Traditional/alternative medicines and the right to health : key elements for a convention on global health

Little has been done to investigate and promote the importance of non-conventional medicines (NCMs) in the realization of the right to health, yet all over the world people regularly resort to NCMs to secure healing or to prevent or mitigate the occurrence of a wide range of morbidities. This study aims to elucidate the theoretical framework of the role of NCMs in realizing the right to health, to identify the potential manifestations and causes of violations of the right to health in their practice, and to propose the practice of NCMs that could be included in a Framework Convention on Global Health. We use both the documentary analysis and the violation of rights approaches. Through a non-directive review of the literature, we have tried to clarify the concepts and uniqueness of NCMs. We have also tried to unveil the challenges facing NCMs in a context where conventional medicines assume extensive power. The human rights approach has enabled us to bring to light the potential challenges to the rights of the various stakeholders that NCMs create. We argue that NCMs can contribute to realizing the right to health through their availability, accessibility, acceptability, and relative quality. The Framework Convention on Global Health could contribute to the effective realization of this right by integrating basic principles to ensure the recognition, protection, promotion, and conservation of NCMs—at least of those NCMs that have shown evidence of efficacy—as well as catalyzing increased international cooperation in this area

Resolving the apparent transmission paradox of African sleeping sickness

Human African trypanosomiasis (HAT), or African sleeping sickness, is a fatal disease found throughout sub-Saharan Africa. The disease is close to elimination in many areas, although it was similarly close to elimination once before and subsequently reemerged, despite seemingly low rates of transmission. Determining how these foci persisted and overcame an apparent transmission paradox is key to finally eliminating HAT. By assessing clinical, laboratory, and mathematical data, we propose that asymptomatic infections contribute to transmission through the presence of an overlooked reservoir of skin-dwelling parasites. Our assessment suggests that a combination of asymptomatic and parasitaemic cases is sufficient to maintain transmission at foci without animal reservoirs, and we argue that the current policy not to treat asymptomatic HAT should be reconsidered

Caractéristiques des gîtes larvaires associées à la prolifération des vecteurs du paludisme dans la Zone de Santé de Ngaba-Kinshasa

La zone de Ngaba est située dans la Ville de Kinshasa et elle compte une population de 254947dont une large proportion souffre de paludisme (69,1% pour l’année 2017), un taux de loin plus élevé que dans les autres zones de santé environnantes. Cette situation découle d'une importante prolifération des anophèles dans le site. Cette étude est conduite pour explorer et déterminer les facteurs associés à la prolifération des vecteurs du paludisme dans cette zone malgré les conditions environnementales qui s’avèrent défavorables à une telle prolifération. Une meilleure compréhension de ces facteurs va contribuer à une mitigation plus efficace, voire à une élimination de cette condition. Au cours de l’année 2018, nous avons mené un travail de terrain consistant dans la visite de nombreuses gites potentielles de prolifération des anophèles dans cette zone en vue d’y prélever des données sur le type de gîtes, l'origine de l'eau (eau de pluie ou autre), la nature de la collection d'eau (flaque), caractéristiques de l'eau (claire), les paramètres bioécologiques (physico-chimique) des gîtes, l'exposition au soleil (ensoleillé), présence ou non de la végétation, présence des composés organiques (aucune), la nature du sol (humide et marécageux). L’analyse de ces données à travers un modèle multivarié nous a montré que les cours et plans d'eau de Ngaba sont pollués mais les anophèles s'y sont/seraient adaptées. Plusieurs facteurs tels que le type de gîtes, l'origine de l'eau (eau de pluie), la nature de la collection d'eau (flaque), caractéristiques de l'eau (claire), les paramètres bioécologiques (physico-chimique) des gîtes, l'exposition au soleil (ensoleillé), présence de la végétation (aucune couverture végétale), présence des composés organiques (aucune), la nature du sol (humide et marécageux) et la densité larvaire sont présents à Ngaba et sont associés à la prolifération des vecteurs du paludisme.  La zone de Ngaba est située dans la Ville de Kinshasa et elle compte une population de 254947dont une large proportion souffre de paludisme (69,1% pour l’année 2017), un taux de loin plus élevé que dans les autres zones de santé environnantes. Cette situation découle d'une importante prolifération des anophèles dans le site. Cette étude est conduite pour explorer et déterminer les facteurs associés à la prolifération des vecteurs du paludisme dans cette zone malgré les conditions environnementales qui s’avèrent défavorables à une telle prolifération. Une meilleure compréhension de ces facteurs va contribuer à une mitigation plus efficace, voire à une élimination de cette condition. Au cours de l’année 2018, nous avons mené un travail de terrain consistant dans la visite de nombreuses gites potentielles de prolifération des anophèles dans cette zone en vue d’y prélever des données sur le type de gîtes, l'origine de l'eau (eau de pluie ou autre), la nature de la collection d'eau (flaque), caractéristiques de l'eau (claire), les paramètres bioécologiques (physico-chimique) des gîtes, l'exposition au soleil (ensoleillé), présence ou non de la végétation, présence des composés organiques (aucune), la nature du sol (humide et marécageux). L’analyse de ces données à travers un modèle multivarié nous a montré que les cours et plans d'eau de Ngaba sont pollués mais les anophèles s'y sont/seraient adaptées. Plusieurs facteurs tels que le type de gîtes, l'origine de l'eau (eau de pluie), la nature de la collection d'eau (flaque), caractéristiques de l'eau (claire), les paramètres bioécologiques (physico-chimique) des gîtes, l'exposition au soleil (ensoleillé), présence de la végétation (aucune couverture végétale), présence des composés organiques (aucune), la nature du sol (humide et marécageux) et la densité larvaire sont présents à Ngaba et sont associés à la prolifération des vecteurs du paludisme

Neopterin is a cerebrospinal fluid marker for treatment outcome evaluation in patients affected by Trypanosoma brucei gambiense sleeping sickness.

