Thierry Fusai - Academia.edu (original) (raw)

Papers by Thierry Fusai

Research paper thumbnail of Intrathoracic Pressure Impulse Predicts Pulmonary Contusion Volume in Ballistic Blunt Thoracic Trauma

The Journal of Trauma: Injury, Infection, and Critical Care, 2010

Background: Blunt thoracic trauma including behind armour blunt trauma or impact from a less leth... more Background: Blunt thoracic trauma including behind armour blunt trauma or impact from a less lethal kinetic weapon (LLKW) projectile may cause injuries, including pulmonary contusions that can result in potentially lethal secondary complications. These lung injuries may be caused by intrathoracic pressure waves. The aim of this study was to observe dynamic changes in intrathoracic hydrostatic pressure during ballistic blunt thoracic trauma and to find correlations between these hydrostatic pressure parameters (especially the impulse parameter) and physical damages. Methods: Thirty anesthetized pigs sustained a blunt thoracic trauma. In group 1 (n ϭ 20), pigs were protected by a National Institute of Justice class III or IV bulletproof vest and shot with 7.62 NATO bullets. In group 2 (n ϭ 10), pigs were shot by an LLKW. Intrathoracic pressure was recorded with an intraesophageal pressure sensor and three parameters were determined: intrathoracic maximum pressure, intrathoracic maximum pressure impulse (PI max), and the Pd.P/dt max , derived from Viano's viscous criterion. Relative right lower lung lobe contusion volume was also measured. Results: Different thoracic loading conditions were obtained. PI max best correlated with relative pulmonary contusion volume (R 2 ϭ 0.64 and p Ͻ 0.0001). This result was homogenous for all experiments and was not related to the type of chest impact (LLKW-induced trauma or behind armour blunt trauma). Conclusions: The PI max is a good predictor of pulmonary contusion volume after ballistic blunt thoracic trauma. It is a useful criterion when the kinetic energy record or thoracic wall displacement data are unavailable, and the recording and calculation of this physical value are quite simple on animals.

Research paper thumbnail of Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum

Journal of Antimicrobial Chemotherapy, 2001

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amod... more The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC 50 values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC 50 for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 M, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Research paper thumbnail of Antibody response against saliva antigens of Anopheles gambiae and Aedes aegypti in travellers in tropical Africa

Microbes and …, 2007

Exposure to vectors of infectious diseases has been associated with antibody responses against sa... more Exposure to vectors of infectious diseases has been associated with antibody responses against salivary antigens of arthropods among people living in endemic areas. This immune response has been proposed as a surrogate marker of exposure to vectors appropriate for evaluating the protective efficacy of antivectorial devices. The existence and potential use of such antibody responses in travellers transiently exposed to Plasmodium or arbovirus vectors in tropical areas has never been investigated. The IgM and IgG antibody responses of 88 French soldiers against the saliva of Anopheles gambiae and Aedes aegypti were evaluated before and after a 5-month journey in tropical Africa. Antibody responses against Anopheles and Aedes saliva increased significantly in 41% and 15% of the individuals, respectively, and appeared to be specific to the mosquito genus. A proteomic and immunoproteomic analysis of anopheles and Aedes saliva allowed for the identification of some antigens that were recognized by most of the exposed individuals. These results suggest that antibody responses to the saliva of mosquitoes could be considered as specific surrogate markers of exposure of travellers to mosquito vectors that transmit arthropod borne infections.

Research paper thumbnail of In vitro reversal of chloroquine resistance in Plasmodium falciparum with dihydroethanoanthracene derivatives

The American journal of tropical medicine and hygiene, 2002

The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were ass... more The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were assessed in vitro against Plasmodium falciparum chloroquine resistant parasites W2, Palo Alto, FCR3, and Bres1. Like verapamil or promethazine, the four dihydroethanoanthracenic derivatives tested can be added to the growing list of agents that show capability in enhancing the activity of chloroquine against resistant parasites. The structurally related tricyclic antihistaminic compounds examined in this study exerted different intrinsic antimalarial activity, but the same chloroquine-potentiating activity as verapamil or promethazine. They may act both on the rate of chloroquine accumulation and on its access to ferriprotoporphyrin IX. The reversal mechanism would be assumed to result from competition between DEA derivatives and chloroquine for efflux translocation sites, thus causing an increase in steady-state accumulation of chloroquine and a return to susceptibility. Restoration of the...

Research paper thumbnail of Antibody responses to several malaria pre-erythrocytic antigens as a marker of malaria exposure among travelers

The American journal of tropical medicine and hygiene, 2006

Protective devices against vectors are used by travelers in malaria-endemic areas but their effic... more Protective devices against vectors are used by travelers in malaria-endemic areas but their efficacy for protection against mosquitoes has rarely been evaluated. The level of exposure to malaria transmission of 205 soldiers deployed in Africa and the efficacy of their anti-vector prophylaxis was evaluated by comparison of their IgM and IgG responses against five pre-erythrocytic Plasmodium falciparum antigens (circumsporozoite protein, sporozoite threonine- and asparagine-rich protein, sporozoite- and liver-stage antigen, liver stage antigen 1, and SR11.1) before and at the end of their deployment, and three months after returning to France for 106 of these soldiers. The immune responses increased significantly during the mission in 35% (95% confidence interval = 28-42%) of the individuals. The permanent use of insecticide-treated bed nets and long-sleeve battle dress at night were associated with protective efficacy. The analysis of these antibody responses was sensitive enough to ...

Research paper thumbnail of In vitro activity of artemether against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial drugs

The American journal of tropical medicine and hygiene, 1998

The in vitro activity of artemether against 56 African isolates of Plasmodium falciparum from Sen... more The in vitro activity of artemether against 56 African isolates of Plasmodium falciparum from Senegal was evaluated using an isotope-based drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95% confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95% CI = 2.08-4.84 nM versus mean IC50 = 2.80 nM, 95% CI = 2.00-3.60 nM). There was a significant positive correlation between responses to artemether and mefloquine (r2 = 0.36, P < 0.001), artemether and quinine (r2 = 0.085, P < 0.05), artemether and halofantrine (r2 = 0.075, P < 0.05), quinine and mefloquine (r2 = 0.205, P < 0.01), quinine and halofantrine (r2 = 0.124, P < 0.05), and mefloquine and halofantrine (r2 = 0.801, P < 0.001). A positive correlation between these drugs suggests in vitro cross...

