentinel sites, identified to species and analysed for sporozoites. Anopheles mosquitoes were collected resting indoors and tested for insecticide resistance following the standard WHO protocol. Annual cross sectional household parasite surveys were carried out to monitor the impact of the control programme on prevalence of Plasmodium falciparum in children aged 1 to 15 years. RESULTS: A total of 3,769 and 2,853 Anopheles gambiae s.l. and Anopheles funestus, respectively, were captured from window exit traps throughout the period. In 2010 resistance to the pyrethroids lambda-cyhalothrin and permethrin and the carbamate, bendiocarb was detected in An. funestus. In 2006, the sporozoite rate in An. gambiae s.s. was 4% and this reduced to 1% over 4 rounds of spraying. The sporozoite rate for An. funestus was also reduced from 2% to 0 by 2008. Of the 437 Anopheles arabiensis identified, none were infectious. Overall prevalence of P. falciparum in the sentinel sites fell from 60% to 32% between October 2006 and October 2008. CONCLUSION: Both An. gambiae s.s. and An. funestus were controlled effectively with the DDT-based IRS programme in Zambézia, reducing disease transmission and burden. However, the discovery of pyrethroid resistance in the province and Mozambique's policy change away from DDT to pyrethroids for IRS threatens the gains made here

PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation

Assembling a global database of malaria parasite prevalence for the Malaria Atlas Project

BACKGROUND: Open access to databases of information generated by the research community can synergize individual efforts and are epitomized by the genome mapping projects. Open source models for outputs of scientific research funded by tax-payers and charities are becoming the norm. This has yet to be extended to malaria epidemiology and control. METHODS: The exhaustive searches and assembly process for a global database of malaria parasite prevalence as part of the Malaria Atlas Project (MAP) are described. The different data sources visited and how productive these were in terms of availability of parasite rate (PR) data are presented, followed by a description of the methods used to assemble a relational database and an associated geographic information system. The challenges facing spatial data assembly from varied sources are described in an effort to help inform similar future applications. RESULTS: At the time of writing, the MAP database held 3,351 spatially independent PR estimates from community surveys conducted since 1985. These include 3,036 Plasmodium falciparum and 1,347 Plasmodium vivax estimates in 74 countries derived from 671 primary sources. More than half of these data represent malaria prevalence after the year 2000. CONCLUSION: This database will help refine maps of the global spatial limits of malaria and be the foundation for the development of global malaria endemicity models as part of MAP. A widespread application of these maps is envisaged. The data compiled and the products generated by MAP are planned to be released in June 2009 to facilitate a more informed approach to global malaria control

Population, behavioural and environmental drivers of malaria prevalence in the Democratic Republic of Congo

<p>Abstract</p> <p>Background</p> <p>Malaria is highly endemic in the Democratic Republic of Congo (DRC), but the limits and intensity of transmission within the country are unknown. It is important to discern these patterns as well as the drivers which may underlie them in order for effective prevention measures to be carried out.</p> <p>Methods</p> <p>By applying high-throughput PCR analyses on leftover dried blood spots from the 2007 Demographic and Health Survey (DHS) for the DRC, prevalence estimates were generated and ecological drivers of malaria were explored using spatial statistical analyses and multilevel modelling.</p> <p>Results</p> <p>Of the 7,746 respondents, 2268 (29.3%) were parasitaemic; prevalence ranged from 0-82% within geographically-defined survey clusters. Regional variation in these rates was mapped using the inverse-distance weighting spatial interpolation technique. Males were more likely to be parasitaemic than older people or females (p < 0.0001), while wealthier people were at a lower risk (p < 0.001). Increased community use of bed nets (p = 0.001) and community wealth (p < 0.05) were protective against malaria at the community level but not at the individual level. Paradoxically, the number of battle events since 1994 surrounding one's community was negatively associated with malaria risk (p < 0.0001).</p> <p>Conclusions</p> <p>This research demonstrates the feasibility of using population-based behavioural and molecular surveillance in conjunction with DHS data and geographic methods to study endemic infectious diseases. This study provides the most accurate population-based estimates to date of where illness from malaria occurs in the DRC and what factors contribute to the estimated spatial patterns. This study suggests that spatial information and analyses can enable the DRC government to focus its control efforts against malaria.</p

Functional Energetics of CD4+-Cellular Immunity in Monoclonal Antibody-Associated Progressive Multifocal Leukoencephalopathy in Autoimmune Disorders

