SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: African trypanosomiasis

177

Human African trypanosomiasis (HAT), also known as sleeping sickness, persists as a public health problem in several sub-Saharan countries. Evidence-based, spatially explicit estimates of population at risk are needed to inform planning and implementation of field interventions, monitor disease trends, raise awareness and support advocacy. Comprehensive, geo-referenced epidemiological records from HAT-affected countries were combined with human population layers to map five categories of risk, ranging from “very high” to “very low,” and to estimate the corresponding at-risk population.

Concepts: Health, Epidemiology, Statistics, Mathematics, Demography, African trypanosomiasis, Tsetse fly, Sleeping sickness

172

Gender remains a recognized but relatively unexamined aspect of the potential challenges for treatment programmes for Neglected Tropical Diseases (NTDs). We sought to explore the role of gender in access to treatment in the Uganda National Neglected Tropical Disease Control Programme.

Concepts: Infectious disease, African trypanosomiasis

171

Sleeping sickness, also called human African trypanosomiasis, is transmitted by the tsetse, a blood-sucking fly confined to sub-Saharan Africa. The form of the disease in West and Central Africa is carried mainly by species of tsetse that inhabit riverine woodland and feed avidly on humans. In contrast, the vectors for the East and Southern African form of the disease are usually savannah species that feed mostly on wild and domestic animals and bite humans infrequently, mainly because the odours produced by humans can be repellent. Hence, it takes a long time to catch many savannah tsetse from people, which in turn means that studies of the nature of contact between savannah tsetse and humans, and the ways of minimizing it, have been largely neglected.

Concepts: Africa, Sub-Saharan Africa, Democratic Republic of the Congo, African trypanosomiasis, Southern Africa, Subregion, Tsetse fly, Sleeping sickness

170

BACKGROUND: Trypanosomosis, a protozoal disease affecting livestock, transmitted by Glossina (tsetse) flies is a major constraint to agricultural production in Sub-Saharan Africa. It is accepted that utilization of the native trypanotolerance exhibited in some of the African cattle breeds to improve trypanotolerance of more productive but susceptible breeds, will offer a cost effective and sustainable solution to the problem. The success of this approach is based on the premise that quantitative trait loci previously identified under relatively controlled situations confer useful trypanotolerance under natural field situations. As part of a study to authenticate this hypothesis, a population of 192 cattle, consisting of six batches of N'Dama and Kenya-Boran backcross animals [(N'Dama x Kenya-Boran) x Kenya-Boran] born over the period 2002 to 2006 was constructed. Some of the batches also included pure Kenya-Boran cattle, or N'Dama x Kenya- Boran F1 animals. Each batch was exposed as yearlings to natural field trypanosomosis challenge over a period of about one year; the entire challenge period extending from December 2003 to June 2007. Performance of the animals was evaluated by weekly or biweekly measurements of body weight, packed blood cell volume (PCV), parasitemia score, and number of trypanocide treatments. From these basic data, 49 phenotypes were constructed reflecting dynamics of body weight, packed cell volume (PCV) and parasitemia under challenge. RESULTS: Females were distinctly more trypanotolerant than males. F1, backcross and pure Kenya- Boran animals ranked in that order with respect to trypanotolerance. Overall batch effects were highly significant (p<0.001) for most traits, and were generally more significant than the gender or genetic type effects. The superior trypanotolerance of the F1 animals was expressed in all three components of animal defense strategies against pathogens: Avoidance resistance, and tolerance. CONCLUSIONS: The results show that trypanotolerance derived from the N'Dama is expressed under field conditions; and that the trait is primarily additive in nature, being expressed in heterozygous condition and in a three-quarters Boran genetic background. The results further, underscore the complexity of the trait in the field manifesting all three host disease-control strategies, and show the importance of gender and local environmental conditions in determining response to challenge.

Concepts: Genetics, Male, Effect, Quantitative trait locus, African trypanosomiasis, Tsetse fly, Mean corpuscular volume, Trypanosomiasis

170

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma C(max) values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible.

