On the road to eliminate malaria in Sri Lanka: lessons from history, challenges, gaps in knowledge and research needs

Malaria is one of the most important tropical diseases that has caused devastation throughout the history of mankind. Malaria eradication programmes in the past have had many positive effects but failed to wipe out malaria from most tropical countries, including Sri Lanka. Encouraged by the impressive levels of reduction in malaria case numbers during the past decade, Sri Lanka has launched a programme to eliminate malaria by year 2014. This article reviews the historical milestones associated with the malaria eradication programme that failed subsequently and the events that led to the launch of the ongoing malaria elimination plans at national-level and its strategies that are operational across the entire country. The existing gaps in knowledge are also discussed together with the priority areas for research to fill in these gaps that are posing as challenges to the envisaged goal of wiping out malaria from this island nation

Theory and simulation of molecular interactions in biological systems

Doctor of PhilosophyDepartment of ChemistryPaul E. SmithThe impact of computer simulations has become quite significant especially with the development of supercomputers during the last couple of decades. They are used in a wide range of purposes such as exploring experimentally inaccessible phenomena and providing an alternative when experiments are expensive, dangerous, time consuming, difficult and controversial. In terms of applications in biological systems molecular modeling techniques can be used in rational drug design, predicting structures of proteins and circumstances where the atomic level descriptions provided by them are valuable for the understanding of the systems of interest. Hence, the potential of computer simulations of biomolecular systems is undeniable. Irrespective of the promising uses of computer simulations, it cannot be guaranteed that the results will be realistic. The precision of a molecular simulation depends on the degree of sampling achieved during the simulation while the accuracy of the results depends on the satisfactory description of intramolecular and intermolecular interactions in the system, i.e. the force field. Recently, we have been developing a force field for molecular dynamics simulations of biological systems based on the Kirkwood Buff (KB) theory of solutions, not only with an emphasis on the accurate description of intermolecular interactions, but also by reproducing several physical properties such as partial molar volume, compressibility and composition dependent chemical potential derivatives to match with respective experimental values. In this approach simulation results in terms of KB integrals can be directly compared with experimental data through a KB analysis of the solution properties and therefore it provides a simple and clear method to test the capability of the KB derived force field. Initially, we have provided a rigorous framework for the analysis of experimental and simulation data concerning open and closed multicomponent systems using the KB theory of solutions. The results are illustrated using computer simulations for various concentrations of the solutes Gly, Gly₂ and Gly₃ in both open and closed systems, and in the absence or presence of NaCl as a cosolvent. Then, we have attempted to quantify the interactions between amino acids in aqueous solutions using the KB theory of solutions. The results are illustrated using computer simulations for various concentrations of the twenty zwitterionic amino acids at ambient temperature and pressure. Next, several amino acids were also studied at higher temperatures and pressures and the results are discussed in terms of the preferential (solute over solvent) interactions between the amino acids. Finally, we have described our most recent efforts towards a complete force field for peptides and proteins. The results are illustrated using molecular dynamics simulations of several tripeptides, selected peptides and selected globular proteins at ambient temperature and pressure followed by replica exchange molecular dynamics simulations of a few selected peptides

Studies on prevalence of anopheline species and community perception of malaria in Jaffna district, Sri Lanka

