Density-dependent processes in the transmission of human onchocerciasis: relationship between the numbers of microfilariae ingested and successful larval development in the simuliid vector

A previous paper reported that the intake of Onchocerca volvulus microfilariae (mff) by different species of Simulium is essentially proportional to the parasite load in the skin of infected carriers. This paper examines the fate of the ingested mff in susceptible vectors to assess the relationship between parasite intake and infective larval output in blackfly species with and without well-developed cibarial armatures. Analysis is based on data from 3 onchocerciasis endemic areas: Guatemala (S. ochraceum s.l.), West Africa (S. damnosum s.l./S. sirbanum) and the Amazonian focus between South Venezuela and Northern Brazil (S. guianense and S. oyapockense s.l.). The data, which include published and unedited information collected in the field, record experimental studies of parasite uptake by wild flies maintained in captivity until the completion of the extrinsic incubation period. The relationship between L3 output (measured as the mean number of successful larvae/fly or, as the proportion of flies with infective larvae) and average microfilarial intake, was strongly non-linear. This non-linearity was best represented by a sigmoid function in case of armed simuliids (S. ochraceum s.l., S. oyapockense s.l.), or by a hyperbolic expression in that of unarmed flies (S. damnosum s.l., S. guianense). These results are compatible, respectively, with the patterns of ‘initial facilitation' and ‘limitation' described in culicid vectors of lymphatic filariases. A maximum mean number of 1-3 L3/fly was observed in all 4 vectors. It is concluded that O. volvulus larval development to the infective stage is regulated by density-dependent mechanisms acting at the early phase of microfilarial migration out of the blackfly's bloodmeal. Damage by the bucco-pharyngeal armature may also be density dependent. A hypothesis, based on this density dependence is forwarded to explain initial facilitation, so far only recorded in vectors with well-developed cibarial teeth. Our results provide quantitative support for the conjecture that chemotherapy alone is likely to have a greater impact on reducing onchocerciasis transmission in endemic areas where the main vector has a toothed fore-gut than in foci where the vectors have unarmed cibari

The geographic distribution of onchocerciasis in the 20 participating countries of the African Programme for Onchocerciasis Control:(2) pre-control endemicity levels and estimated number infected

BACKGROUND: The original aim of the African Programme for Onchocerciasis Control (APOC) was to control onchocerciasis as a public health problem in 20 African countries. In order to identify all high risk areas where ivermectin treatment was needed to achieve control, APOC used Rapid Epidemiological Mapping of Onchocerciasis (REMO). REMO involved spatial sampling of villages to be surveyed, and examination of 30 to 50 adults per village for palpable onchocercal nodules. REMO has now been virtually completed and we report the results in two articles. A companion article reports the delineation of high risk areas based on expert analysis. The present article reports the results of a geostatistical analysis of the REMO data to map endemicity levels and estimate the number infected. METHODS: A model-based geostatistical analysis of the REMO data was undertaken to generate high-resolution maps of the predicted prevalence of nodules and of the probability that the true nodule prevalence exceeds the high risk threshold of 20%. The number infected was estimated by converting nodule prevalence to microfilaria prevalence, and multiplying the predicted prevalence for each location with local data on population density. The geostatistical analysis included the nodule palpation data for 14,473 surveyed villages. RESULTS: The generated map of onchocerciasis endemicity levels, as reflected in the prevalence of nodules, is a significant advance with many new endemic areas identified. The prevalence of nodules was > 20% over an area of 2.5 million km2 with an estimated population of 62 million people. The results were consistent with the delineation of high risk areas of the expert analysis except for borderline areas where the prevalence fluctuated around 20%. It is estimated that 36 million people would have been infected in the APOC countries by 2011 if there had been no ivermectin treatment. CONCLUSIONS: The map of onchocerciasis endemicity levels has proven very valuable for onchocerciasis control in the APOC countries. Following the recent shift to onchocerciasis elimination, the map continues to play an important role in planning treatment, evaluating impact and predicting treatment end dates in relation to local endemicity levels

