Efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria: revisiting molecular markers in an area of emerging AQ and SP resistance in Mali

<p>Abstract</p> <p>Background</p> <p>To update the National Malaria Control Programme of Mali on the efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated <it>falciparum </it>malaria.</p> <p>Methods</p> <p>During the malaria transmission seasons of 2002 and 2003, 455 children – between six and 59 months of age, with uncomplicated malaria in Kolle, Mali, were randomly assigned to one of three treatment arms. <it>In vivo </it>outcomes were assessed using WHO standard protocols. Genotyping of <it>msp1</it>, <it>msp2 </it>and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites (molecular correction).</p> <p>Results</p> <p>Day 28 adequate clinical and parasitological responses (ACPR) were 14.1%, 62.3% and 88.9% in 2002 and 18.2%, 60% and 85.2% in 2003 for chloroquine, amodiaquine and sulphadoxine-pyrimethamine, respectively. After molecular correction, ACPRs (cACPR) were 63.2%, 88.5% and 98.0% in 2002 and 75.5%, 85.2% and 96.6% in 2003 for CQ, AQ and SP, respectively. Amodiaquine was the most effective on fever. Amodiaquine therapy selected molecular markers for chloroquine resistance, while in the sulphadoxine-pyrimethamine arm the level of <it>dhfr </it>triple mutant and <it>dhfr</it>/<it>dhps </it>quadruple mutant increased from 31.5% and 3.8% in 2002 to 42.9% and 8.9% in 2003, respectively. No infection with <it>dhps </it>540E was found.</p> <p>Conclusion</p> <p>In this study, treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine. The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy.</p

In vitro vasorelaxation mechanisms of bioactive compounds extracted from Hibiscus sabdariffa on rat thoracic aorta

<p>Abstract</p> <p>Background</p> <p>In this study, we suggested characterizing the vasodilator effects and the phytochemical characteristics of a plant with food usage also used in traditional treatment of arterial high blood pressure in Senegal.</p> <p>Methods</p> <p>Vascular effects of crude extract of dried and powdered calyces of <it>Hibiscus sabdariffa </it>were evaluated on isolated thoracic aorta of male Wistar rats on organ chambers. The crude extract was also enriched by liquid-liquid extraction. The various cyclohexane, dichloromethane, ethyl acetate, butanol extracts obtained as well as the residual marc were subjected to Sephadex LH-20 column chromatography. The different methanolic eluate fractions were then analyzed by Thin Layer (TLC) and High Performance Liquid Chromatography (HPLC) and their vascular effects also evaluated.</p> <p>Results</p> <p>The H. Sabdariffa crude extract induced mainly endothelium-dependent relaxant effects. The endothelium-dependent relaxations result from NOS activation and those who not dependent to endothelium from activation of smooth muscle potassium channels. The phytochemical analysis revealed the presence of phenolic acids in the ethyl acetate extract and anthocyans in the butanolic extract. The biological efficiency of the various studied extracts, in term of vasorelaxant capacity, showed that: Butanol extract > Crude extract > Residual marc > Ethyl acetate extract. These results suggest that the strong activity of the butanolic extract is essentially due to the presence of anthocyans found in its fractions 43-67.</p> <p>Conclusion</p> <p>These results demonstrate the vasodilator potential of <it>hibiscus sabdariffa </it>and contribute to his valuation as therapeutic alternative.</p

Molecular characterization and Antibiotic resistance profiles of Escherichia coli extended-spectrum β-lactamases producer strains isolated from urine samples in Benin

Urinary tract infections are the second common reason of medical consultations and antibiotics prescription. Escherichia coli is known to cause most urinary tract infections. The aim of this study was to characterize and determine the antibiotic resistance profile of E. coli extended-spectrum βlactamases (ESBL) producer strains isolated from urine samples. The urine samples collected came from hospitalized and non-hospitalized patient referred to Hubert Koutoukou Manga (HKM), National and University Hospital Center (Cotonou, Benin). The resistance to antibiotics was determined according to the disk diffusion method. The production of penicillinase and ESBLs was researched respectively by the acidimetric test and double disk synergy method. The presences of genes encoding βlactamases were detected by Polymerase Chain Reaction (PCR). Our data revealed that 60 % of E. coli strains (101) were isolated from female patients. Also, 69.31 % of the strains were isolated from non-hospitalized patients. The high resistance levels were recorded with amoxicillin (96.04 %) and amoxicillin + clavulanic acid (66.34 %). Twenty percent (20%) of strains were ESBLs. Among ESBLs strains, 70% comes from non-hospitalized patients. Eighty percent of E. coli strains produced penicillinase among which 25 % were ESBL producers. All the ESBL producers strains carried blaTEM gene whereas only 30 % carried the blaSHV gene. This study updates the data on the prevalence to antibiotic resistance of E. coli ESBL producers strains for better management of urinary tract infections

