Delayed-Onset Hemolytic Anemia in Patients with Travel-Associated Severe Malaria Treated with Artesunate, France, 2011–2013

French Artesunate Working GroupInternational audienceArtesunate is the most effective treatment for severe malaria. However, delayed-onset hemolytic anemia has been observed in ≈20% of travelers who receive artesunate, ≈60% of whom require transfusion. This finding could discourage physicians from using artesunate. We prospectively evaluated a cohort of 123 patients in France who had severe imported malaria that was treated with artesunate; our evaluation focused on outcome, adverse events, and postartesunate delayed-onset hemolysis (PADH). Of the 123 patients, 6 (5%) died. Overall, 97 adverse events occurred. Among the 78 patients who received follow-up for >8 days after treatment initiation, 76 (97%) had anemia, and 21 (27%) of the 78 cases were recorded as PADH. The median drop in hemoglobin levels was 1.3 g/dL; 15% of patients with PADH had hemoglobin levels of <7 g/dL, and 1 required transfusion. Despite the high incidence of PADH, the resulting anemia remained mild in 85% of cases. This reassuring result confirms the safety and therapeutic benefit of artesunate

Cancer de la prostate au Centre Hospitalier Universitaire Aristidie Le Dantec de Dakar : aspects épidemiologiques sur les cinq dernières années: Prostate cancer in Aristide Le Dantec hospital of Dakar: epidemiological aspects over the last five years

Context and objective. Prostate cancer represents a major public health issue, but data from sub-Saharan Africa are scarce. This study aimed to describe the epidemiological aspects of prostate cancer during the last five years in Aristide Le Decantec hospital of Dakar.&nbsp;Methods. it’s a retrospective and descriptive study involving 5 last years including all patients with histologically confirmed prostate cancer. The studied parameters were: prevalence, incidence, age, clinical stage, lethality and death rate.&nbsp;Results. Two hundred and thirty-three patients were enrolled. The prevalence of prostate cancer during the study period was 0.8%. Depending on the stage, metastatic cancer was the most common form with 45.9% of cases. The new cases were 199 with an average of 39.8 per year. The total incidence of prostate cancer over the study period was 0.7%. The mean age of the patients at the diagnosis time was 68.6 ± 9.2 years. The lethality was 0.5%. The global death rate was 0.9 ‰. The specific death rate was 0.9‰. The annual mortality rate was higher in 2017 (36.4%) compared to other years. Depending on the stage, the death rate was higher in metastatic stages patients.&nbsp;Conclusion. The incidence of prostate cancer is increasing in our medical center. Metastatic forms remain more common with higher death rate. Early detection campaigns for prostate cancer should be considered. Contexte et objectif. Le cancer de la prostate représente un enjeu majeur de santé publique et mais il reste très peu documenté en Afrique subsaharienne. L’objectif de cette étude était d’évaluer les aspects épidémiologiques du cancer de la prostate sur les 5 dernières années dans notre centre.&nbsp;Méthodes. Il s’agissait d’une étude documentaire et descriptive sur 5 ans ayant colligé les dossiers de tous les patients avec cancer de la prostate histologiquement confirmé. Les paramètres étudiés étaient : la prévalence, l’incidence, l’âge, le stade clinique, la létalité et la mortalité.&nbsp;Résultats. Deux cent trente-trois patients ont été retenus. La prévalence du cancer de la prostate durant la période étudiée était de 0,8%. En fonction du stade, le stade de cancer métastatique était prépondérant (45,9%). Les nouveaux cas étaient de 199, soit une moyenne de 39,8 nouveaux cas par an. L’incidence totale du cancer de la prostate sur la période étudiée était de 0,7%. L’âge moyen des patients au moment du diagnostic était de 68,6 ± 9,2 ans. Le taux létalité était de 0,5%. La mortalité globale était de 0,9‰. Le taux de mortalité annuelle était plus important en 2017 (36,4%) en comparaison aux autres années étudiées. En fonction du stade, le taux de mortalité était plus important pour les stades métastatiques.&nbsp;Conclusion. L’incidence du cancer de la prostate est en augmentation dans notre centre. Les formes métastatiques restent prédominantes assombrissant le pronostic vital. Des campagnes de dépistage précoce du cancer de la prostate sont à envisager

Plasmodium falciparum Clearance Is Rapid and Pitting Independent in Immune Malian Children Treated With Artesunate for Malaria

