BACKGROUND & AIMS: :Falciparum malaria is a potentially deadly infectious disease, imposing a sure and fast biologic diagnosis, an early and efficient treatment. We report a case of severe imported Falciparium malaria who received artesunate, and we rewiew the different diagnostic methods of malaria as well as the clinico-biological characteristics of severe malaria. Recent data concerning malaria treatment are presented, as a pharmacokinetic study leaded during this case.

背景与目标： : 恶性疟疾是一种潜在的致命传染病，它具有可靠而快速的生物学诊断，是一种早期有效的治疗方法。我们报告了一例接受青蒿琥酯的严重输入性恶性疟疾病例，并重新介绍了疟疾的不同诊断方法以及严重疟疾的临床生物学特征。作为在这种情况下进行的药代动力学研究，介绍了有关疟疾治疗的最新数据。

BACKGROUND & AIMS: :Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.

背景与目标： : 血浆蛋白酶是参与宿主细胞血红蛋白降解的天冬氨酸蛋白酶，被疟原虫用作食物来源。血浆蛋白酶作为药物靶标非常有希望，尤其是与抑制也参与血红蛋白分解代谢的falcipains结合使用时。在这篇综述中，鉴于过渡态模拟物作为潜在的铅开发化合物的兴趣，我们讨论了血浆蛋白酶i-iv的机理。总结了针对plasmepsin II的抑制剂开发以及相关的晶体结构，以概述该领域。计算技术的应用，尤其是通过线性相互作用能方法进行的结合亲和力预测，在疟疾血浆蛋白酶抑制剂的开发中非常成功，并进行了详细讨论。同源性建模和分子对接在当前的抑制剂设计项目中很有用，并且分析了此类方法与结合自由能计算的结合。

BACKGROUND & AIMS: :Methanolic and water extracts of five medicinal plant species used for treatment of malaria in traditional/cultural health systems of Kwale people in Kenya were tested for antimalarial activity against Plasmodium falciparum and Plasmodium berghei, respectively and for their cytotoxic effects. The most active extracts (IC(50)<10 microg/ml) screened against chloroquine (CQ) sensitive (D6) and resistant (W2) P. falciparum clones, were the water and methanol extracts of Maytenus undata (Thunb.) Blakelock (Celasteraceae), methanol extracts of Flueggea virosa (Willd.) Voigt (Euphorbiaceae), Maytenus putterlickioides (Loes.) Excell and Mendoca (Celastraceae), and Warburgia stuhlmannii Engl. (Canellaceae). These extracts showed various cytotoxic levels on Vero E6 cells with the water extract of M. undata exhibiting least cytotoxicity. At least one of the extracts of the plant species exhibited a high chemo suppression of parasitaemia >70% in a murine model of P. berghei infected mice. These results indicate that there is potential for isolation of a lead compound from the extracts of the five plants. W. stuhlmannii and M. putterlickioides have not been reported before for antiplasmodial activity.

背景与目标： : 测试了肯尼亚夸莱人传统/文化卫生系统中用于治疗疟疾的五种药用植物的甲醇和水提取物分别对恶性疟原虫和伯氏疟原虫的抗疟活性及其细胞毒性作用。针对氯喹 (CQ) 敏感 (D6) 和抗性 (W2) 恶性疟原虫克隆筛选出的最具活性的提取物 (IC(50)<10 microg/ml) 是美泰努斯 (Thunb) 的水和甲醇提取物。)Blakelock (Celasteraceae)，Flueggea virosa (Willd) 的甲醇提取物。)Voigt (大戟科)，Maytenus putterlickioides (Loes。)Excell和Mendoca (Celastraceae) 和Warburgia stuhlmannii Engl。(Canellaceae)。这些提取物对Vero E6细胞显示出各种细胞毒性水平，而M. undata的水提取物表现出最小的细胞毒性。在伯氏疟原虫感染小鼠的鼠模型中，植物物种的至少一种提取物表现出对寄生虫血症> 70% 的高化学抑制。这些结果表明，有可能从五种植物的提取物隔离出铅化合物。W. stuhlmannii和M. putterlickioides以前没有报道其抗血浆活性。

