MedWorm: Sleeping Sickness

Infectious disease: Genomics decodes drug action

Nature — Wed, 08 Feb 2012 05:00:00 +0100

Authors: Alan H. Fairlamb Drugs used to treat African sleeping sickness are outdated, and how they enter cells and exert biological effects is poorly understood. A genome-wide study using RNA interference provides valuable insight. See Letter p.232 (Source: Nature)

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What ‘Uniting to combat tropical diseases’ will really require

MSF News — Tue, 31 Jan 2012 21:26:00 +0100

By Unni Karunakara, physician and international president of Médecins Sans Frontières (MSF) (Originally published Jan. 31 in the Huffington Post UK online) Performing a spinal tap under field conditions is nerve-wracking. Sticking a needle into someone’s spine to extract spinal fluid is painful and risky and that’s just the doctor’s perspective. But it’s also something that our doctors have to do every day as part of routine tests for advanced-stage sleeping sickness. Try too, then, to imagine the experience from the patient’s side. When I was responsible for MSF’s sleeping sickness programs in Republic of Congo, even the prospect of the test was sometimes too much and people took to their heels rather than undergo the procedure. So we at MSF welcome the commitments made a...

WHO, Drug Firms Pledge to Control 10 Tropical Diseases

MedPage Today Infectious Disease — Tue, 31 Jan 2012 00:07:26 +0100

(MedPage Today) -- Ten neglected tropical diseases -- ranging from sleeping sickness to leprosy -- can be "eliminated or controlled" by the year 2020, the director of the World Health Organization said. (Source: MedPage Today Infectious Disease)

Combatting tropical diseases

MSF News — Mon, 30 Jan 2012 19:55:00 +0100

The Gates Foundation-hosted conference held in London Monday, ‘Uniting To Combat Tropical Diseases,’ draws attention to devastating tropical illnesses that have been neglected for too long. However, the ambitious goals to eliminate or control 10 neglected tropical diseases will only be credible when some critical remaining gaps are filled, according to Médecins Sans Frontières (MSF). “Though we are delighted that the World Health Organisation (WHO), donors and development agencies are finally drawing attention to neglected tropical diseases, we are concerned that challenges for some of these diseases are being glossed over,” says Daniel Berman, deputy director of MSF’s Access Campaign. “Expanded drug donations from the pharmaceutical industry will be part of the solution, bu...

Combating sleeping sickness

MSF News — Mon, 30 Jan 2012 12:23:54 +0100

MSF takes an innovative approach to eliminating sleeping sickness, taking mobile clinics by Land Rover and boat to far-flung parts of sub-Saharan Africa. (Source: MSF News)

DNDi and Abbott expand partnership to boost innovation for neglected tropical diseases

EurekAlert! - Social and Behavioral Science — Mon, 30 Jan 2012 05:00:00 +0100

(Drugs for Neglected Diseases Initiative) The Drugs for Neglected Diseases initiative and Abbott have signed a four-year joint research and non-exclusive licensing agreement to undertake research on new treatments for several of the world's most neglected tropical diseases, including Chagas disease, helminth infections, leishmaniasis and sleeping sickness. (Source: EurekAlert! - Social and Behavioral Science)

New Hope For Tackling Sleeping Sickness With Genetic Screens

Health News from Medical News Today — Thu, 26 Jan 2012 10:00:00 +0100

Research led by scientists at the London School of Hygiene & Tropical Medicine has exploited a revolutionary genetic technique to discover how human African Trypanosomiasis (HAT) drugs target the parasite which causes the disease. The new knowledge could help lead to the development of better treatments for the tens of thousands of people in sub-Saharan Africa who are affected each year. The findings, published in Nature, are based on the simultaneous analysis of thousands of genes and the action of the five drugs effective against HAT, also known as sleeping sickness... (Source: Health News from Medical News Today)

Sleeping sickness tests may identify better therapies

New Scientist - Health — Wed, 25 Jan 2012 18:00:00 +0100

Just five drugs work against sleeping sickness and all can be toxic – new lab tests are the first step towards finding safer alternatives (Source: New Scientist - Health)

High-throughput decoding of antitrypanosomal drug efficacy and resistance

Nature AOP — Wed, 25 Jan 2012 05:00:00 +0100

Authors: Sam Alsford, Sabine Eckert, Nicola Baker, Lucy Glover, Alejandro Sanchez-Flores, Ka Fai Leung, Daniel J. Turner, Mark C. Field, Matthew Berriman & David Horn The concept of disease-specific chemotherapy was developed a century ago. Dyes and arsenical compounds that displayed selectivity against trypanosomes were central to this work, and the drugs that emerged remain in use for treating human African trypanosomiasis (HAT). The importance of understanding the mechanisms underlying selective drug action and resistance for the development of improved HAT therapies has been recognized, but these mechanisms have remained largely unknown. Here we use all five current HAT drugs for genome-scale RNA interference target sequencing (RIT-seq) screens in Trypanosoma brucei, revealing the ...

Inhibitors Incorporating Zinc‐Binding Groups Target the GlcNAc‐PI de‐N‐acetylase in Trypanosoma brucei, the Causative Agent of African Sleeping Sickness

Chemical Biology and Drug Design — Sat, 21 Jan 2012 19:14:29 +0100

Substrate inhibition and allosteric regulation by heparan sulfate of Trypanosoma brucei cathepsin L.

Biochimica et Biophysica Acta — Tue, 03 Jan 2012 05:00:00 +0100

Authors: Costa TF, Reis FC, Lima AP Abstract The cysteine protease brucipain is an important drug target in the protozoan Trypanosoma brucei, the causative agent of both Human African trypanosomiasis and Animal African trypanosomiasis. Brucipain is closely related to mammalian cathepsin L and currently used as a framework for the development of inhibitors that display anti-parasitic activity. We show that recombinant brucipain lacking the C-terminal extension undergoes inhibition by the substrate benzyloxycarbonyl-FR-7-amino-4-methylcoumarin at concentrations above the K(m), but not by benzyloxycarbonyl-VLR-7-amino-4-methylcoumarin. The allosteric modulation exerted by the substrate is controlled by temperature, being apparent at 25°C but concealed at 37°C. The behavior of the en...

Urban transmission of human african trypanosomiasis, Gabon.

Emerging Infectious Diseases — Sun, 01 Jan 2012 05:00:00 +0100

We describe a confirmed case of human African trypanosomiasis (HAT) in an expatriate returning to France from Gabon after a probable tsetse fly bite in the urban setting of Libreville. This case indicates a possible urban transmission of HAT in Gabon and stresses the need for entomologic studies in Libreville. PMID: 22261276 [PubMed - in process] (Source: Emerging Infectious Diseases)

Identification of Trypanosoma brucei leucyl-tRNA synthetase inhibitors by pharmacophore- and docking-based virtual screening and synthesis.

Bioorganic and Medicinal Chemistry — Fri, 30 Dec 2011 05:00:00 +0100

In this study, a 3D model of T. brucei LeuRS (TbLeuRS) synthetic active site was constructed and subjected to virtual screening using a combination of pharmacophore- and docking-based methods. A new 2-pyrrolinone scaffold was discovered and the structure-activity relationship (SAR) studies aided by the docking model and organic synthesis were carried out. Compounds with various substituents on R(1), R(2) and R(3) were synthesized and their SAR was discussed. PMID: 22249121 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)

[Gustavo Pittaluga and the expedition to study sleeping sickness in the Spanish territories of the Gulf of Guinea (1909)].

Revista de Neurologia — Sun, 25 Dec 2011 20:54:49 +0100

CONCLUSIONS. This expedition took place in the context of the impulse of renovation of Spanish science headed by Cajal through the Junta de Ampliacion de Estudios, recently created. In the investigations performed in Guinea, Pittaluga demonstrated a high scientific standard in the fields of clinical medicine, hygiene, parasitology and entomology, comparable with other contemporary European studies. PMID: 22187212 [PubMed - in process] (Source: Revista de Neurologia)

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Robert Killick-Kendrick obituary

Guardian Unlimited Science — Fri, 23 Dec 2011 16:07:31 +0100

Our friend and colleague Robert Killick-Kendrick, who has died aged 82, was a research scientist with a particular interest in the parasitic protozoa that cause diseases in humans and other mammals, including malaria, African trypanosomiasis (sleeping sickness) and leishmaniasis.Bob was born in Hampton, Middlesex, and educated at Woking grammar school. He left at 16, worked for a year in the Ministry of Agriculture and Fisheries in Weybridge, then spent two years in the Royal Army Medical Corps. He joined the London School of Hygiene and Tropical Medicine in 1949 as a laboratory assistant. We first met Bob there in 1952 as a couple of naive PhD students, and benefited greatly from his skill and experience.Bob worked for eight years from 1955 in Nigeria, once trekking 415 miles (664km)...

Regulation and function of polyamines in African trypanosomes.

Trends in Parasitology — Tue, 20 Dec 2011 05:00:00 +0100

Authors: Willert E, Phillips MA Abstract The polyamine biosynthetic pathway is an important drug target for the treatment of human African trypanosomiasis (HAT), raising interest in understanding polyamine function and their mechanism of regulation. Polyamine levels are tightly controlled in mammalian cells, but similar regulatory mechanisms appear absent in trypanosomes. Instead trypanosomatid S-adenosylmethionine decarboxylase (AdoMetDC), which catalyzes a key step in the biosynthesis of the polyamine spermidine, is activated by dimerization with an inducible protein termed prozyme. Prozyme is an inactive paralog of the active AdoMetDC enzyme that evolved by gene duplication and is found only in the trypanosomatids. In Trypanosoma brucei, AdoMetDC activity appears to be controlle...

Inhibitors incorporating zinc binding groups target the GlcNAc‐PI de‐N‐acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness

Chemical Biology and Drug Design — Fri, 16 Dec 2011 05:00:00 +0100

AbstractDisruption of glycosylphosphatidylinositol (GPI) biosynthesis is genetically and chemically validated as a drug target against the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The N‐acetylglucosamine‐phosphatidylinositol de‐N‐acetylase (deNAc) is a zinc metalloenzyme responsible for the second step of GPI biosynthesis. We recently reported the synthesis of eight deoxy‐2‐C‐branched monosaccharides containing carboxylic acid, hydroxamic acid or N‐hydroxyurea substituents at the C2 position that may act as zinc binding groups. Here, we describe the synthesis of a glucocyclitol‐phospholipid incorporating a hydroxamic acid moiety, and report the biochemical evaluation of the monosaccharides and the glucocyclitol‐phospholipi...

Human African Trypanosomiasis in Non‐Endemic Countries (2000–2010)

Journal of Travel Medicine — Thu, 08 Dec 2011 05:00:00 +0100

Conclusions. The risk of HAT in travelers and migrants, albeit low, cannot be overlooked. In non‐DECs, rarity, nonspecific symptoms, and lack of knowledge and awareness in health staff make diagnosis difficult. Misdiagnosis is frequent, thus leading to invasive diagnosis methods, unnecessary treatments, and increased risk of fatality. Centralized distribution of drugs for HAT by WHO enables an HAT surveillance system for non‐DECs to be maintained. This system provides valuable information on disease transmission and complements data collected in DECs. (Source: Journal of Travel Medicine)

Design, Synthesis and Biological Evaluation of Trypanosoma brucei Trypanothione Synthetase Inhibitors.

ChemMedChem — Thu, 08 Dec 2011 05:00:00 +0100

Authors: Spinks D, Torrie LS, Thompson S, Harrison JR, Frearson JA, Read KD, Fairlamb AH, Wyatt PG, Gilbert IH Abstract Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62 000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have p...