Background & objectives: Over two decades of civil unrest and the conflict situation have had detrimental effects on vector control activities and management of malaria in Jaffna district which is an endemic region for malaria in Sri Lanka. With the background that only a few small-scale studies on malaria and its vectors have been reported from this district, a study was designed to explore the current status of malaria in the Jaffna district in relation to vector and community aspects.Methods: Adults and larvae of anopheline mosquitoes were collected monthly from selected endemic localities. Species prevalence of the collected mosquitoes was studied while the collected adults of Anopheles subpictus, a potential vector in the district, was screened for sibling species composition based on morphological characteristics and exposed to common insecticides using WHO bioassay kits. Knowledge, attitude and practices (KAP) of the community were tested using a pre-tested structured questionnaire in high-risk and low-risk localities in the district.Results: The anopheline mosquito species distribution in the district was—An. culicifacies (0.5%), An. subpictus (46%), An. varuna (4%), An. nigerrimus (44%) and An. pallidus (5.5%). Among the collected larvae the percent prevalence of An. culicifacies was 13% and other species follows as: An. subpictus (71%), An. varuna (4%), An. nigerrimus (10%) and An. pallidus (2%). Sibling species B, C and D of An. subpictus were present in the district with the predominance of B in both coastal and inland areas, while all members showed both indoor and outdoor resting characteristics, they were highly resistant to DDT (4%) and highly susceptible to malathion (5%). KAP study in the district showed a reasonable level of knowledge, positive attitude and practices towards malaria.Conclusion: An. subpictus, the reported major vector of Jaffna and a well-established secondary vector of malaria in the country, continues to be the predominant anopheline species. The distribution of sibling species of An. subpictus complex in the Jaffna district, revealed for the first time, has implications for future studies on its bionomics and malaria transmission pattern in this area and the planning of control strategies for this region. The community perception of disease, which revealed a satisfactory knowledge indicates the potential for better community participation in future malaria control activities in this region. As potential vectors are still present, health authorities need to be vigilant to prevent any future epidemics of malaria

Transition between immune and disease states in a cellular automaton model of clonal immune response

In this paper we extend the Celada-Seiden (CS) model of the humoral immune response to include infectious virus and cytotoxic T lymphocytes (cellular response). The response of the system to virus involves a competition between the ability of the virus to kill the host cells and the host's ability to eliminate the virus. We find two basins of attraction in the dynamics of this system, one is identified with disease and the other with the immune state. There is also an oscillating state that exists on the border of these two stable states. Fluctuations in the population of virus or antibody can end the oscillation and drive the system into one of the stable states. The introduction of mechanisms of cross-regulation between the two responses can bias the system towards one of them. We also study a mean field model, based on coupled maps, to investigate virus-like infections. This simple model reproduces the attractors for average populations observed in the cellular automaton. All the dynamical behavior connected to spatial extension is lost, as is the oscillating feature. Thus the mean field approximation introduced with coupled maps destroys oscillations.Comment: 27 pages LaTeX + 7 Figures Postscrip

Plasmodium vivax: paroxysm-associated lipids mediate leukocyte aggregation

<p>Abstract</p> <p>Background</p> <p>Paroxysms are recurrent febrile episodes, characteristic of <it>Plasmodium vivax </it>infections, which coincide with the rupture of schizont-infected erythrocytes in the patients' circulation. The present study describes the formation of prominent aggregates of leukocytes <it>in vitro </it>in the presence of parasite and host factors released during paroxysms.</p> <p>Methods</p> <p>Whole blood cells from uninfected malaria-naïve donors were incubated with plasma taken during a paroxysm or normal human plasma as a control and cell smears were observed under the microscope for the presence of leukocyte aggregates. Plasma factors involved in mediating the leukocyte aggregation were identified using immune depletion and reconstitution experiments. Furthermore, biochemical characterization was carried out to determine the chemical nature of the active moieties in plasma present during paroxysms.</p> <p>Results</p> <p>Leukocyte aggregates were seen exclusively when cells were incubated in plasma collected during a paroxysm. Immune depletion and reconstitution experiments revealed that the host cytokines TNF-alpha, GM-CSF, IL-6 and IL-10 and two lipid fractions of paroxysm plasma comprise the necessary and sufficient mediators of this phenomenon. The two lipid components of the paroxysm plasmas speculated to be of putative parasite origin, were a phospholipid-containing fraction and another containing cholesterol and triglycerides. The phospholipid fraction was dependent upon the presence of cytokines for its activity unlike the cholesterol/triglyceride-containing fraction which in the absence of added cytokines was much more active than the phospholipids fraction. The biological activity of the paroxysm plasmas from non-immune patients who presented with acute <it>P. vivax </it>infections was neutralized by immune sera raised against schizont extracts of either <it>P. vivax </it>or <it>Plasmodium falciparum</it>. However, immune sera against <it>P. vivax </it>were more effective than that against <it>P. falciparum </it>indicating that the parasite activity involved may be antigenically at least partially parasite species-specific.</p> <p>Conclusion</p> <p>Leukocyte aggregation was identified as associated with paroxysms in <it>P. vivax </it>infections. This phenomenon is mediated by plasma factors including host-derived cytokines and lipids of putative parasite origin. The characteristics of the phospholipid fraction in paroxysm plasma are congruent with those of the parasite-derived, TNF-inducing GPI moieties described by others. The more active cholesterol/triglyceride(s), however, represent a novel malarial toxin, which is a new class of biologically active lipid associated with the paroxysm of <it>P. vivax </it>malaria.</p