BACKGROUND & AIMS: :The asexual blood stage of Plasmodium falciparum is comprised of morphologically distinct ring, trophozoite and schizont stages. Each of these developmental stages possesses a distinct pattern of gene expression. Regulation of P. falciparum gene expression is thought to occur, at least in part, at the promoter level. Previously, we have found that although the hrp3 mRNA is only seen in ring-stage parasites, deletion of a specific sequence in the 5' end of the promoter region decreased ring-stage expression of hrp3 and enabled detection of its transcripts in trophozoite-stage parasites. In order to investigate this stage specific regulation of gene expression, we employed a series of nested deletions of the 1.7-kb hrp3 promoter. Firefly luciferase gene was used as a reporter to evaluate the role of promoter sequences in gene regulation. Using this approach, we identified a ring-stage specific regulatory region on the hrp3 promoter located between -1.7 kb and -1.1 kb from the ATG initiation codon. Small 100-150 bp truncations on this enhancer-like region failed to uncover discrete regulatory sequences, suggesting the multipartite nature of this element. The data presented in this study demonstrate that stage specific promoter activity of the hrp3 gene in P. falciparum blood stage parasites is supported, at least in-part, by a small promoter region that can function in the absence of a larger chromosomal context.

背景与目标： : 恶性疟原虫的无性血液阶段由形态上不同的环，滋养体和裂殖体阶段组成。这些发育阶段中的每个阶段都具有独特的基因表达模式。恶性疟原虫基因表达的调节被认为至少部分发生在启动子水平。以前，我们已经发现，尽管hrp3 mRNA仅在环状寄生虫中可见，但启动子区域5' 末端的特定序列的缺失会降低hrp3的环状表达，并能够在滋养体中检测其转录本阶段寄生虫。为了研究这一阶段基因表达的特异性调控，我们采用了一系列1.7-kb hrp3启动子的嵌套缺失。萤火虫荧光素酶基因被用作报告基因，以评估启动子序列在基因调控中的作用。使用这种方法，我们从ATG起始密码子确定了位于-1.7 kb和-1.1 kb之间的hrp3启动子上的环阶段特异性调节区域。在该增强子样区域上的小100 150 bp截断未能发现离散的调节序列，表明该元件的多部分性质。这项研究中提供的数据表明，恶性疟原虫血液阶段寄生虫中hrp3基因的阶段特异性启动子活性至少部分受到小启动子区域的支持，该启动子区域可以在没有较大染色体背景的情况下起作用。

BACKGROUND & AIMS: BACKGROUND:Sequestration of infected red blood cells (iRBCs) in the microcirculation is central to the pathophysiology of falciparum malaria. It is caused by cytoadhesion of iRBCs to vascular endothelium, mediated through the binding of Plasmodium falciparum erythrocyte membrane protein-1 to several endothelial receptors. Binding to CD36, the major vascular receptor, is stabilized through dephosphorylation of CD36 by an alkaline phosphatase. This is inhibited by the alkaline phosphatase-inhibitor levamisole, resulting in decreased cytoadhesion. METHODS:Patients with uncomplicated falciparum malaria were randomized to receive either quinine treatment alone or treatment with a single 150-mg dose of levamisole as an adjunct to quinine. Peripheral blood parasitemia and parasite stage distribution were monitored closely over time. RESULTS:Compared with those in control subjects, peripheral blood parasitemias of mature P. falciparum parasites increased during the 24 h after levamisole administration (n=21; P=.006). The sequestration ratio (between observed and expected peripheral blood parasitemia) of early trophozoite and midtrophozoite parasites increased after levamisole treatment, with near complete prevention of early trophozoite sequestration and >65% prevention of midtrophozoite sequestration. CONCLUSION:These findings strongly suggest that levamisole decreases iRBC sequestration in falciparum malaria in vivo and should be considered as a potential adjunctive treatment for severe falciparum malaria. TRIAL REGISTRATION:Current Controlled Trials identifier: 15314870.

背景与目标：

BACKGROUND & AIMS: :Using an in vitro culture system, we observed the migration of malaria ookinetes on the surface of the mosquito midgut and invasion of the midgut epithelium. Ookinetes display constrictions during migration to the midgut surface and a gliding motion once on the luminal midgut surface. Invasion of a midgut cell always occurs at its lateral apical surface. Invasion is rapid and is often followed by invasion of a neighboring midgut cell by the ookinete. The morphology of the invaded cells changes dramatically after invasion, and invaded cells die rapidly. Midgut cell death is accompanied by activation of a caspase-3-like protease, suggesting cell death is apoptotic. The events occurring during invasion were identical for two different species of Plasmodium and two different genera of mosquitoes; they probably represent a universal mechanism of mosquito midgut penetration by the malaria parasite.

