Primaquine (PQ) has activity against mature P. falciparum gametocytes and proven transmission blocking efficacy (TBE) between humans and mosquitoes. WHO formerly recommended a single transmission blocking dose of 0.75 mg/kg but this was little used. Then in 2012, faced with the emergence of artemisinin-resistant P. falciparum (ARPf) in SE Asia, the WHO recommended a lower dose of 0.25 mg/kg to be added to artemisinin-based combination therapy in falciparum-infected patients in low transmission areas. This dose was considered safe in glucose-6-phosphate dehydrogenase deficiency (G6PDd) and not requiring G6PD testing. Subsequent single low-dose primaquine (SLDPQ) studies have demonstrated safety in different G6PD variants. Dosing remains challenging in children under the age of 5 because of the paucity of PQ pharmacokinetic (PK) data. We plan to assess the anti-infectivity efficacy of SLDPQ using an allometrically scaled, weight-based regimen, with a target dose of 0.25 mg/kg, in children with acute uncomplicated falciparum malaria. This study is an open label, randomised 1:1, phase IIb study to assess TBE, tolerability, pharmacokinetics and acceptability of artesunate pyronaridine (ASPYR) administered alone or combined with SLDPQ in 56 Burkinabe children aged ≥ 6 months– < 5 years, with uncomplicated P. falciparum and a haemoglobin (Hb) concentration of ≥ 5 g/dL. We will assess TBE, using direct membrane feeding assays (DMFA), and further investigate PQ pharmacokinetics, adverse events, Hb dynamics, G6PD, sickle cells, thalassaemia and cytochrome 2D6 (CYP2D6) status, acceptability of flavoured PQ [CAST—ClinSearch Acceptability Score Test®], and the population’s knowledge, attitude and practices on malaria. We expect children to accept tablets, confirm the TBE and gametocytocidal effects of SLDPQ and then construct a PK infectivity model (including age, sex, baseline Hb, G6PD and CYP2D6 status) to define the dose response TBE relationship that may lead to fine tuning our SLDPQ regimen. Our study will complement others that have examined factors associated with Hb dynamics and PQ PK. It will provide much needed, high-quality evidence of SLDPQ in sick African children and provide reassurance that SLDPQ should be used as a strategy against emerging ARPf in Africa. ISRCTN16297951. Registered on September 26, 2021

Since the end of the 1990s, we have witnessed a slow evolution in France leading to the disappearance of disciplines related to tropical diseases. At the hospital level, this is reflected by the progressive inclusion of clinical services dedicated to the treatment of infectious and tropical diseases within an infectious diseases or internal medicine pole, and, in medical biology, by the replacement of parasitological biologists having acquired a specialization in mycology, by mycological biologists having acquired a specialization in parasitology. This orientation may seem normal, the reduction of skills in parasitological and clinical diagnosis being linked to the success of hygiene and food control measures, which have led to the virtual disappearance, in our country, of autochthonous parasitic diseases such as fasciolosis, taeniasis, or amoebiasis. Priority is therefore given to mycology, especially respiratory infections, which are predominant in protected and aging populations. However, should this be done at the expense of diagnostic and treatment skills for diseases affecting populations in countries with limited resources?

Accurate and reliable diagnostic tools are an essential requirement for neglected tropical diseases (NTDs) programmes. However, the NTD community has historically underinvested in the development and improvement of diagnostic tools, potentially undermining the successes achieved over the last 2 decades. Recognizing this, the WHO, in its newly released draft roadmap for NTD 2021-2030, has identified diagnostics as one of four priority areas requiring concerted action to reach the 2030 targets. As a result, WHO established a Diagnostics Technical Advisory Group (DTAG) to serve as the collaborative mechanism to drive progress in this area. Here, the purpose and role of the DTAG are described in the context of the challenges facing NTD programmes.

