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[
Med Trop (Mars),
2005]
Initial clinical trials in 1980 showed that ivermectin was remarkably effective against Onchocerca volvulus. Some 25 years after more than 50 million people are treated annually with Mectizan mainly within the framework of the African Programme for Onchocerciasis Control (APOC). This success has been possible thanks to Merck Mectizan Donation Program and to distribution through a novel strategy based on the strong involvement of endemic communities. In the last few years Mectizan has been used in combination with albendazole to control lymphatic filariasis on a large-scale basis in African countries. More recently ivermectin (under the tradename Stromectol) received market approval in France for treatment of gastrointestinal strongyloidiasis and scabies. Clinical trials are under way to evaluate the activity of ivermectin on nematodes (Loa loa, Mansonella sp., intestinal nematodes, cutaneous and visceral larva migrans) and ectoparasites (Pediculus humanus capitis, Phtirius pubis, Tunga penetrans, myiases). Trials are also ongoing to explain the mechanisms underlying the severe adverse events sometimes observed in patients presenting high Loa loa microfilaraemia and to develop preventive measures. Fundamental research will provide a better understanding of the mode of action of ivermectin at the molecular and cellular level, evaluate the risk of resistance of human parasites, and to determine the extent to which ivermectin could be used in association with other agents for the treatment of nonparasitic diseases.
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[
Med Trop (Mars),
1997]
Before the 1980s, the only available method for control of onchocerciasis was elimination of blackfly vector populations. This strategy was used with considerable success in the Onchocerciasis Control Programme in West Africa (OCP). The discovery of ivermectin, the first effective drug suitable for mass treatment of onchocerciasis, has revived international interest not only in fundamental research but also in development of new strategies to control onchocerciasis in the countries outside the OCP area. This report gives an overview of current parasitological, clinical, epidemiological and diagnostic data about onchocerciasis. Although little is known about the early development of Onchocerca volvulus in the human host, significant insight has been gained into the population dynamics of the parasite. The pathogenesis of cutaneous and ocular manifestations in onchocerciasis is now better understood. Epidemiological studies are under way to evaluate the extent of systemic manifestations. Recently developed diagnostic methods are more sensitive than conventional parasitological techniques. A new method for rapid assessment of endemic level has provided a detailed picture of the distribution of onchocerciasis. Species- and strain-specific DNA probes have been developed for identification of parasites in West Africa. New methods for quantifying disability allow evaluation of the socio-economic impact of the cutaneous and ocular complications of onchocerciasis.
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[
Med Trop (Mars),
1998]
Two methods are being used to control onchocerciasis. The first has a delayed effect and consists in reducing or interrupting transmission of Onchocerca volvulus by eradication of the vector at its most vulnerable developmental stage, i.e. the larval stage. The second method has more immediate effects and consists in mass treatment using ivermectin, the only widely available drug, to reduce the density of microfilariae (the pathogenic stage of the parasite) in the population. Both strategies have been implemented within the framework of two international programs: the Onchocerciasis Control Program (OCP) in West Africa, which started in 1974 and will continue until the end of 2002, and the African Program for Onchocerciasis Control (APOC), which was launched in 1995 and will last for 12 years. This article presents an overview of the efficacy of available control tools, as well as the objectives, strategies, organization, and results of the two ongoing control programs. Also dealt with are future perspectives of onchocerciasis control including monitoring techniques to maintain OCP gains, and research to develop new control tools and optimize the program efficacy.
