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trypanozoon: infectivity to humans is linked to reduced transmissibility in tsetse. i. comparison of human serum-resistant and human serum-sensitive field isolates.the transmissibility of recent isolates of human serum-sensitive (hss) and human serum-resistant (hsr) trypanozoon was compared by transmission of 37 stocks through an inbred line of glossina m. morsitans. as in previous studies maturation was found to be dependent on fly sex with males producing significantly greater proportions of salivary gland infections than females. hss stocks were, however, 1.8 times more likely to mature to mammalian infective form than hsr stocks in male tsetse and 2.7 ...19957498437
the effects of different eland and waterbuck sera on trypanosoma brucei rhodesiense clones from lion and from man. 19826764401
will the real trypanosoma brucei rhodesiense please step forward?the sleeping sickness trypanosomes trypanosoma brucei rhodesiense and t. brucei gambiense are morphologically indistinguishable from each other and from t. brucei brucei, which does not infect humans. the relationships between these three subspecies have been controversial. several years ago, the characterization of t. brucei gambiense was reviewed in an attempt to clarify and draw together the results, and to put them in the context of the biology of the organism. the discovery of a gene associ ...200212473364
a gene expressed only in serum-resistant variants of trypanosoma brucei rhodesiense.the human infective african trypanosomes are host range variants of trypanosoma brucei which are resistant to a lytic component in primate serum. t. b. rhodesiense occurs both as a form sensitive to lysis by normal human serum and as a form resistant to this lysis. switching from one phenotype to the other has been observed in both directions. in the cloned t. b. rhodesiense etar1-repertoire we have detected 1.5-kb mrnas only present in the resistant forms. in t. b. gambiense, which always occur ...19892528066
further studies on difluoromethylornithine in african trypanosomes.dl-alpha-difluoromethylornithine (dfmo), a specific enzyme-activated irreversible inhibitor of ornithine decarboxylase (odc) was previously shown to cure mice infected with trypanosoma brucei brucei, a parasite of game and cattle in africa and trypanosoma brucei rhodesiense, a human african sleeping sickness pathogen. our studies now indicate that dfmo blocks ornithine decarboxylase and lowers trypanosome polyamine levels in vivo. polyamine uptake in t.b. brucei also resembles that previously de ...19816175860
isolation and characterization of a new serodeme of trypanosoma rhodesiense.the isolation and characterization of a new serodeme of trypanosoma brucei rhodesiense is described. a clone of organisms derived from a human infection produced chronic infections in mice. additional clones of differing antigenic specificities were isolated from peaks of parasitemia which occurred in these mice. the variable antigen types (vats) of these clones were determined by agglutination, immunofluorescence, and protection of actively immunized mice. thirteen distinct vats were isolated a ...197992203
tsetse movement in wind fields: possible epidemiological and entomological implications for trypanosomiasis and its control.this paper presents evidence that tsetse flies (glossina) can be dispersed by wind. this dispersal in west africa is suggested to be along a south-west north-east axis. the implications of wind dispersal of glossina for chemical and genetic control operations is discussed. field experiments necessary to test this hypothesis are recommended. a study of human trypanosomiasis foci in west africa has revealed that foci are orientated in roughly parallel lines in a south-west north-east direction. th ...197935935
trypanosoma brucei rhodesiense infection in vervet monkeys. i. parasitologic, hematologic, immunologic and histologic results.twenty vervet monkeys infected with t. rhodesiense (eatro 1989) developed chronic disease with an average duration of 65 days (variation 35-107 days). with respect to the course of the disease, and to the hematologic, immunologic and histological findings, the disease faithfully mirrored human t. rhodesiense infection. in all animals, parasitization of the csf occurred only a few weeks after infection, and was accompanied by an increase in the cell count and the appearance of igm in the csf. the ...19827164166
multicentre evaluation of an antigen-detection elisa for the diagnosis of trypanosoma brucei rhodesiense sleeping sickness.the performance of an enzyme-linked immunosorbent assay (antigen elisa) for the detection, in serum or cerebrospinal fluid, of an invariant trypanosome antigen to diagnose trypanosoma brucei rhodesiense sleeping sickness was evaluated in four clinical treatment centres. the test, which was carried out in polystyrene test-tubes, was positive in 88 (88.9%) of 99 parasitologically confirmed cases that were tested at the national institute for medical research, tabora, united republic of tanzania; 9 ...19921568281
diagnosis of human african trypanosomiasis. 19921417169
veterinary link to drug resistance in human african trypanosomiasis? 200111530144