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Human African trypanosomiasis in Angola: clinical observations, treatment, and use of PCR for stage determination of early stage of the disease

Transactions of the Royal Society of Tropical Medicine and Hygiene — Mon, 05 Dec 2011 22:39:33 +0100

Abstract: Biological and clinical observations are described for 224 patients infected by human African trypanosomiasis (HAT) in Angola in 2007 and 2008. Seven patients were initially classified in stage 1 (S1), 17 intermediate stage (IS) (WBC (Source: Transactions of the Royal Society of Tropical Medicine and Hygiene)

Sialidases play a key role in infection and anaemia in Trypanosoma congolense animal trypanosomiasis

Cellular Microbiology — Thu, 01 Dec 2011 05:00:00 +0100

SUMMARYAnimal African trypanosomiasis is a major constraint to livestock productivity and has an important impact on millions of people in developing African countries. This parasitic disease, caused mainly by Trypanosoma congolense, results in severe anaemia leading to animal death. In order to characterise potential targets for an anti‐disease vaccine, we investigated a multigenic trans‐sialidase family (TcoTS) in T. congolense. Sialidase and trans‐sialidase activities were quantified for the first time, as well as the tightly regulated TcoTS expression pattern throughout the life cycle. Active enzymes were expressed in bloodstream form parasites and released into the blood during infection. Using genetic tools, we demonstrated a significant correlation between TcoTS silencing and ...

Risk for human african trypanosomiasis, central Africa, 2000-2009.

Emerging Infectious Diseases — Thu, 01 Dec 2011 05:00:00 +0100

Authors: Simarro PP, Cecchi G, Franco JR, Paone M, Fèvre EM, Diarra A, Postigo JA, Mattioli RC, Jannin JG Abstract Comprehensive georeference records for human African trypanosomiasis in Cameroon, Central African Republic, Chad, Congo, Equatorial Guinea, and Gabon were combined with human population layers to estimate a kernel-smoothed relative risk function. Five risk categories were mapped, and ≈3.5 million persons were estimated to be at risk for this disease. PMID: 22172322 [PubMed - in process] (Source: Emerging Infectious Diseases)

Condition still critical

MSF News — Tue, 22 Nov 2011 23:33:00 +0100

Decades of conflict and a lack of government investment have made it hard for people in Democratic Republic of Congo (DRC) to access basic healthcare. Epidemics have spread unchecked and treatment of deadly diseases has been neglected. Eastern DRC is still volatile, marked by shifting alliances between armed groups, ongoing military operations, instability, insecurity, banditry and violence. Attacks against civilians and aid organizations are rising, making both the population and humanitarian aid workers increasingly vulnerable. Rape, murder, kidnapping and random acts of violence are daily occurrences for millions of people. The instability continues to push people from their homes and at times limits MSF’s ability to provide free, lifesaving healthcare. Lack of investment in th...

[Media Watch] Sleeping sickness

The Lancet Infectious Diseases — Tue, 22 Nov 2011 11:05:03 +0100

(Source: The Lancet Infectious Diseases)

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Trypanosoma brucei: Inhibition of acetyl-CoA carboxylase by haloxyfop.

Experimental Parasitology — Sat, 19 Nov 2011 05:00:00 +0100

Authors: Vigueira PA, Paul KS Abstract Trypanosoma brucei, a eukaryotic pathogen that causes African sleeping sickness in humans and nagana in cattle, depends on the enzyme acetyl-CoA carboxylase (ACC) for full virulence in mice. ACC produces malonyl-CoA, the two carbon donor for fatty acid synthesis. We assessed the effect of haloxyfop, an aryloxyphenoxypropionate herbicide inhibitor of plastid ACCs in many plants as well as Toxoplasma gondii, on T. brucei ACC activity and growth in culture. Haloxyfop inhibited TbACC in cell lysate (EC(50) 67μM), despite the presence of an amino acid motif typically associated with resistance. Haloxyfop also reduced growth of bloodstream and procyclic form parasites (EC(50) of 0.8 and 1.2mM). However, the effect on growth was likely due to off-ta...

Proteomic profiling and potential cellular target identification of K11777, a clinical cysteine protease inhibitor, in Trypanosoma brucei

RSC - Chem. Commun. latest articles — Thu, 17 Nov 2011 20:56:09 +0100

Chem. Commun., 2011, Accepted ManuscriptDOI: 10.1039/C1CC16178D, CommunicationPeng-Yu Yang, Min Wang, Cynthia Y He, Shao YaoMore than a billion people suffer from neglected tropical diseases (NTDs), including malaria, sleeping sickness and Chagas' disease. Most drugs available to date however are limited by parasite resistance and...The content of this RSS Feed (c) The Royal Society of Chemistry (Source: RSC - Chem. Commun. latest articles)

Pharmacological Validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness

Journal of Medicinal Chemistry — Tue, 08 Nov 2011 21:13:23 +0100

Journal of Medicinal ChemistryDOI: 10.1021/jm201148s (Source: Journal of Medicinal Chemistry)

Target Organ Damage in African American Hypertension: Role of APOL1

Current Hypertension Reports — Tue, 08 Nov 2011 16:50:04 +0100

Abstract Apolipoprotein L1 (APOL1) gene association studies and results of the African American Study of Kidney Disease and Hypertension are disproving the longstanding concept that mild to moderate essential hypertension contributes substantially to end-stage renal disease susceptibility in African Americans. APOL1 coding variants underlie a spectrum of kidney diseases, including that attributed to hypertension (labeled arteriolar or hypertensive nephrosclerosis), focal segmental glomerulosclerosis, and HIV-associated nephropathy. APOL1 nephropathy risk variants persist because of protection afforded from the parasite that causes African sleeping sickness. This breakthrough will lead to novel treatments for hypertensive African Americans with low-level proteinuria, for whom...

Improved detection of Trypanosoma brucei by lysis of red blood cells, concentration and LED fluorescence microscopy.

Acta Tropica — Fri, 04 Nov 2011 04:00:00 +0100

Authors: Biéler S, Matovu E, Mitashi P, Ssewannyana E, Bi Shamamba SK, Bessell PR, Ndung'u JM Abstract Confirmatory diagnosis of African trypanosomiasis relies on demonstration of parasites in body fluids by bright field microscopy. The parasitaemia in infected patients and animals is usually low, and concentration methods are used to try and increase the chances of seeing parasites. Recently, fluorescence microscopes using light-emitting diodes (LED) have been developed. Since they emit strong light, their use does not require a dark room, making field application a possibility. We have combined LED fluorescence microscopy with lysis of red blood cells (RBC) to improve the sensitivity and speed of detecting trypanosomes. In studies conducted at four centers in Uganda and the Demo...

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Trypanosoma brucei AP endonuclease 1 has a major role in the repair of abasic sites and protection against DNA-damaging agents.

DNA Repair — Sat, 29 Oct 2011 04:00:00 +0100

Authors: Charret KS, Requena CE, Castillo-Acosta VM, Ruiz-Pérez LM, González-Pacanowska D, Vidal AE Abstract DNA repair mechanisms guarantee the maintenance of genome integrity, which is critical for cell viability and proliferation in all organisms. As part of the cellular defenses to DNA damage, apurinic/apyrimidinic (AP) endonucleases repair the abasic sites produced by spontaneous hydrolysis, oxidative or alkylation base damage and during base excision repair (BER). Trypanosoma brucei, the protozoan pathogen responsible of human sleeping sickness, has a class II AP endonuclease (TBAPE1) with a high degree of homology to human APE1 and bacterial exonuclease III. The purified recombinant enzyme cleaves AP sites and removes 3'-phosphoglycolate groups from 3'-ends. To study its c...

Multi-Target-Directed Ligands as innovative tools to combat trypanosomatid diseases.

Current Topics in Medicinal Chemistry — Thu, 27 Oct 2011 04:00:00 +0100

Authors: Bolognesi ML Abstract Of the tropical diseases, trypanosomiases and leishmaniases should most concern the pharmaceutical community because of their high prevalence in developing countries and the lack of effective drug treatments. Despite this, they have not historically received much attention in terms of investment and research effort, nor do they now. In very recent years, thanks to the involvement of several nonprofit organizations, the chemotherapeutic options have expanded with the introduction of the first combination therapy. The optimal efficacy and safety of nifurtimox-eflornithine combination against second-stage human African trypanosomiasis is an encouraging first step towards simpler and more affordable therapies. Along the same line, I propose that single ch...

Long-Term Protection Against Skin Cancer May Be Provided By Sleeping Sickness Drug

Health News from Medical News Today — Mon, 24 Oct 2011 08:00:00 +0100

An antiparasitic agent used to treat African sleeping sickness might someday be used to prevent nonmelanoma skin cancers. Researchers found that DFMO, or Î±-difluoromethylornithine, still appeared to protect against nonmelanoma skin cancers years after people stopped taking the drug, according to a poster presented at the 10th AACR International Conference on Frontiers in Cancer Prevention Research, being held Oct. 22-25, 2011. In this follow-up study, researchers evaluated prolonged evidence of a protective effect of DFMO among 209 people who had participated in an earlier study... (Source: Health News from Medical News Today)

Sleeping sickness drug may provide long-term protection against skin cancer

EurekAlert! - Biology — Sun, 23 Oct 2011 04:00:00 +0100

(American Association for Cancer Research) An antiparasitic agent used to treat African sleeping sickness might someday be used to prevent nonmelanoma skin cancers. Researchers found that DFMO, or α-difluoromethylornithine, still appeared to protect against nonmelanoma skin cancers years after people stopped taking the drug, according to a poster presented at the 10th AACR International Conference on Frontiers in Cancer Prevention Research, held Oct. 22-25, 2011. (Source: EurekAlert! - Biology)

Social parasites.

Current Opinion in Microbiology — Fri, 21 Oct 2011 04:00:00 +0100

Authors: Lopez MA, Nguyen HT, Oberholzer M, Hill KL Abstract Protozoan parasites cause tremendous human suffering worldwide, but strategies for therapeutic intervention are limited. Recent studies illustrate that the paradigm of microbes as social organisms can be brought to bear on questions about parasite biology, transmission and pathogenesis. This review discusses recent work demonstrating adaptation of social behaviors by parasitic protozoa that cause African sleeping sickness and malaria. The recognition of social behavior and cell-cell communication as a ubiquitous property of bacteria has transformed our view of microbiology, but protozoan parasites have not generally been considered in this context. Works discussed illustrate the potential for concepts of sociomicrobiology...

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Analysis of blood‐brain barrier permeability of monovalent Nanobodies using microdialysis

British Journal of Pharmacology — Thu, 20 Oct 2011 04:00:00 +0100

CONCLUSIONS AND IMPLICATIONS: Nanobodies can perfuse into the brain parenchyma, especially in pathological conditions where the blood‐brain barrier integrity is compromised. (Source: British Journal of Pharmacology)

Uganda: Seven Million Ugandans At Risk of Sleeping Sickness

AllAfrica News: Health and Medicine — Wed, 12 Oct 2011 15:31:46 +0100

State minister for animal husbandry, Bright Rwamirama said the country is about 60 percent tsetse fly infested with over 9 million animals also at risk. (Source: AllAfrica News: Health and Medicine)

New Prodrugs of the Antiprotozoal Drug Pentamidine.

ChemMedChem — Fri, 07 Oct 2011 04:00:00 +0100

The objective of this investigation was the systematic characterisation and evaluation of eight pentamidine prodrugs in order to identify the most appropriate strategy to improve the properties of the parent drug. For this reason, all prodrugs were examined with respect to their solubility, stability, enzymatic activation, distribution, CNS delivery, and oral bioavailability. The results of this work have allowed reliable conclusions to be drawn regarding the best prodrug principle for the antiprotozoal drug pentamidine. PMID: 21984033 [PubMed - as supplied by publisher] (Source: ChemMedChem)

[Congenital human African trypanosomiasis: An observation at the University Hospital of Brazzaville (Congo)].

