Salinomycin and other ionophores as a new class of antimalarial drugs with transmission-blocking activity

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads

Untreated Human Infections by Trypanosoma brucei gambiense Are Not 100% Fatal

The final outcome of infection by Trypanosoma brucei gambiense, the main agent of sleeping sickness, has always been considered as invariably fatal. While scarce and old reports have mentioned cases of self-cure in untreated patients, these studies suffered from the lack of accurate diagnostic tools available at that time. Here, using the most specific and sensitive tools available to date, we report on a long-term follow-up (15 years) of a cohort of 50 human African trypanosomiasis (HAT) patients from the Ivory Coast among whom 11 refused treatment after their initial diagnosis. In 10 out of 11 subjects who continued to refuse treatment despite repeated visits, parasite clearance was observed using both microscopy and polymerase chain reaction (PCR). Most of these subjects (7/10) also displayed decreasing serological responses, becoming progressively negative to trypanosome variable antigens (LiTat 1.3, 1.5 and 1.6). Hence, in addition to the “classic” lethal outcome of HAT, we show that alternative natural progressions of HAT may occur: progression to an apparently aparasitaemic and asymptomatic infection associated with strong long-lasting serological responses and progression to an apparently spontaneous resolution of infection (with negative results in parasitological tests and PCR) associated with a progressive drop in antibody titres as observed in treated cases. While this study does not precisely estimate the frequency of the alternative courses for this infection, it is noteworthy that in the field national control programs encounter a significant proportion of subjects displaying positive serologic test results but negative results in parasitological testing. These findings demonstrate that a number of these subjects display such infection courses. From our point of view, recognising that trypanotolerance exists in humans, as is now widely accepted for animals, is a major step forward for future research in the field of HAT

Malaria transmission pattern resilience to climatic variability is mediated by insecticide-treated nets

<p>Abstract</p> <p>Background</p> <p>Malaria is an important public-health problem in the archipelago of Vanuatu and climate has been hypothesized as important influence on transmission risk. Beginning in 1988, a major intervention using insecticide-treated bed nets (ITNs) was implemented in the country in an attempt to reduce <it>Plasmodium </it>transmission. To date, no study has addressed the impact of ITN intervention in Vanuatu, how it may have modified the burden of disease, and whether there were any changes in malaria incidence that might be related to climatic drivers.</p> <p>Methods and findings</p> <p>Monthly time series (January 1983 through December 1999) of confirmed <it>Plasmodium falciparum </it>and <it>Plasmodium vivax </it>infections in the archipelago were analysed. During this 17 year period, malaria dynamics underwent a major regime shift around May 1991, following the introduction of bed nets as a control strategy in the country. By February of 1994 disease incidence from both parasites was reduced by at least 50%, when at most 20% of the population at risk was covered by ITNs. Seasonal cycles, as expected, were strongly correlated with temperature patterns, while inter-annual cycles were associated with changes in precipitation. Following the bed net intervention, the influence of environmental drivers of malaria dynamics was reduced by 30–80% for climatic forces, and 33–54% for other factors. A time lag of about five months was observed for the qualitative change ("regime shift") between the two parasites, the change occurring first for <it>P. falciparum</it>. The latter might be explained by interspecific interactions between the two parasites within the human hosts and their distinct biology, since <it>P. vivax </it>can relapse after a primary infection.</p> <p>Conclusion</p> <p>The Vanuatu ITN programme represents an excellent example of implementing an infectious disease control programme. The distribution was undertaken to cover a large, local proportion (~80%) of people in villages where malaria was present. The successful coverage was possible because of the strategy for distribution of ITNs by prioritizing the free distribution to groups with restricted means for their acquisition, making the access to this resource equitable across the population. These results emphasize the need to implement infectious disease control programmes focusing on the most vulnerable populations.</p

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs

Anesthésie pour chirurgie du membre supérieur : intérêt, avantages et apport du bloc infra-claviculaire échoguidé