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[
Ann Trop Med Parasitol,
2001]
The population structure of Onchocerca volvulus macrofilariae was studied in villages of central Cameroon where onchocerciasis is hyper-endemic. One nodule selected at random was removed from each of 576 adult males, and examined by histology. The numbers of male and female worms/nodule, and the status of the female worms (fecund, non-fecund, or dead) were recorded. The observations were analysed to evaluate whether the mean numbers of worms of each category varied in relation to the patient's age, the level of endemicity in his village, the anatomical localization of the nodule, the weight of the nodule, and the total number of palpable nodules harboured by the patient. The results obtained were very similar to those reported from West Africa. The mean numbers of dead female worms/nodule were relatively high in the villages with the lowest levels of endemicity. The mean numbers of fecund females and of live males were significantly higher in the nodules located around the knees. These results provide information which might be useful in modelling the population dynamics of O. volvulus, and also in the context of trials of any potentially macrofilaricidal drugs.
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Philos Trans R Soc Lond B Biol Sci,
1999]
Human onchocerciasis (river blindness) is the filarial infection caused by Onchocerca volvulus and transmitted among people through the bites of the Simulium vector. Some 86 million people around the world are at risk of acquiring the nematode, with 18 million people infected and 600,000 visually impaired, half of them partially or totally blind. 99% of cases occur in tropical Africa; scattered foci exist in Latin America. Until recently control programmes, in operation since 1975, have consisted of antivectorial measures. With the introduction of ivermectin in 1988, safe and effective chemotherapy is now available. With the original Onchocerciasis Control Programme of West Africa coming to an end, both the new African Programme for Onchocerciasis Control and the Onchocerciasis Elimination Programme for the Americas, rely heavily on ivermectin self-sustained mass delivery. In consequence, the need for understanding the processes regulating parasite abundance in human and simuliid populations is of utmost importance. We present a simple mathematical framework built around recent analyses of exposure- and density-dependent processes operating, respectively, within the human and vector hosts. An expression for the basic reproductive ratio, R0, is derived and related to the minimum vector density required for parasite persistence in localities of West Africa in general and northern Cameroon in particular. Model outputs suggest that constraints acting against parasite establishment in both humans and vectors are necessary to reproduce field observations, but those in humans may not fully protect against reinfection. Analyses of host age-profiles of infection prevalence, intensity, and aggregation for increasing levels of endemicity and intensity of transmission in the Vina valley of northern Cameroon are in agreement with these results and discussed in light of novel work on onchocerciasis immunology.
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[
Biochemistry,
2012]
Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.
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[
Sante
]
Onchocerciasis is an infection with the nematode Onchocerca volvulus. The main clinical symptoms are caused by the microfilariae. They include ocular lesions leading to blindness. Onchocerciasis is widely distributed in Africa from the Sahara to the southern tip, and is also found in some areas of South and Central America. Ivermectin was shown to be an effective treatment in the early 1980's, and is safe and better tolerated than diethylcarbamazine. We report the results of ivermectin treatment of onchocerciasis, and various features of the control obtained by large-scale ivermectin treatment programs. In large-scale programs, ivermectin (150 micrograms/kg) is administered once a year. This dose paralyses the microfilariae, such that they are carried away by the lymph to the lymph nodes where they are destroyed. This dose thereby reduces the load of microfilaria by 90%. The effects of a dose of ivermectin last about two or three years, and the lesions in the anterior segment of the eye can be cured or substantially reduced. Regular treatment prevents severe lesions of the posterior segment of the eye. The effects of repeated treatment on lesions of the retina are currently under investigation. Frequent doses of ivermectin prevent the development of embryo parasites in the females, and reduces the number of adults by attrition. Large-scale treatment programs reduce the transmission of the parasite by its vectors. There are several problems impeding large-scale treatment programs. Choosing patients for priority treatment requires expensive and sometimes aggressive methods of diagnosis. Thus new techniques for the identification of communities in which onchocerciasis is a serious public health problem are required. The choice of strategies for distribution, to optimize the cost, benefit ratio and feasibility, remain controversial. Wide distribution by mobile teams is effective, but expensive. Active distribution by trained community distributors is a cheaper potential alternative. Clinic-based or passive distribution requires the population to present to be able to obtain ivermectin. Thus, although cheap, this approach is generally poorly effective. A further complication is the clearly defined criteria on which these methods should be evaluated.