Archives de Pediatrie — Sat, 01 Oct 2011 04:00:00 +0100

Authors: Oba A, Gahtse A, Ekouya Bowassa G, Nika E, Obengui PMID: 21873039 [PubMed - in process] (Source: Archives de Pediatrie)

Lipid metabolism and other metabolic changes in vervet monkeys experimentally infected with Trypanosoma brucei rhodesiense

Journal of Medical Primatology — Sat, 01 Oct 2011 04:00:00 +0100

Conclusions Further investigations should focus on levels of total cholesterol during the follow‐up period in curatively treated vervet monkeys. Apart from their importance in disease staging, the changes in lipids levels may also affect the pharmacokinetics of some trypanocides. (Source: Journal of Medical Primatology)

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Drug resistance in human African trypanosomiasis

Future Microbiology — Fri, 30 Sep 2011 11:09:48 +0100

Future Microbiology , September 2011, Vol. 6, No. 9, Pages 1037-1047. (Source: Future Microbiology)

Research points to smaller, cheaper tsetse traps

SciDev.Net — Wed, 28 Sep 2011 17:09:35 +0100

Traps for sleeping sickness vectors could be made cheaper, finds a field study. (Source: SciDev.Net)

The Chemistry and Biology of Trypanosomal trans-Sialidases: Virulence Factors in Chagas Disease and Sleeping Sickness.

Chembiochem — Wed, 28 Sep 2011 04:00:00 +0100

Authors: Schauer R, Kamerling JP Abstract trans-Sialidases constitute a special group of the sialidase family. They occur in some trypanosome species and, in a unique reversible reaction, transfer sialic acids from one glycosidic linkage with galactose (donor) to another galactose (acceptor), to form (α2-3)-sialyl linkages. Trypanosomes cause such devastating human diseases as Chagas disease in South America (Trypanosoma cruzi) or sleeping sickness in Africa (Trypanosoma brucei). The trans-sialidases strongly contribute to the pathogenicity of the trypanosomes by scavenging sialic acids from the host or blood meal to coat the parasite surface; this aids their survival strategy in the insect's intestine, and in the blood circulation or cells of the host, and serves to compromise th...

Within-species genetic variability in tsetse's obligate symbiont, Wigglesworthia, is influenced by host phylogeographic patterns and incomplete lineage sorting.

Applied and Environmental Microbiology — Fri, 23 Sep 2011 04:00:00 +0100

In this study, we investigate the tsetse (Diptera: Glossinidae) bacterial symbiont, Wigglesworthia glossinidia, to determine whether observed codiversification of symbiont and tsetse host species extends to a single host species (Glossina fuscipes fuscipes) in Uganda. To explore symbiont genetic variation in G. f. fuscipes populations, we screened two variable loci (lon, lepA) from W. g. fuscipes and examined phylogeographic and demographic characteristics in multiple host populations. Symbiont genetic variation was apparent within and among populations. We identified two distinct symbiont lineages, in north and south Uganda, respectively. Incongruence Length Difference (ILD) tests indicate that the two lineages corresponded exactly to northern and southern G. f. fuscipes mtDNA haplogroups...

UPMC researcher wins MacArthur grant

bizjournals.com Health Care:Hospitals headlines — Tue, 20 Sep 2011 14:20:26 +0100

A Pittsburgh researcher has been named one of 22 MacArthur Fellows for 2011. Elodie Ghedin, 44, of the University of Pittsburgh School of Medicine is a parasitologist/virologist whose work involves "decoding the genomes of virulent human pathogens that cause such diseases as leishmaniasis, sleeping sickness, and river blindness and threaten the lives of millions in the developing world," the MacArthur Foundation said Tuesday. Other MacArthur Fellows include a journalist, a radio producer, an architect and a public historian... (Source: bizjournals.com Health Care:Hospitals headlines)

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Putting sleeping sickness on the radar

Guardian Unlimited Science — Mon, 19 Sep 2011 15:59:00 +0100

The winner of this year's Max Perutz Science Writing Award reveals her work to combat a deadly illnessIt is the start of an invasion. There are no gunfire or explosions, just the mundane tickle of a fly landing on your skin. In Sub-Saharan Africa, this moment can be just as deadly as bombs and guns if that tickle is a blood-sucking tsetse fly. As the fly bites, the tiny protozoan parasites that cause sleeping sickness rush into your blood stream. What was a brief brush of legs and wings is suddenly a potential death sentence.Your body is now a battlefield. The parasites begin to multiply and overwhelm your defences, causing waves of fever as you try to fight back. If you are lucky, you get an accurate early diagnosis and access to one of the two drugs available for the first stage of the d...

African Sleeping Sickness: First Field-Based Molecular Diagnostic Test In Sight

Health News from Medical News Today — Mon, 19 Sep 2011 07:00:00 +0100

The Geneva-based not-for-profit foundation FIND and Japanese diagnostics company Eiken have announced that a next-generation molecular test designed specifically for sleeping sickness - a deadly parasitic disease also known as human African trypanosomiasis (HAT) - is ready to enter accelerated field trials in sites across the Democratic Republic of Congo and Uganda. If all goes well, the LAMP (Loop-mediated Isothermal Amplification) test - which has completed design and development phases - will be available for clinical use in 2012... (Source: Health News from Medical News Today)

First field-based molecular diagnostic test for African sleeping sickness in sight

EurekAlert! - Medicine and Health — Thu, 15 Sep 2011 04:00:00 +0100

(Burness Communications) The Geneva-based not-for-profit foundation FIND and Japanese diagnostics company Eiken announced today that a next-generation molecular test designed specifically for sleeping sickness -- a deadly parasitic disease also known as human African trypanosomiasis -- is ready to enter accelerated field trials in sites across the Democratic Republic of Congo and Uganda. (Source: EurekAlert! - Medicine and Health)

Contribution of Innate Immune Responses Towards Resistance to African Trypanosome Infections

Scandinavian Journal of Immunology — Wed, 14 Sep 2011 04:00:00 +0100

AbstractDuring the course of African trypanosomiasis, an intact monocytic cell system appears to be crucial for the initiation and maintenance of anti‐trypanosome responses and could be critical for the survival of trypanosome‐infected host. Monocytic cells in turn require support from other components of the innate immunity as well as adaptive immunity for effective and sustained control of trypanosome infections. In this review, the contribution of specific components of the innate immune system towards resistance to African trypanosomes is discussed in the context of host survival and the ideas presented are expected to stimulate more debate and research on host innate mechanisms of defense against African trypanosomiasis. (Source: Scandinavian Journal of Immunology)

Identification of Inhibitors of the Leishmania cdc-Related Protein Kinase CRK3.

ChemMedChem — Tue, 13 Sep 2011 04:00:00 +0100

Authors: Cleghorn LA, Woodland A, Collie IT, Torrie LS, Norcross N, Luksch T, Mpamhanga C, Walker RG, Mottram JC, Brenk R, Frearson JA, Gilbert IH, Wyatt PG Abstract New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ~3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectiv...

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Global Update: Sleeping Sickness: Blood Test Could Be a Breakthrough in Field Diagnosis of Tropical Diseases

NYT Health — Mon, 12 Sep 2011 17:45:55 +0100

The test is portable and in an hour produces a simple color-change result that can be read with the naked eye. (Source: NYT Health)

Prevalence and Types of Coinfections in Sleeping Sickness Patients in Kenya (2000/2009)

Clinical and Developmental Immunology — Mon, 12 Sep 2011 16:38:54 +0100

In conclusion, the study has shown that HAT patients have multiple co-infections which may influence the disease pathogenesis and complicate management of HAT. (Source: Clinical and Developmental Immunology)

Anti-trypanosomal activity of Fexinidazole - A New Oral Nitroimidazole Drug Candidate for the Treatment of Sleeping Sickness.

Antimicrobial Agents and Chemotherapy — Mon, 12 Sep 2011 04:00:00 +0100

Authors: Kaiser M, Bray MA, Cal M, Trunz BB, Torreele E, Brun R Abstract Fexinidazole is a 5-nitroimidazole drug currently in clinical development for the treatment of human sleeping sickness (human African trypanosomiasis (HAT)) caused by infection with species of the protozoan parasite Trypanosoma brucei. The compound and its two principal metabolites the sulfoxide and sulfone have been assessed for their ability to kill a range of T. brucei parasite strains in vitro and to cure both acute and chronic HAT disease models in the mouse. The parent molecule and both metabolites have shown trypanocidal activity in vitro in the 0.7 - 3.3 μM (0.2 to 0.9 μg/ml) range against all parasite strains tested. In vivo fexinidazole is orally effective in curing both acute and chronic disease i...

Glasgow Scientists Report Major Advance In Sleeping Sickness Drug

Health News from Medical News Today — Thu, 08 Sep 2011 07:00:00 +0100

A new study published in the open-access journal PLoS Neglected Tropical Diseases on September 6th presents a key advance in developing a safer cure for sleeping sickness. Led by Professor Peter Kennedy, researchers at the University of Glasgow's Institute for Infection, Immunology and Inflammation have created a version of the drug most commonly used to treat sleeping sickness which can be administered orally in pill form. Sleeping sickness - or human African trypanosomiasis (HAT) - is a neglected tropical disease of major importance... (Source: Health News from Medical News Today)

Human African trypanosomiasis in endemic populations and travellers

European Journal of Clinical Microbiology and Infectious Diseases — Thu, 08 Sep 2011 06:05:22 +0100

Abstract Human African trypanosomiasis (HAT) or sleeping sickness is caused by the protozoan parasites Trypanosoma brucei (T.b.) gambiense (West African form) and T.b. rhodesiense (East African form) that are transmitted by the bite of the tsetse fly, Glossina spp.. Whereas most patients in endemic populations are infected with T.b. gambiense, most tourists are infected with T.b. rhodesiense. In endemic populations, T.b. gambiense HAT is characterized by chronic and intermittent fever, headache, pruritus, and lymphadenopathy in the first stage and by sleep disturbances and neuro-psychiatric disorders in the second stage. Recent descriptions of the clinical presentation of T.b. rhodesiense in endemic populations show a high variability in different foci. The symptomatology of t...

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Safer sleeping sickness pill hope

Scotsman.com News - Health — Tue, 06 Sep 2011 23:24:20 +0100

Scottish scientists believe they have made a key step forward in developing a safer cure for sleeping sickness, which affects thousands of people in developing countries. Als (Source: Scotsman.com News - Health)

Uganda: Elephantiasis Cases Up

AllAfrica News: Health and Medicine — Tue, 30 Aug 2011 15:58:03 +0100

Cases of sleeping sickness, elephantiasis and hydrocele are increasing in Alebtong district. About 30 people have been diagnosed with the neglected tropical diseases and are receiving treatment from Alebtong Health Centre IV. (Source: AllAfrica News: Health and Medicine)

Towards the Development of Novel Trypanosoma brucei RNA Editing Ligase 1 Inhibitors

BMC Pharmacology — Mon, 29 Aug 2011 23:00:00 +0100

Conclusions: We are hopeful that these new predicted inhibitors will aid medicinal chemists in developing novel therapeutics to fight human African trypanosomiasis. (Source: BMC Pharmacology)

Analysis of catalytic determinants of diaminopimelate and ornithine decarboxylases using alternate substrates.