the epidemiology and control of human african trypanosomiasis.human african trypanosomiasis is caused by trypanosoma brucei gambiense in west and central africa, and by trypanosoma brucei rhodesiense in east and southern africa. in recent years there has been a dramatic resurgence of gambian trypanosomiasis in central africa, especially in the democratic republic of congo, angola and sudan. the disease is quiescent in most of west africa, as is rhodesian trypanosomiasis the other side of the continent. the epidemiology of gambian trypanosomiasis is reviewe ...200111461032
inhibition of succinyl coa synthetase histidine-phosphorylation in trypanosoma brucei by an inhibitor of bacterial two-component systems.recent drug screenings for new antibacterial drugs directed against histidine phospho-relay signalling pathways in bacteria have resulted in compounds which potently inhibit the histidine kinase activity of bacterial two-component systems. the present study demonstrates that one of these compounds, ly266500, is also a potent inhibitor of histidine phosphorylation in the unicellular eukaryotic parasite trypanosoma brucei, both in vitro and in whole cells. in vitro, it inhibits histidine phosphory ...199910376993
evidence for multiple origins of human infectivity in trypanosoma brucei revealed by minisatellite variant repeat mapping.in recent years a wide variety of biochemical and molecular typing systems has been employed in the study of parasite diversity aimed at investigating the level of genetic diversity and delineating the relationship between different species and subspecies. however, such methods have failed to differentiate between two of the classically defined subspecies of the protozoan parasite trypanosoma brucei: the human infective, t. b. rhodesiense, which causes african sleeping sickness, and the non-huma ...200111428466
expression and localization of serum resistance associated protein in trypanosoma brucei rhodesiense.the trypanosome lytic factor (tlf) is a primate specific innate defense mechanism that restricts the host range of african trypanosomes. trypanosoma brucei rhodesiense, the causative agent of the acute form of human sleeping sickness, is resistant to the cytolytic action of tlf. by differential display pcr we have identified a gene in t. b. rhodesiense that is preferentially expressed in cell lines resistant to tlf. the protein sequence predicted from the gene shows homology to the trypanosome v ...199910593181
plasma nitrate and interferon-gamma in trypanosoma brucei rhodesiense infections: evidence that nitric oxide production is induced during both early blood-stage and late meningoencephalitic-stage infections. 199910450441
evaluation of african medicinal plants for their in vitro trypanocidal activity.petroleum ether, dichloromethane, methanol and water extracts from 24 plants, belonging to 19 families, which are reported in the literature as traditional remedies for sleeping sickness (human african trypanosomiasis) were screened for in vitro activity against trypanosoma brucei rhodesiense, as well as fro cytotoxicity for a human fibroblast cell-line (wi-38). the trypanocidal activity of the natural compounds berberine and harmane, both documented as being trypanocidal, was also evaluated. pr ...19969121161
application of multicomponent reactions to antimalarial drug discovery. part 2: new antiplasmodial and antitrypanosomal 4-aminoquinoline gamma- and delta-lactams via a 'catch and release' protocol.a parallel synthesis of a new series of 4-aminoquinoline gamma- and delta-lactams synthesized via the ugi 3-component 4-centre multicomponent reaction is described. the basicity of the quinoline nitrogen was exploited in the purification of compounds via a 'catch and release' protocol. yields ranging from 60% to 77% and purities as high as 96% were obtained. compound 29, the most active against a chloroquine-resistant w2 strain of plasmodium falciparum with an ic(50) of 0.096 microm, also inhibi ...200616690319
in vitro antitrypanosomal activity of african plants used in traditional medicine in uganda to treat sleeping sickness.in uganda, as in many other african countries, herbal treatment of various diseases is still common. in the present study, 9 plant species collected from tanzania and uganda and used by traditional healers in southern-eastern uganda for the treatment of human african trypanosomiasis (sleeping sickness) were extracted and screened for their in vitro activity against trypanosoma brucei rhodesiense, one of the two causative agents of sleeping sickness. eight lipophilic extracts of 5 plants revealed ...19968980587
the alamar blue assay to determine drug sensitivity of african trypanosomes (t.b. rhodesiense and t.b. gambiense) in vitro.alamar blue, an indicator for metabolic cell function, was evaluated as a fluorescent and as a colorimetric dye in drug sensitivity assays for human pathogenic african trypanosomes, trypanosoma brucei rhodesiense and t.b. gambiense. the experimental conditions were adjusted to find those where the relationship between trypanosome number and alamar blue signal was linear over the widest possible range. fluorescent signals correlated to trypanosome numbers from 10(4) trypanosomes/ml (t.b. rhodesie ...19979386789
mechanism of lysis of trypanosoma brucei gambiense by human serum.resistance to lysis by human serum (hs) is an important parameter used to distinguish trypanosoma brucei brucei from both trypanosoma brucei rhodesiense and trypanosoma brucei gambiense. neither the exact nature of the trypanolytic factor (tlf) nor the mechanism of action by which hs lyses susceptible trypanosomes is well understood. this report tries to elucidate the role played by the variable surface glycoprotein (vsg) coat and trypanosome surface-related processes in the mechanism of hs lysi ...19947799165
