162 research outputs found
Progress towards new treatments for human African trypanosomiasis
No full textThe treatment of African trypanosomiasis has essentially remained unchanged for decades. A mountain of excellent work has been produced on many aspects of trypanosome biochemistry, biology, genetics, etc., but this has not translated into new therapies, although the disease burden has steadily increased through the latter half of the twentieth century. The only new drug to be introduced in the last 50 years or so is eflornithine, in the late 1970s, for the treatment of late-stage gambiense sleeping sickness only. However, this was in many ways unsatisfactory and melarsoprol remained the first-line treatment for late-stage sleeping sickness until an alarming increase in treatment failures necessitated change. Since the emerging sleeping sickness epidemic became widely recognised, around the year 2000, needs-driven development of new drugs, and the preservation of the production of old drugs, has been the result of dedicated work by organisations such as the World Health Organisation, the Drugs for Neglected Diseases initiative (DNDi), the Access to Essential Medicines campaign, and the Consortium for Parasitic Drug Development (CPDD) among others, much of it in partnership with academia and the pharmaceutical industry. This has already resulted in milestones such as the donations of free treatments by producers; improved drug distribution, case finding and clinical care; an improved 10-day melarsoprol treatment; the first clinical trial for an oral sleeping sickness drug—pafuramidine and the introduction of eflornithine–nifurtimox combination therapy to begin replacing melarsoprol. While these efforts have undoubtedly contributed to reducing the disease burden in central Africa, newer treatments are still very necessary, especially as most current treatments are threatened by drug resistance. Here, we review recent advances in understanding drug resistance mechanisms, progress towards new drugs, and new delivery systems to improve efficacy
Normal human serum lysis of non-human trypanosomes and resistance of <i>T. b. rhodesiense</i> and <i>T. b. gambiense</i>
No full text<i>Trypanosoma brucei</i> can be segregated into three morphologically identical sub-species based on host, geography and pathology. <i>T. b. Brucei</i> is limited to domestic and wild animals throughout sub-Saharan Africa and is non-infective to humans due to trypanosome lytic factors found in human serum. There are two trypanosome lytic factors in human serum (TLF-1 & 2), both containing the proteins Apolipoprotein L1 (APOL1) and Haptoglobin-related protein (HPR). It has been conclusively demonstrated that the lytic component of TLF is APOL1, although HPR is required for maximal lysis by facilitating uptake of TLF particles via the HpHbR cell surface receptor. <i>T. b. Gambiense</i> and <i>T. b. Rhodesiense</i> are able to resist these lytic factors to cause human African sleeping sickness. <i>T. b. Rhodesiense</i> is able to neutralise APOL1 due to expression of Serum Resistance-Associated gene (SRA). SRA is not found in the more prevalent human infective sub-species, <i>T. b. Gambiense</i>, which causes over 97 % of reported human cases. Study of <i>T. b. Gambiense</i> is complicated in that there are two distinct groups. Group 1 is invariably resistant to lysis and by far the more prevalent group. Group 2 <i>T. b. Gambiense</i> exhibit a variable resistance phenotype and are only found at a small number of Côte d’Ivoire and Burkina Faso foci. Little is known as to how both groups are able to resist lysis by normal human serum; however, members of group 1 <i>T. b. Gambiense</i> display both reduced expression and activity of HpHbR that may contribute to the resistance phenotype
Withstanding the challenges of host immunity: Antigenic variation and the trypanosome surface coat
Get PDFProlonged survival in the face of host immunity has been a major force shaping the biology and evolution of the African trypanosomes, and nowhere are the effects of this force more apparent than in the antigenic variation of the trypanosome variant surface glycoprotein (VSG) coat. The coat protects the trypanosome within it from immune effectors, and spontaneous and stochastic events occurring at the molecular level cause individual trypanosomes to change the VSG variant they are expressing. The consequence of this switching at the population level is a diverse population that can pre-empt the specific immune responses that arise against VSG. The template for changes to VSG is an extensive archive of silent VSG genes and pseudogenes. VSG from the archive are activated not only as full-length genes but also through the combination of segments to form mosaic VSG genes, a process that augments the potential for antigenic variation by introducing combinatorial variation and allowing VSG pseudogenes to be used. The main part of the archive occupies subtelomeres and so is itself prone to mutation and rapid evolution, which are important features when superinfection or reinfection of partially immune hosts is necessary. The antigenic variation 'diversity phenotype' is thus a multifaceted one, enlisting and coordinating fundamental mechanisms of cell biology to bring about a process that unfolds across populations, thereby facilitating the success of the African trypanosomes
Chronic pathology of experimental Trypanosoma evansi infection is the combined result of an extra-medullary erythropoiesis abrogation, a failing host B cell response, and the induction of a unique Th1 cell population