背景与目标： : 使用体外培养系统，我们观察到疟疾在蚊子中肠表面的迁移和中肠上皮的入侵。Okinetes在迁移到中肠表面时显示收缩，并且在腔中肠表面上一次滑动。中肠细胞的入侵总是发生在其外侧顶表面。入侵是迅速的，通常是由卵代细胞入侵邻近的中肠细胞。入侵后，被入侵细胞的形态发生急剧变化，被入侵细胞迅速死亡。中肠细胞死亡伴随着caspase-3-like蛋白酶的激活，表明细胞死亡是凋亡的。入侵期间发生的事件对于两种不同的疟原虫和两种不同的蚊子属是相同的; 它们可能代表了疟疾寄生虫对蚊子中肠渗透的普遍机制。

BACKGROUND & AIMS: :Pulmonary complication is a rare manifestation of childhood malaria and isolated pleural effusion without pulmonary edema has never been reported in children. We report here an 11-year-old boy who suffered from cerebral malaria and massive right pleural effusion. The patient was treated with intravenous artesunate, albumin, and other supportive treatments. He recovered completely after eight days. The clinical and laboratory courses suggested that the plasma leakage played a role in the pathogenesis of pleural effusion.

背景与目标： : 肺部并发症是儿童疟疾的罕见表现，儿童中从未报道过无肺水肿的孤立胸腔积液。我们在这里报告了一个11岁的男孩，他患有脑疟疾和大量的右胸腔积液。患者接受静脉青蒿琥酯，白蛋白和其他支持治疗。八天后他完全康复了。临床和实验室课程表明，血浆渗漏在胸腔积液的发病机理中起作用。

BACKGROUND & AIMS: :Controlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymorphisms on parasite fitness have been characterized in vitro and in animal models. Additional insights have come from analyses of samples from clinical studies, both evaluating parasites under different selective pressures and determining the clinical consequences of infection with different parasites. With some exceptions, resistance-mediating polymorphisms lead to malaria parasites that, compared with wild type, grow less well in culture and in animals, and are replaced by wild type when drug pressure diminishes in the clinical setting. In some cases, the fitness costs of resistance may be offset by compensatory mutations that increase virulence or changes that enhance malaria transmission. However, not enough is known about effects of resistance mediators on parasite fitness. A better appreciation of the costs of fitness-mediating mutations will facilitate the development of optimal guidelines for the treatment and prevention of malaria.

背景与目标： : 控制抗疟药耐药性的传播，特别是恶性疟原虫对青蒿素类联合疗法的耐药性，是当务之急。现有数据表明，与其他微生物一样，抗药性疟疾寄生虫的传播受到经常伴随抗药性的健身成本的限制。已在假定的药物转运蛋白和靶酶中发现了疟疾寄生虫的抗性介导多态性。这些多态性对寄生虫适应性的影响已在体外和动物模型中得到表征。来自临床研究样本的分析还提供了其他见解，既评估了不同选择压力下的寄生虫，又确定了感染不同寄生虫的临床后果。除某些例外，抗性介导的多态性导致疟疾寄生虫，与野生型相比，其在培养物和动物中的生长较差，并且在临床环境中药物压力降低时被野生型取代。在某些情况下，抗药性的适应性成本可能会被增加毒力的补偿性突变或增强疟疾传播的变化所抵消。然而，对抗性介质对寄生虫适应性的影响知之甚少。更好地了解健康中介突变的成本将有助于制定治疗和预防疟疾的最佳指南。

BACKGROUND & AIMS: :Acute respiratory distress syndrome is a well-known complication in Plasmodium falciparum infection. It is less frequently described in Plasmodium vivax, and only one case is reported in Plasmodium ovale. Here we present the second description of this pulmonary complication in a P. ovale acute infection.