Biochimica et Biophysica Acta — Mon, 29 Aug 2011 19:08:19 +0100

Authors: Fogle EJ, Toney MD Abstract Diaminopimelate decarboxylase (DAPDC) and ornithine decarboxylase (ODC) are pyridoxal 5'-phosphate dependent enzymes that are critical to microbial growth and pathogenicity. The latter is the target of drugs that cure African sleeping sickness, while the former is an attractive target for antibacterials. These two enzymes share the (β/α)(8) (i.e., TIM barrel) fold with alanine racemase, another pyridoxal 5'-phosphate dependent enzyme critical to bacterial survival. The active site structural homology between DAPDC and ODC is striking even though DAPDC catalyzes the decarboxylation of a D stereocenter with inversion of configuration and ODC catalyzes the decarboxylation of an L stereocenter with retention of configuration. Here, the structural ...

[Congenital human African trypanosomiasis: An observation at the University Hospital of Brazzaville (Congo).]

Archives de Pediatrie — Fri, 26 Aug 2011 23:00:00 +0100

Authors: Oba A, Gahtse A, Ekouya Bowassa G, Nika E, Obengui PMID: 21873039 [PubMed - as supplied by publisher] (Source: Archives de Pediatrie)

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Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities.

The Biochemical Journal — Thu, 18 Aug 2011 10:31:45 +0100

Authors: Birkholtz LM, Williams M, Niemand J, Louw AI, Persson L, Heby O New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking...

Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488.

ChemMedChem — Tue, 09 Aug 2011 23:00:00 +0100

Authors: Smith VC, Cleghorn LA, Woodland A, Spinks D, Hallyburton I, Collie IT, Yi Mok N, Norval S, Brenk R, Fairlamb AH, Frearson JA, Read KD, Gilbert IH, Wyatt PG Screening of the Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC(50) value of 59 nM as determined in our T. brucei in vitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure-activity relationships (SAR) and to optimise the antiproliferative activity and...

IL‐10 limits production of pathogenic TNF by M1 myeloid cells through induction of nuclear NF‐κB p50 member in Trypanosoma congolense infection‐resistant C57BL/6 mice

European Journal of Immunology — Mon, 01 Aug 2011 04:00:00 +0100

AbstractA balance between parasite elimination and control of infection‐associated pathogenicity is crucial for resistance to African trypanosomiasis. By producing TNF and NO, CD11b+ myeloid cells with a classical activation status (M1) contribute to parasitemia control in experimental Trypanosoma congolense infection in resistant C57BL/6 mice. However, in these mice, IL‐10 is required to regulate M1‐associated inflammation, avoiding tissue/liver damage and ensuring prolonged survival. In an effort to dissect the mechanisms behind the anti‐inflammatory activity of IL‐10 in T. congolense‐infected C57BL/6 mice, we show, using an antibody blocking the IL‐10 receptor, that IL‐10 impairs the accumulation and M1 activation of TNF/iNOS‐producing CD11b+Ly6C+ cells in the liver. U...

IL‐10 limits production of pathogenic TNF by M1 myeloid cells through induction of nuclear NF‐kB p50 member in Trypanosoma congolense infection resistant C57BL/6 mice

European Journal of Immunology — Sun, 31 Jul 2011 23:00:00 +0100

AbstractA balance between parasite elimination and control of infection‐associated pathogenicity is crucial for resistance to African trypanosomiasis. By producing TNF and NO, CD11b+ myeloid cells with a classical activation status (M1) contribute to parasitemia control in experimental Trypanosoma congolense infection in resistant C57BL/6 mice. However, in these mice, IL‐10 is required to regulate M1‐associated inflammation, avoiding tissue/liver damage and ensuring prolonged survival. In an effort to dissect the mechanisms behind the anti‐inflammatory activity of IL‐10 in T. congolense infected C57BL/6 mice, we show using antibody blocking IL‐10 receptor that IL‐10 impairs the accumulation and M1 activation in the liver of TNF/iNOS producing CD11b+Ly6C+ cells. Using infected...

IL-10 limits production of pathogenic TNF by M1 myeloid cells through induction of nuclear NF-kB p50 member in Trypanosoma congolense infection resistant C57BL/6 mice.

European Journal of Immunology — Sun, 31 Jul 2011 23:00:00 +0100

Authors: Bosschaerts T, Morias Y, Stijlemans B, Hérin M, Porta C, Sica A, Mantovani A, De Baetselier P, Beschin A A balance between parasite elimination and control of infection-associated pathogenicity is crucial for resistance to African trypanosomiasis. By producing TNF and NO, CD11b(+) myeloid cells with a classical activation status (M1) contribute to parasitemia control in experimental Trypanosoma congolense infection in resistant C57BL/6 mice. However, in these mice, IL-10 is required to regulate M1-associated inflammation, avoiding tissue/liver damage and ensuring prolonged survival. In an effort to dissect the mechanisms behind the anti-inflammatory activity of IL-10 in T. congolense infected C57BL/6 mice, we show using antibody blocking IL-10 receptor that IL-10 impairs the ...

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Drug hope for sleeping sickness care

Scotsman.com News - Health — Thu, 28 Jul 2011 00:00:00 +0100

NEW research on a drug used to treat sleeping sickness could lead to improved therapies for the disease. (Source: Scotsman.com News - Health)

Mono-, di- and trisubstituted derivatives of eflornithine: synthesis for in vivo delivery of DL-alpha-difluoromethylornithine in plasma.

Arzneimittel-Forschung — Wed, 27 Jul 2011 09:15:03 +0100

Authors: Cloete TT, Johansson CC, N'Da DD, Vodnala SK, Rottenberg ME, Breytenbach JC, Ashton M The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine their partition coefficients, and to assess whether they deliver the parent drug in the plasma. If increased plasma concentrations of eflornithine could be achieved in this way, an oral dosage form would be possible. The derivatives, nine in total, were successfully synthesized by multi-step derivatisation of eflornithine on either its alpha-carboxylic or/and alpha-amino or/and delta-amino groups by either esterification or/and amidation or/and carbamylation, and their structures ...

Population genetics of Glossina palpalis palpalis from central African sleeping sickness foci

Parasites and Vectors — Sun, 17 Jul 2011 23:00:00 +0100

A strong isolation by distance explains most of the population structure of Glossina palpalis palpalis populations observed in our sampling sites in Cameroon and DRC.Image: Trapping tsetse flies in Bipindi using a pyramidal trap in a favourable biotope. (Source: Parasites and Vectors)

Human host determinants influencing the outcome of Trypanosoma brucei gambiense infections

Parasite Immunology — Sun, 17 Jul 2011 20:43:55 +0100

SummarySince first identified, human African trypanosomiasis (HAT) or sleeping sickness has been described as invariably fatal. Increasing data however argue that infection by Trypanosoma brucei gambiense, the causative agent of HAT, results in a wide range of outcomes in its human host and importantly that a number of subjects in endemic areas are apparently able to control infection to low levels, undetectable by the classical parasitological tests used in the field. Thus, trypanotolerance seems to occur in humans as has already been described in cattle or in the rodent experimental models of infection. This review focuses on the description of the diversity of outcomes resulting from T. b. gambiense in humans and on the host factors involved. The consequences/impacts on HAT epidemiolo...

An optimized in vitro blood-brain barrier model reveals bidirectional transmigration of African trypanosome strains.

Microbiology — Wed, 06 Jul 2011 23:00:00 +0100

Authors: Untucht C, Rasch J, Fuchs E, Rohde M, Bergmann S, Steinert M The transmigration of African trypanosomes across the human blood-brain barrier (BBB) is the critical step during the course of the Human African Trypanosomiasis (HAT). The parasites Trypanosoma brucei gambiense and T. b. rhodesiense are transmitted to humans during a bite of Tsetse flies. Trypanosomes multiply within the blood stream and finally invade the central nervous system (CNS), which leads to the death of untreated patients. In order to establish an adequate in vitro BBB model for parasite transmigration, different human cell lines were used including ECV304, HBMEC, and HUVEC as well as C6 rat astrocytes. Validation of the BBB models with E. coli HB101 and E. coli K1 revealed that a combination of ECV304 cel...

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Structure of Trypanosoma brucei flagellum accounts for its bihelical motion [Biophysics and Computational Biology]

Proceedings of the National Academy of Sciences — Mon, 04 Jul 2011 23:00:00 +0100

Trypanosoma brucei is a parasitic protozoan that causes African sleeping sickness. It contains a flagellum required for locomotion and viability. In addition to a microtubular axoneme, the flagellum contains a crystalline paraflagellar rod (PFR) and connecting proteins. We show here, by cryoelectron tomography, the structure of the flagellum in three bending states. The PFR lattice in straight flagella repeats every 56 nm along the length of the axoneme, matching the spacing of the connecting proteins. During flagellar bending, the PFR crystallographic unit cell lengths remain constant while the interaxial angles vary, similar to a jackscrew. The axoneme drives the expansion and compression of the PFR lattice. We propose that the PFR modifies the in-plane axoneme motion to produce the cha...

Protein functional links in Trypanosoma brucei, identified by gene fusion analysis

BMC Evolutionary Biology - Latest articles — Mon, 04 Jul 2011 23:00:00 +0100

Conclusions: This is the first study of protein functional links in T. brucei identified by gene fusion analysis. We have used strict threshold and only discuss results which are highly likely to be genuine and which either have already been or can be experimentally verified. We discuss the possible impact of the identification of these novel putative protein-protein interactions, to the development of new trypanosome therapeutic drugs. (Source: BMC Evolutionary Biology - Latest articles)

Findings

Science: Current Issue — Sat, 02 Jul 2011 06:32:29 +0100

Buying Time for Snake Bite Victims | Deciphering Ovarian Cancer | The Mental Hazards of City Living | Sleeping Sickness Drug Shows Promise | Young Monkeys Don't Pardon the Interruption (Source: Science: Current Issue)

Africa: Oral Drug for Sleeping Sickness Passes Early Tests

AllAfrica News: Health and Medicine — Fri, 01 Jul 2011 14:28:11 +0100

The first oral drug candidate designed specifically for easy treatment of sleeping sickness was shown to be safe and effective in pre-clinical trials, a conference heard this week. (Source: AllAfrica News: Health and Medicine)

Oral drug for sleeping sickness passes early tests

SciDev.Net — Thu, 30 Jun 2011 17:23:24 +0100

An unusual collaboration is developing a cheaper, safer, oral drug to combat sleeping sickness. (Source: SciDev.Net)

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Press Release: SCYNEXIS-Anacor-DNDi: An Innovative Partnership Advances Novel Drug to Combat Sleeping Sickness

Pharmaceutical Online News — Wed, 29 Jun 2011 20:22:00 +0100

The Drugs for Neglected Diseases initiative (DNDi), Anacor Pharmaceuticals, and SCYNEXIS Inc. today announced the successful completion of pre-clinical studies for the first new oral drug candidate discovered specifically to combat human African trypanosomiasis (HAT), also known as sleeping sickness. (Source: Pharmaceutical Online News)

SCYNEXIS-Anacor-DNDi: An Innovative Partnership Advances Novel Drug to Combat Sleeping Sickness

Pharmaceutical Online News — Wed, 29 Jun 2011 20:22:00 +0100

Anacor Pharmaceuticals Partnership Advances Novel Drug Candidate To Combat Sleeping Sickness

Health News from Medical News Today — Wed, 29 Jun 2011 11:00:00 +0100

Anacor Pharmaceuticals (NASDAQ:ANAC), the Drugs for Neglected Diseases initiative (DNDi), and SCYNEXIS Inc. today announced the successful completion of pre-clinical studies for the first new oral drug candidate discovered specifically to combat human African trypanosomiasis (HAT), also known as sleeping sickness. An article released today in the open-access journal PLoS Neglected Tropical Diseases, reveals the initial successful results of pre-clinical studies of the new compound, which will soon advance to Phase I human clinical trials... (Source: Health News from Medical News Today)