Feasibility of Onchocerciasis Elimination with Ivermectin Treatment in Endemic Foci in Africa: First Evidence from Studies in Mali and Senegal

The control of onchocerciasis, or river blindness, is based on annual or six-monthly ivermectin treatment of populations at risk. This has been effective in controlling the disease as a public health problem, but it is not known whether it can also eliminate infection and transmission to the extent that treatment can be safely stopped. Many doubt that this is feasible in Africa. A study was undertaken in three hyperendemic onchocerciasis foci in Mali and Senegal where treatment has been given for 15 to 17 years. The results showed that only few infections remained in the human population and that transmission levels were everywhere below postulated thresholds for elimination. Treatment was subsequently stopped in test areas in each focus, and follow-up evaluations did not detect any recrudescence of infection or transmission. Hence, the study has provided the first evidence that onchocerciasis elimination is feasible with ivermectin treatment in some endemic foci in Africa. Although further studies are needed to determine to what extent these findings can be extrapolated to other areas in Africa, the principle of onchocerciasis elimination with ivermectin treatment has been established

Macrofilaricides and onchocerciasis control, mathematical modelling of the prospects for elimination

BACKGROUND: In most endemic parts of the world, onchocerciasis (river blindness) control relies, or will soon rely, exclusively on mass treatment with the microfilaricide ivermectin. Worldwide eradication of the parasite by means of this drug is unlikely. Macrofilaricidal drugs are currently being developed for human use. METHODS: We used ONCHOSIM, a microsimulation mathematical model of the dynamics of onchocerciasis transmission, to explore the potentials of a hypothetical macrofilaricidal drug for the elimination of onchocerciasis under different epidemiological conditions, as characterized by previous intervention strategies, vectorial capacity and levels of coverage. RESULTS: With a high vector biting rate and poor coverage, a very effective macrofilaricide would appear to have a substantially higher potential for achieving elimination of the parasite than does ivermectin. CONCLUSIONS: Macrofilaricides have a substantially higher potential for achieving onchocerciasis elimination than ivermectin, but high coverage levels are still key. When these drugs become available, onchocerciasis elimination strategies should be reconsidered. In view of the impact of control efforts preceding the introduction of macrofilaricides on the success of elimination, it is important to sustain current control efforts

Defining Research to Improve Health Systems

Robert Terry and colleagues present working definitions of operational research, implementation research, and health systems research within the context of research to strengthen health systems

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

Wood biscuit measuring and sorting system

V diplomskem delu je predstavljena izdelava naprave za dimenzijsko kontrolo lesenih veznih lamel. Opisana je avtomatska mehanska linija naprave, ki zajema zalogovnik, dvigalo, rotacijski vibracijski dodajalnik, merilno mesto ter sistem za ločevanje dobrih in slabih lamel. Osrednji del diplomskega dela predstavlja razvoj programske opreme v okolju Microsoft Visual Studio 2013. Programska oprema zajema krmiljenje vhodno-izhodnih signalov preko vzporednih vrat ter 32-kanalnega digitalnega vhodno-izhodnega modula, sistem programskih prekinitev za obdelavo slik v realnem času, funkcije za sledenje kosov in algoritem za iskanje povezanih komponent, funkcije meritev ter grafični uporabniški vmesnik.The aim of this thesis is to present the development of a wood biscuit measuring and sorting system. A description of an automatic mechanical line consisting of a reservoir, an elevator, a vibrating rotary supplier, a measuring system and a sorting system that separates perfect wood biscuits from imperfect ones is included. The core part of the thesis is a presentation of software development in Microsoft Visual Studio 2013. The developed software includes controlling input/output signals via a parallel port and a 32-channel digital input/output module, a system of software interruptions for real time picture processing, functions that allow tracing of individual items, an algorithm for connected-component labelling, measuring functions and a graphic user interface