the serum resistance-associated (sra) gene of trypanosoma brucei rhodesiense encodes a variant surface glycoprotein-like protein.in the trypanosoma brucei species, t. b. rhodesiense and t. b. gambiense represent the human infective host range variants, while t. b. brucei is lysed upon exposure to a cytotoxic factor in normal human serum. t. b. rhodesiense can occur in a serum-resistant and a serum-sensitive form. the resistance towards normal human serum was shown to be a labile character and to be determined by the environment in which the parasites live. we have clearly demonstrated the presence of rna transcripts uniqu ...19947739673
in vitro trypanocidal activity of some rare tanzanian medicinal plants.extracts prepared from 15 rare tanzanian medicinal plants were tested for their in vitro antitrypanosomal activity against human pathogenic trypanosomes (trypanosoma brucei rhodesiense). of 37 extracts investigated, two were found to have strong activity with ic50 values below 1 microgram/ml and ten extracts revealed promising activities with ic50 values between 1 and 5 micrograms/ml.19979241382
[distribution and spread of human african trypanosomiasis: value of genetic identification of the trypanosomes].numerous factors extrinsic to trypanosome populations have been implicated in the distribution and spread of human african trypanosomiasis (hat), but quantification of these factors has proven difficult. an easier method of monitoring hat consists of tracking parasites by genetic identification of trypanosomes in hosts and vectors. this method requires distinction between trypanosoma brucei rhodesiense and trypanosoma brucei gambiense followed by determination of the genotype of each subspecies ...200111803837
lessons learned from the emergence of a new trypanosoma brucei rhodesiense sleeping sickness focus in uganda.during the latter months of 1998, cases of sleeping sickness caused by trypanosoma brucei rhodesiense presented in soroti district, eastern uganda, a region which had not previously experienced cases of the disease. cattle are the main reservoir for t b rhodesiense, by contrast with sleeping sickness caused by trypanosoma brucei gambiense in west africa where there appears to be no epidemiologically significant animal reservoir. several factors have been identified that interacted to produce ide ...200312505033
a vsg expression site-associated gene confers resistance to human serum in trypanosoma rhodesiense.infectivity of trypanosoma brucei rhodesiense to humans is due to its resistance to a lytic factor present in human serum. in the etat 1 strain this character was associated with antigenic variation, since expression of the etat 1.10 variant surface glycoprotein was required to generate resistant (r) clones. in addition, in this strain transcription of a gene termed sra was detected in r clones only. we show that the etat 1.10 expression site is the one selectively transcribed in r variants. thi ...19989865701
2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase.this paper describes the synthesis of 4'-substituted and 3',4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. compounds were then assayed against the recombinant parasite and human enzymes. some of the compounds showed good activity. they were also tested against the intact parasites using in vitro assays. good activity was found against trypanosoma cruzi, moderate activity against trypanosoma brucei and leishmania d ...200314556785
anthranoid compounds with antiprotozoal activity from vismia orientalis.a phytochemical investigation of the 80% ethanolic extract of stem bark of vismia orientalis engl. (guttiferae or clusiaceae), a plant used in traditional medicine in tanzania, resulted in the isolation and spectroscopic characterisation of 3-geranyloxy-6-methyl-1,8-dihydroxyanthraquinone, emodin, vismione d and bianthrone a1. vismione d exhibited a broad range of antiprotozoal activities against trypanosoma brucei rhodesiense and t. cruzi (ic50 < 10 micrograms/ml), leishmania donovani (ic50 0.3 ...200415368649
activity of human trypanosome lytic factor in mice.the inability of the cattle pathogen trypanosoma brucei brucei to infect humans is due to an innate factor in human serum termed trypanosome lytic factor (tlf). human haptoglobin-related protein is the proposed toxin in tlf and can exist either as a component of a minor subclass of high-density lipoprotein (tlf-1) or as a lipid free, high molecular weight protein complex (tlf-2). the trypanolytic activity of both tlf-1 and tlf-2 has been studied in vitro but their relative contributions to prote ...200111606222
in vivo trypanocidal activities of new s-adenosylmethionine decarboxylase inhibitors.a series of novel aromatic derivatives based on the structure of methylglyoxal bis(guanylhydrazone) (mgbg) was examined for trypanocidal activities in human and veterinary trypanosomes of african origin. one agent, cgp 40215a, a bicyclic analog of mgbg which also resembles the diamidines diminazene (berenil) and pentamidine, was curative of infections by 19 isolates of trypanosoma brucei subspecies as well as a trypanosoma congolense isolate. several of these isolates were resistant to standard ...19968726018