Association of HLA class I and II genes with cutaneous leishmaniasis: a case control study from Sri Lanka and a systematic review

Three dimensional model of HLA-B protein based on PDB entry 1HSA (DOI: 10.2210/pdb1hsa/pdb ). Amino acids at positions 55 and 57 in the alpha1 and alpha2 domains of the molecule which constitute the antigen recognition region are highlighted. (TIF 376 kb

Effectiveness of a serological tool to predict malaria transmission intensity in an elimination setting.

BACKGROUND: Sri Lanka achieved the WHO certificate as a malaria free country in September 2016, thus monitoring of malaria transmission using sensitive and effective tools is an important need. Use of age-specific antibody prevalence as a serological tool to predict transmission intensity is proven to be a cost effective and reliable method under elimination settings. This paper discusses the correlation of four anti-malarial antibodies against vivax and falciparum malaria with the declining transmission intensities in two previously high malaria endemic districts i.e. Kurunegala and Moneragala of Sri Lanka. METHODS: Sera was collected from 1,186 individuals from the two districts and were subjected to standard ELISA together with control sera from non-immune individuals to obtain Optical Density (OD) values for four anti-malarial antibodies i.e. anti-MSP1 and anti-AMA1 for both Plasmodium vivax and Plasmodium falciparum. The sero-positive samples were determined as mean OD + 3SD of the negative controls. The sero-prevalence was analyzed against the demographic characteristics of the population. A simple reversible catalytic model was fitted into sero-prevalence data to predict the sero-conversion and sero-reversion rates. RESULTS: Over 60% of the population was sero-positive for one or more antibodies except young children (<10 years). The sero-prevalence was zero in young children and very low in young adults when compared to the older age groups. The model developed for falciparum malaria that assumed the presence of a change in transmission was not significant in the Kurunegala district although significant reduction in transmission was observed when the model was used for P. vivax antibody data in that district. In Moneragala district however, all the serological markers indicated a change in transmission that has occurred approximately 15 years ago. CONCLUSIONS: Assessment of MSP1 and AMA1 anti-malarial antibodies of P. vivax and P. falciparum proved to be useful indicators in predicting transmission under elimination settings as prevailed in Sri Lanka. The sero-conversion rates for the two districts studied are shown to be very low or zero indicating the absence of active and/or hidden transmission confirming a "true" state of elimination at least, in the two study districts in Sri Lanka

Experimental triplet and quadruplet fluctuation densities and spatial distribution function integrals for pure liquids

Citation: Ploetz, E. A., Karunaweera, S., & Smith, P. E. (2015). Experimental triplet and quadruplet fluctuation densities and spatial distribution function integrals for pure liquids. Journal of Chemical Physics, 142(4), 14. doi:10.1063/1.4905562Fluctuation solution theory has provided an alternative view of many liquid mixture properties in terms of particle number fluctuations. The particle number fluctuations can also be related to integrals of the corresponding two body distribution functions between molecular pairs in order to provide a more physical picture of solution behavior and molecule affinities. Here, we extend this type of approach to provide expressions for higher order triplet and quadruplet fluctuations, and thereby integrals over the corresponding distribution functions, all of which can be obtained from available experimental thermodynamic data. The fluctuations and integrals are then determined using the International Association for the Properties of Water and Steam Formulation 1995 (IAPWS-95) equation of state for the liquid phase of pure water. The results indicate small, but significant, deviations from a Gaussian distribution for the molecules in this system. The pressure and temperature dependence of the fluctuations and integrals, as well as the limiting behavior as one approaches both the triple point and the critical point, are also examined. (C) 2015 AIP Publishing LLC