Research paper thumbnail of Urban malaria in Dakar, Senegal: chemosusceptibility and genetic diversity of Plasmodium falciparum isolates

The American journal of tropical medicine and hygiene, 2006

The chemosusceptibility and genetic polymorphism of Plasmodium falciparum populations from 48 pat... more The chemosusceptibility and genetic polymorphism of Plasmodium falciparum populations from 48 patients hospitalized for malaria at the Hospital Principal in Dakar, Senegal were investigated during the 2002 malaria transmission season. Sixty-two percent of the isolates collected were from patients with severe malaria and 38% were from patients with mild malaria. In vitro activities of chloroquine, quinine, cycloguanil, atovaquone, mefloquine, halofantrine, and artesunate were evaluated. The prevalence of mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) and dihyropteroate synthetase (dhps) genes and the P. falciparum chloroquine resistance transporter (Pfcrt) gene associated with cycloguanil, pyrimethamine, sulfadoxine, and chloroquine resistance were estimated. The genetic polymorphism of the parasite populations was evaluated by analysis of the highly polymorphic regions of merozoite surface protein 1 (msp1) block 2 and msp2. Seventy percent of the isolates were...

Research paper thumbnail of Platelets Alter Gene Expression Profile in Human Brain Endothelial Cells in an In Vitro Model of Cerebral Malaria

Plos One, 2011

Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in... more Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in humans, suggesting that platelets play a role in the pathogenesis of this syndrome. In vitro co-cultures have shown that platelets can act as a bridge between Plasmodium falciparum-infected red blood cells (pRBC) and human brain microvascular endothelial cells (HBEC) and potentiate HBEC apoptosis. Using cDNA microarray technology, we analyzed transcriptional changes of HBEC in response to platelets in the presence or the absence of tumor necrosis factor (TNF) and pRBC, which have been reported to alter gene expression in endothelial cells. Using a rigorous statistical approach with multiple test corrections, we showed a significant effect of platelets on gene expression in HBEC. We also detected a strong effect of TNF, whereas there was no transcriptional change induced specifically by pRBC. Nevertheless, a global ANOVA and a two-way ANOVA suggested that pRBC acted in interaction with platelets and TNF to alter gene expression in HBEC. The expression of selected genes was validated by RT-qPCR. The analysis of gene functional annotation indicated that platelets induce the expression of genes involved in inflammation and apoptosis, such as genes involved in chemokine-, TREM1-, cytokine-, IL10-, TGFb-, deathreceptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM.

Research paper thumbnail of Comment évaluer la morbidité attribuable au paludisme en zone d’endémie ?

Revue d'Épidémiologie et de Santé Publique, 2005

ABSTRACT Il n’existe pas de signe pathognomonique du paludisme. Les accès de fièvre, l’anémie, le... more ABSTRACT Il n’existe pas de signe pathognomonique du paludisme. Les accès de fièvre, l’anémie, les signes de gravité comme le coma ou les détresses respiratoires ne peuvent être aisément attribués à une infection plasmodiale dans les populations qui sont infectées la plupart du temps. L’attribution de manifestations cliniques au paludisme est problématique dans les populations exposées régulièrement à la transmission des plasmodiums humains. Plus la transmission est forte et régulière, plus le taux de prévalence des infections plasmodiales asymptomatiques est élevé. Chez les populations vivant dans les zones où la transmission est intense et pérenne, ce taux est parfois supérieur à 90 % de la population, et la détection d’une infection plasmodiale ne suffit alors pas pour attribuer des manifestations cliniques au paludisme. L’acquisition d’une immunité partielle et labile permettant aux personnes régulièrement infectées de supporter des parasitémies sans présenter de manifestation clinique est donc un obstacle à l’évaluation de la morbidité palustre en zone d’endémie.L’association positive entre la densité parasitaire et la fièvre permet d’estimer la fraction des accès cliniques attribuables au paludisme. Il a été montré que cette relation entre parasitémie et risque de fièvre n’était pas continue et qu’un seuil pyrogène de la parasitémie, dépendant de l’âge et du niveau d’endémicité, permettait de distinguer les épisodes cliniques dus au paludisme.Le problème du diagnostic et de l’évaluation de la morbidité palustre se pose dans au moins trois circonstances: en santé publique pour l’estimation du poids du paludisme dans les structures sanitaires, en recherche clinique pour l’évaluation des traitements et des mesures prophylactiques (médicaments, vaccins, protections anti-vectorielles) et en recherche fondamentale pour l’étude de la physiopathologie et des déterminants immunologiques et génétiques de la sensibilité clinique au paludisme.Dans ces différentes circonstances, il est ni possible ni approprié d’utiliser la même définition diagnostique ou la même méthode de recrutement des cas. Pour évaluer la morbidité palustre, la recherche des cas peut être passive (dans des structures sanitaires par exemple) ou active (en population). Le choix des méthodes de diagnostic et de recrutement des cas dépend des objectifs et des approches, pragmatiques ou explicatives, dont la différence radicale reste souvent insoupçonnée ou ignorée.There are no specific clinical signs or symptoms of malaria. Fever attacks, anemia, or signs of severity like coma or respiratory distress cannot easily be attributed to malaria in people who are infected most of the time. Ascribing clinical manifestations to malaria is problematic in populations that are regularly exposed to the transmission of human plasmodia. The more transmission is intense and regular, the higher the prevalence of asymptomatic infections. In areas of intense and perennial malaria transmission, more than 90% of the population may be infected and the simple detection of a plasmodial infection is not enough to attribute clinical manifestations to malaria. Naturally acquired anti-malaria immunity permitting asymptomatic infections is incomplete and temporary. It is an obstacle to the estimation of the malaria burden in endemic areas. The positive association between parasite density and fever allows the attribution of clinical attacks to malaria. The relationship between parasitaemia and the risk of fever is not continuous. An age- and endemicity-dependent threshold effect of parasite density has been demonstrated and can be used to distinguish clinical attacks due to malaria from others. Clinical diagnosis and evaluation of malaria are problematic in three situations: in public health to estimate the malaria burden for health services, in clinical research to evaluate treatments or prophylactic measures (drug, vaccine, anti-vectorial devices), and in basic research on pathophysiology, immunology or genetic susceptibility to clinical malaria. No one diagnostic definition nor procedure for detecting cases is adequate for all three purposes. Case detection may be passive (in health structures for example) or active (in population). The choice of methods for diagnosis and recruitment depends on the objectives and whether a “pragmatic” or “explicative” approach is used. The radical differences between these approaches are often unsuspected or ignored.