deoxyuridine triphosphate nucleotidohydrolase as a potential antiparasitic drug target.this paper describes a structure-activity study to identify novel, small-molecule inhibitors of the enzyme deoxyuridine 5'-triphosphate nucleotidohydrolase (dutpase) from parasitic protozoa. the successful synthesis of a variety of analogues of dump is described in which the substituents are introduced at the 3'- and 5'-positions, together with variation in the heteroatom at the 5'-position. the compounds were assayed against recombinant plasmodium falciparum and leishmania major enzymes and the ...200516161998
treatment and control of human african trypanosomiasis.access to treatment is a multi-step process and little progress has been made to improve treatments for sleeping sickness over the past 50 years. the current strategy is based on diagnostic tools developed in the 1960s while available drugs are still the same as those developed in the middle of the last century. strategic opportunities can only be based on two achievements: improved diagnosis and safer drugs. this paper reviews the development of new diagnostic tools and drugs and the opportunit ...200415640711
crisis, what crisis? control of rhodesian sleeping sickness.there is an urgent need for cost-effective strategies for the sustainable control of trypanosoma brucei rhodesiense (rhodesian) sleeping sickness, which is a fatal zoonotic disease that has caused devastating epidemics during the past century. sleeping sickness continues to be controlled by crisis management, using active case detection, treatment and vector control - activities that occur only during major epidemics; during the intervening periods, farmers and communities must fend for themselv ...200616458071
eflornithine for the treatment of human african trypanosomiasis.eflornithine is the only new molecule registered for the treatment of human african trypanosomiasis over the last 50 years. it is the drug used mainly as a back-up for melarsoprol refractory trypanosoma brucei gambiense cases. the most commonly used dosage regimen for the treatment of t. b. gambiensesleeping sickness consists of 100 mg kg(-1) body weight at intervals of 6 h for 14 days (150 mg kg(-1) body weight in children) of eflornithine given as short infusions. its efficacy against trypanos ...200312811548
human african trypanosomiasis: in and out of africa. 200616606904
lethal african trypanosomiasis in a traveler: mri and neuropathology.the authors report a case of human african trypanosomiasis with cns involvement caused by trypanosoma brucei rhodesiense in a 52-year-old woman, which relapsed after melarsoprol treatment. after a second regimen, she developed a severe toxic polyneuropathy, progressing to coma and eventually death. mri revealed rapidly progressive multiple white matter lesions as well as damage of the central gray matter and cortex. the autopsy results confirmed the diagnosis of human african trypanosomiasis.200616606924
african trypanosome interactions with an in vitro model of the human blood-brain barrier.the neurological manifestations of sleeping sickness in man are attributed to the penetration of the blood-brain barrier (bbb) and invasion of the central nervous system by trypanosoma brucei gambiense and trypanosoma brucei rhodesiense. however, how african trypanosomes cross the bbb remains an unresolved issue. we have examined the traversal of african trypanosomes across the human bbb using an in vitro bbb model system constructed of human brain microvascular endothelial cells (bmecs) grown o ...200415562595
experimental therapy of african trypanosomiasis with a nanobody-conjugated human trypanolytic factor.high systemic drug toxicity and increasing prevalence of drug resistance hampers efficient treatment of human african trypanosomiasis (hat). hence, development of new highly specific trypanocidal drugs is necessary. normal human serum (nhs) contains apolipoprotein l-i (apol-i), which lyses african trypanosomes except resistant forms such as trypanosoma brucei rhodesiense. t. b. rhodesiense expresses the apol-i-neutralizing serum resistance-associated (sra) protein, endowing this parasite with th ...200616604085
trypanocidal activity of methylene blue. evidence for in vitro efficacy and in vivo failure.human african trypanosomiasis remains a difficult health problem to treat because of the few compounds available nowadays and their toxicity. the disease also affects animals and is therefore responsible for economic difficulties and zoonotic risks. there is an urgent need to develop new drugs for treatment of african trypanosomiasis. methylene blue is a safe and easy-to-use drug employed in human therapy. it is also known to have antimalarial activity. in this study, methylene blue trypanocidal ...200616340192
discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening.a high-throughput screening campaign of a library of 100,000 lead-like compounds identified 2-iminobenzimidazoles as a novel class of trypanothione reductase inhibitors. these 2-iminobenzimidazoles display potent trypanocidal activity against trypanosoma brucei rhodesiense, do not inhibit closely related human glutathione reductase and have low cytotoxicity against mammalian cells.200717194585
african trypanosomiasis in a british soldier.human african trypanosomiasis (sleeping sickness) is a parasitic infection transmitted by day-biting tsetse flies. the diagnostic gold standard is microscopy of blood, lymph node aspirates or csf. the disease is invariably fatal, if not treated. there are over 300 000 new cases of sleeping sickness each year, and approximately 100,000 deaths.200617295013