Background. In Plasmodium falciparum-infected patients treated with artemisinins, parasitemia declines through so-called pitting, an innate splenic process that transforms infected red blood cells (iRBCs) into onceinfected RBCs (O-iRBCs). Methods. We measured pitting in 83 French travelers and 42 Malian children treated for malaria with artesunate. Results. In travelers, O-iRBCs peaked at 107.7% initial parasitemia. In Malian children aged 1.5-4 years, OiRBCs peaked at higher concentrations than in children aged 9-13 years (91.60% vs 31.95%; P = .0097). The parasite clearance time in older children was shorter than in younger children (P = .0001), and the decline in parasitemia in children aged 1.5-4 years often started 6 hours after treatment initiation, a lag phase generally absent in infants and older children. A 6-hour lag phase in artificial pitting of artesunate-exposed iRBCs was also observed in vitro. The proportion of iRBCs recognized by autologous immunoglobulin G (IgG) correlated with the parasite clearance time (r = −0.501; P = .0006) and peak O-iRBC concentration (r = −0.420; P = .0033). Conclusions. Antimalarial immunity correlates with fast artemisinin-induced parasite clearance and low pitting rates. In nonimmune populations, artemisinin-induced P. falciparum clearance is related to pitting and starts after a 6-hour lag phase. In immune populations, passively and naturally acquired immune mechanisms operating faster than pitting may exist. This mechanism may mitigate the emergence of artemisinin-resistant P. falciparum in Africa

Willingness to use and distribute HIV self-test kits to clients and partners: a qualitative analysis of female sex workers' collective opinion and attitude in Cote d'Ivoire, Mali, and Senegal

Background: In West Africa, female sex workers are at increased risk of HIV acquisition and transmission. HIV self-testing could be an effective tool to improve access to and frequency of HIV testing to female sex workers, their clients and partners. This article explores their perceptions regarding HIV self-testing use and the redistribution of HIV self-testing kits to their partners and clients. Methods: Embedded within ATLAS, a qualitative study was conducted in Côte-d’Ivoire, Mali, and Senegal in 2020. Nine focus group discussions were conducted. A thematic analysis was performed. Results: A total of 87 participants expressed both positive attitudes toward HIV self-testing and their willingness to use or reuse HIV self-testing. HIV self-testing was perceived to be discreet, confidential, and convenient. HIV self-testing provides autonomy from testing by providers and reduces stigma. Some perceived HIV self-testing as a valuable tool for testing their clients who are willing to offer a premium for condomless sex. While highlighting some potential issues, overall, female sex workers were optimistic about linkage to confirmatory testing following a reactive HIV self-testing. Female sex workers expressed positive attitudes toward secondary distribution to their partners and clients, although it depended on relationship types. They seemed more enthusiastic about secondary distribution to their regular/emotional partners and regular clients with whom they had difficulty using condoms, and whom they knew enough to discuss HIV self-testing. However, they expressed that it could be more difficult with casual clients; the duration of the interaction being too short to discuss HIV self-testing, and they fear violence and/or losing them. Conclusion: Overall, female sex workers have positive attitudes toward HIV self-testing use and are willing to redistribute to their regular partners and clients. However, they are reluctant to promote such use with their casual clients. HIV self-testing can improve access to HIV testing for female sex workers and the members of their sexual and social network

Patterns of anemia during malaria

International audienceWe read with interest the article by Rehman et al. on post-artesunate hemolysis (PADH). 1 Hemolysis is indeed commonly associated with the class of artemisinin drugs when used for the treatment of severe malaria. Their review confirmed the high incidence of this adverse event related to the mode of action of artemisinins and the physiological role of the spleen. 2 As the authors wisely pointed out, delayed hemolysis should not jeopardize the deployment of artesunate as the first-line treatment of severe malaria worldwide. While PADH is indeed rarely (if ever) fatal, artesunate significantly reduces mortality as compared to quinine, markedly so in patients with parasitemia greater than 10% on admission. 3 Importantly, PADH has been further characterized by a pathophysiological study in travelers treated with artesunate for severe malaria. 4 Early peak concentrations of circulating once-infected erythrocytes are predictive for the occurrence of PADH and may therefore serve as a future candidate marker for PADH. Rehman et al. referred to different anemia patterns in their analysis of published reports. This definition was based on initial descriptions by Zoller et al. 5 and on a more refined definition proposed in a closed meeting organized by the Medicine for Malaria Venture (MMV) in March 2013 in Vienna (http://www.mmv.org/sites/default/files/uploads/docs/events/2013/InjectableArtesunateExpertGroupMeeting.pdf) 6 and later published in the above mentioned pathophysiological paper. 4 Whereas initial reports were acknowledged in the article by Rehman et al., the optimized nosological classification was not referenced in the manuscript. This omission is likely due to the disclosure in the MMV report (which became publicly available in 2013) of the then unpublished, optimized case definition proposed by our group, without precise referencing of the source of that particular set of information. Sharing unpublished results or concepts during subject-specific meetings, like the one efficiently organized by MMV in Vienna, is important as it allows the malaria community to adapt rapidly and efficiently to new problems with a public health impact. When reports of such meetings carefully acknowledge all respective contributions, this ultimately contributes to maintaining rich exchanges between attendees

Inhibition of tumor necrosis factor-induced phenotypes by short intracellular versions of latent membrane protein-1.