Research paper thumbnail of Vaccins contre le paludisme : perspectives et réalité

Médecine et Maladies Infectieuses, 2006

The development of a malaria vaccine has been accelerating in the last ten years. The number of c... more The development of a malaria vaccine has been accelerating in the last ten years. The number of clinical trials has increased and some malaria antigens have been tested in endemic areas. No potential vaccine has yet shown sufficient and lasting efficacy to justify its inclusion in a public health program. However, trials have unambiguously shown that some level of anti-malaria

Research paper thumbnail of Plasmodium falciparum proteome changes in response to doxycycline treatment

Malaria Journal, 2010

Background: The emergence of Plasmodium falciparum resistance to most anti-malarial compounds has... more Background: The emergence of Plasmodium falciparum resistance to most anti-malarial compounds has highlighted the urgency to develop new drugs and to clarify the mechanisms of anti-malarial drugs currently used. Among them, doxycycline is used alone for malaria chemoprophylaxis or in combination with quinine or artemisinin derivatives for malaria treatment. The molecular mechanisms of doxycycline action in P. falciparum have not yet been clearly defined, particularly at the protein level.

Research paper thumbnail of Salivary Gland Protein Repertoire from Aedes aegypti Mosquitoes

Vector-Borne and Zoonotic Diseases, 2010

Diseases caused by arthropod-borne viruses are a significant threat to the health of human and an... more Diseases caused by arthropod-borne viruses are a significant threat to the health of human and animal populations throughout the world. Better knowledge of the molecules synthesized in the salivary gland and saliva of hematophagous arthropods could be of use for improving the control of pathogen transmission. Recently, a sialome analysis of three Aedes aegypti mosquito colonies (PAEA, Rockefeller, and Formosus) carried out in our laboratory allowed us to identify 44 saliva proteins. Of these secreted proteins, none was exclusively expressed in one colony, suggesting that expression of salivary proteins is highly conserved across populations. In another study, we reported that some of these salivary proteins could be used as the genus-specific markers for travelers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; exposure to mosquito vectors. Here, comparison of salivary gland protein profiles between these same three Ae. aegypti colonies was performed using the one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) difference gel electrophoresis method. As observed at the saliva level, no significant differences were detected between these three colonies. The salivary gland protein repertoire from the Ae. aegypti mosquito was analyzed using a proteomic approach. One hundred and twenty proteins were identified in these salivary glands representing the largest description of the Ae. aegypti salivary gland protein catalog. We succeeded in identifying 15 secreted proteins, some of which have already been reported as being involved in blood feeding. A comparison of the proteins identified between the salivary glands and the sialome is discussed.

Research paper thumbnail of Sialome Individuality Between Aedes aegypti Colonies

Vector-Borne and Zoonotic Diseases, 2009

Aedes aegypti is responsible for the transmission of arboviruses. The Yellow Fever, Dengue and Ch... more Aedes aegypti is responsible for the transmission of arboviruses. The Yellow Fever, Dengue and Chikungunya viruses are transmitted to the vertebrate host by injection of infected saliva during the blood meal of its vectors. Saliva contains different components with various biochemical activities; anti-hemostatic, angiogenic, inflammatory, and immunomodulatory. This work compares the sialomes of three Ae. aegypti colonies (Rockefeller, PAEA, and Formosus), where the repertoire of salivary proteins from these colonies was analyzed by a proteomic approach. This study indicated that major proteins were detectable in the three colonies. However, differences in the abundance of some saliva proteins have been observed between the three Ae. aegypti colonies.

Research paper thumbnail of In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs

Tropical Medicine and International Health, 2002

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amod... more The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, artesunate, atovaquone, cycloguanil and pyrimethamine were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo, Ndiop), using an isotopic micro-drug susceptibility test. The IC50 values for ferrochloroquine ranged from 0.55 to 28.2 nM and the geometric mean IC50 for the 55 isolates was 7.9 nM (95% CI, 6.5-9.7 nM). Ferrochloroquine was 35 times more active than chloroquine (35-fold greater against chloroquine-resistant isolates), quinine, mefloquine, amodiaquine, cycloguanil and pyrimethamine. Weak positive correlations were observed between the responses to ferrochloroquine and that to chloroquine, quinine, and amodiaquine, but not compulsorily predictive of cross-resistance. There was no significant correlation between the response to ferrochloroquine and that to mefloquine, halofantrine, artesunate, atovaquone, cycloguanil and pyrimethamine. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Research paper thumbnail of Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium

The FASEB Journal, 2009

Cerebral malaria (CM) is characterized by accumulation of circulating cells within brain microves... more Cerebral malaria (CM) is characterized by accumulation of circulating cells within brain microvessels, among which platelets play an important role. In vitro, platelets modulate the cytoadherence of Plasmodium falciparum-parasitized red blood cells (PRBCs) to brain endothelial cells. Here we show for the first time that platelet microparticles (PMPs) are able to bind to PRBCs, thereby transferring platelet antigens to the PRBC surface. This binding is largely specific to PRBCs, because PMPs show little adherence to normal red blood cells. PMP adherence is also dependent on the P. falciparum erythrocyte membrane protein 1 variant expressed by PRBCs. PMP binding to PRBCs decreases after neutralization of PRBC surface proteins by trypsin or after treatment of PMPs with a mAb to platelet-endothelial cell adhesion molecule-1 (CD31) and glycoprotein IV (CD36). Furthermore, PMP uptake is a dynamic process that can be achieved by human brain endothelial cells (HBECs), inducing changes in the endothelial phenotype. Lastly, PMPs dramatically increase PRBC cytoadherence to HBECs. In conclusion, our study identifies several mechanisms by which PMPs may participate in CM pathogenesis while interacting with both PRBCs and HBECs. PMPs thereby provide a novel target for antagonizing interactions between vascular cells that promote microvascular sludging and blood brain barrier alteration during CM.-Faille, D., Combes, V., Mitchell, A. J., Fontaine, A., Juhan-Vague, I., Alessi, M.-C., Chimini, G., Fusaï, T., Grau, G. E. Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium. FASEB J. 23, 3449 -3458 (2009). www.fasebj.org

Research paper thumbnail of Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: A receptor for human placental infection

Proceedings of the National Academy of Sciences, 1999

Malaria during the first pregnancy causes a high rate of fetal and neonatal death. The decreasing... more Malaria during the first pregnancy causes a high rate of fetal and neonatal death. The decreasing susceptibility during subsequent pregnancies correlates with acquisition of antibodies that block binding of infected red cells to chondroitin sulfate A (CSA), a receptor for parasites in the placenta. Here we identify a domain within a particular Plasmodium falciparum erythrocyte membrane protein 1 that binds CSA. We cloned a var gene expressed in CSA-binding parasitized red blood cells (PRBCs). The gene had eight receptor-like domains, each of which was expressed on the surface of Chinese hamster ovary cells and was tested for CSA binding. CSA linked to biotin used as a probe demonstrated that two Duffy-binding-like (DBL) domains (DBL3 and DBL7) bound CSA. DBL7, but not DBL3, also bound chondroitin sulfate C (CSC) linked to biotin, a negatively charged sugar that does not support PRBC adhesion. Furthermore, CSA, but not CSC, blocked the interaction with DBL3; both CSA and CSC blocked binding to DBL7. Thus, only the DBL3 domain displays the same binding specificity as PRBCs. Because protective antibodies present after pregnancy block binding to CSA of parasites from different parts of the world, DBL-3, although variant, may induce cross-reactive immunity that will protect pregnant women and their fetuses.

Research paper thumbnail of Antibody response against saliva antigens of Anopheles gambiae and Aedes aegypti in travellers in tropical Africa

Exposure to vectors of infectious diseases has been associated with antibody responses against sa... more Exposure to vectors of infectious diseases has been associated with antibody responses against salivary antigens of arthropods among people living in endemic areas. This immune response has been proposed as a surrogate marker of exposure to vectors appropriate for evaluating the protective efficacy of antivectorial devices. The existence and potential use of such antibody responses in travellers transiently exposed to Plasmodium or arbovirus vectors in tropical areas has never been investigated. The IgM and IgG antibody responses of 88 French soldiers against the saliva of Anopheles gambiae and Aedes aegypti were evaluated before and after a 5-month journey in tropical Africa. Antibody responses against Anopheles and Aedes saliva increased significantly in 41% and 15% of the individuals, respectively, and appeared to be specific to the mosquito genus. A proteomic and immunoproteomic analysis of anopheles and Aedes saliva allowed for the identification of some antigens that were recognized by most of the exposed individuals. These results suggest that antibody responses to the saliva of mosquitoes could be considered as specific surrogate markers of exposure of travellers to mosquito vectors that transmit arthropod borne infections.

Research paper thumbnail of Dihydroethanoanthracene Derivatives Reverse In Vitro Quinoline Resistance in Plasmodium falciparum Malaria

Medicinal Chemistry, 2008

The capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quino... more The capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quinoline antimalarial drugs, such as chloroquine (CQ), quinine (QN), mefloquine (MQ) and monodesethylamodiaquine (MDAQ), was assessed against 27 Plasmodium falciparum isolates. Four of these compounds were 9,10-dihydroethanoanthracene derivatives (DEAs). These DEAs reversed 75 to 92% of the CQ resistant strains. These synthetic compounds were more effective in combination with CQ than verapamil, ketotifen, chlorpromazine, reserpine or nicardipine, which reversed less than 50% of the CQ resistant strains. DEAs significantly reversed 67 to 100% of MDAQ resistant parasites. These compounds were more effective in combination with MDAQ than ketotifen (60% of reversal), chlorpromazine (45%), verapamil (33%), reserpine (30%) or nicardipine (9%). The reversal activity of MQ resistance was less pronounced, regardless of the molecule tested, and was homogeneous with a rate ranging from 42% for ketotifen to 58% for reserpine, nicardipine, verapamil and cyproheptadine. The four DEAs significantly reversed 50 to 55% of the parasites resistant to MQ. Fifty-six to 78 % of the QN resistant parasites were reversed by the synthetic DEAs. There were few differences in the rate of reversal activity on QN resistant strains between the ten compounds, with rates ranging between 56 to 78% for the ten chemosensitizers. The use of DEAs in combination with quinoline seems to be thus a promising strategy for limiting the development of drug resistant strains and for treating patients in drug resistant areas.

Research paper thumbnail of Antimalarial drug use in general populations of tropical Africa

Malaria Journal, 2008

The burden of Plasmodium falciparum malaria has worsened because of the emergence of chloroquine ... more The burden of Plasmodium falciparum malaria has worsened because of the emergence of chloroquine resistance. Antimalarial drug use and drug pressure are critical factors contributing to the selection and spread of resistance. The present study explores the geographical, socio-economic and behavioural factors associated with the use of antimalarial drugs in Africa.

Research paper thumbnail of Influence of oxygen on asexual blood cycle and susceptibility of Plasmodium falciparum to chloroquine: requirement of a standardized in vitro assay

Malaria Journal, 2007

The main objective of this study was to assess the influence of gas mixtures on in vitro Plasmodi... more The main objective of this study was to assess the influence of gas mixtures on in vitro Plasmodium falciparum growth and 50% inhibitory concentration (IC 50 ) for chloroquine.