Vitamin D is a steroid hormone implicated in the regulation of neuronal integrity and many brain functions. Its influence, as a nutrient and a hormone, on the physiopathology of the most common neurodegenerative diseases is continuously emphasized by new studies. This review addresses what is currently known about the action of vitamin D on the nervous system and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. Further vitamin D research is necessary to understand how the action of this “neuroactive” steroid can help to optimize the prevention and treatment of several neurological diseases.

Nucleolipid supramolecular assemblies are promising Drug Delivery Systems (DDS), particularly for nucleic acids. Studies based on negatively and positively charged nucleolipids (diC16dT and DOTAU, respectively) demonstrated appropriate stability, safety, and purity profile to be used as DDS. Methylene Blue (MB) remains a good antimalarial drug candidate, and could be considered for the treatment of uncomplicated or severe malaria. However, the development of MB as an antimalarial drug has been hampered by a high dose regimen required to obtain a proper effect, and a short plasmatic half life. We demonstrated that nanoparticles formed by nucleolipid encapsulation of MB using diC16dT and DOTAU (MB-NPs) is an interesting approach to improve drug stability and delivery. MB-NPs displayed sizes, PDI, zeta values, and colloidal stability allowing a possible use in intravenous formulations. Nanoparticles partially protected MB from oxido-reduction reactions, thus preventing early degradation during storage, and allowing prolongated pharmacokinetic in plasma. MB-NPs' efficacy, tested in vitro on sensitive or multidrug resistant strains of Plasmodium falciparum, was statistically similar to MB alone, with a slightly lower IC50. This nucleolipid-based approach to protect drugs against degradation represents a new alternative tool to be considered for malaria treatment.

Univ. Bordeaux, U1212 INSERM–UMR 532 Léo Saignat, F-33076 Bordeaux, France. Emillet@u-bordeaux.fr Unité de Parasitologie et Entomologie, D Infectieuses, Institut de Recherche Biomédic Aix-Marseille Univ., IRD, SSA, AP-HM, VITR IHU Méditerranée Infection, Marseille, Fra Univ. Bordeaux, 146 rue Léo Saignat, F-330 Centre National de Référence du Paludisme † Electronic supplementary informa 10.1039/c9ra02576f Cite this: RSC Adv., 2019, 9, 18844

IMPORTANCE: Despite annually adapted recommendations to prevent malaria in travelers to endemic areas, France is still the industrialized country reporting the highest number of imported cases of malaria. Better understanding of the epidemiologic context and evolution during the past 2 decades may help to define a better preventive strategy. OBJECTIVE: To study epidemiologic trends of imported cases of malaria in travelers in geographic territories of France on the European continent (metropolitan France) from 1996 through 2016 to potentially explain the persistence of high imported malaria incidence despite national preventive measures. DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, between January 1 and May 31, 2018, data were extracted from the French National Reference Center of Malaria Surveillance. Trends in patients with imported malaria in association with age, sex, ethnicity, purpose of travel, malaria species, severity of illness, case mortality rate, and endemic countries visited were analyzed in 43 333 malaria cases among civilian travelers living in metropolitan France. MAIN OUTCOMES AND MEASURES: Evolution of the main epidemiologic characteristics of patients with imported malaria. RESULTS: Among the 43 333 patients with imported malaria in civilian travelers included in the study, 24949 were male (62.4%), and 8549 were younger than 18 years (19.9%). A total of 28 658 malaria cases (71.5%) were among African individuals, and 10618 cases (26.5%) among European individuals. From 1996 through 2016, the number of confirmed malaria cases peaked at 3400 cases in 2000, then declined to 1824 cases in 2005 and stabilized thereafter to approximately 1720 malaria cases per year. A total of 37065 cases (85.5%) were due to Plasmodium falciparum. The proportion of malaria cases among African individuals rose from 53.5% in 1996 to 83.4% in 2016, and the most frequent motivation for traveling was visiting friends and relatives (25 329 [77.1%]; P<.001). Despite an increase in the proportion of severe cases, which rose from 131 cases (8.9%) in 1996 to 279 cases (16.7%) in 2016 (P<.001), mortality remained stable, being approximately 0.4% during the study period. CONCLUSIONS AND RELEVANCE: Beyond the apparent stability of the number of imported malaria cases in France, significant changes appear to have occurred among the population who developed malaria infection following travel in endemic areas. These changes may imply that adaptation of the preventive strategy is needed to reduce the burden of the disease among travelers.