Molecular Dynamic Simulation Reveals Structure Differences in APOL1 Variants and Implication in Pathogenesis of Chronic Kidney Disease.

BACKGROUND: According to observational studies, two polymorphisms in the apolipoprotein L1 (APOL1) gene have been linked to an increased risk of chronic kidney disease (CKD) in Africans. One polymorphism involves the substitution of two amino-acid residues (S342G and I384M; known as G1), while the other involves the deletion of two amino-acid residues in a row (N388 and Y389; termed G2). Despite the strong link between APOL1 polymorphisms and kidney disease, the molecular mechanisms via which these APOL1 mutations influence the onset and progression of CKD remain unknown. METHODS: To predict the active site and allosteric site on the APOL1 protein, we used the Computed Atlas of Surface Topography of Proteins (CASTp) and the Protein Allosteric Sites Server (PASSer). Using an extended molecular dynamics simulation, we investigated the characteristic structural perturbations in the 3D structures of APOL1 variants. RESULTS: According to CASTp's active site characterization, the topmost predicted site had a surface area of 964.892 Å2 and a pocket volume of 900.792 Å3. For the top three allosteric pockets, the allostery probability was 52.44%, 46.30%, and 38.50%, respectively. The systems reached equilibrium in about 125 ns. From 0-100 ns, there was also significant structural instability. When compared to G1 and G2, the wildtype protein (G0) had overall high stability throughout the simulation. The root-mean-square fluctuation (RMSF) of wildtype and variant protein backbone Cα fluctuations revealed that the Cα of the variants had a large structural fluctuation when compared to the wildtype. CONCLUSION: Using a combination of different computational techniques, we identified binding sites within the APOL1 protein that could be an attractive site for potential inhibitors of APOL1. Furthermore, the G1 and G2 mutations reduced the structural stability of APOL1

Expanding Research Capacity in Sub-Saharan Africa Through Informatics, Bioinformatics, and Data Science Training Programs in Mali

Bioinformatics and data science research have boundless potential across Africa due to its high levels of genetic diversity and disproportionate burden of infectious diseases, including malaria, tuberculosis, HIV and AIDS, Ebola virus disease, and Lassa fever. This work lays out an incremental approach for reaching underserved countries in bioinformatics and data science research through a progression of capacity building, training, and research efforts. Two global health informatics training programs sponsored by the Fogarty International Center (FIC) were carried out at the University of Sciences, Techniques and Technologies of Bamako, Mali (USTTB) between 1999 and 2011. Together with capacity building efforts through the West Africa International Centers of Excellence in Malaria Research (ICEMR), this progress laid the groundwork for a bioinformatics and data science training program launched at USTTB as part of the Human Heredity and Health in Africa (H3Africa) initiative. Prior to the global health informatics training, its trainees published first or second authorship and third or higher authorship manuscripts at rates of 0.40 and 0.10 per year, respectively. Following the training, these rates increased to 0.70 and 1.23 per year, respectively, which was a statistically significant increase (p &lt; 0.001). The bioinformatics and data science training program at USTTB commenced in 2017 focusing on student, faculty, and curriculum tiers of enhancement. The program’s sustainable measures included institutional support for core elements, university tuition and fees, resource sharing and coordination with local research projects and companion training programs, increased student and faculty publication rates, and increased research proposal submissions. Challenges reliance of high-speed bandwidth availability on short-term funding, lack of a discounted software portal for basic software applications, protracted application processes for United States visas, lack of industry job positions, and low publication rates in the areas of bioinformatics and data science. Long-term, incremental processes are necessary for engaging historically underserved countries in bioinformatics and data science research. The multi-tiered enhancement approach laid out here provides a platform for generating bioinformatics and data science technicians, teachers, researchers, and program managers. Increased literature on bioinformatics and data science training approaches and progress is needed to provide a framework for establishing benchmarks on the topics

A Mendelian randomization study of genetic liability to post-traumatic stress disorder and risk of ischemic stroke.