Research paper thumbnail of Intrathoracic Pressure Impulse Predicts Pulmonary Contusion Volume in Ballistic Blunt Thoracic Trauma

The Journal of Trauma: Injury, Infection, and Critical Care, 2010

Background: Blunt thoracic trauma including behind armour blunt trauma or impact from a less leth... more Background: Blunt thoracic trauma including behind armour blunt trauma or impact from a less lethal kinetic weapon (LLKW) projectile may cause injuries, including pulmonary contusions that can result in potentially lethal secondary complications. These lung injuries may be caused by intrathoracic pressure waves. The aim of this study was to observe dynamic changes in intrathoracic hydrostatic pressure during ballistic blunt thoracic trauma and to find correlations between these hydrostatic pressure parameters (especially the impulse parameter) and physical damages. Methods: Thirty anesthetized pigs sustained a blunt thoracic trauma. In group 1 (n ϭ 20), pigs were protected by a National Institute of Justice class III or IV bulletproof vest and shot with 7.62 NATO bullets. In group 2 (n ϭ 10), pigs were shot by an LLKW. Intrathoracic pressure was recorded with an intraesophageal pressure sensor and three parameters were determined: intrathoracic maximum pressure, intrathoracic maximum pressure impulse (PI max), and the Pd.P/dt max , derived from Viano's viscous criterion. Relative right lower lung lobe contusion volume was also measured. Results: Different thoracic loading conditions were obtained. PI max best correlated with relative pulmonary contusion volume (R 2 ϭ 0.64 and p Ͻ 0.0001). This result was homogenous for all experiments and was not related to the type of chest impact (LLKW-induced trauma or behind armour blunt trauma). Conclusions: The PI max is a good predictor of pulmonary contusion volume after ballistic blunt thoracic trauma. It is a useful criterion when the kinetic energy record or thoracic wall displacement data are unavailable, and the recording and calculation of this physical value are quite simple on animals.

Research paper thumbnail of Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum

Journal of Antimicrobial Chemotherapy, 2001

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amod... more The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC 50 values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC 50 for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 M, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Research paper thumbnail of Antibody response against saliva antigens of Anopheles gambiae and Aedes aegypti in travellers in tropical Africa

Microbes and …, 2007

Exposure to vectors of infectious diseases has been associated with antibody responses against sa... more Exposure to vectors of infectious diseases has been associated with antibody responses against salivary antigens of arthropods among people living in endemic areas. This immune response has been proposed as a surrogate marker of exposure to vectors appropriate for evaluating the protective efficacy of antivectorial devices. The existence and potential use of such antibody responses in travellers transiently exposed to Plasmodium or arbovirus vectors in tropical areas has never been investigated. The IgM and IgG antibody responses of 88 French soldiers against the saliva of Anopheles gambiae and Aedes aegypti were evaluated before and after a 5-month journey in tropical Africa. Antibody responses against Anopheles and Aedes saliva increased significantly in 41% and 15% of the individuals, respectively, and appeared to be specific to the mosquito genus. A proteomic and immunoproteomic analysis of anopheles and Aedes saliva allowed for the identification of some antigens that were recognized by most of the exposed individuals. These results suggest that antibody responses to the saliva of mosquitoes could be considered as specific surrogate markers of exposure of travellers to mosquito vectors that transmit arthropod borne infections.

Research paper thumbnail of In vitro reversal of chloroquine resistance in Plasmodium falciparum with dihydroethanoanthracene derivatives

The American journal of tropical medicine and hygiene, 2002

The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were ass... more The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were assessed in vitro against Plasmodium falciparum chloroquine resistant parasites W2, Palo Alto, FCR3, and Bres1. Like verapamil or promethazine, the four dihydroethanoanthracenic derivatives tested can be added to the growing list of agents that show capability in enhancing the activity of chloroquine against resistant parasites. The structurally related tricyclic antihistaminic compounds examined in this study exerted different intrinsic antimalarial activity, but the same chloroquine-potentiating activity as verapamil or promethazine. They may act both on the rate of chloroquine accumulation and on its access to ferriprotoporphyrin IX. The reversal mechanism would be assumed to result from competition between DEA derivatives and chloroquine for efflux translocation sites, thus causing an increase in steady-state accumulation of chloroquine and a return to susceptibility. Restoration of the...

Research paper thumbnail of Antibody responses to several malaria pre-erythrocytic antigens as a marker of malaria exposure among travelers

The American journal of tropical medicine and hygiene, 2006

Protective devices against vectors are used by travelers in malaria-endemic areas but their effic... more Protective devices against vectors are used by travelers in malaria-endemic areas but their efficacy for protection against mosquitoes has rarely been evaluated. The level of exposure to malaria transmission of 205 soldiers deployed in Africa and the efficacy of their anti-vector prophylaxis was evaluated by comparison of their IgM and IgG responses against five pre-erythrocytic Plasmodium falciparum antigens (circumsporozoite protein, sporozoite threonine- and asparagine-rich protein, sporozoite- and liver-stage antigen, liver stage antigen 1, and SR11.1) before and at the end of their deployment, and three months after returning to France for 106 of these soldiers. The immune responses increased significantly during the mission in 35% (95% confidence interval = 28-42%) of the individuals. The permanent use of insecticide-treated bed nets and long-sleeve battle dress at night were associated with protective efficacy. The analysis of these antibody responses was sensitive enough to ...

Research paper thumbnail of In vitro activity of artemether against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial drugs

The American journal of tropical medicine and hygiene, 1998

The in vitro activity of artemether against 56 African isolates of Plasmodium falciparum from Sen... more The in vitro activity of artemether against 56 African isolates of Plasmodium falciparum from Senegal was evaluated using an isotope-based drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95% confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95% CI = 2.08-4.84 nM versus mean IC50 = 2.80 nM, 95% CI = 2.00-3.60 nM). There was a significant positive correlation between responses to artemether and mefloquine (r2 = 0.36, P < 0.001), artemether and quinine (r2 = 0.085, P < 0.05), artemether and halofantrine (r2 = 0.075, P < 0.05), quinine and mefloquine (r2 = 0.205, P < 0.01), quinine and halofantrine (r2 = 0.124, P < 0.05), and mefloquine and halofantrine (r2 = 0.801, P < 0.001). A positive correlation between these drugs suggests in vitro cross...