Homeostatic Scaling of Excitability in Recurrent Neural Networks

Neurons adjust their intrinsic excitability when experiencing a persistent change in synaptic drive. This process can prevent neural activity from moving into either a quiescent state or a saturated state in the face of ongoing plasticity, and is thought to promote stability of the network in which neurons reside. However, most neurons are embedded in recurrent networks, which require a delicate balance between excitation and inhibition to maintain network stability. This balance could be disrupted when neurons independently adjust their intrinsic excitability. Here, we study the functioning of activity-dependent homeostatic scaling of intrinsic excitability (HSE) in a recurrent neural network. Using both simulations of a recurrent network consisting of excitatory and inhibitory neurons that implement HSE, and a mean-field description of adapting excitatory and inhibitory populations, we show that the stability of such adapting networks critically depends on the relationship between the adaptation time scales of both neuron populations. In a stable adapting network, HSE can keep all neurons functioning within their dynamic range, while the network is undergoing several (patho)physiologically relevant types of plasticity, such as persistent changes in external drive, changes in connection strengths, or the loss of inhibitory cells from the network. However, HSE cannot prevent the unstable network dynamics that result when, due to such plasticity, recurrent excitation in the network becomes too strong compared to feedback inhibition. This suggests that keeping a neural network in a stable and functional state requires the coordination of distinct homeostatic mechanisms that operate not only by adjusting neural excitability, but also by controlling network connectivity

Onchocerciasis: The Pre-control Association between Prevalence of Palpable Nodules and Skin Microfilariae

*Background*: The prospect of eliminating onchocerciasis from Africa by mass treatment with ivermectin has been rejuvenated following recent successes in foci in Mali, Nigeria and Senegal. Elimination prospects depend strongly on local transmission conditions and therefore on pre-control infection levels. Pre-control infection levels in Africa have been mapped largely by means of nodule palpation of adult males, a relatively crude method for detecting infection. We investigated how informative pre-control nodule prevalence data are for estimating the pre-control prevalence of

Two Distinct Triatoma dimidiata (Latreille, 1811) Taxa Are Found in Sympatry in Guatemala and Mexico

Approximately 10 million people are infected with Trypanosoma cruzi, the causative agent of Chagas disease, which remains the most serious parasitic disease in the Americas. Most people are infected via triatomine vectors. Transmission has been largely halted in South America in areas with predominantly domestic vectors. However, one of the main Chagas vectors in Mesoamerica, Triatoma dimidiata, poses special challenges to control due to its diversity across its large geographic range (from Mexico into northern South America), and peridomestic and sylvatic populations that repopulate houses following pesticide treatment. Recent evidence suggests T. dimidiata may be a complex of species, perhaps including cryptic species; taxonomic ambiguity which confounds control. The nuclear sequence of the internal transcribed spacer 2 (ITS2) of the ribosomal DNA and the mitochondrial cytochrome b (mt cyt b) gene were used to analyze the taxonomy of T. dimidiata from southern Mexico throughout Central America. ITS2 sequence divides T. dimidiata into four taxa. The first three are found mostly localized to specific geographic regions with some overlap: (1) southern Mexico and Guatemala (Group 2); (2) Guatemala, Honduras, El Salvador, Nicaragua, and Costa Rica (Group 1A); (3) and Panama (Group 1B). We extend ITS2 Group 1A south into Costa Rica, Group 2 into southern Guatemala and show the first information on isolates in Belize, identifying Groups 2 and 3 in that country. The fourth group (Group 3), a potential cryptic species, is dispersed across parts of Mexico, Guatemala, and Belize. We show it exists in sympatry with other groups in Peten, Guatemala, and Yucatan, Mexico. Mitochondrial cyt b data supports this putative cryptic species in sympatry with others. However, unlike the clear distinction of the remaining groups by ITS2, the remaining groups are not separated by mt cyt b. This work contributes to an understanding of the taxonomy and population subdivision of T. dimidiata, essential for designing effective control strategies