the trypanolytic factor of human serum.african trypanosomes (the prototype of which is trypanosoma brucei brucei) are protozoan parasites that infect a wide range of mammals. human blood, unlike the blood of other mammals, has efficient trypanolytic activity, and this needs to be counteracted by these parasites. resistance to this activity has arisen in two subspecies of trypanosoma brucei - trypanosoma brucei rhodesiense and trypanosoma brucei gambiense - allowing these parasites to infect humans, and this results in sleeping sickne ...200616710327
chemotherapeutic strategies against trypanosoma brucei: drug targets vs. drug targeting.trypanosoma brucei rhodesiense and t. b. gambiense are the causative agents of sleeping sickness, a fatal disease that affects 36 countries in sub-saharan africa. nevertheless, only a handful of clinically useful drugs are available. these drugs suffer from severe side-effects. the situation is further aggravated by the alarming incidence of treatment failures in several sleeping sickness foci, apparently indicating the occurrence of drug-resistant trypanosomes. because of these reasons, and sin ...200717346174
delayed recovery of adrenocortical and testicular function after chemotherapy of human trypanosomiasis.the following indicators of pituitary, adreno-cortical and testicular function were measured in 58 male african trypanosomiasis patients from western kenya; plasma cortisol, luteinizing hormone (lh) and testosterone levels. the measurements were carried out by specific radioimmunoassay methods in early and late stage infected patients on admission to hospital and in both groups of patients after one month of chemotherapy. packed cell volume (pcv) and hemoglobin levels were also measured in all t ...19947942356
diphenyl furans and aza analogs: effects of structural modification on in vitro activity, dna binding, and accumulation and distribution in trypanosomes.human african trypanosomiasis is a devastating disease with only a few treatment options, including pentamidine. diamidine compounds such as pentamidine, db75, and db820 are potent antitrypanosomal compounds. previous investigations have shown that diamidines accumulate to high concentrations in trypanosomes. however, the mechanism of action of this class of compounds remains unknown. a long-hypothesized mechanism of action has been binding to dna and interference with dna-associated enzymes. th ...200717517831
the persistence of genetic homogeneity among trypanosoma brucei rhodesiense isolates from patients in north-west tanzania.trypanosomes isolated during 1991 from nine patients with rhodesian sleeping sickness in north-west tanzania were genetically characterized by electrophoresis of ten enzymes. eight isolates were allocated to a known zymodeme (z306); another had an enzyme profile (z379) not previously encountered. an example of z306 has been previously isolated in 1971, nearby in a part of rwanda adjacent to the border with tanzania; in addition, a closely related isolate, in z307, was collected in 1959 from a pa ...19948023757
synthesis and evaluation of novel 7-trifluoromethyl-4-(4-substituted anilino)quinolines as antiparasitic and antineoplastic agents.several novel derivatives bearing the 7-trifluoromethyl-4-(4-substituted anilino)-quinoline skeleton were synthesized and evaluated for their in vitro activity against the blood streaming form of the parasites trypanosoma brucei rhodesiense, the trypomastigotes of trypanosoma cruzi cultured in rat skeletal myoblasts, the amastigotes form of leishmania donovani, plasmodium falciparum (k1 strain) infected erythrocyte suspension, as well as their toxicity towards rat skeletal l-6 cells. in addition ...200314558440
resolution of the species problem in african trypanosomes.there is a general assumption that eukaryote species are demarcated by morphological or genetic discontinuities. this stems from the idea that species are defined by the ability of individuals to mate and produce viable progeny. at the microscopic level, where organisms often proliferate more by asexual than sexual reproduction, this tidy classification system breaks down and species definition becomes messy and problematic. the dearth of morphological characters to distinguish microbial species ...200717451719
antitrypanosomal activity of a new triazine derivative, sipi 1029, in vitro and in model infections.a recently developed diaminotriazine derivative [o,o'-bis(1, 2-dihydro-2,2-tetramethylene-4,6-diamino-s-triazin-1-yl)-1, 6-hexanediol dihydrochloride; t-46; sipi 1029] was examined for activity against african trypanosomes in in vitro and in vivo model systems. in vitro, sipi 1029 was 50% inhibitory for growth of bloodstream trypomastigotes of four strains of trypanosoma brucei brucei and trypanosoma brucei rhodesiense at 0.15 to 2.15 nm (50% inhibitory concentrations). in in vivo mouse laborato ...19989756783
[the controversial story of the human trypanolytic factor]. 200818950568
sleeping sickness--a re-emerging disease in the serengeti?sleeping sickness is a re-emerging disease in the serengeti ecosystem affecting both local people and tourists. here we report the results of a survey to assess the prevalence of trypanosomiasis in both domestic and wild animals from this area. five hundred and eighteen cattle samples were collected from 12 villages that bordered the serengeti national park and 220 samples from 15 different wild animal species were collected from within the park. pcr analysis, directed against the human serum re ...200717298919
