Treatment of many infectious diseases is under threat from drug resistance. Understanding the mechanisms of resistance is as high a priority as the development of new drugs. We have investigated the basis for cross-resistance between the diamidine and melaminophenyl arsenical classes of drugs in African trypanosomes. We induced high levels of pentamidine resistance in a line without the tbat1 gene that encodes the P2 transporter previously implicated in drug uptake. We isolated independent clones that displayed very considerable crossresistance with melarsen oxide but not phenylarsine oxide and reduced uptake of [ 3 H]pentamidine. In particular, the highaffinity pentamidine transport (HAPT1) activity was absent in the pentamidine-adapted lines, whereas the low affinity pentamidine transport (LAPT1) activity was unchanged. The parental tbat1 Ϫ/Ϫ line was sensitive to lysis by melarsen oxide, and this process was inhibited by low concentrations of pentamidine, indicating the involvement of HAPT1. This pentamidine-inhibitable lysis was absent in the adapted line KO-B48. Likewise, uptake of the fluorescent diamidine 4Ј,6-diamidino-2-phenylindole dihydrochloride was much delayed in live KO-B48 cells and insensitive to competition with up to 10 M pentamidine. No overexpression of the Trypanosoma brucei brucei ATPbinding cassette transporter TbMRPA could be detected in KO-B48. We also show that a laboratory line of Trypanosoma brucei gambiense, adapted to high levels of resistance for the melaminophenyl arsenical drug melarsamine hydrochloride (Cymelarsan), had similarly lost TbAT1 and HAPT1 activity while retaining LAPT1 activity. It seems therefore that selection for resistance to either pentamidine or arsenical drugs can result in a similar phenotype of reduced drug accumulation, explaining the occurrence of cross-resistance.Trypanosoma brucei subspp. are protozoan parasites that cause human African trypanosomiasis (i.e., sleeping sickness) and the corresponding veterinary condition in livestock. Treatment of both the human and livestock diseases depends on a very small set of mostly very old drugs. The first-line treatment for the late stage of both West African and East African human African trypanosomiasis is melarsoprol, an organoarsenic compound of the melaminophenyl arsenical class, introduced in 1949 (Jannin and Cattand, 2004). A similar but water-soluble melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), is increasingly used for animal trypanosomiasis. Early-stage West African sleeping sickness is routinely treated with the diamidine drug pentamidine, introduced in 1937 (Jannin and Cattand, 2004). The corresponding widely used veterinary diamidine is diminazene aceturate (Berenil). The only new trypanocide to be developed in recent decades, DB75, is also a diamidine and currently in clinical trials as an orally available prodrug.It has been known for decades that cross-resistance between melaminophenyl arsenicals and diamidine drugs sometimes occurs (Fulton and Grant, 1955;Williamson a...
BackgroundThe Hygiene Hypothesis proposes that infection exposure protects against inflammatory conditions. Helminths possess allergen-like molecules and may specifically modulate allergy-related immunological pathways to inhibit responses which protect against them. Mass drug administration is recommended for helminth-endemic communities to control helminth-induced pathology, but may also result in increased rates of inflammation-mediated diseases in resource-poor settings. Immunological studies integrated with implementation of helminth control measures may elucidate how helminth elimination contributes to ongoing epidemics of inflammatory diseases. We present the design of the Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA), a cluster-randomised trial evaluating the risks and benefits of intensive versus standard anthelminthic treatment for allergy-related diseases and other health outcomes.Methods/DesignThe setting is comprised of island fishing communities in Mukono district, Uganda. Twenty-six communities have been randomised in a 1:1 ratio to receive standard or intensive anthelminthic intervention for a three-year period. Baseline characteristics were collected immediately prior to intervention rollout, commenced in February 2013. Primary outcomes are reported wheeze in the past 12 months and atopy (skin prick test response and allergen-specific immunoglobulin (asIg) E concentration). Secondary outcomes are visible flexural dermatitis, helminth infections, haemoglobin, growth parameters, hepatosplenomegaly, and responses to vaccine antigens. The trial provides a platform for in-depth analysis of clinical and immunological consequences of the contrasting interventions.DiscussionThe baseline survey has been completed successfully in a challenging environment. Baseline characteristics were balanced between trial arms. Prevalence of Schistosoma mansoni, hookworm, Strongyloides stercoralis and Trichuris trichiura was 52%, 23%, 13%, and 12%, respectively; 31% of Schistosoma mansoni infections were heavy (>400 eggs/gram). The prevalence of reported wheeze and positive skin prick test to any allergen was 5% and 20%, respectively. Respectively, 77% and 87% of participants had Dermatophagoides- and German cockroach-specific IgE above 0.35 kUA/L. These characteristics suggest that the LaVIISWA study will provide an excellent framework for investigating beneficial and detrimental effects of worms and their treatment, and the mechanisms of such effects.Trial registrationThis trial was registered with Current Controlled Trials (identifier: ISRCTN47196031) on 7 September 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0702-5) contains supplementary material, which is available to authorized users.