Innovative Partnership Advances Novel Drug Candidate To Combat Sleeping Sickness

Health News from Medical News Today — Wed, 29 Jun 2011 09:00:00 +0100

The Drugs for Neglected Diseases initiative (DNDi), Anacor Pharmaceuticals, and SCYNEXIS Inc. announced the successful completion of pre-clinical studies for the first new oral drug candidate discovered specifically to combat human African trypanosomiasis (HAT), also known as sleeping sickness. An article released in the open-access journal PLoS Neglected Tropical Diseases, reveals the initial successful results of pre-clinical studies of the new compound, which will soon advance to Phase I human clinical trials... (Source: Health News from Medical News Today)

Potential treatment for sleeping sickness to be tested

L.A. Times - Health — Tue, 28 Jun 2011 22:46:00 +0100

Clinical trials are set for an inexpensive, oral drug to treat trypanosomiasis, a promising alternative to current remedies, which are typically not available in the African countries where the deadly disease is most common.Current drugs used for trypanosomiasis require sophisticated diagnosis and drug infusions not typically available in the African regions most affected, and the drugs themselves are frequently lethal. (Source: L.A. Times - Health)

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Hitting Sleeping Sickness Where It Lives

ScienceNOW — Tue, 28 Jun 2011 22:00:00 +0100

Scientists unveil novel compound that kills brain-attacking parasites (Source: ScienceNOW)

Innovative partnership advances novel drug candidate to combat sleeping sickness

EurekAlert! - Social and Behavioral Science — Tue, 28 Jun 2011 04:00:00 +0100

(Burness Communications) The Drugs for Neglected Diseases initiative (DNDi), Anacor Pharmaceuticals and SCYNEXIS Inc. today announced the successful completion of pre-clinical studies for the first new oral drug candidate discovered specifically to combat human African trypanosomiasis, also known as sleeping sickness. An article released today in the open-access journal PLoS Neglected Tropical Diseases, reveals the initial successful results of pre-clinical studies of the new compound, which will soon advance to Phase I human clinical trials. (Source: EurekAlert! - Social and Behavioral Science)

Genetic diversity and population structure of Glossina pallidipes in Uganda and western Kenya

Parasites and Vectors — Mon, 27 Jun 2011 23:00:00 +0100

Conclusion: Our research demonstrated that G. pallidipes populations in Kenya and Uganda do not form a contiguous tsetse belt. While Lambwe Valley appears to be a source population for flies colonizing southeastern Uganda, this dispersal does not extend to western Uganda. The complicated phylogeography of G. pallidipes warrants further efforts to distinguish the role of historical and modern gene flow and possible sex-biased dispersal in structuring populations. (Source: Parasites and Vectors)

Development of novel drugs for human African trypanosomiasis

Future Microbiology — Mon, 27 Jun 2011 14:45:52 +0100

Future Microbiology , June 2011, Vol. 6, No. 6, Pages 677-691. (Source: Future Microbiology)

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Trypanosoma brucei infection in a HIV positive Ugandan male.

Fri, 24 Jun 2011 03:15:02 +0100

We present characteristic clinical and microbiologic features of a fatal case of African Sleeping Sickness in an HIV-infected individual. PMID: 21657140 [PubMed - in process] (Source: Clinical Laboratory Science : Journal of the American Society for Medical Technology)

Human African trypanosomiasis: a review of non-endemic cases in the past 20 years

International Journal of Infectious Diseases — Sun, 19 Jun 2011 23:00:00 +0100

Summary: Human African trypanosomiasis (HAT) is caused by sub-species of the parasitic protozoan Trypanosoma brucei and is transmitted by tsetse flies, both of which are endemic only to sub-Saharan Africa. Several cases have been reported in non-endemic areas, such as North America and Europe, due to travelers, ex-patriots or military personnel returning from abroad or due to immigrants from endemic areas. In this paper, non-endemic cases reported over the past 20 years are reviewed; a total of 68 cases are reported, 19 cases of Trypanosoma brucei gambiense HAT and 49 cases of Trypanosoma brucei rhodesiense HAT. Patients ranged in age from 19 months to 72 years and all but two patients survived. Physicians in non-endemic areas should be aware of the signs and symptoms of this disease, as w...

Health care‐seeking behaviour and diagnostic delays for Human African Trypanosomiasis in the Democratic Republic of the CongoComportement de recours aux soins de santé et retards dans le diagnostic de la trypanosomiase humaine africaine en République démocratique du CongoComportamiento de búsqueda de cuidados sanitarios y retraso en el diagnóstico para la Tripanosomiasis Humana Africana en la República Democrática del Congo

Tropical Medicine and International Health — Fri, 17 Jun 2011 01:23:15 +0100

Conclusions Substantial patient as well as health system delays are incurred in HAT cases detected passively. Public health centres are performing poorly in the diagnostic work‐up for HAT, mainly because HAT is a relatively rare disease with few and non‐specific early symptoms. Integration of HAT diagnosis and treatment into general health services requires strong technical support and well‐organized supervision and referral mechanisms.Objectif: Près de la moitié des patients souffrant de la trypanosomiase humaine africaine (THA) rapportés en République Démocratique du Congo (RDC) sont actuellement détectés dans des établissements de santé fixes et non par des équipes mobiles. Compte tenu de la récente politique d’intégrer la lutte contre la THA dans les services ...

Carlina Oxide – A Natural Polyacetylene from Carlina acaulis (Asteraceae) with Potent Antitrypanosomal and Antimicrobial Properties

Planta Medica — Tue, 14 Jun 2011 23:00:00 +0100

Planta MedDOI: 10.1055/s-0031-1279984AbstractCarlina acaulis (Asteraceae) has a long history of medicinal use in Europe due to its antimicrobial properties. The strong activity of Carlina oxide, the main compound of the essential oil of C. acaulis against two MRSA strains, Streptococcus pyogenes, Pseudomonas aeruginosa, Candida albicans, and C. glabrata was confirmed. A strong and selective activity against Trypanosoma brucei brucei with an IC50 of 1.0 µg/mL and a SI of 446 compared to human HeLa cells was recorded. The selective toxicity of Carlina oxide makes it a promising lead compound for the development of drugs to treat African trypanosomiasis and multiresistant gram-positive bacteria.[...]© Georg Thieme Verlag KG Stuttgart · New YorkArticle in Thieme eJournals:Table of con...

High Throughput Analysis of an RNAi Library Identifies Novel Kinase targets in Trypanosoma brucei

Chemical Biology and Drug Design — Fri, 10 Jun 2011 23:00:00 +0100

Abstract:New drugs are needed to treat Human African Trypanosomiasis because the currently approved treatments are toxic or limited in efficacy. One strategy for developing new drugs involves discovering novel genes whose products can be targeted for modulation by small molecule chemotherapeutic agents. The Trypanosoma brucei genome contains many genes with the potential to become such targets. Kinases represent one group of genes that regulate many important cell functions and can be modulated by small molecules, thus represent a promising group of enzymes to screen for potential therapeutic targets. RNAi screens could help identify the most promising kinase targets, but the lack of suitable assays represents a barrier for optimizing the use of this technology in T. brucei. Here we descri...

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High‐Throughput Analysis of an RNAi Library Identifies Novel Kinase Targets in Trypanosoma brucei

Chemical Biology and Drug Design — Fri, 10 Jun 2011 23:00:00 +0100

New drugs are needed to treat human African trypanosomiasis because the currently approved treatments are toxic or limited in efficacy. One strategy for developing new drugs involves discovering novel genes whose products can be targeted for modulation by small‐molecule chemotherapeutic agents. The Trypanosoma brucei genome contains many genes with the potential to become such targets. Kinases represent one group of genes that regulate many important cell functions and can be modulated by small molecules, thus representing a promising group of enzymes to screen for potential therapeutic targets. RNAi screens could help identify the most promising kinase targets, but the lack of suitable assays represents a barrier for optimizing the use of this technology in T. brucei. Here, we describe...

A Handful Of 'Antipoverty' Vaccines Exist For Neglected Diseases, But The World's Poorest Billion People Need More [Fighting Critical Diseases]

Health Affairs — Tue, 07 Jun 2011 23:00:00 +0100

So-called neglected tropical diseases are the most common infections of the world’s poor. Almost all of the "bottom billion"—the 1.4 billion people who live below the poverty level defined by the World Bank—suffer from one or more neglected diseases including hookworm infection, sleeping sickness, or Chagas disease. These diseases are actually a cause of poverty because of their adverse effects on child growth and development and worker productivity. Vaccines to combat such diseases have come to be known as "antipoverty vaccines." Unfortunately, the recent surge in the development and delivery of vaccines to combat the major childhood killers—such as pneumococcal pneumonia and measles—has bypassed neglected diseases. Nevertheless, some vaccines for these ...

Diagnosis of human sleeping sickness: sense and sensitivity.

Trends in Parasitology — Mon, 06 Jun 2011 23:00:00 +0100

Authors: Wastling SL, Welburn SC In 1997 the World Health Organization (WHO) advocated increased access to diagnosis and treatment, as well as reinforcement of surveillance, for the control of sleeping sickness (human African trypanosomiasis, HAT). This coincided with the end of decades of civil conflicts in several endemic regions and negotiation of a sustainable supply of 'free' curative drugs and, as a result, HAT is at its lowest level in 50 years. However, reported cases underestimate prevalence and downplay HAT when compared with data generated by advanced diagnostic capacity for human immunodeficiency virus (HIV), tuberculosis (TB) and malaria, and, because HAT case numbers fall between epidemics, diagnostics become less commercially appealing. Here recent trends in the developm...

ZC3H Stabilization of Life Cycle-enriched mRNAs [Microbiology]

Journal of Biological Chemistry — Thu, 02 Jun 2011 23:00:00 +0100

CCCH zinc finger proteins (ZC3Hs) are a novel class of RNA-binding protein involved in post-transcriptional mechanisms controlling gene expression. We show TbZC3H20 from Trypanosoma brucei, the causative agent of sleeping sickness and other diseases, stabilizes two developmentally regulated transcripts encoding a mitochondrial carrier protein (MCP12) and trans-sialidase (TS-like E). TbZC3H20 is shown to be an RNA-binding protein that is enriched in insect procyclic form T. brucei and is the first ZC3H discovered controlling gene expression through modulating mRNA abundance in trypanosomes. Previous studies have demonstrated that RNA recognition motif-containing and PUF family RNA-binding proteins can control gene expression by stabilizing specific target mRNA levels. This work is the first...

Antiparasitic Therapy

Mayo Clinic Proceedings — Mon, 30 May 2011 23:00:00 +0100

Parasitic diseases affect more than 2 billion people globally and cause substantial morbidity and mortality, particularly among the world's poorest people. This overview focuses on the treatment of the major protozoan and helminth infections in humans. Recent developments in antiparasitic therapy include the expansion of artemisinin-based therapies for malaria, new drugs for soil-transmitted helminths and intestinal protozoa, expansion of the indications for antiparasitic drug treatment in patients with Chagas disease, and the use of combination therapy for leishmaniasis and human African trypanosomiasis. (Source: Mayo Clinic Proceedings)

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Challenges of controlling sleeping sickness in areas of violent conflict: experience in the Democratic Republic of Congo

Conflict and Health — Wed, 25 May 2011 23:00:00 +0100

We present here the challenges of carrying out HAT control programmes in general and in a conflict-affected region of DRC. We discuss the difficulties of measuring disease burden, medical care complexities, waning international support, and research and development barriers for HAT.DiscussionIn 2007, Medecins Sans Frontieres (MSF) began screening for HAT in the Haut-Uele and Bas-Uele districts of Orientale Province in northeastern DRC, an area of high prevalence affected by armed conflict. Through early 2009, HAT prevalence rate of 3.4% was found, reaching 10% in some villages. More than 46,000 patients were screened and 1,570 treated for HAT during this time. In March 2009, two treatment centres were forced to close due to insecurity, disrupting patient treatment, follow-up, and transmiss...