No full textTrypanosoma evansi (T. evansi) parasieten worden in verschillende delen van de wereld aangetroffen en infecteren meerdere diersoorten. In zeldzame gevallen worden zelfs menselijke infecties gemeld. Bij vee veroorzaakt de infectie een chronische ziekte, ‘surra’ genaamd. Wanneer een dier door T. evansi parasieten geïnfecteerd wordt, kan deze laatste niet alleen ontsnappen aan het immuunsysteem van de gastheer, maar vernietigt ook het B-cel geheugen, waardoor zelfs het beschermende effect van vaccines tegen andere ziektes uitgewist wordt. Ondanks de ernstige gevolgen van surra is er momenteel geen vaccin tegen T. evansi infecties. Daarom is het cruciaal om de mechanismen te begrijpen die betrokken zijn bij onderdrukking van het immuunsysteem van de gastheer. Door het screenen van 10 veldisolaten van T. evansi met verschillende virulentieniveaus, identificeerde dit doctoraatsonderzoek een experimenteel ziektemodel dat de belangrijkste kenmerken van natuurlijke chronische vee infecties nabootst. Single cell RNA sequencing (scRNA-seq) en andere op eiwitten gebaseerde analyses van dit model geven nu een nieuw diepgaand inzicht op cellulair niveau, in de interactie tussen de parasiet en de immuniteit van de gastheer. De verkregen resultaten tonen aan dat de spierafbraak, waargenomen bij chronisch geïnfecteerde muizen, wordt veroorzaakt door een verhoging van het melkzuurgehalte in het bloed. Deze toename houdt verband met aanhoudende bloedarmoede. Dit laatste wordt veroorzaakt door het falen van het beenmerg en de milt om voldoende rode bloedcellen aan te maken tijdens infectie. Bovendien wordt, naarmate de infectie voortschrijdt, de humorale immuunrespons vernietigd door de uitputting van de B-cel pool, de cellen verantwoordelijk voor de productie van antilichamen
Emerging trends in the diagnosis of human African trypanosomiasis
No full textHuman African trypanosomiasis (HAT) or sleeping sickness is caused by protozoan parasites Trypanosoma brucei gambiense and T. b. rhodesiense. Despite the enormous technological progress in molecular parasitology in recent years, the diagnosis of HAT is still problematic due to the lack of specific tools. To date, there are two realities when it comes to HAT; the first one being the world of modern experimental laboratories, equipped with the latest state-of-the-art technology, and the second being the world of HAT diagnosis, where the latest semi-commercial test was introduced 30 years ago (Magnus et al. 1978). Hence, it appears that the lack of progress in HAT diagnosis is not primarily due to a lack of scientific interest or a lack of research funds, but mainly results from the many obstacles encountered in the translation of basic research into field-applicable diagnostics. This review will provide an overview of current diagnostic methods and highlight specific difficulties in solving the shortcomings of these methods. Future perspectives for accurate, robust, affordable diagnostics will be discussed as well
Role of heat shock protein 60 and the variant surface glycoprotein in immunomodulation and uptake of host macromolecules
No full textDoctorat en Sciencesinfo:eu-repo/semantics/nonPublishe
African trypanosomiasis and antibodies : implications for vaccination, therapy and diagnosis
No full textAfrican trypanosomiasis causes devastating effects on human populations and livestock herds in large parts of sub-Saharan Africa. Control of the disease is hampered by the lack of any efficient vaccination results in a field setting, and the severe side effects of current drug therapies. In addition, with the exception of Trypanosoma brucei gambiense infections, the diagnosis of trypanosomiasis has to rely on microscopic analysis of blood samples, as other specific tools are nonexistent, However, new developments in biotechnology, which include loop-mediated isothermal amplification as an adaptation to conventional PCR, as well as the antibody engineering that has allowed the development of Nanobody (R) technology, offer new perspectives in both the detection and treatment of trypanosomiasis. In addition, recent data on parasite-induced B-cell memory destruction offer new insights into mechanisms of vaccine failure, and should lead us towards new strategies to overcome trypanosome defenses operating against the host immune system
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Andlegt ofbeldi gegn börnum: Birtingarmyndir, afleiðingar og langtímaáhrif
No full textÍ ritgerð þessari verður fjallað um andlegt ofbeldi gegn börnum af hendi foreldra. Farið verður yfir mismunandi birtingarmyndir andlegs ofbeldis auk þeirra orsaka, afleiðinga og langtímaáhrifa sem það hefur í för með sér. Einnig verður varpað ljósi á það sem einkennir börn sem þolendur andlegs ofbeldis og foreldra sem gerendur þess. Svo hægt sé að setja viðfangsefnið í samhengi verður fjallað um fræðilegar kenningar og líkön. Tengslakenningu Bowlby, fjölskyldukerfiskenningu Bowen, vistfræðikenningu Bronfenbrenner og vistfræðilíkan Belsky. Þessar kenningar snerta allar á mismunandi áhrifaþáttum í lífum barna sem hafa mismunandi verkun. Einnig verður snert á líkani Maccoby og Martins sem snýr að fari foreldra og þeim afstöðum og uppeldisháttum sem foreldrar notast við hverju sinni. Auk fræðilegs samhengis verður rýnt í tölfræði frá Barna- og fjölskyldustofu um fjölda tilkynninga til barnaverndarnefnda um misbrest í uppeldi barna og hvernig verkferlar barnaverndarnefnda fara fram þegar mál er tekið til skoðunar. Starf félagsráðgjafa snýr að miklu leyti að vinnu með börnum og fjölskyldum þeirra. Þá er mikilvægt að fagaðilar notist við gagnreyndar vinnuaðferðir í starfi sínu og hafi viðeigandi þekkingu og hæfni til að sinna því. Vegna þess verður varpað ljósi á niðurstöður rannsókna sem snúa að mati fagaðila á eigin hæfni til vinnu með fjölskyldum, þar sem börn verða fyrir andlegu ofbeldi.
Megin niðurstöður ritgerðarinnar sýndu fram á að andlegt ofbeldi gagnvart barni geti komið fram í ýmsum birtingarmyndum, svo sem hunsun eða sífelldri niðurlægingu. Afleiðingar þess geta skert lífsgæði barna og stuðlað að kvíða, hræðslu og námsörðugleikum. Jafnframt geta langtímaáhrif andlegs ofbeldis í æsku haft veruleg áhrif á líf fullorðinna einstaklinga, til dæmis hvað varðar geðheilbrigði og tengslamyndun
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