Research paper thumbnail of Urban malaria in Dakar, Senegal: chemosusceptibility and genetic diversity of Plasmodium falciparum isolates

The American journal of tropical medicine and hygiene, 2006

The chemosusceptibility and genetic polymorphism of Plasmodium falciparum populations from 48 pat... more The chemosusceptibility and genetic polymorphism of Plasmodium falciparum populations from 48 patients hospitalized for malaria at the Hospital Principal in Dakar, Senegal were investigated during the 2002 malaria transmission season. Sixty-two percent of the isolates collected were from patients with severe malaria and 38% were from patients with mild malaria. In vitro activities of chloroquine, quinine, cycloguanil, atovaquone, mefloquine, halofantrine, and artesunate were evaluated. The prevalence of mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) and dihyropteroate synthetase (dhps) genes and the P. falciparum chloroquine resistance transporter (Pfcrt) gene associated with cycloguanil, pyrimethamine, sulfadoxine, and chloroquine resistance were estimated. The genetic polymorphism of the parasite populations was evaluated by analysis of the highly polymorphic regions of merozoite surface protein 1 (msp1) block 2 and msp2. Seventy percent of the isolates were...

Research paper thumbnail of Platelets Alter Gene Expression Profile in Human Brain Endothelial Cells in an In Vitro Model of Cerebral Malaria

Plos One, 2011

Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in... more Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in humans, suggesting that platelets play a role in the pathogenesis of this syndrome. In vitro co-cultures have shown that platelets can act as a bridge between Plasmodium falciparum-infected red blood cells (pRBC) and human brain microvascular endothelial cells (HBEC) and potentiate HBEC apoptosis. Using cDNA microarray technology, we analyzed transcriptional changes of HBEC in response to platelets in the presence or the absence of tumor necrosis factor (TNF) and pRBC, which have been reported to alter gene expression in endothelial cells. Using a rigorous statistical approach with multiple test corrections, we showed a significant effect of platelets on gene expression in HBEC. We also detected a strong effect of TNF, whereas there was no transcriptional change induced specifically by pRBC. Nevertheless, a global ANOVA and a two-way ANOVA suggested that pRBC acted in interaction with platelets and TNF to alter gene expression in HBEC. The expression of selected genes was validated by RT-qPCR. The analysis of gene functional annotation indicated that platelets induce the expression of genes involved in inflammation and apoptosis, such as genes involved in chemokine-, TREM1-, cytokine-, IL10-, TGFb-, deathreceptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM.

Research paper thumbnail of Comment évaluer la morbidité attribuable au paludisme en zone d’endémie ?

Revue d'Épidémiologie et de Santé Publique, 2005

ABSTRACT Il n’existe pas de signe pathognomonique du paludisme. Les accès de fièvre, l’anémie, le... more ABSTRACT Il n’existe pas de signe pathognomonique du paludisme. Les accès de fièvre, l’anémie, les signes de gravité comme le coma ou les détresses respiratoires ne peuvent être aisément attribués à une infection plasmodiale dans les populations qui sont infectées la plupart du temps. L’attribution de manifestations cliniques au paludisme est problématique dans les populations exposées régulièrement à la transmission des plasmodiums humains. Plus la transmission est forte et régulière, plus le taux de prévalence des infections plasmodiales asymptomatiques est élevé. Chez les populations vivant dans les zones où la transmission est intense et pérenne, ce taux est parfois supérieur à 90 % de la population, et la détection d’une infection plasmodiale ne suffit alors pas pour attribuer des manifestations cliniques au paludisme. L’acquisition d’une immunité partielle et labile permettant aux personnes régulièrement infectées de supporter des parasitémies sans présenter de manifestation clinique est donc un obstacle à l’évaluation de la morbidité palustre en zone d’endémie.L’association positive entre la densité parasitaire et la fièvre permet d’estimer la fraction des accès cliniques attribuables au paludisme. Il a été montré que cette relation entre parasitémie et risque de fièvre n’était pas continue et qu’un seuil pyrogène de la parasitémie, dépendant de l’âge et du niveau d’endémicité, permettait de distinguer les épisodes cliniques dus au paludisme.Le problème du diagnostic et de l’évaluation de la morbidité palustre se pose dans au moins trois circonstances: en santé publique pour l’estimation du poids du paludisme dans les structures sanitaires, en recherche clinique pour l’évaluation des traitements et des mesures prophylactiques (médicaments, vaccins, protections anti-vectorielles) et en recherche fondamentale pour l’étude de la physiopathologie et des déterminants immunologiques et génétiques de la sensibilité clinique au paludisme.Dans ces différentes circonstances, il est ni possible ni approprié d’utiliser la même définition diagnostique ou la même méthode de recrutement des cas. Pour évaluer la morbidité palustre, la recherche des cas peut être passive (dans des structures sanitaires par exemple) ou active (en population). Le choix des méthodes de diagnostic et de recrutement des cas dépend des objectifs et des approches, pragmatiques ou explicatives, dont la différence radicale reste souvent insoupçonnée ou ignorée.There are no specific clinical signs or symptoms of malaria. Fever attacks, anemia, or signs of severity like coma or respiratory distress cannot easily be attributed to malaria in people who are infected most of the time. Ascribing clinical manifestations to malaria is problematic in populations that are regularly exposed to the transmission of human plasmodia. The more transmission is intense and regular, the higher the prevalence of asymptomatic infections. In areas of intense and perennial malaria transmission, more than 90% of the population may be infected and the simple detection of a plasmodial infection is not enough to attribute clinical manifestations to malaria. Naturally acquired anti-malaria immunity permitting asymptomatic infections is incomplete and temporary. It is an obstacle to the estimation of the malaria burden in endemic areas. The positive association between parasite density and fever allows the attribution of clinical attacks to malaria. The relationship between parasitaemia and the risk of fever is not continuous. An age- and endemicity-dependent threshold effect of parasite density has been demonstrated and can be used to distinguish clinical attacks due to malaria from others. Clinical diagnosis and evaluation of malaria are problematic in three situations: in public health to estimate the malaria burden for health services, in clinical research to evaluate treatments or prophylactic measures (drug, vaccine, anti-vectorial devices), and in basic research on pathophysiology, immunology or genetic susceptibility to clinical malaria. No one diagnostic definition nor procedure for detecting cases is adequate for all three purposes. Case detection may be passive (in health structures for example) or active (in population). The choice of methods for diagnosis and recruitment depends on the objectives and whether a “pragmatic” or “explicative” approach is used. The radical differences between these approaches are often unsuspected or ignored.