Challenges of controlling sleeping sickness in areas of violent conflict: experience in the Democratic Republic of Congo.

Rural Remote Health — Wed, 25 May 2011 23:00:00 +0100

We present here the challenges of carrying out HAT control programmes in general and in a conflict-affected region of DRC. We discuss the difficulties of measuring disease burden, medical care complexities, waning international support, and research and development barriers for HAT. DISCUSSION: In 2007, Medecins Sans Frontieres (MSF) began screening for HAT in the Haut-Uele and Bas-Uele districts of Orientale Province in northeastern DRC, an area of high prevalence affected by armed conflict. Through early 2009, HAT prevalence rate of 3.4% was found, reaching 10% in some villages. More than 46,000 patients were screened and 1,570 treated for HAT during this time. In March 2009, two treatment centres were forced to close due to insecurity, disrupting patient treatment, follow-up, and transm...

Sterol 14alpha-Demethylase (CYP51) as a Therapeutic Target for Human Trypanosomiasis and Leishmaniasis.

Current Topics in Medicinal Chemistry — Wed, 25 May 2011 23:00:00 +0100

Authors: Lepesheva GI, Waterman MR Pathogenic protozoa threaten lives of several hundred million people throughout the world and are responsible for large numbers of deaths globally. The parasites are transmitted to humans by insect vectors, more than a hundred of infected mammalian species forming reservoir. With human migrations, HIV-coinfections, and blood bank contamination the diseases are now spreading beyond the endemic tropical countries, being found in all parts of the world including the USA, Canada and Europe. In spite of the widely appreciated magnitude of this health problem, current treatment for sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and leishmaniasis (Leishmania spp.) remains unsatisfactory. The drugs are decades old, their efficacy a...

Trypanocidal Activity of Nitroaromatic Prodrugs: Current Treatments and Future Perspectives.

Current Topics in Medicinal Chemistry — Wed, 25 May 2011 23:00:00 +0100

Authors: Wilkinson SR, Bot C, Kelly JM, Hall BS Chagas disease and African sleeping sickness are trypanosomal infections that represent important public health problems in Latin America and Africa, respectively. The restriction of these diseases to the poorer parts of the world has meant that they have been largely neglected and limited progress has been made in their treatment. The nitroheterocyclic prodrugs nifurtimox and benznidazole, in use against Chagas disease for >40 years, remain the only agents available for this infection. In the case of African sleeping sickness, nifurtimox has recently been added to the arsenal of medicines, with the nitroheterocycle fexinidazole currently under evaluation. For a long time, the cytotoxic mechanism of these drugs was poorly understood: n...

Editorial: African trypanosomiasis

Parasite Immunology — Mon, 23 May 2011 23:00:00 +0100

(Source: Parasite Immunology)

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Sub-Saharan Africa news in brief: 5–18 May 2011

SciDev.Net — Wed, 18 May 2011 16:58:55 +0100

Genes that protect cattle from sleeping sickness, Southern Sudan to boost agri-research, faster HIV diagnosis in Mozambique, and more. (Source: SciDev.Net)

Drug delivery systems in the treatment of African trypanosomiasis infections

Expert Opinion: Expert Opinion on Drug Delivery: Table of Contents — Wed, 18 May 2011 12:47:30 +0100

Expert Opinion on Drug Delivery, Volume 8, Issue 6, Page 735-747, June 2011. (Source: Expert Opinion: Expert Opinion on Drug Delivery: Table of Contents)

Study finds gene clues to African cattle disease

Reuters: Health — Mon, 16 May 2011 19:26:12 +0100

LONDON (Reuters) - Scientists studying the tsetse fly-borne disease "sleeping sickness" and a devastating version found in cattle say they have found two genes that may in future help rescue the livelihoods of millions of farmers in Africa. (Source: Reuters: Health)

Antiprotozoal compounds: state of the art and new developments

International Journal of Antimicrobial Agents — Thu, 05 May 2011 23:00:00 +0100

This article aims to provide a concise overview of the state-of-the-art treatment for the most important tropical protozoal infections as well as new approaches. (Source: International Journal of Antimicrobial Agents)

Understanding sleeping sickness

Nature Methods — Wed, 27 Apr 2011 23:00:00 +0100

Nature Methods 8, 370 (2011). doi:10.1038/nmeth0511-370b Author: Nicole Rusk High-coverage sequencing of RNA interference targets gives insight into parasite phenotypes. (Source: Nature Methods)

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Solving The Sleeping Sickness 'Mystery'

Health News from Medical News Today — Wed, 27 Apr 2011 18:00:00 +0100

Since before the 1300s, people living in many parts of Africa have been dying from a disease known as sleeping sickness. Despite public health campaigns that explain ways to stop infection-primarily by killing the disease-spreading tsetse fly-successful eradication has remained out of reach. That's partly because epidemiologists can't predict where cases will emerge next. "It's in places where people thought it shouldn't be, and it's not in places where they're sure it should be," says Joseph Messina, a geographer at Michigan State University... (Source: Health News from Medical News Today)

Antimicrobial Peptide Killing of African Trypanosomes

Parasite Immunology — Sun, 24 Apr 2011 06:08:03 +0100

SummaryThe diseases caused by trypanosomes are medically and economically devastating to the population of sub‐Saharan Africa. Parasites of the genus Trypanosoma, infect both humans, causing African sleeping sickness, and livestock, causing Nagana. The development of effective treatment strategies has suffered from the severe side effects of approved drugs, resistance and major difficulties in delivering drugs. Antimicrobial peptides are ubiquitous components of immune defense and are being rigorously pursued as novel sources of new therapeutics for a variety of pathogens. Here we review the role of antimicrobial peptides in the innate immune response of the tsetse fly to African trypanosomes, catalogue trypanocidal antimicrobial peptides from diverse organisms and highlight the suscepti...

Insight To Help Tackle Sleeping Sickness Offered By Parasite Strategy

Health News from Medical News Today — Fri, 22 Apr 2011 08:00:00 +0100

Fresh insight into the survival strategy of the parasite that causes sleeping sickness could help inform new treatments for the disease. Scientists have found that the parasite, which can transform itself into either of two physical forms, has developed a careful balance between these. One of these types ensures infection in the bloodstream of a victim, and the other type is taken up by the tsetse fly and spread to another person or animal... (Source: Health News from Medical News Today)

City scientists offer hope of new sleeping sickness treatments

Scotsman.com News - Health — Fri, 22 Apr 2011 00:00:00 +0100

NEW treatments to help tackle sleeping sickness could be on the horizon, thanks to research by Edinburgh University scientists. (Source: Scotsman.com News - Health)

Parasite strategy offers insight to help tackle sleeping sickness

ScienceDaily Headlines — Thu, 21 Apr 2011 16:23:23 +0100

Fresh insight into the survival strategy of the parasite that causes sleeping sickness could help inform new treatments for the disease. (Source: ScienceDaily Headlines)

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Transmission Stages Dominate Trypanosome Within-Host Dynamics during Chronic Infections.

Cell Host and Microbe — Wed, 20 Apr 2011 23:00:00 +0100

Authors: Macgregor P, Savill NJ, Hall D, Matthews KR Sleeping sickness is characterized by waves of the extracellular parasite Trypanosoma brucei in host blood, with infections continuing for months or years until inevitable host death. These waves reflect the dynamic conflict between the outgrowth of a succession of parasite antigenic variants and their control by the host immune system. Although a contributor to these dynamics is the density-dependent differentiation from proliferative "slender forms" to transmissible "stumpy forms," an absence of markers discriminating stumpy forms has prevented accurate parameterization of this component. Here, we exploit the stumpy-specific PAD1 marker, which functionally defines transmission competence, to quantitatively monitor stumpy formation ...

First evidence that parasite infecting apparent aparasitemic serological suspects in human African trypanosomiasis are Trypanosoma brucei gambiense and are similar to those found in patients.

Infection, Genetics and Evolution — Sat, 16 Apr 2011 23:00:00 +0100

Authors: Kaboré J, Koffi M, Bucheton B, Macleod A, Duffy C, Ilboudo H, Camara M, De Meeûs T, Belem AM, Jamonneau V Thanks to its sensitivity and its ease of use in the field, the card agglutination test for trypanosomiasis (CATT) is widely used for serological screening of Trypanosoma brucei gambiense human African trypanosomiasis (HAT). Positive subjects are then examined by microscopy to confirm the disease. However, the CATT exhibits false-positive results raising the question of whether CATT-positive subjects who are not confirmed by microscopic detection of trypanosomes (SERO) are truly exposed to T.b. gambiense infection. For this purpose, we applied microsatellite genotyping on DNA extracted from blood of both HAT confirmed patients and SERO subjects in Guinea and Côte d'Ivoi...

Millions Suffering From Parasite Infection Could Benefit From Safer Treatment

Health News from Medical News Today — Fri, 15 Apr 2011 08:00:00 +0100

A safer and more effective treatment for 10 million people in developing countries who suffer from infections caused by trypanosome parasites could become a reality thanks to new research from Queen Mary, University of London published today (15 April). Scientists have uncovered the mechanisms behind a drug used to treat African sleeping sickness and Chagas disease, infections caused by trypanosome parasites which result in 60,000 deaths each year. The study, appearing in the Journal of Biological Chemistry, investigated how the drug nifurtimox works to kill off the trypanosome... (Source: Health News from Medical News Today)

Population genetic structure of Guinea Trypanosoma brucei gambiense isolates according to host factors.

Infection, Genetics and Evolution — Wed, 13 Apr 2011 23:00:00 +0100

Authors: Kaboré J, Macleod A, Jamonneau V, Ilboudo H, Duffy C, Camara M, Camara O, Belem AM, Bucheton B, De Meeûs T Human African trypanosomiasis (HAT) or sleeping sickness is a major public health problem in sub-Saharan Africa and is due to the kinetoplastid parasite Trypanosoma brucei gambiense in West and Central Africa. The exact role of multiple infections, the basis of clinical diversity observed in patients and the determinism that leads trypanosomes into different body fluids of the host remain opened questions to date. In this paper we investigate, in three Guinean foci, whether strains found in blood, lymph or cerebrospinal fluid (CSF) or in patients at different phase of HAT (phase 1, early phase 2 and late phase 2) are representative of the focus they belong to. Amplifica...