Observational studies have shown an association between post-traumatic stress disorder (PTSD) and ischemic stroke (IS) but given the susceptibility to confounding it is unclear if these associations represent causal effects. Mendelian randomization (MR) facilitates causal inference that is robust to the influence of confounding. Using two sample MR, we investigated the causal effect of genetic liability to PTSD on IS risk. Ancestry-specific genetic instruments of PTSD and four quantitative sub-phenotypes of PTSD, including hyperarousal, avoidance, re-experiencing, and total symptom severity score (PCL-Total) were obtained from the Million Veteran Programme (MVP) using a threshold P value (P) of <5 × 10-7, clumping distance of 1000 kilobase (Mb) and r2 < 0.01. Genetic association estimates for IS were obtained from the MEGASTROKE consortium (Ncases = 34,217, Ncontrols = 406,111) for European ancestry individuals and from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) (Ncases = 3734, Ncontrols = 18,317) for African ancestry individuals. We used the inverse-variance weighted (IVW) approach as the main analysis and performed MR-Egger and the weighted median methods as pleiotropy-robust sensitivity analyses. In European ancestry individuals, we found evidence of an association between genetic liability to PTSD avoidance, and PCL-Total and increased IS risk (odds ratio (OR)1.04, 95% Confidence Interval (CI) 1.007-1.077, P = 0.017 for avoidance and (OR 1.02, 95% CI 1.010-1.040, P = 7.6 × 10-4 for PCL total). In African ancestry individuals, we found evidence of an association between genetically liability to PCL-Total and reduced IS risk (OR 0.95 (95% CI 0.923-0.991, P = 0.01) and hyperarousal (OR 0.83 (95% CI 0.691-0.991, P = 0.039) but no association was observed for PTSD case-control, avoidance, or re-experiencing. Similar estimates were obtained with MR sensitivity analyses. Our findings suggest that specific sub-phenotypes of PTSD, such as hyperarousal, avoidance, PCL total, may have a causal effect on people of European and African ancestry's risk of IS. This shows that the molecular mechanisms behind the relationship between IS and PTSD may be connected to symptoms of hyperarousal and avoidance. To clarify the precise biological mechanisms involved and how they may vary between populations, more research is required

Alkaline Leaching of Metals from Cathodic Materials of Spent Lithium-Ion Batteries

International audienceThe aim of this study was to recover metals from the positive electrode material for recycling in lithium-ion batteries. It was focused on research to optimize the hydrometallurgical pretreatment process of cathode materials for Li-ion batteries by varying parameters such as NaOH concentration, the ratio of solvent volume to mass of the test sample (liquid-solid ratio (L/S)) and reaction time. Thus, from used batteries collected in a local market (Colobane, Senegal), cathodic materials dried in an oven at 50°C for 24 hours, submitted to alkaline leaching with NaOH 2, 3 or 4N, followed by filtration, all at room temperature. The filtrates obtained were analyzed by atomic absorption spectrophotometry. The results obtained were showed that Al collectors could be better extracted with 4N NaOH for 5 hours at a ratio liquid/solid (L/S) = 10/1, with small quantities of the metals Co, Mn, Ni and Li found in the filtrates

Influence of the physicochemical parameters of solvents in the extraction of bioactive compounds from Parinari macrophylla Sabine (Chrysobalanaceae)