Research paper thumbnail of Vaccins contre le paludisme : perspectives et réalité

Médecine et Maladies Infectieuses, 2006

The development of a malaria vaccine has been accelerating in the last ten years. The number of c... more The development of a malaria vaccine has been accelerating in the last ten years. The number of clinical trials has increased and some malaria antigens have been tested in endemic areas. No potential vaccine has yet shown sufficient and lasting efficacy to justify its inclusion in a public health program. However, trials have unambiguously shown that some level of anti-malaria

Research paper thumbnail of Plasmodium falciparum proteome changes in response to doxycycline treatment

Malaria Journal, 2010

Background: The emergence of Plasmodium falciparum resistance to most anti-malarial compounds has... more Background: The emergence of Plasmodium falciparum resistance to most anti-malarial compounds has highlighted the urgency to develop new drugs and to clarify the mechanisms of anti-malarial drugs currently used. Among them, doxycycline is used alone for malaria chemoprophylaxis or in combination with quinine or artemisinin derivatives for malaria treatment. The molecular mechanisms of doxycycline action in P. falciparum have not yet been clearly defined, particularly at the protein level.

Research paper thumbnail of Salivary Gland Protein Repertoire from Aedes aegypti Mosquitoes

Vector-Borne and Zoonotic Diseases, 2010

Diseases caused by arthropod-borne viruses are a significant threat to the health of human and an... more Diseases caused by arthropod-borne viruses are a significant threat to the health of human and animal populations throughout the world. Better knowledge of the molecules synthesized in the salivary gland and saliva of hematophagous arthropods could be of use for improving the control of pathogen transmission. Recently, a sialome analysis of three Aedes aegypti mosquito colonies (PAEA, Rockefeller, and Formosus) carried out in our laboratory allowed us to identify 44 saliva proteins. Of these secreted proteins, none was exclusively expressed in one colony, suggesting that expression of salivary proteins is highly conserved across populations. In another study, we reported that some of these salivary proteins could be used as the genus-specific markers for travelers&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; exposure to mosquito vectors. Here, comparison of salivary gland protein profiles between these same three Ae. aegypti colonies was performed using the one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) difference gel electrophoresis method. As observed at the saliva level, no significant differences were detected between these three colonies. The salivary gland protein repertoire from the Ae. aegypti mosquito was analyzed using a proteomic approach. One hundred and twenty proteins were identified in these salivary glands representing the largest description of the Ae. aegypti salivary gland protein catalog. We succeeded in identifying 15 secreted proteins, some of which have already been reported as being involved in blood feeding. A comparison of the proteins identified between the salivary glands and the sialome is discussed.

Research paper thumbnail of Sialome Individuality Between Aedes aegypti Colonies

Vector-Borne and Zoonotic Diseases, 2009

Aedes aegypti is responsible for the transmission of arboviruses. The Yellow Fever, Dengue and Ch... more Aedes aegypti is responsible for the transmission of arboviruses. The Yellow Fever, Dengue and Chikungunya viruses are transmitted to the vertebrate host by injection of infected saliva during the blood meal of its vectors. Saliva contains different components with various biochemical activities; anti-hemostatic, angiogenic, inflammatory, and immunomodulatory. This work compares the sialomes of three Ae. aegypti colonies (Rockefeller, PAEA, and Formosus), where the repertoire of salivary proteins from these colonies was analyzed by a proteomic approach. This study indicated that major proteins were detectable in the three colonies. However, differences in the abundance of some saliva proteins have been observed between the three Ae. aegypti colonies.

Research paper thumbnail of In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs

Tropical Medicine and International Health, 2002

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amod... more The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, artesunate, atovaquone, cycloguanil and pyrimethamine were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo, Ndiop), using an isotopic micro-drug susceptibility test. The IC50 values for ferrochloroquine ranged from 0.55 to 28.2 nM and the geometric mean IC50 for the 55 isolates was 7.9 nM (95% CI, 6.5-9.7 nM). Ferrochloroquine was 35 times more active than chloroquine (35-fold greater against chloroquine-resistant isolates), quinine, mefloquine, amodiaquine, cycloguanil and pyrimethamine. Weak positive correlations were observed between the responses to ferrochloroquine and that to chloroquine, quinine, and amodiaquine, but not compulsorily predictive of cross-resistance. There was no significant correlation between the response to ferrochloroquine and that to mefloquine, halofantrine, artesunate, atovaquone, cycloguanil and pyrimethamine. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Research paper thumbnail of Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium

The FASEB Journal, 2009

Cerebral malaria (CM) is characterized by accumulation of circulating cells within brain microves... more Cerebral malaria (CM) is characterized by accumulation of circulating cells within brain microvessels, among which platelets play an important role. In vitro, platelets modulate the cytoadherence of Plasmodium falciparum-parasitized red blood cells (PRBCs) to brain endothelial cells. Here we show for the first time that platelet microparticles (PMPs) are able to bind to PRBCs, thereby transferring platelet antigens to the PRBC surface. This binding is largely specific to PRBCs, because PMPs show little adherence to normal red blood cells. PMP adherence is also dependent on the P. falciparum erythrocyte membrane protein 1 variant expressed by PRBCs. PMP binding to PRBCs decreases after neutralization of PRBC surface proteins by trypsin or after treatment of PMPs with a mAb to platelet-endothelial cell adhesion molecule-1 (CD31) and glycoprotein IV (CD36). Furthermore, PMP uptake is a dynamic process that can be achieved by human brain endothelial cells (HBECs), inducing changes in the endothelial phenotype. Lastly, PMPs dramatically increase PRBC cytoadherence to HBECs. In conclusion, our study identifies several mechanisms by which PMPs may participate in CM pathogenesis while interacting with both PRBCs and HBECs. PMPs thereby provide a novel target for antagonizing interactions between vascular cells that promote microvascular sludging and blood brain barrier alteration during CM.-Faille, D., Combes, V., Mitchell, A. J., Fontaine, A., Juhan-Vague, I., Alessi, M.-C., Chimini, G., Fusaï, T., Grau, G. E. Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium. FASEB J. 23, 3449 -3458 (2009). www.fasebj.org