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The Unknown Risk of Vertical Transmission in Sleeping Sickness--a Literature Review

MSF Field Research — Sat, 09 Apr 2011 00:44:54 +0100

Title: The Unknown Risk of Vertical Transmission in Sleeping Sickness--a Literature ReviewAuthors: Lindner, Andreas K; Priotto, GerardoAbstract: Children with human African trypanosomiasis (HAT) present with a range of generally non-specific symptoms. Late diagnosis is frequent with often tragic outcomes. Trypanosomes can infect the foetus by crossing the placenta. Unequivocal cases of congenital infection that have been reported include newborn babies of infected mothers who were diagnosed with HAT in the first 5 days of life and children of infected mothers who had never entered an endemic country themselves. (Source: MSF Field Research)

Trypanocidal Activity of Nifurtimox [Enzymology]

Journal of Biological Chemistry — Thu, 07 Apr 2011 23:00:00 +0100

The prodrug nifurtimox has been used for more than 40 years to treat Chagas disease and forms part of a recently approved combinational therapy that targets West African trypanosomiasis. Despite this, its mode of action is poorly understood. Detection of reactive oxygen and nitrogen intermediates in nifurtimox-treated extracts led to the proposal that this drug induces oxidative stress in the target cell. Here, we outline an alternative mechanism involving reductive activation by a eukaryotic type I nitroreductase. Several enzymes proposed to metabolize nifurtimox, including prostaglandin F2α synthase and cytochrome P450 reductase, were overexpressed in bloodstream-form Trypanosoma brucei. Only cells with elevated levels of the nitroreductase displayed altered susceptibility to this nitro...

Polysomnography as a diagnosis and post-treatment follow-up tool in human African trypanosomiasis: A case study in an infant

Journal of the Neurological Sciences — Wed, 06 Apr 2011 23:00:00 +0100

We present here the case of a 30-month old girl (E20 KOLNG) diagnosed with stage 1 HAT during a field survey in June 2007 in Congo. She was followed-up every six months for 18months in a village dispensary facility at Mpouya. Her health status deteriorated in December 2008, although cerebrospinal fluid (CSF) white blood cell (WBC) count was normal. The child was hospitalized at Brazzaville and a daytime polysomnographic recording (electroencephalogram, electrooculogram, and electromyogram) was performed (Temec Vitaport 3® portable recorder) to avoid a new lumbar puncture. The child presented a complete polysomnographic syndrome of HAT with a major disturbance of the distribution of sleep and wake episodes and the occurrence of sleep onset REM periods (SOREMPs). The relapse at stage 2 was ...

Sleeping sickness

Clinical Microbiology and Infection — Tue, 05 Apr 2011 07:37:06 +0100

AbstractHuman African trypanosomiasis (HAT), or sleeping sickness is a vector‐borne disease that flourishes in impoverished, rural part of sub‐Saharan Africa. It is caused by infection with the protozoan parasite Trypanosoma brucei and is transmitted by tsetse flies of the genus Glossina. The majority of cases are due to T. b. gambiense that gives rise to the chronic, anthroponotic endemic disease in Western and Central Africa. Infection with T. b. rhodesiense leads to the acute, zoonotic form of Eastern and Southern Africa. The parasites live and multiply extracellularly in blood and tissue fluids of their human host. They have elaborated a variety of strategies for invading hosts, to escape the immune system and to take advantage of host growth factors. HAT is a challenging and deadl...

Novel Compounds For Fighting Against Parasitic Diseases

Health News from Medical News Today — Tue, 05 Apr 2011 07:00:00 +0100

Trypanosomatid parasites cause diseases like African sleeping sickness, Chagas' disease and leishmaniasis. Leishmaniasis affects about 12 million people worldwide, mostly in developing countries. Current drug treatments are inadequate due to drug toxicity and resistance. Now, a group of European scientists has discovered new compounds that may help to fight these diseases more effectively... (Source: Health News from Medical News Today)

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Health care‐seeking behaviour and diagnostic delays for Human African Trypanosomiasis in the Democratic Republic of the Congo

Tropical Medicine and International Health — Mon, 28 Mar 2011 23:00:00 +0100

Biomed Analysis: Eliminating sleeping sickness for good

SciDev.Net — Thu, 24 Mar 2011 15:44:05 +0100

After recent gains against trypanosomiasis, new diagnostic and treatment tools mean we can make the final push, says Priya Shetty. (Source: SciDev.Net)

'Sleeping Sickness' Pandemic Offers Insight Into Parkinson's

Health News from Medical News Today — Wed, 23 Mar 2011 07:00:00 +0100

A bizarre disease that caused sufferers to fall into a deep 'sleep' while still being aware of their surroundings can offer us insight into the nature of Parkinson's disease. Dr Paul Foley from Neuroscience Research Australia says the pandemic of encephalitis lethargica, which swept the world in the 1920s, caused Parkinson's-like symptoms in many sufferers, most of whom were less than 30 years old... (Source: Health News from Medical News Today)

Microfluidics to diagnose sleeping sickness

Chemistry World | Latest News — Wed, 23 Mar 2011 01:10:42 +0100

An understanding of the physics of particle sorting can help separate parasites from blood for clearer analysis (Source: Chemistry World | Latest News)

Plant Extracts, Isolated Phytochemicals, and Plant-Derived Agents Which Are Lethal to Arthropod Vectors of Human Tropical Diseases - A Review

Planta Medica — Tue, 22 Mar 2011 00:00:00 +0100

Planta MedDOI: 10.1055/s-0030-1270949AbstractThe recent scientific literature on plant-derived agents with potential or effective use in the control of the arthropod vectors of human tropical diseases is reviewed. Arthropod-borne tropical diseases include: amebiasis, Chagas disease (American trypanosomiasis), cholera, cryptosporidiosis, dengue (hemorrhagic fever), epidemic typhus (Brill-Zinsser disease), filariasis (elephantiasis), giardia (giardiasis), human African trypanosomiasis (sleeping sickness), isosporiasis, leishmaniasis, Lyme disease (lyme borreliosis), malaria, onchocerciasis, plague, recurrent fever, sarcocystosis, scabies (mites as causal agents), spotted fever, toxoplasmosis, West Nile fever, and yellow fever. Thus, coverage was given to work describing plant-derived extract...

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Influence of trypanocidal therapy on the haematology of vervet monkeys experimentally infected with Trypanosoma brucei rhodesiense.

Acta Tropica — Mon, 21 Mar 2011 00:00:00 +0100

Authors: Ngotho M, Kagira JM, Kariuki C, Maina N, Thuita JK, Mwangangi DM, Farah IO, Hau J The aim of this study was to characterise the sequential haematological changes in vervet monkeys infected with Trypanosoma brucei rhodesiense and subsequently treated with sub-curative diminazene aceturate (DA) and curative melarsoprol (MelB) trypanocidal drugs. Fourteen vervet monkeys, on a serial timed-kill pathogenesis study, were infected intravenously with 10(4) trypanosomes of a stabilate T. b. rhodesiense KETRI 2537. They were treated with DA at 28 days post infection (dpi) and with MelB following relapse of infection at 140 dpi. Blood samples were obtained from the monkeys weekly, and haematology conducted using a haematological analyser. All the monkeys developed a disease associated wi...

Prevention and control of malaria and sleeping sickness in Africa: Where are we and where are we going?

Parasites and Vectors — Wed, 16 Mar 2011 00:00:00 +0100

The International Symposium on Malaria and Human African Trypanosomiasis: New Strategies for their Prevention & Control was held 7- 8 October, 2010 in Cotonou, Benin with about 250 participants from 20 countries. This scientific event aimed at identifying the gaps and research priorities in the prevention and control of malaria and sleeping sickness in Africa and to promote exchange between North and South in the fields of medical entomology, epidemiology, immunology and parasitology. A broad range of influential partners from academia (scientists), stakeholders, public health workers and industry attempted the meeting and about 40 oral communications and 20 posters were presented by phD students and internationally-recognized scientists from the North and the South. Finally, a special awa...

Trypanocidal furamidine analogues: influence of pyridine nitrogens on trypanocidal activity, transport kinetics and resistance patterns.

Antimicrobial Agents and Chemotherapy — Mon, 14 Mar 2011 00:00:00 +0100

Authors: Ward CP, Wong PE, Burchmore RJ, de Koning HP, Barrett MP Current therapies for Human African trypanosomiasis (HAT) are unsatisfactory and under threat from emerging drug resistance linked to the loss of transporters e.g. the P2 aminopurine transporter (TbAT1). Here we compare the uptake and trypanocidal properties of furamidine (DB75), recently evaluated in clinical trials against stage 1 (haemolymphatic) HAT, and two aza analogues, DB820 and CPD0801 (DB829) which are candidate compounds against stage 2 (neurological) disease. IC50 values determined in vitro were sub-micromolar against both wild-type and transporter mutant parasites, with DB75 displaying better and DB820 similar trypanotoxicity compared to the widely used veterinary trypanocide diminazene, while CPD0801 was le...

State of the Art in African Trypanosome Drug Discovery.

Current Topics in Medicinal Chemistry — Mon, 14 Mar 2011 00:00:00 +0100

Authors: Jacobs RT, Nare B, Phillips MA African sleeping sickness is endemic in sub-Saharan Africa where the WHO estimates that 60 million people are at risk for the disease. Human African trypanosomiasis (HAT) is 100% fatal if untreated and the current drug therapies have significant limitations due to toxicity and difficult treatment regimes. No new chemical agents have been approved since eflornithine in 1990. The pentamidine analog DB289, which was in late stage clinical trials for the treatment of early stage HAT recently failed due to toxicity issues. A new protocol for the treatment of late-stage T. brucei gambiense that uses combination nifurtomox/eflornithine (NECT) was recently shown to have better safety and efficacy than eflornithine alone, while being easier to administer....

Finding New Hits in Neglected Disease Projects: Target or Phenotypic Based Screening?

Current Topics in Medicinal Chemistry — Mon, 14 Mar 2011 00:00:00 +0100

Authors: Gilbert IH, Leroy D, Frearson JA In this article, we discuss the merits of both target-based and phenotypic screening strategies to find starting points for drug discovery projects in neglected tropical disease including: human African trypanosomiasis, Chagas disease, leishmaniasis and malaria. Techological advances now mean that it is possible to undertake high quality screens against isolated molecular targets at considerable scale. However target selection is a minefield of potential issues and often molecules identified and developed as potent inhibitors of targets do not translate into actives against the whole parasite. The potential for rapid resistance development is also a key issue when tackling individual molecular targets. In phenotypic screening, compounds are scr...

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Bacterial Diversity Associated with Populations of Glossina spp. from Cameroon and Distribution within the Campo Sleeping Sickness Focus.

Microbial Ecology — Wed, 09 Mar 2011 00:00:00 +0100

Authors: Geiger A, Fardeau ML, Njiokou F, Joseph M, Asonganyi T, Ollivier B, Cuny G Tsetse flies were sampled in three villages of the Campo sleeping sickness focus in South Cameroon. The aim of this study was to investigate the flies' gut bacterial composition using culture-dependent techniques. Out of the 32 flies analyzed (27 Glossina palpalis palpalis, two Glossina pallicera, one Glossina nigrofusca, and two Glossina caliginea), 17 were shown to be inhabited by diverse bacteria belonging to the Proteobacteria, the Firmicutes, or the Bacteroidetes phyla. Phylogenetic analysis based on 16S rRNA gene sequences indicated the presence of 16 bacteria belonging to the genera Acinetobacter (4), Enterobacter (4), Enterococcus (2), Providencia (1), Sphingobacterium (1), Chryseobacterium (1),...

Guinea: Tsetse Fly 'On Verge of Elimination'

AllAfrica News: Health and Medicine — Fri, 04 Mar 2011 03:30:30 +0100

Scientists are hopeful that they have for the first time eliminated tsetse flies, which carry sleeping sickness, following an innovative control campaign on a group of islands off West Africa. (Source: AllAfrica News: Health and Medicine)

Quinols Inhibit the Trypanothione Peroxidase System [Enzymology]

Journal of Biological Chemistry — Fri, 04 Mar 2011 00:00:00 +0100

Better drugs are urgently needed for the treatment of African sleeping sickness. We tested a series of promising anticancer agents belonging to the 4-substituted 4-hydroxycyclohexa-2,5-dienones class (“quinols”) and identified several with potent trypanocidal activity (EC50 < 100 nm). In mammalian cells, quinols are proposed to inhibit the thioredoxin/thioredoxin reductase system, which is absent from trypanosomes. Studies with the prototypical 4-benzothiazole-substituted quinol, PMX464, established that PMX464 is rapidly cytocidal, similar to the arsenical drug, melarsen oxide. Cell lysis by PMX464 was accelerated by addition of sublethal concentrations of glucose oxidase implicating oxidant defenses in the mechanism of action. Whole cells treated with PMX464 showed a loss of trypanot...