BACKGROUND: Post-therapeutic follow-up is essential to confirm cure and to detect early treatment failures in patients affected by sleeping sickness (HAT). Current methods, based on finding of parasites in blood and cerebrospinal fluid (CSF) and counting of white blood cells (WBC) in CSF, are imperfect. New markers for treatment outcome evaluation are needed. We hypothesized that alternative CSF markers, able to diagnose the meningo-encephalitic stage of the disease, could also be useful for the evaluation of treatment outcome. METHODOLOGY/PRINCIPAL FINDINGS: Cerebrospinal fluid from patients affected by Trypanosoma brucei gambiense HAT and followed for two years after treatment was investigated. The population comprised stage 2 (S2) patients either cured or experiencing treatment failure during the follow-up. IgM, neopterin, B2MG, MMP-9, ICAM-1, VCAM-1, CXCL10 and CXCL13 were first screened on a small number of HAT patients (n = 97). Neopterin and CXCL13 showed the highest accuracy in discriminating between S2 cured and S2 relapsed patients (AUC 99% and 94%, respectively). When verified on a larger cohort (n = 242), neopterin resulted to be the most efficient predictor of outcome. High levels of this molecule before treatment were already associated with an increased risk of treatment failure. At six months after treatment, neopterin discriminated between cured and relapsed S2 patients with 87% specificity and 92% sensitivity, showing a higher accuracy than white blood cell numbers. CONCLUSIONS/SIGNIFICANCE: In the present study, neopterin was highlighted as a useful marker for the evaluation of the post-therapeutic outcome in patients suffering from sleeping sickness. Detectable levels of this marker in the CSF have the potential to shorten the follow-up for HAT patients to six months after the end of the treatment

Cerebrospinal fluid neopterin as marker of the meningo-encephalitic stage of Trypanosoma brucei gambiense sleeping sickness.

BACKGROUND: Sleeping sickness, or human African trypanosomiasis (HAT), is a protozoan disease that affects rural communities in sub-Saharan Africa. Determination of the disease stage, essential for correct treatment, represents a key issue in the management of patients. In the present study we evaluated the potential of CXCL10, CXCL13, ICAM-1, VCAM-1, MMP-9, B2MG, neopterin and IgM to complement current methods for staging Trypanosoma brucei gambiense patients. METHODS AND FINDINGS: Five hundred and twelve T. b. gambiense HAT patients originated from Angola, Chad and the Democratic Republic of the Congo (D.R.C.). Their classification as stage 2 (S2) was based on the number of white blood cells (WBC) (>5/µL) or presence of parasites in the cerebrospinal fluid (CSF). The CSF concentration of the eight markers was first measured on a training cohort encompassing 100 patients (44 S1 and 56 S2). IgM and neopterin were the best in discriminating between the two stages of disease with 86.4% and 84.1% specificity respectively, at 100% sensitivity. When a validation cohort (412 patients) was tested, neopterin (14.3 nmol/L) correctly classified 88% of S1 and S2 patients, confirming its high staging power. On this second cohort, neopterin also predicted both the presence of parasites, and of neurological signs, with the same ability as IgM and WBC, the current reference for staging. CONCLUSIONS: This study has demonstrated that neopterin is an excellent biomarker for staging T. b. gambiense HAT patients. A rapid diagnostic test for detecting this metabolite in CSF could help in more accurate stage determination

Sleeping sickness: the wake-up of translational biomarker research

Comunicaciones a congreso

No evidence for association with APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations:

Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken a candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT

Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues

This work was supported by the Leverhulme Trust (Grant number RL2012-025). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1 , a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3 , a diazirine- and alkyne-containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1 , to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP-tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the α- and β-subunits of the ATP synthase. The FoF1-ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or disease model.Publisher PDFPeer reviewe

Murine Models for Trypanosoma brucei gambiense Disease Progression—From Silent to Chronic Infections and Early Brain Tropism

Trypanosoma brucei gambiense is responsible for more than 90% of reported cases of human African trypanosomosis (HAT). Infection can last for months or even years without major signs or symptoms of infection, but if left untreated, sleeping sickness is always fatal. In the present study, different T. b. gambiense field isolates from the cerebrospinal fluid of patients with HAT were adapted to growth in vitro. These isolates belong to the homogeneous Group 1 of T. b. gambiense, which is known to induce a chronic infection in humans. In spite of this, these isolates induced infections ranging from chronic to silent in mice, with variations in parasitaemia, mouse lifespan, their ability to invade the CNS and to elicit specific immune responses. In addition, during infection, an unexpected early tropism for the brain as well as the spleen and lungs was observed using bioluminescence analysis. The murine models presented in this work provide new insights into our understanding of HAT and allow further studies of parasite tropism during infection, which will be very useful for the treatment and the diagnosis of the disease