development of drug resistance in trypanosoma brucei rhodesiense and trypanosoma brucei gambiense. treatment of human african trypanosomiasis with natural products (review).human african trypanosomiasis is an infectious disease which has resulted in the deaths of thousands of people in sub-saharan africa. two subspecies of the protozoan parasite trypanosoma brucei are the causative agents of the infection, whereby t. b. gambiense leads to chronic development of the disease and t. b. rhodesiense establishes an acute form, which is fatal within months or even weeks. current chemotherapy treatment is complex, since special drugs have to be used for the different devel ...200818813846
the trypanosome lytic factor of human serum and the molecular basis of sleeping sickness.trypanosoma brucei brucei infects a wide range of mammals but is unable to infect humans because this subspecies is lysed by normal human serum (nhs). the trypanosome lytic factor is associated with high density lipoproteins (hdls). several hdl-associated components have been proposed as candidate lytic factors, and contradictory hypotheses concerning the mechanism of lysis have been suggested. elucidation of the process by which trypanosoma brucei rhodesiense resists lysis and causes human slee ...200415217727
adenosine kinase of t. b. rhodesiense identified as the putative target of 4-[5-(4-phenoxyphenyl)-2h-pyrazol-3-yl]morpholine using chemical proteomics.human african trypanosomiasis (hat), a major parasitic disease spread in africa, urgently needs novel targets and new efficacious chemotherapeutic agents. recently, we discovered that 4-[5-(4-phenoxyphenyl)-2h-pyrazol-3-yl]morpholine (compound 1) exhibits specific antitrypanosomal activity with an ic(50) of 1.0 microm on trypanosoma brucei rhodesiense (t. b. rhodesiense), the causative agent of the acute form of hat.200919707572
temporal and spatial epidemiology of sleeping sickness and use of geographical information system (gis) in kenya.in kenya, sleeping sickness (ss) caused by trypanosoma brucei rhodesiense is confined to the nyanza and western provinces tsetse belts. over the last two decades, the disease has exhibited great spatial variability in its spread and distribution. the objectives of the study were to map the spatial and temporal distribution of ss and determine possible risk factors associated with the disease in western kenya.200919326704
overcoming resistance with designer immunotoxins.normal human serum contains apolipoprotein l-i (apol-i), which lyses african trypanaosomes. resistant forms, such as trypanosoma brucei rhodesiense express apol-i-neutralising serum resistance-associated protein, which enables this parasite to infect humans and cause human african trypanosomiasis. this paper describes the construction of a mutant apol-i conjugated to a nanobody that targets the variant surface glycoprotein of trypanosomes. treatment with this engineered immunotoxin has resulted ...200616805725
the burden of human african trypanosomiasis.human african trypanosomiasis (hat, or sleeping sickness) is a protozoan parasitic infection caused by trypanosoma brucei rhodesiense or trypanosoma brucei gambiense. these are neglected tropical diseases, and t.b. rhodesiense hat is a zoonosis. we review current knowledge on the burden of hat in sub-saharan africa, with an emphasis on the disability-adjusted life year (daly), data sources, and methodological issues relating to the use of this metric for assessing the burden of this disease. we ...200819104653
distinct and overlapping roles for two dicer-like proteins in the rna interference pathways of the ancient eukaryote trypanosoma brucei.trypanosoma brucei is one of the most ancient eukaryotes where rna interference (rnai) is operational and is the only single-cell pathogen where rnai has been extensively studied and used as a tool for functional analyses. here, we report that the t. brucei rnai pathway, although relying on a single argonaute protein (ago1), is initiated by the activities of two distinct dicer-like enzymes. both tbdcl1, a mostly cytoplasmic protein, and the previously undescribed nuclear enzyme tbdcl2 contribute ...200919815526
comparative detection of trypanosomal dna by loop-mediated isothermal amplification and pcr from flinders technology associates cards spotted with patient blood.we analyzed dna eluted from fta (flinders technology associates) cards spotted with blood from human african trypanosomiasis (hat) patients admitted at lwala hospital in eastern uganda and kaliua health centre in northwestern tanzania. the aims were to evaluate loop-mediated isothermal amplification (lamp) for detection of trypanosomal dna in clinical samples and to characterize the infecting trypanosomes to the subspecies level. lamp targeting the trypanozoon conserved random inserted mobile el ...201020410347
the epidemiology of trypanosomiasis in rumphi district, malawi: a ten year retrospective study.human african trypanosomiasis (hat) is caused by two species of the tsetse fly vectored protozoan hemoflagellates belonging to trypanosma brucei, namely t.b gambiense which predominates in western africa and follows a chronic disease course and t.b rhodensiense which is more prevalent in southern and eastern africa, malawi included, and follows a more acute and aggressive disease course. previous studies in the democratic republic of congo, angola, uganda and sudan have demonstrated that the pre ...200919780474
synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds.trypanothione reductase (tr) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. herein we show that the combination of two structural motifs of known tr inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. the binding efficacy of these conjugates is enhanced over that of th ...200919847846
trypanosomiasis and the brain.neurological involvement following trypanosome infection has been recognised for over a century. however, there are still many unanswered questions concerning the mechanisms used by the parasite to gain entry to the cns and the pathogenesis of the resulting neuroinflammatory reaction. there is a paucity of material from human cases of the disease therefore the majority of current research relies on the use of animal models of trypanosome infection. this review reports contemporary knowledge, fro ...201020028610
mechanism of trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor.human innate immunity against most african trypanosomes, including trypanosoma brucei brucei, is mediated by a minor subclass of toxic serum hdl, called trypanosome lytic factor-1 (tlf-1). this hdl contains two primate specific proteins, apolipoprotein l-1 and haptoglobin (hp)-related protein, as well as apolipoprotein a-1. these assembled proteins provide a powerful defense against trypanosome infection. trypanosoma brucei rhodesiense causes human african sleeping sickness because it has evolve ...201020805508
phase ii evaluation of sensitivity and specificity of pcr and nasba followed by oligochromatography for diagnosis of human african trypanosomiasis in clinical samples from d.r. congo and uganda.the polymerase chain reaction (pcr) and nucleic acid sequence-based amplification (nasba) have been recently modified by coupling to oligochromatography (oc) for easy and fast visualisation of products. in this study we evaluate the sensitivity and specificity of the pcr-oc and nasba-oc for diagnosis of trypanosoma brucei gambiense and trypanosoma brucei rhodesiense human african trypanosomiasis (hat).201020625557
diamidines for human african trypanosomiasis.aromatic diamidines are potent trypanocides. pentamidine, a diamidine, has been used for more than 60 years to treat human african trypanosomiasis (hat); however, the drug must be administered parenterally and is active against first-stage hat only, prior to the parasites causing neurological deterioration through invasion of the cns. a major research effort to design novel diamidines has led to the development of orally active prodrugs and, remarkably, a new generation of compounds that can pen ...201020721830
dental management of the tropical disease human african trypanosomiasis: an unusual case of pseudobulbar palsy.human african trypanosomiasis (sleeping sickness) is a parasitic tropical disease endemic to sub-saharan africa. due to migration and holiday travel patterns cases are increasing in the united kingdom. the neurological sequelae have dental management implications both directly from the consequent physical disability and indirectly from the oral side-effects of the medications used to manage symptoms. changes in disease demographics require the dental profession to increase its awareness of migra ...201121217721
the trypanolytic factor-mechanism, impacts and applications.the trypanosoma brucei subspecies t. brucei brucei is non-human infective due to susceptibility to lysis by trypanolytic factor (tlf) in human serum. reviewed here are the advances which have revealed apolipoprotein l1 (apol1), found in high density lipoprotein, as the lysis-inducing component of tlf, the means of uptake via haptoglobin-related protein receptor and the mechanism of resistance in t. b. rhodesiense via its serum resistance-associated (sra) protein. the first practical steps to app ...201020646962
targeting the polyamine biosynthetic enzymes: a promising approach to therapy of african sleeping sickness, chagas' disease, and leishmaniasis.trypanosomatids depend on spermidine for growth and survival. consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (odc), s-adenosylmethionine decarboxylase (adometdc), spermidine synthase, trypanothione synthetase (trys), and trypanothione reductase (tryr), are promising targets for drug development. the odc inhibitor alpha-difluoromethylornithine (dfmo) is about to become a first-line drug against human late-stage gambiense sleeping sic ...200717610127
apol1 variants and kidney disease. there is no such thing as a free lunch.a recent study by genovese et al. unraveled the findings of the intensively discussed gene region around myh9 and its association with non-diabetic chronic kidney disease in african-americans. first, it is not the genetic variation in myh9 but in the neighbouring apol1 that causes the strong association with disease in african-americans and second, the study showed strong evidence for a positive selection against vulnerability for trypanosoma brucei rhodesiense infection but at the price of a hi ...201121216884
the scourge of human african trypanosomiasis.human african trypanosomiasis (sleeping sickness) is a parasitic disease caused by two different trypanosome subspecies, trypanosoma brucei rhodesiense and t.b. gambiense. each causes a different form of the disease. untreated, the outcome of both infections is death. sleeping sickness occurs exclusively on the african continent, south of the sahara. it is restricted to the distribution area of its vector, glassina or tsetse fly. 36 out of the 52 african countries are considered endemic for slee ...199512319651