Letters6 February 2018Systemic Infection With Dirofilaria repens in Southwestern FranceRomain Blaizot, MD, Marie-Catherine Receveur, MD, Pascal Millet, MD, PhD, Domenico Otranto, DVM, PhD, and Denis J.M. Malvy, MD, PhDRomain Blaizot, MDUniversity Hospital of Bordeaux, Bordeaux, France (R.B., M.R., P.M., D.J.M.)Search for more papers by this author, Marie-Catherine Receveur, MDUniversity Hospital of Bordeaux, Bordeaux, France (R.B., M.R., P.M., D.J.M.)Search for more papers by this author, Pascal Millet, MD, PhDUniversity Hospital of Bordeaux, Bordeaux, France (R.B., M.R., P.M., D.J.M.)Search for more papers by this author, Domenico Otranto, DVM, PhDUniversity of Bari Aldo Moro, Bari, Italy (D.O.)Search for more papers by this author, and Denis J.M. Malvy, MD, PhDUniversity Hospital of Bordeaux, Bordeaux, France (R.B., M.R., P.M., D.J.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0426 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Dirofilariasis is a zoonotic infection caused mainly by Dirofilaria repens, a ubiquitous filaroid helminth in dogs and cats that is transmitted to humans by mosquitoes. Humans are accidental hosts (1). The adult worm of D repens causes subcutaneous and conjunctival infections that are considered benign. Dirofilariasis has traditionally been endemic only in Mediterranean areas (1). In Europe, dogs are the principal source of human infection; Aedes vexans, Culex pipiens, and Aedes albopictus mosquitoes are the main vectors (1).Objective: To report a human case of D repens infection acquired in southwestern France.Case Report: In September 2016, a 70-year-old ...References1. Simón F, Siles-Lucas M, Morchón R, González-Miguel J, Mellado I, Carretón E, et al. Human and animal dirofilariasis: the emergence of a zoonotic mosaic. Clin Microbiol Rev. 2012;25:507-44. [PMID: 22763636] doi:10.1128/CMR.00012-12 CrossrefMedlineGoogle Scholar2. Raccurt CP. [Dirofilariasis, an emerging and underestimated zoonoses in France]. Med Trop (Mars). 1999;59:389-400. [PMID: 10816755] MedlineGoogle Scholar3. Mittal M, Sathish KR, Bhatia PG, Chidamber BS. Ocular dirofilariasis in Dubai, UAE. Indian J Ophthalmol. 2008;56:325-6. [PMID: 18579995] CrossrefMedlineGoogle Scholar4. Latrofa MS, Weigl S, Dantas-Torres F, Annoscia G, Traversa D, Brianti E, et al. A multiplex PCR for the simultaneous detection of species of filarioids infesting dogs. Acta Trop. 2012;122:150-4. [PMID: 22248527] doi:10.1016/j.actatropica.2012.01.006 CrossrefMedlineGoogle Scholar5. Fontanelli Sulekova L, Gabrielli S, De Angelis M, Milardi GL, Magnani C, Di Marco B, et al. Dirofilaria repens microfilariae from a human node fine-needle aspirate: a case report. BMC Infect Dis. 2016;16:248. [PMID: 27266512] doi:10.1186/s12879-016-1582-3 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: University Hospital of Bordeaux, Bordeaux, France (R.B., M.R., P.M., D.J.M.)University of Bari Aldo Moro, Bari, Italy (D.O.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0426.Reproducible Research Statement:Study protocol and statistical code: Not available. Data set: Available from Dr. Blaizot (e-mail, romain.[email protected]fr).This article was published at Annals.org on 31 October 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byDirofilaria repens microfilaremia in humans: Case description and literature reviewDirofilaria hongkongensis infection presenting as recurrent shoulder massZoonotic nematodes of wild carnivoresExposure of humans to the zoonotic nematode Dirofilaria immitis in Northern PortugalRecent advances on Dirofilaria repens in dogs and humans in Europe 6 February 2018Volume 168, Issue 3Page: 228-229KeywordsBloodDisclosureDoxycyclineFacial nerveFilariasisHematologic testsInfectious diseasesMosquitoesPolymerase chain reactionZoonoses ePublished: 31 October 2017 Issue Published: 6 February 2018 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