BackgroundParasitic helminths are potent immunomodulators and chronic infections may protect against allergy‐related disease and atopy. We conducted a cross‐sectional survey to test the hypothesis that in heavily helminth‐exposed fishing villages on Lake Victoria, Uganda, helminth infections would be inversely associated with allergy‐related conditions.MethodsA household survey was conducted as baseline to an anthelminthic intervention trial. Outcomes were reported wheeze in last year, atopy assessed both by skin prick test (SPT) and by the measurement of allergen‐specific IgE to dust mites and cockroach in plasma. Helminth infections were ascertained by stool, urine and haemoparasitology. Associations were examined using multivariable regression.ResultsTwo thousand three hundred and sixteen individuals were surveyed. Prevalence of reported wheeze was 2% in under‐fives and 5% in participants ≥5 years; 19% had a positive SPT; median Dermatophagoides‐specific IgE and cockroach‐specific IgE were 1440 and 220 ng/ml, respectively. S. mansoni, N. americanus, S. stercoralis, T. trichiura, M. perstans and A. lumbricoides prevalence was estimated as 51%, 22%, 12%, 10%, 2% and 1%, respectively. S. mansoni was positively associated with Dermatophagoides‐specific IgE [adjusted geometric mean ratio (aGMR) (95% confidence interval) 1.64 (1.23, 2.18)]; T. trichiura with SPT [adjusted odds ratio (aOR) 2.08 (1.38, 3.15)]; M. perstans with cockroach‐specific IgE [aGMR 2.37 (1.39, 4.06)], A. lumbricoides with wheeze in participants ≥5 years [aOR 6.36 (1.10, 36.63)] and with Dermatophagoides‐specific IgE [aGMR 2.34 (1.11, 4.95)]. No inverse associations were observed.ConclusionsContrary to our hypothesis, we found little evidence of an inverse relationship between helminths and allergy‐related outcomes, but strong evidence that individuals with certain helminths were more prone to atopy in this setting.
Background: There is exponential growth in the interest and implementation of genomics research in Africa. This growth has been facilitated by the Human Hereditary and Health in Africa (H3Africa) initiative, which aims to promote a contemporary research approach to the study of genomics and environmental determinants of common diseases in African populations. Objective: The purpose of this article is to describe important challenges affecting genomics research implementation in Africa. Methods: The observations, challenges and recommendations presented in this article were obtained through discussions by African scientists at teleconferences and face-to-face meetings, seminars at consortium conferences and in-depth individual discussions. Results: Challenges affecting genomics research implementation in Africa, which are related to limited resources include ill-equipped facilities, poor accessibility to research centers, lack of expertise and an enabling environment for research activities in local hospitals. Challenges related to the research study include delayed funding, extensive procedures and interventions requiring multiple visits, delays setting up research teams and insufficient staff training, language barriers and an underappreciation of cultural norms. While many African countries are struggling to initiate genomics projects, others have set up genomics research facilities that meet international standards. Conclusions: The lessons learned in implementing successful genomics projects in Africa are recommended as strategies to overcome these challenges. These recommendations may guide the development and application of new research programs in low-resource settings.
OBJECTIVESRecent reports suggest that Schistosoma infection may increase the risk of acquiring human immunodeficiency virus (HIV). We used data from a large cross-sectional study to investigate whether Schistosoma mansoni infection is associated with increased HIV prevalence.METHODSWe conducted a household survey of residents in island fishing communities in Mukono district, Uganda, between October 2012 and July 2013. HIV status was assessed using rapid test kits. Kato-Katz (KK) stool tests and urine-circulating cathodic antigen (CCA) were used to test for Schistosoma infection. Multivariable logistic regression, allowing for the survey design, was used to investigate the association between S. mansoni infection and HIV infection.RESULTSData from 1412 participants aged 13 years and older were analysed (mean age 30.3 years, 45% female). The prevalence of HIV was 17.3%. Using the stool Kato-Katz technique on a single sample, S. mansoni infection was detected in 57.2% (719/1257) of participants; urine CCA was positive in 73.8% (478/650) of those tested. S. mansoni infection was not associated with HIV infection. [KK (aOR = 1.04; 95% CI: 0.74–1.47, P = 0.81), CCA (aOR = 1.53; 95% CI: 0.78–3.00, P = 0.19)]. The median S. mansoni egg count per gram was lower in the HIV-positive participants (P = 0.005).CONCLUSIONSThese results add to the evidence that S. mansoni has little effect on HIV transmission, but may influence egg excretion.
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