Concepts: Central nervous system, Nervous system, Pharmacology, Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Euglenozoa, Trypanosome

169

BACKGROUND: Specific land cover types and activities have been correlated with Trypanosoma brucei rhodesiense distributions, indicating the importance of landscape for epidemiological risk. However, methods proposed to identify specific areas with elevated epidemiological risk (i.e. where transmission is more likely to occur) tend to be costly and time consuming. This paper proposes an exploratory spatial analysis using geo-referenced human African trypanosomiasis (HAT) cases and matched controls from Serere hospital, Uganda (December 1998 to November 2002) to identify areas with an elevated epidemiological risk of HAT. METHODS: Buffers 3 km from each case and control were used to represent areas in which village inhabitants would carry out their daily activities. It was hypothesised that the selection of areas where several case village buffers overlapped would enable the identification of locations with increased risk of HAT transmission, as these areas were more likely to be frequented by HAT cases in several surrounding villages. The landscape within these overlap areas should more closely relate to the environment in which transmission occurs as opposed to using the full buffer areas. The analysis was carried out for each of four annual periods, for both cases and controls, using a series of threshold values (number of overlapping buffers), including a threshold of one, which represented the benchmark (e.g. use of the full buffer area as opposed to the overlap areas). RESULTS: A greater proportion of the overlap areas for cases consisted of seasonally flooding grassland and lake fringe swamp, than the control overlap areas, correlating well with the preferred habitat of the predominant tsetse species within the study area (Glossina fuscipes fuscipes). The use of overlap areas also resulted in a greater difference between case and control landscapes, when compared with the benchmark (using the full buffer area). CONCLUSIONS: These results indicate that the overlap analysis has enabled the selection of areas more likely to represent epidemiological risk zones than similar analyses using full buffer areas. The identification of potential epidemiological risk zones using this method requires fewer data than other proposed methods and further development may provide vital information for the targeting of control measures.

Concepts: Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Euglenozoa, Buffer, Tsetse fly, Sleeping sickness, Sterile insect technique

168

Human African Trypanosomiasis is a vector-borne disease of sub-Saharan Africa that causes significant morbidity and mortality. Current therapies have many drawbacks, and there is an urgent need for new, better medicines. Ideally such new treatments should be fast-acting cidal agents that cure the disease in as few doses as possible. Screening assays used for hit-discovery campaigns often do not distinguish cytocidal from cytostatic compounds and further detailed follow-up experiments are required. Such studies usually do not have the throughput required to test the large numbers of hits produced in a primary high-throughput screen. Here, we present a 384-well assay that is compatible with high-throughput screening and provides an initial indication of the cidal nature of a compound. The assay produces growth curves at ten compound concentrations by assessing trypanosome counts at 4, 24 and 48 hours after compound addition. A reduction in trypanosome counts over time is used as a marker for cidal activity. The lowest concentration at which cell killing is seen is a quantitative measure for the cidal activity of the compound. We show that the assay can identify compounds that have trypanostatic activity rather than cidal activity, and importantly, that results from primary high-throughput assays can overestimate the potency of compounds significantly. This is due to biphasic growth inhibition, which remains hidden at low starting cell densities and is revealed in our static-cidal assay. The assay presented here provides an important tool to follow-up hits from high-throughput screening campaigns and avoid progression of compounds that have poor prospects due to lack of cidal activity or overestimated potency.

Concepts: Pharmacology, Drug discovery, Chemical compound, Trypanosoma brucei, African trypanosomiasis, Euglenozoa, Trypanosome, High-throughput screening

162

African trypanosomes are unicellular flagellated parasites causing trypanosomiases in Africa, a group of severe diseases also known as sleeping sickness in human and nagana in cattle. These parasites are almost exclusively transmitted by the bite of the tsetse fly. In this review, we describe and compare the three developmental programs of the main trypanosome species impacting human and animal health, with focus on the most recent observations. From here, some reflections are made on research issues concerning trypanosome developmental biology in the tsetse fly that are to be addressed in the future.

Concepts: Human, Africa, Species, African trypanosomiasis, Tsetse fly, Sleeping sickness, Trypanosomiasis, Animal trypanosomiasis

161

The WHO has established the disability-adjusted life year (DALY) as a metric for measuring the burden of human disease and injury globally. However, most DALY estimates have been calculated as national totals. We mapped spatial variation in the burden of human African trypanosomiasis (HAT) in Uganda for the years 2000-2009. This represents the first geographically delimited estimation of HAT disease burden at the sub-country scale.

Concepts: Disease, African trypanosomiasis, Map, Quality-adjusted life year, Tsetse fly, Sleeping sickness, Disability-adjusted life year, Disease burden

161

The emphasis placed on the activities of mobile teams in the detection of gambiense human African trypanosomiasis (HAT) can at times obscure the major role played by fixed health facilities in HAT control and surveillance. The lack of consistent and detailed data on the coverage of passive case-finding and treatment further constrains our ability to appreciate the full contribution of the health system to the control of HAT.

Concepts: Parasitic diseases, Trypanosoma brucei, African trypanosomiasis, Major, Trypanosome, Tsetse fly, Sleeping sickness, ObsCure II