International audienceTumor necrosis factor (TNF) is a potent multi-functional cytokine with a homeostatic role in host defence. In case of deregulation, TNF is implicated in numerous pathologies. The latent membrane protein-1 (LMP1) is expressed by Epstein-Barr virus during viral latency and displaying properties of a constitutively activated member of the TNF receptor family. Both TNFR1 and LMP1 share a similar set of proximal adapters and signalling pathways although they display different biological responses. We previously demonstrated that the intracellular part of LMP1, LMP1-CT, a dominant-negative form of LMP1, inhibits LMP1 signalling. Here, we developed shorter versions derived from C-terminal part of LMP1 to investigate their roles on LMP1 and TNF signalling. We constructed several mutants of LMP1 containing a part of cytoplasmic signalling region fused to the green fluorescent protein. These mutants selectively impair signalling by LMP1 and TNF but not by IL-1beta which uses other adapters. Dominant-negative effect was due to binding and sequestration of LMP1 adapters RIP, TRAF2 and TRADD as assessed by coimmunoprecipitation experiments and confocal analysis. Expression of these mutants impairs the recruitment of these adapters by TNFR1 and TNF-associated phenotypes. These mutants did not display cytostatic properties but were able to modulate TNF-induced phenotypes, apoptosis or cell survival, depending on the cell context. Interestingly, these mutants are able to inhibit a pro-inflammatory response in endothelial cells. These data demonstrate that LMP1 derived molecules can be used to design compounds with potential therapeutic roles in diseases due to TNF overactivation

A microfluidic device to study red blood cell deformability

International audienceIn this paper we present a microfluidic architecture dedicated to the study of Red Blood Cells (RBCs) deformability in microchannel smaller than the cell shape (biconcave disc of 7-8 μm in diameter) and cell capability to pass through slits separated by a gap value down to 2 μm, acting as a filter. This device is use in the context of RBCs disorders affecting their deformability, which is analysed versus number of cells trapped in the filter. This device can be seen as mimicking the human spleen. Microfabrication of the chip is based on polydimethylsiloxane (PDMS) associated to a two level thick photoresist mould (SU8). One level is used for microfluidic access with a 25 μm thickness towards the studied zone. The second level concerns the mimicking zones where RBCs flow through 5 μm down to 2 μm-wide slits acting like a mechanical filter. This level has a thickness of 5 μm. Devices have been tested on RBCs having specific disorder on their mechanical elasticity in order to validate the design principle. Two cases are presented in this paper: a.) Sickle RBCs inducing cell rigidity at two levels b.) Parasitized RBCs by Plasmodium falciparum. On both cases, we clearly show that deformability of RBCs influences the capability to pass through small slits (down to 2um) and thus is in relation with the pathology stage. This spleen-like microfluidic chip mimicking the RBCs filtering function is a promising tool for the exploration of RBC disorders combined with mechanical alterations

Inhibition of Latent Membrane Protein 1 Impairs the Growth and Tumorigenesis of Latency II Epstein-Barr Virus-Transformed T Cells

International audienceEpstein-Barr virus (EBV) is a common human herpesvirus. Infection with EBV is associated with several human malignancies in which the virus expresses a set of latent proteins, among which is latent membrane protein 1 (LMP1). LMP1 is able to transform numerous cell types and is considered the main oncogenic protein of EBV. The mechanism of action is based on mimicry of activated members of the tumor necrosis factor (TNF) receptor superfamily, through the ability of LMP1 to bind similar adapters and to activate signaling pathways. We previously generated two unique models: a monocytic cell line and a lymphocytic (NC5) cell line immortalized by EBV that expresses the type II latency program. Here we generated LMP1 dominant negative forms (DNs), based on fusion between green fluorescent protein (GFP) and transformation effector site 1 (TES1) or TES2 of LMP1. Then we generated cell lines conditionally expressing these DNs. These DNs inhibit NF-κB and Akt pathways, resulting in the impairment of survival processes and increased apoptosis in these cell lines. This proapoptotic effect is due to reduced interaction of LMP1 with specific adapters and the recruitment of these adapters to DNs, which enable the generation of an apoptotic complex involving TRADD, FADD, and caspase 8. Similar results were obtained with cell lines displaying a latency III program in which LMP1-DNs decrease cell viability. Finally, we prove that synthetic peptides display similar inhibitory effects in EBV-infected cells. DNs derived from LMP1 could be used to develop therapeutic approaches for malignant diseases associated with EBV