The impairment of hippocampal neurogenesis at the early stages of Alzheimer's disease (AD) is believed to support early cognitive decline. Converging studies sustain the idea that vitamin D might be linked to the pathophysiology of AD and to hippocampal neurogenesis. Nothing being known about the effects of vitamin D on hippocampal neurogenesis in AD, we assessed them in a mouse model of AD. In a previous study, we observed that dietary vitamin D supplementation in female AD-like mice reduced cognitive decline only when delivered during the symptomatic phase. With these data in hand, we wondered whether the consequences of vitamin D administration on hippocampal neurogenesis are stage-dependent. Male wild-type and transgenic AD-like mice (5XFAD model) were fed with a diet containing either no vitamin D (0VD) or a normal dose of vitamin D (NVD) or a high dose of vitamin D (HVD), from month 1 to month 6 (preventive arm) or from month 4 to month 9 (curative arm). Working memory was assessed using the Y-maze, while amyloid burden, astrocytosis, and neurogenesis were quantified using immunohistochemistry. In parallel, the effects of vitamin D on proliferation and differentiation were assayed on primary cultures of murine neural progenitor cells. Improved working memory and neurogenesis were observed when high vitamin D supplementation was administered during the early phases of the disease, while a normal dose of vitamin D increased neurogenesis during the late phases. Conversely, an early hypovitaminosis D increased the number of amyloid plaques in AD mice while a late hypovitaminosis D impaired neurogenesis in AD and WT mice. The observed in vivo vitamin D-associated increased neurogenesis was partially substantiated by an augmented in vitro proliferation but not an increased differentiation of neural progenitors into neurons. Finally, a sexual dimorphism was observed. Vitamin D supplementation improved the working memory of males and females, when delivered during the pre-symptomatic and symptomatic phases, respectively. Our study establishes that (i) neurogenesis is improved by vitamin D in a male mouse model of AD, in a time-dependent manner, and (ii) cognition is enhanced in a gender-associated way. Additional pre-clinical studies are required to further understand the gender- and time-specific mechanisms of action of vitamin D in AD. This may lead to an adaptation of vitamin D supplementation in relation to patient's gender and age as well as to the stage of the disease.

ABSTRACT We report evidence, confirmed by the lack of travel activity outside of France and genetic diversity analysis using polymorphic microsatellite markers, that Plasmodium falciparum malaria infection effectively treated with an artemisinin-based combination can remain dormant and relapse during pregnancy at least 2 years after treatment.

Objective: To explore the possible association between polymorphisms in CDI genes and both asymptomatic and mild Plasmodium fidciparum infection. Methods: Two clusters of 85 school children, from the village of Dienga (Gabon) were investigated. The first group was analysed for the prevalence and the multiplicity of asymptomatic Plasmodiun f;Jripurum infection, whereas the second group was screened for the frequency of malarial attacks. Results: Our findings showed that homozygosity for the CDIE*02 allele was associated with a low frequency of malarial attacks. Furthermore, a strong association between CDI E*02 homozygotes and the resistance to multiple malarial attacks was identified. The CDIA*01 allele showed a weak association with a small number of malarial attacks. Conclusion: Our results suggest a possible role of CDIE polymorphisms in malaria protection among school children and that CDle molecules are involved in anti -malarial immunity.