International audienceThe extraction of bioactive compounds from medicinal plants requires methods which are as diverse as the chemical nature of the compounds themselves. In this study, a 96-well microplate was used where solvent mixtures spanning wide ranges of selectivity and polarity were tested with the objective of extracting a broad range bioactive compounds from plant material. Microplate wells were filled with plant material and the solvents and their mixtures were added. The obtained extracts were assessed in terms of their total antioxidant activity, oxygen radical absorbance capacity and effects on cell viability. An aqueous extract, generally used by traditional therapists, was also included in the study. The results showed that the extracts using methanol with acetic acid (0.1%, v:v), chloroform/ethanol, butanol/DMF, butanol/acetonitrile, ethylene glycol with acetic acid (0.1%, v:v), MTBE/DMSO, ethylene glycol, pentane/ethanol (v:v), ethanol, DMF, DMF with acetic acid (0.1%, v:v), DMSO, DMSO with acetic acid (0.1%, v:v) and THF had a higher antioxidant activity than the aqueous extract. Extracts with greater antioxidant activity than the aqueous extract were obtained largely from solvent mixtures with the exception of ethanol, DMF, DMSO and THF. The antioxidant activity obtained in TEAC varied between 1474.1±4.4 and 3183.0±16.0 μmol TE/g dry extract respectively for aqueous and THF extracts; in ORAC between 1727.7±8.4 and 2683.5±11.7 μmol TE/g dry extract for aqueous and DMSO acetic acid 1%, respectively, with mean ±SEM. In TEAC the THF extract had the highest antioxidant potential with 3183.0±16.0 μmol TE / g dry extract. The DMSO acetic acid (0.1%, v:v) extract had the highest antioxidant potential in ORAC with 2683.5±11.7 μmol TE / g dry extract. Cell viability test using β-pancreatic cells showed that only the acidified methanol extract was toxic after one hour of incubation. After 24 hours, cell viability was less than 70% for extracts using butanol/acetonitrile, MTBE/DMF, acidified methanol, pentane/ethanol and acidified DMF

A Unique Virulence Gene Occupies a Principal Position in Immune Evasion by the Malaria Parasite <i>Plasmodium falciparum</i>

<div><p>Mutually exclusive gene expression, whereby only one member of a multi-gene family is selected for activation, is used by the malaria parasite <i>Plasmodium falciparum</i> to escape the human immune system and perpetuate long-term, chronic infections. A family of genes called <i>var</i> encodes the chief antigenic and virulence determinant of <i>P</i>. <i>falciparum</i> malaria. <i>var</i> genes are transcribed in a mutually exclusive manner, with switching between active genes resulting in antigenic variation. While recent work has shed considerable light on the epigenetic basis for <i>var</i> gene activation and silencing, how switching is controlled remains a mystery. In particular, switching seems not to be random, but instead appears to be coordinated to result in timely activation of individual genes leading to sequential waves of antigenically distinct parasite populations. The molecular basis for this apparent coordination is unknown. Here we show that <i>var2csa</i>, an unusual and highly conserved <i>var</i> gene, occupies a unique position within the <i>var</i> gene switching hierarchy. Induction of switching through the destabilization of <i>var</i> specific chromatin using both genetic and chemical methods repeatedly led to the rapid and exclusive activation of <i>var2csa</i>. Additional experiments demonstrated that these represent “true” switching events and not simply de-silencing of the <i>var2csa</i> promoter, and that activation is limited to the unique locus on chromosome 12. Combined with translational repression of <i>var2csa</i> transcripts, frequent “default” switching to this locus and detection of <i>var2csa</i> untranslated transcripts in non-pregnant individuals, these data suggest that <i>var2csa</i> could play a central role in coordinating switching, fulfilling a prediction made by mathematical models derived from population switching patterns. These studies provide the first insights into the mechanisms by which <i>var</i> gene switching is coordinated as well as an example of how a pharmacological agent can disrupt antigenic variation in <i>Plasmodium falciparum</i>.</p></div

Effect of over-expression of PfSET2 dom-neg on <i>var</i> gene expression.

<p>(A) Schematic diagram of the domain structure of PfSET2. The top image shows the conserved domains identified using SMART (Simple Modular Architecture Research Tool, <a href="http://smart.embl-heidelberg.de" target="_blank">http://smart.embl-heidelberg.de</a>). PHD domains are shown as blue polygons while the methyltransferase domain (labeled SET) is shown in red. The SET2 Rpb1 Interacting Region (SRIR) is shown as a white triangle. (B) <i>var</i> gene expression is shown as a pie-chart, with each slice of the pie representing the fraction of the total <i>var</i> mRNA pool transcribed from each <i>var</i> gene. The left chart shows the <i>var</i> gene expression pattern in a population over-expressing firefly luciferase. This is unchanged from the untransfected population and the annotation number of the dominant gene is shown in white text. The chart on the right shows the <i>var</i> gene expression pattern in a population after over-expression of the PfSET2 dominant negative construct for 6 weeks. <i>var2csa</i> (PF3D7_1200600, shown in green) has become the dominant transcript. Individual copy number values for each transcript are shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005234#pgen.1005234.s001" target="_blank">S1 Fig</a>.</p