Research paper thumbnail of Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: A receptor for human placental infection

Proceedings of the National Academy of Sciences, 1999

Malaria during the first pregnancy causes a high rate of fetal and neonatal death. The decreasing... more Malaria during the first pregnancy causes a high rate of fetal and neonatal death. The decreasing susceptibility during subsequent pregnancies correlates with acquisition of antibodies that block binding of infected red cells to chondroitin sulfate A (CSA), a receptor for parasites in the placenta. Here we identify a domain within a particular Plasmodium falciparum erythrocyte membrane protein 1 that binds CSA. We cloned a var gene expressed in CSA-binding parasitized red blood cells (PRBCs). The gene had eight receptor-like domains, each of which was expressed on the surface of Chinese hamster ovary cells and was tested for CSA binding. CSA linked to biotin used as a probe demonstrated that two Duffy-binding-like (DBL) domains (DBL3 and DBL7) bound CSA. DBL7, but not DBL3, also bound chondroitin sulfate C (CSC) linked to biotin, a negatively charged sugar that does not support PRBC adhesion. Furthermore, CSA, but not CSC, blocked the interaction with DBL3; both CSA and CSC blocked binding to DBL7. Thus, only the DBL3 domain displays the same binding specificity as PRBCs. Because protective antibodies present after pregnancy block binding to CSA of parasites from different parts of the world, DBL-3, although variant, may induce cross-reactive immunity that will protect pregnant women and their fetuses.

Research paper thumbnail of Antibody response against saliva antigens of Anopheles gambiae and Aedes aegypti in travellers in tropical Africa

Exposure to vectors of infectious diseases has been associated with antibody responses against sa... more Exposure to vectors of infectious diseases has been associated with antibody responses against salivary antigens of arthropods among people living in endemic areas. This immune response has been proposed as a surrogate marker of exposure to vectors appropriate for evaluating the protective efficacy of antivectorial devices. The existence and potential use of such antibody responses in travellers transiently exposed to Plasmodium or arbovirus vectors in tropical areas has never been investigated. The IgM and IgG antibody responses of 88 French soldiers against the saliva of Anopheles gambiae and Aedes aegypti were evaluated before and after a 5-month journey in tropical Africa. Antibody responses against Anopheles and Aedes saliva increased significantly in 41% and 15% of the individuals, respectively, and appeared to be specific to the mosquito genus. A proteomic and immunoproteomic analysis of anopheles and Aedes saliva allowed for the identification of some antigens that were recognized by most of the exposed individuals. These results suggest that antibody responses to the saliva of mosquitoes could be considered as specific surrogate markers of exposure of travellers to mosquito vectors that transmit arthropod borne infections.

Research paper thumbnail of Dihydroethanoanthracene Derivatives Reverse In Vitro Quinoline Resistance in Plasmodium falciparum Malaria

Medicinal Chemistry, 2008

The capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quino... more The capacity of ten molecules for reversing resistance in Plasmodium falciparum in vitro to quinoline antimalarial drugs, such as chloroquine (CQ), quinine (QN), mefloquine (MQ) and monodesethylamodiaquine (MDAQ), was assessed against 27 Plasmodium falciparum isolates. Four of these compounds were 9,10-dihydroethanoanthracene derivatives (DEAs). These DEAs reversed 75 to 92% of the CQ resistant strains. These synthetic compounds were more effective in combination with CQ than verapamil, ketotifen, chlorpromazine, reserpine or nicardipine, which reversed less than 50% of the CQ resistant strains. DEAs significantly reversed 67 to 100% of MDAQ resistant parasites. These compounds were more effective in combination with MDAQ than ketotifen (60% of reversal), chlorpromazine (45%), verapamil (33%), reserpine (30%) or nicardipine (9%). The reversal activity of MQ resistance was less pronounced, regardless of the molecule tested, and was homogeneous with a rate ranging from 42% for ketotifen to 58% for reserpine, nicardipine, verapamil and cyproheptadine. The four DEAs significantly reversed 50 to 55% of the parasites resistant to MQ. Fifty-six to 78 % of the QN resistant parasites were reversed by the synthetic DEAs. There were few differences in the rate of reversal activity on QN resistant strains between the ten compounds, with rates ranging between 56 to 78% for the ten chemosensitizers. The use of DEAs in combination with quinoline seems to be thus a promising strategy for limiting the development of drug resistant strains and for treating patients in drug resistant areas.

Research paper thumbnail of Antimalarial drug use in general populations of tropical Africa

Malaria Journal, 2008

The burden of Plasmodium falciparum malaria has worsened because of the emergence of chloroquine ... more The burden of Plasmodium falciparum malaria has worsened because of the emergence of chloroquine resistance. Antimalarial drug use and drug pressure are critical factors contributing to the selection and spread of resistance. The present study explores the geographical, socio-economic and behavioural factors associated with the use of antimalarial drugs in Africa.

Research paper thumbnail of Influence of oxygen on asexual blood cycle and susceptibility of Plasmodium falciparum to chloroquine: requirement of a standardized in vitro assay

Malaria Journal, 2007

The main objective of this study was to assess the influence of gas mixtures on in vitro Plasmodi... more The main objective of this study was to assess the influence of gas mixtures on in vitro Plasmodium falciparum growth and 50% inhibitory concentration (IC 50 ) for chloroquine.