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system- (CNS-) infection that typically occurs in a subset of immunocompromised individuals. An increasing incidence of PML has recently been reported in patients receiving monoclonal antibody (mAb) therapy for the treatment of autoimmune diseases, particularly those treated with natalizumab, efalizumab and rituximab. Intracellular CD4(+)-ATP-concentration (iATP) functionally reflects cellular immunocompetence and inversely correlates with risk of infections during immunosuppressive therapy. We investigated whether iATP may assist in individualized risk stratification for opportunistic infections during mAb-treatment. METHODOLOGY/PRINCIPAL FINDINGS: iATP in PHA-stimulated, immunoselected CD4(+)-cells was analyzed using an FDA-approved assay. iATP of mAb-associated PML (natalizumab (n = 8), rituximab (n = 2), efalizumab (n = 1)), or other cases of opportunistic CNS-infections (HIV-associated PML (n = 2), spontaneous PML, PML in a psoriasis patient under fumaric acids, natalizumab-associated herpes simplex encephalitis (n = 1 each)) was reduced by 59% (194.5±29 ng/ml, mean±SEM) in comparison to healthy controls (HC, 479.9±19.8 ng/ml, p<0.0001). iATP in 14 of these 16 patients was at or below 3(rd) percentile of healthy controls, similar to HIV-patients (n = 18). In contrast, CD4(+)-cell numbers were reduced in only 7 of 15 patients, for whom cell counts were available. iATP correlated with mitochondrial transmembrane potential (ΔΨ(m)) (iATP/ΔΨ(m)-correlation:tau = 0.49, p = 0.03). Whereas mean iATP of cross-sectionally analysed natalizumab-treated patients was unaltered (448.7±12 ng/ml, n = 150), iATP was moderately decreased (316.2±26.1 ng/ml, p = 0.04) in patients (n = 7) who had been treated already during the pivotal phase III trials and had received natalizumab for more than 6 years. 2/92 (2%) patients with less than 24 months natalizumab treatment revealed very low iATP at or below the 3(rd) percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations. CONCLUSION: Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders

Development of a new version of the Liverpool Malaria Model. II. Calibration and validation for West Africa

<p>Abstract</p> <p>Background</p> <p>In the first part of this study, an extensive literature survey led to the construction of a new version of the <it>Liverpool Malaria Model </it>(LMM). A new set of parameter settings was provided and a new development of the mathematical formulation of important processes related to the vector population was performed within the LMM. In this part of the study, so far undetermined model parameters are calibrated through the use of data from field studies. The latter are also used to validate the new LMM version, which is furthermore compared against the original LMM version.</p> <p>Methods</p> <p>For the calibration and validation of the LMM, numerous entomological and parasitological field observations were gathered for West Africa. Continuous and quality-controlled temperature and precipitation time series were constructed using intermittent raw data from 34 weather stations across West Africa. The meteorological time series served as the LMM data input. The skill of LMM simulations was tested for 830 different sets of parameter settings of the undetermined LMM parameters. The model version with the highest skill score in terms of entomological malaria variables was taken as the final setting of the new LMM version.</p> <p>Results</p> <p>Validation of the new LMM version in West Africa revealed that the simulations compare well with entomological field observations. The new version reproduces realistic transmission rates and simulated malaria seasons are comparable to field observations. Overall the new model version performs much better than the original model. The new model version enables the detection of the epidemic malaria potential at fringes of endemic areas and, more importantly, it is now applicable to the vast area of malaria endemicity in the humid African tropics.</p> <p>Conclusions</p> <p>A review of entomological and parasitological data from West Africa enabled the construction of a new LMM version. This model version represents a significant step forward in the modelling of a weather-driven malaria transmission cycle. The LMM is now more suitable for the use in malaria early warning systems as well as for malaria projections based on climate change scenarios, both in epidemic and endemic malaria areas.</p

The effect of ω-fatty acids on mrna expression level of PPARγ in patients with gastric adenocarcinoma

Background: The antineoplastic role of peroxisome proliferator-activated receptor gamma (PPARγ) ligandshas previously been demonstrated in several gastric cancer cell lines. Activation of PPARγ by polyunsaturated fatty acids (PUFAs) inhibits growth and proliferationof tumor cells. In this double-blind clinical study, we evaluate the effect of PUFAs on PPARγ mRNA expression in patients with gastric adenocarcinoma. Materials and Methods: A total of 34 chemotherapy-naive patients diagnosed with gastric adenocarcinoma were enrolled in the present study. According to treatment strategies, all subjects were divided into two groups, the first group (17 individuals) received cisplatin without supplements and the second group (17 individuals) received cisplatin plus orally administered PUFAs supplements for 3 weeks. The gastric biopsy samples were obtained from all participants before and after treatment, and PPARγ mRNA expression levels were evaluated by quantitative real-time polymerase chain reaction using validated reference genes. Results: Our findings revealed that PPARγ mRNA expression is significantly upregulated in group II afterreceiving cisplatin plus orally administered PUFAs supplements for three weeks (p < 0.0001), whereas PPARγ mRNA expression did not show significant alteration in group I after receiving cisplatin alone. Conclusion: The results of the study evidence that PPARγ may act as a potential target for the therapy of human gastric adenocarcinoma