Le bloc infra-claviculaire (BIC), en raison de la proximité de la plèvre était craint par la majeure partie des anesthésistes et peu utilisé. Aujourd’hui,&nbsp; l’avènement de l’échographie en anesthésie a permis de réactualiser la pratique de ce bloc. Le but de cette étude était de présenter l’intérêt du BIC échoguidé dans l’anesthésie du membre supérieur, ses avantages et éventuels inconvénients en comparaison d’avec les autres types de bloc. Nous avons mené une étude prospective, observationnelle descriptive sur une période de neuf mois (mars à décembre 2020) réalisée dans la clinique d’anesthésie réanimation du centre médical du camp général Aboubacar Sangoulé Lamizana (CMCGASL) à Ouagadougou. Tous les patients devant subir une chirurgie du membre supérieur réalisée sous BIC échoguidé sans neurostimulation ont été inclus. Trente-huit (38) blocs infra claviculaires ont été réalisés pendant la période d’étude. L’âge moyen de nos patients était de 35,34 ans +/- 10 avec des extrêmes de 23 et 62 ans. Le site de la chirurgie était l’avant-bras dans 27 cas (72%), la main dans 8 cas (21%), le coude dans 2 cas (5%) et l’extrémité inférieure du bras dans un seul cas (2%). La durée moyenne de réalisation du BIC était de 8,86 minutes +/- 4 minutes. La quantité d’anesthésique local (mélange de ropivacaine et xylocaine) utilisée était en moyenne de 19 ml +/- 2,21 ml. Le bloc sensitif était efficace dans 36 cas (94,7%). Il était insuffisant pour la chirurgie avec des zones non anesthésiées dans 2 cas (5,3%) La durée moyenne du bloc sensitif était de 494 minutes (8 heures 15 minutes). En post opératoire les complications&nbsp; recherchées étaient le pneumothorax et les paresthésies. Aucun patient n’avait présenté ce type de complication. Le BIC échoguidé est un bloc tout aussi efficace et sur que le bloc supraclaviculaire et le bloc axillaire dans la chirurgie du membre supérieur. La position requise pour sa réalisation lui donne un avantage certain sur le bloc axillaire et le bloc au canal huméral. Infra-clavicular brachial plexus block (ICB), has been feared and hardly used by most anesthetists because of the proximity of the pleura. Today, the use of ultrasound in anesthesia has reinstituted this block as a valid therapeutic option. The aim of this study was to present the value of ultrasound-guided ICB in upper limb anesthesia, its advantages and disadvantages compared to other types of block. We&nbsp; conducted a prospective descriptive study over a period of nine months (March to December 2020) in the anesthesia and intensive care unit of the medical center of the General Aboubacar Sangoulé Lamizana Camp (CMCGASL) in Ouagadougou. All the patients who had upper limb surgery performed under ultrasound- guided ICB without neurostimulation were included in the study. Thirty-eight (38) infra- clavicular blocks were performed during the study period. The average age of our patients was 35.34 years +/- 10. The site of surgery was the forearm in 27 cases (72%), the hand in 8 cases (21%), the elbow in 2 cases (5%) and the lower extremity of the arm in only one case (2%). The lenght of the ICB procedure was averagely 8.86 minutes +/- 4 minutes. The local anesthetic used was a mixture of ropivacaine and xylocaine. The average volume of local anesthesic administered was 19 ml +/- 2.21 ml. Sensory block was effective in 36 cases (94.7%). There were two block failures (5.3%). The average duration of the sensory block was 494 minutes (8 hours 15 minutes). After the surgery the complications sought for were pneumothorax and paresthesia. No patient presented this type of complication. Ultrasound-guided ICB is an efficient and safe block as are supra clavicular and axillary block in upper limb surgery. The position required for its realisation gives it a clear advantage over axillary and humeral canal block.&nbsp

Role of native Plasmodium falciparum hemozoin in innate immunity

Role of native Plasmodium falciparum hemozoin in innate immunit

Molecular Epidemiology of Peste Des Petits Ruminants Virus in West Africa: Is Lineage IV Replacing Lineage II in Burkina Faso?

This study aimed at investigating the genetic lineages of peste des petits ruminants virus (PPRV) currently circulating in Burkina Faso. As part of PPR surveillance in 2021 and 2022, suspected outbreaks in different regions were investigated. A risk map was produced to determine high-risk areas for PPR transmission. Based on alerts, samples were obtained from three regions and all sampled localities were confirmed to fall within PPR high risk areas. We collected swab samples from the eyes, mouth, and nose of sick goats. Some tissue samples were also collected from dead animals suspected to be infected by PPRV. In total, samples from 28 goats were analysed. Virus confirmation was performed with RT-PCR amplification targeting the nucleocapsid (N) gene. Partial N gene sequencing (350 bp) was carried out using the RT-PCR products of positives samples to characterise the circulating lineages. Eleven sequences, including ten new sequences, have been obtained. Our study identified the presence of the PPRV lineage IV in the three studied regions in Burkina Faso with a genetic heterogeneity recorded for the sequences analysed. Previously published data and results of this study suggest that PPRV lineage IV seems to be replacing lineage II in Burkina Faso

A transdisciplinary approach for the development of sustainable yam (Dioscorea sp.) production in West Africa

Yam (Dioscorea sp.) is an understudied tuber crop despite its importance for food security, income generation, culture, and health in West Africa. Traditional yam cropping practices in West Africa deliver low yields and lead to environmental degradation. In the context of a ‘research for development’ project, we developed and implemented a participatory and transdisciplinary research approach as a means to derive more sustainable yam production practices. We identified and studied different soil and plant management technologies adapted to varying biophysical and socio-economic contexts. For this purpose, we established innovation platforms (IPs) in four yam growing regions of West Africa, to validate the new technologies and to promote their adoption. These co-developed technologies were set up and tested first in researcher-managed plots before doing the same in farmer-managed plots. The new technologies resulted in a significant increase in yam productivity compared to conventional practices. The results discussed in the IPs gained interest from regional stakeholders and were shared through the media at local and national levels. Overall, this development-focused research approach showcases the relevance of purposeful stakeholder involvement to improve agricultural research outcomesISSN:2071-105