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[
J Infect Dis,
2015]
BACKGROUND: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. METHODS: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 M) in vitro. RESULTS: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 M for imatinib, 3.72 M for dasatinib, and 81.35 M for nilotinib; for L3 larvae, 11.27 M, 13.64 M, and 70.98 M, respectively; for adult males, 41.6 M, 3.87 M, and 68.22 M, respectively; and for adult females, 42.89 M, 9.8 M, and >100 M, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. CONCLUSIONS: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.
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[
Worm Breeder's Gazette,
1976]
We have studied maternal effects in 23 zyg ts mutants to estimate the times of expression of genes whose products are required in embryogenesis. We have used the following three tests, called arbitrarily A, B, and C. A test: Heterozygous (m/+) L4's are shifted to 25 C and allowed to self-fertilize. If 100% of their eggs yield larvae (25% of which express the mutant phenotype as adults), then the mutant is scored as maternal (M). If 25% of the F1 eggs fail to hatch, then the mutant is scored as non-maternal (N). An M result indicates that expression of the + allele in the parent allows m/m zygotes to hatch and grow to adulthood. A result of N indicates the opposite: that the + allele must be expressed in the zygote for hatching to occur. Out of 23 zyg mutants tested, 3 were scored N and 20 were scored M in the A test. Therefore, for most of the genes defined by these mutants, expression in the parent is sufficient for zygote survival, even if the gene is not expressed in the zygote. B test: Homozygous (m/m) hermaphrodites reared at 25 C are mated with N2 (+/+) males. If eggs fail to hatch at 25 C, but mated hermaphrodites shifted to 16 C produce cross progeny to give proof of mating, then the mutant is scored M. If cross progeny appear in the 25 C mating, then the mutant is scored N. An M result indicates that expression of the + allele in the zygote is not sufficient to allow m/+ progeny of an m/m hermaphrodite to survive. Conversely an N result indicates either that zygotic expression of the + allele is sufficient for survival, or that a sperm function or factor needed for early embryogenesis can be supplied paternally (see C test below). Out of the 23 zyg mutants tested, 11 were scored M and 12 were scored N. The combined results of A and B tests and their simplest interpretation are as follows. Ten mutants are M,M; the genes defined by these mutants must be expressed in the hermaphrodite parent for the zygote to survive. Ten mutants are M,N; these genes can be expressed either in the parent or in the zygote. Two mutants are N,N; these genes must be expressed in the zygote. One mutant is N,M; this gene must be expressed both in the maternal parent and in the zygote. C test: Homozygous (m/m) hermaphrodites reared at 25 C are mated with heterozygous (m/+) males. If rescue by a +/+ male in the B test depends on the + allele, then only half the cross progeny zygotes of a C test mating (m/+ male x m/m hermaphrodite) should survive. However, if rescue depends on a function or cytoplasmic component from the male sperm, then all the cross progeny zygotes in a C test should survive. Of the 10 M,N mutants, 6 have been C tested; one exhibited paternal rescue independent of the + allele. The A and B tests also were carried out on 16 mutants that arrest before the L3 molt (acc mutants). In the A test on 2 of these mutants, all m/m progeny of m/+ parents grew to adulthood at 25 C. Therefore, parental contributions are sufficient to overcome a progeny mutational block as late as the L2 stage. All 16 acc mutants scored N in the B test.
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[
Worm Breeder's Gazette,
1994]
cej-1 Encodes a Novel Protein with Poly-Threonine Motif M. L. A. Khanl, M. Tabish, T. Fukushigel1 S. Tsukita2, M. Itoh , Sh. Tsukita , and S. S. Siddiqui. (1): Lab. of Molecular Biology, Dept of Ecological Engg. Toyohashi Univ. Technology, Toyohashi 441, and (2). National Institute for Physiological Sciences, Okazaki 444, Japan.