improved inhibitors of trypanothione reductase by combination of motifs: synthesis, inhibitory potency, binding mode, and antiprotozoal activities.trypanothione reductase (tr) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. this system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against african sleeping sickness and chagas' disease. over the past two decades, a variety of nonpeptidic small-molecule ligands of the parasitic enzyme were discovered. a current goal is to decipher the binding mode of these known inhibitors in order to op ...201021275053
traversal of human and animal trypanosomes across the blood-brain barrier.the neurological complications of human african trypanosomiasis (hat) in man caused by the unicellular protozoan parasites trypanosoma brucei gambiense and t. b. rhodesiense are a consequence of the penetration of the blood-brain barrier (bbb) by trypanosomes that enter the central nervous system (cns). yet the mechanisms by which african trypanosomes cross the true bbb comprised of brain microvascular endothelial cells (bmecs) remain unclear. human bbb models used to determine how african trypa ...200819016378
il-10 is up regulated in early and transitional stages in vervet monkeys experimentally infected with trypanosoma brucei rhodesiense.il-10 has been suggested as a possible parameter for human african trypanosomiasis stage determination. however, conclusive experimental studies have not been carried out to evaluate this, which is a prerequisite before a potential test can be validated in humans for diagnostic purposes. we used the vervet monkey model of trypanosomiasis to scrutinize il-10 in blood and cerebrospinal fluid (csf). five adult males were experimentally infected with t. b. rhodesiense. the infected animals became an ...200616901747
improved inhibitors of trypanothione reductase by combination of motifs: synthesis, inhibitory potency, binding mode, and antiprotozoal activities.trypanothione reductase (tr) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. this system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against african sleeping sickness and chagas' disease. over the past two decades, a variety of nonpeptidic small-molecule ligands of the parasitic enzyme were discovered. a current goal is to decipher the binding mode of these known inhibitors in order to op ...201021165935
complete structural assignment of serratol, a cembrane-type diterpene from boswellia serrata, and evaluation of its antiprotozoal activity.from the dichloromethane extract obtained from the gum resin of boswellia serrata roxb. (burseraceae), a well-known medicinal plant resin ("indian olibanum"), the cembrane-type diterpene serratol was isolated in high yield. its structure, previously reported without clear specification of double-bond geometry and without specification of stereochemistry, was reanalysed by means of spectroscopic measurements and unambiguously assigned as s(-)-cembra-3 e,7 e,11 e-triene-1-ol. full assignment of al ...201021157686
spatially and genetically distinct african trypanosome virulence variants defined by host interferon-gamma response.we describe 2 spatially distinct foci of human african trypanosomiasis in eastern uganda. the tororo and soroti foci of trypanosoma brucei rhodesiense infection were genetically distinct as characterized by 6 microsatellite and 1 minisatellite polymorphic markers and were characterized by differences in disease progression and host-immune response. in particular, infections with the tororo genotype exhibited an increased frequency of progression to and severity of the meningoencephalitic stage a ...200718008245
lipid metabolism and other metabolic changes in vervet monkeys experimentally infected with trypanosoma brucei rhodesiense.background  human african trypanosomiasis is associated with metabolic changes which have not been well characterized. methods  chlorocebus aethiops were experimentally infected with trypanosoma brucei rhodesiense and late-stage disease induced at 28 days post-infection. ear prick blood for glucose determination and blood samples were obtained at weekly intervals for 56 days. analysis was carried out using dry chemistry analysis. results  in early infection, there was a significant increase in c ...201122070162
using detergent to enhance detection sensitivity of african trypanosomes in human csf and blood by loop-mediated isothermal amplification (lamp).the loop-mediated isothermal amplification (lamp) assay, with its advantages of simplicity, rapidity and cost effectiveness, has evolved as one of the most sensitive and specific methods for the detection of a broad range of pathogenic microorganisms including african trypanosomes. while many lamp-based assays are sufficiently sensitive to detect dna well below the amount present in a single parasite, the detection limit of the assay is restricted by the number of parasites present in the volume ...201121829738
mutual self-defence: the trypanolytic factor story.around 1900 laveran and mesnil discovered that african trypanosomes (prototype: trypanosoma brucei brucei) do not survive in the blood of some primates and humans. the nature of the trypanolytic factor present in these sera has been the focus of a long-standing debate between different groups, but recent developments have allowed the proposal of a coherent model incorporating most seemingly divergent views and providing an interesting example of the complex interplay that continuously occurs bet ...200818675374
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