Le Fonds mondial1, Unitaid, Bill Gates, et autres bailleurs de fonds, financent depuis le debut du xxie siecle des programmes de sante interessant le paludisme, le VIH/sida et la tuberculose. Les hepatites ont ete integrees recemment dans la courte liste des maladies prioritaires, maladies qu’il a ete juge politiquement correct d’eradiquer du monde dans les prochaines annees. La [...]

BACKGROUND:Increasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer's disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates. We first performed a kinematic behavioural examination at 4, 6 and 8 months of age (M4, M6 and M8) followed by a histologic assessment of AD markers. We then performed a comparative transcriptomic analysis of mRNA regulation in the neocortex and hippocampus of 9 months old (M9) female mice.RESULTS:Transcriptomic analysis of the hippocampus and neocortex of both Wt and Tg mice at M9, following 5 months of vitamin D3 treatment, reveals a large panel of dysregulated pathways related to i) immune and inflammatory response, ii) neurotransmitter activity, iii) endothelial and vascular processes and iv) hormonal alterations. The differentially expressed genes are not all direct targets of the vitamin D-VDR pathway and it appears that vitamin D action engages in the crosstalk with estrogen and insulin signaling. The misexpression of the large number of genes observed in this study translates into improved learning and memory performance and a decrease in amyloid plaques and astrogliosis in Tg animals.CONCLUSIONS:This study underlies the multiplicity of action of this potent neurosteroid in an aging and AD-like brain. The classical and non-classical actions of vitamin D3 can act in an additive and possibly synergistic manner to induce neuroprotective activities in a context-specific way.

Alzheimer’s disease (AD) is the most common neurodegenerative disease. AD is neuropathologically characterized by extra-neuronal accumulations of beta-amyloid (Aβ) forming senile plaques and intra-neuronal accumulations of hyperphosphorylated tau proteins, leading to neuroinflammation, synaptic loss and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in pathological features of AD including neurodegeneration. We have investigated for the first time in 5XFAD mice, the disease-modifying therapeutic effect of a systemic administration of XG-102, a small JNK-specific inhibitory peptide currently in clinical development in other pathologies. Three months-old mice were IV treated every 3 weeks, for 3 or 6 months. The outcome of XG-102 treatment on cognitive deficits and AD lesions were assessed using Y maze, fear-conditioning tests, histological and biochemical methods. Chronic treatment of XG-102 for 3 months resulted in a reduction of amyloid plaque burden by 35% in the cortex of 5XFAD treated mice compared with saline-treated 5XFAD mice. After 6 months of treatment, cognitive deficits were reduced by 32% and 46% for the Y Maze and fear conditioning tests respectively. In addition a significant reduction of neuronal death in treated mice was detected. In conclusion, XG-102 could be considered as a potential candidate to be evaluated in MCI (Mild Cognitive Impairment) or mild AD patients in the future.

Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer’s disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider.

ContexteL’hypovitaminose D, tres frequente chez la personne âgee, est associee a des modifications du cerveau et a la survenue de troubles cognitifs et de demence. Compte tenu des progres rapides de la litterature biomedicale dans ce champ, des orientations claires sont necessaires pour les cliniciens et les chercheurs.

Hypovitaminosis D, a common condition in older adults, is associated with brain changes and dementia. Given the fast growing contribution of literature in this research field, clear guidance is needed for clinicians and researchers. International experts met at the invitational summit on "Vitamin D and cognition in older adults" in Boston, MA, July 2013. Based upon literature and expert opinion, the task force focused on key questions on the role of vitamin D in Alzheimer disease and related disorders. Each question was discussed and voted using a Delphi-like approach. Experts reached agreement that hypovitaminosis D increases the risk of cognitive decline and dementia in older adults, may alter the clinical presentation as a consequence of related comorbidities, but should not be used thus far as a diagnostic or prognostic biomarker of Alzheimer disease due to lack of specificity and insufficient evidence. Hypovitaminosis D should be screened in this population because of its high prevalence and supplemented, if necessary, but this advice was not specific to cognition. The task force agreed on 5 overarching principles related to vitamin D and cognition in older adults.