Human host determinants influencing the outcome of T. b. gambiense infections

Parasite Immunology — Tue, 01 Mar 2011 00:00:00 +0100

AbstractSince first identified, Human African trypanosomiasis (HAT) or sleeping sickness has been described as invariably fatal. Increasing data however argue that infection by Trypanosoma brucei gambiense, the causative agent of HAT, results in a wide range of outcomes in its human host and importantly that a number of subjects in endemic areas are apparently able to control infection to low levels, undetectable by the classical parasitological tests used in the field. Thus trypanotolerance seems to occur in humans as has already been described in cattle or in the rodent experimental models of infection. This review focuses on the description of the diversity of outcomes resulting from T.b. gambiense in humans and on the host factors involved. The consequences/impacts on HAT epidemiology ...

Trypanosoma brucei s.l.: Microsatellite markers revealed high level of multiple genotypes in the mid-guts of wild tsetse flies of the Fontem sleeping sickness focus of Cameroon.

Experimental Parasitology — Tue, 01 Mar 2011 00:00:00 +0100

Authors: Simo G, Njitchouang GR, Njiokou F, Cuny G, Asonganyi T To identify Trypanosoma brucei genotypes which are potentially transmitted in a sleeping sickness focus, microsatellite markers were used to characterize Trypanosoma brucei found in the mid-guts of wild tsetse flies of the Fontem sleeping sickness focus in Cameroon. For this study, two entomological surveys were performed during which 2685 tsetse flies were collected and 1596 (59.2%) were dissected. Microscopic examination revealed 1.19% (19/1596) mid-gut infections with trypanosomes; the PCR method identified 4.7% (75/1596) infections with Trypanosoma brucei in the mid-guts. Of these 75 trypanosomes identified in the mid-guts, Trypanosoma brucei gambiense represented 0.81% (13/1596) of them, confirming the circulation of ...

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Comparison of major immunoglobulins intrathecal synthesis patterns in ecuadorian and cuban patients with angiostrongyliasis.

The American Journal of Tropical Medicine and Hygiene — Tue, 01 Mar 2011 00:00:00 +0100

Authors: Padilla-Docal B, Dorta-Contreras AJ, Moreira JM, Martini-Robles L, Muzzio-Aroca J, Alarcón F, Magraner-Tarrau ME, Bu-Coifiu-Fanego R Abstract. Angiostrongylus cantonensis meningitis was first reported in Cuba in 1981, and it was recently reported in South America. The aim of this paper is to evaluate the intrathecal immunoglobulin synthesis patterns from Cuba's and Ecuador's patients with angiostrongyliasis; 8 Ecuadorian patients from two different outbreaks and 28 Cuban patients were studied. Simultaneous blood and cerebrospinal fluid simples were taken. Immunoglobulin (Ig) A, IgM, IgG, and albumin were quantified by radial immunodiffusion. Corresponding Reibergrams were applied. A three-Ig pattern was the most frequent in the two groups, but IgM was presented in all Ecuador...

Disappearance of some human African trypanosomiasis transmission foci in Zambia in the absence of a tsetse fly and trypanosomiasis control program over a period of forty years

Transactions of the Royal Society of Tropical Medicine and Hygiene — Tue, 01 Mar 2011 00:00:00 +0100

Summary: We conducted a situation analysis of human African trypanosomiasis (HAT) in Zambia from January 2000 to April 2007. The aim of this survey was to identify districts in Zambia that were still recording cases of HAT. Three districts namely, Mpika, Chama, and Chipata were found to be still reporting cases of HAT and thus lay in HAT transmission foci in North Eastern Zambia. During the period under review, 24 cases of HAT were reported from these three districts. We thereafter reviewed literature on the occurrence of HAT in Zambia from the early 1960s to mid 1990s. This revealed that HAT transmission foci were widespread in Western, North Western, Lusaka, Eastern, Luapula, and Northern Provinces of Zambia during this period. In this article we have tried to give possible reasons as to...

1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis.

European Journal of Medicinal Chemistry — Thu, 24 Feb 2011 00:00:00 +0100

Authors: Trunz BB, Jędrysiak R, Tweats D, Brun R, Kaiser M, Suwiński J, Torreele E Nitroimidazoles are a well-known class of antibacterial and antiprotozoal drugs but in spite of the widespread clinical and veterinary use of these drugs, this family has been stigmatized in part due to associated genotoxicity problems. Here we report the synthesis, the anti-trypanosomal activity and a structure-activity relationship (SAR) study of a series of about fifty 1-aryl-4-nitro-1H-imidazoles, with an emphasis on selected in vivo active molecules. Compounds 4-nitro-1-{4-(trifluoromethoxy)phenyl}-1H-imidazole and 1-(3,4-dichlorophenyl)-4-nitro-1H-imidazole are curative in mouse models of both acute and chronic African trypanosomiasis when given orally at doses of 25-50 mg/kg for 4 days for the ...

Trypanosoma brucei gambiense: HMI-9 medium containing methylcellulose and human serum supports the continuous axenic in vitro propagation of the bloodstream form.

Experimental Parasitology — Thu, 24 Feb 2011 00:00:00 +0100

The objective of this study was to evaluate if an established method for axenic culture of pleomorphic bloodstream form T.b. brucei strains, based on methylcellulose containing HMI-9 medium, also facilitated the continuous in vitro propagation of other bloodstream form Trypanozoon strains, in particular of T.b. gambiense. Bloodstream form trypanosomes from one T.b. brucei, two T.b. rhodesiense, one T. evansi and seven T.b. gambiense strains were isolated from mouse blood and each was concurrently cultivated in liquid and methylcellulose-containing HMI-9 based medium, either with or without additional human serum supplementation, for over 10 consecutive sub passages. Although HMI-9 based medium supplemented with 1.1% (w/v) methylcellulose supported the continuous cultivation of all non-gamb...

New Face Of Sleeping Sickness Epidemiology Highlights Need For New Tools

Health News from Medical News Today — Wed, 23 Feb 2011 12:00:00 +0100

Recent developments have rekindled hopes of eliminating human African trypanosomiasis (HAT), more familiarly known as sleeping sickness, as a public health problem in those areas of sub-Saharan Africa where the disease is endemic... (Source: Health News from Medical News Today)

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Solving the Sleeping Sickness 'Mystery'

NIGMS Computing Life — Tue, 22 Feb 2011 17:00:00 +0100

Despite public health campaigns that explain ways to stop infection, successfully eradicating sleeping sickness in Africa has remained out of reach. That's partly because epidemiologists can't predict where cases will emerge next. Now, an effort to map the distribution of the fly that spreads the disease may finally offer relief. (Source: NIGMS Computing Life)

New face of sleeping sickness epidemiology highlights need for new tools

EurekAlert! - Infectious and Emerging Diseases — Tue, 22 Feb 2011 05:00:00 +0100

(Public Library of Science) Recent developments have rekindled hopes of eliminating human African trypanosomiasis, more familiarly known as sleeping sickness, as a public health problem in those areas of sub-Saharan Africa where the disease is endemic. (Source: EurekAlert! - Infectious and Emerging Diseases)

Study Illuminating Trypanosome Reproduction May Lead To Treatments For Sleeping Sickness

Health News from Medical News Today — Mon, 21 Feb 2011 08:00:00 +0100

Compelling visual evidence of sexual reproduction in African trypanosomes, single-celled parasites that cause major human and animal diseases, has been found by researchers from the University of Bristol. The research could eventually lead to new approaches for controlling sleeping sickness in humans and wasting diseases in livestock which are caused by trypanosomes carried by the bloodsucking tsetse fly... (Source: Health News from Medical News Today)

Shining a light on trypanosome reproduction

University of Bristol news — Thu, 17 Feb 2011 15:55:04 +0100

Compelling visual evidence of sexual reproduction in African trypanosomes, single-celled parasites that cause major human and animal diseases, has been found by researchers from the University of Bristol. The research could eventually lead to new approaches for controlling sleeping sickness which is caused by trypanosomes carried by the bloodsucking tsetse fly. (Source: University of Bristol news)

Temporal stability of Glossina fuscipes fuscipes populations in Uganda

Parasites and Vectors — Mon, 14 Feb 2011 00:00:00 +0100

Conclusion: Our results suggest that populations of G. f. fuscipes were stable over the 8-12 generations studied. Future studies should aim to reconcile these data with observed seasonal fluctuations in the apparent density of tsetse. (Source: Parasites and Vectors)

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Progress towards the eradication of Tsetse from the Loos islands, Guinea

BioMed Central — Thu, 10 Feb 2011 00:00:00 +0100

Conclusions: This 100% suppression is a promising step in the eradication process, but G. p. gambiensis may still occur at very low, undetectable, densities on the archipelago. Next step will consist in assessing a 0.05 probability of tsetse absence to ascertain a provisional eradication status. Throughout these operations, a key factor has been the involvement of local teams and local communities without whom such results would be impossible to obtain. Work will continue thanks to the partners involved until total eradication of the tsetse on Loos islands can be declared. (Source: BioMed Central)

Transcriptomics and Proteomics in Human African Trypanosomiasis: current status and perspectives.

Journal of Proteomics — Thu, 10 Feb 2011 00:00:00 +0100

The objective of these technologies is to significantly increase our knowledge of the molecular mechanisms governing the parasite establishment in its vector, the development cycle of the parasite during the parasite's intra-vector life, its interactions with the fly and the other microbial inhabitants of the gut, and finally human host-trypanosome interactions. Such fundamental investigations are expected to provide opportunities to identify key molecular events that would constitute accurate targets for further development of tools dedicated to field work for early, sensitive, and stage-discriminant diagnosis, epidemiology, new chemotherapy, and potentially vaccine development, all of which will contribute to fighting the disease. The present review highlights the contributions of the tr...

Requirement for Acetyl‐CoA Carboxylase in Trypanosoma brucei is Dependent Upon the Growth Environment

Molecular Microbiology — Wed, 09 Feb 2011 00:00:00 +0100

SummaryTrypanosoma brucei, the causative agent of human African trypanosomiasis, possesses two fatty acid synthesis pathways: a major de novo synthesis pathway in the ER and a mitochondrial pathway. The 2‐carbon donor for both pathways is malonyl‐CoA, which is synthesized from acetyl‐CoA by Acetyl‐CoA Carboxylase (ACC). Here, we show that T. brucei ACC shares the same enzyme architecture and moderate ∼30% identity with yeast and human ACCs. ACC is cytoplasmic and appears to be distributed throughout the cell in numerous puncta distinct from glycosomes and other organelles. ACC is active in both bloodstream and procyclic forms. Reduction of ACC activity by RNA interference (RNAi) resulted in a stage‐specific phenotype. In procyclic forms, ACC RNAi resulted in 50‐75% reductio...

Improved inhibitors of trypanothione reductase by combination of motifs: synthesis, inhibitory potency, binding mode, and antiprotozoal activities.

ChemMedChem — Mon, 07 Feb 2011 00:00:00 +0100

Authors: Eberle C, Lauber BS, Fankhauser D, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F 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 optimize their structures. We analyzed the binding mode of recently reported 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues using computer modeling methods. This led us to conclude that ...