背景与目标： : 急性呼吸窘迫综合征是恶性疟原虫感染的一种众所周知的并发症。在间日疟原虫中描述的频率较低，而在卵形疟原虫中仅报告了一例。在这里，我们介绍了卵形假单胞菌急性感染中这种肺部并发症的第二种描述。

BACKGROUND & AIMS: AIM:To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions. METHODS:Twenty-six children with severe malaria and convulsions lasting > or =5 min were studied. Fifteen children were given a single dose (0.1 mg kg(-1)) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration-time data were fitted using compartmental models. RESULTS:Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml(-1) (50.2, 107.0) and 41.4 ng ml(-1) (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml(-1)) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died. CONCLUSION:Administration of LZP (0.1 mg kg(-1)) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

背景与目标：

BACKGROUND & AIMS: :Transmission from the vertebrate host to the mosquito vector represents a major population bottleneck in the malaria life cycle that can successfully be targeted by intervention strategies. However, to date only about 25 parasite proteins expressed during this critical phase have been functionally analysed by gene disruption. We describe the first systematic, larger scale generation and phenotypic analysis of Plasmodium berghei knockout (KO) lines, characterizing 20 genes encoding putatively secreted proteins expressed by the ookinete, the parasite stage responsible for invasion of the mosquito midgut. Of 12 KO lines that were generated, six showed significant reductions in parasite numbers during development in the mosquito, resulting in a block in transmission of five KOs. While expression data, time point of essential function and mutant phenotype correlate well in three KOs defective in midgut invasion, in three KOs that fail at sporulation, maternal inheritance of the mutant phenotype suggests that essential function occurs during ookinete formation and thus precedes morphological abnormalities by several days.

背景与目标： : 从脊椎动物宿主到蚊子媒介的传播代表了疟疾生命周期中的主要人口瓶颈，可以通过干预策略成功地将其作为目标。然而，迄今为止，仅通过基因破坏对在此关键阶段表达的约25种寄生虫蛋白进行了功能分析。我们描述了伯氏疟原虫敲除 (KO) 系的首次系统，较大规模的生成和表型分析，表征了20个基因，这些基因编码由卵代表达的推测分泌的蛋白质，这是负责蚊子中肠入侵的寄生虫阶段。在产生的12个KO品系中，有6个在蚊子发育过程中寄生虫数量显着减少，导致5个KO的传播受到阻碍。虽然表达数据，基本功能的时间点和突变表型在中肠入侵有缺陷的三个KOs中具有良好的相关性，在三个在孢子形成时失败的KOs中，突变表型的母体遗传表明基本功能发生在卵代发育过程中，因此先于形态异常几天。

BACKGROUND & AIMS: BACKGROUND:Deltamethrin 62.5 polymer-enhanced suspension concentrate (SC-PE) is one of the World Health Organization-approved insecticides for indoor residual spraying and was recommended to evaluate its residual activity for determination of appropriate spray cycles in different eco-epidemiologic settings. In the current study, efficacy of deltamethrin 62.5 SC-PE was evaluated against vectors of malaria and its impact on malaria incidence in a Plasmodium falciparum hyper-endemic area in Koraput district, Odisha State, India. METHODS:The trial had two comparable arms, arm 1 with residual spraying of deltamethrin 62.5 SC-PE and arm 2 with deltamethrin 2.5% WP (positive control). Comparative assessment of the impact of each intervention arm on entomological (density, parity, infection and human blood index), epidemiological (malaria incidence) parameters, residual efficacy and adverse effects were evaluated. RESULTS:Both the arms were comparable in terms of entomological and epidemiological parameters. While, deltamethrin 62.5 SC-PE was found to be effective for 150 days in mud and wood surfaces and 157 days in cement surfaces; deltamethrin 2.5% was effective only for 105 days on mud surfaces and 113 days on cement and wood surfaces. CONCLUSIONS:Deltamethrin 62.5 SC-PE had prolonged killing effectiveness up to 5 months. Hence, one round of IRS with deltamethrin 62.5 SC-PE would be sufficient to cover two existing malaria peak transmission seasons (July-August and October-November) in many parts of India.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Cerebral malaria is the most severe form of infection with Plasmodium falciparum characterized by a highly inflammatory response. This systematic review aimed to investigate the association between TNF-α levels and cerebral malaria. METHODS:This review followed the Preferred Reporting of Systematic Review and Meta-analyses (PRISMA) guidelines. The search was performed at PubMed, LILACS, Scopus, Web of Science, The Cochrane Library, OpenGrey and Google Scholar. We have included studies of P. falciparum-infected humans with or without cerebral malaria and TNF-α dosage level. All studies were evaluated using a risk of bias tool and the GRADE approach. RESULTS:Our results have identified 2338 studies, and 8 articles were eligible according to this systematic review inclusion criteria. Among the eight articles, five have evaluated TNF- α plasma dosage, while two have evaluated at the blood and one at the brain (post-Morten). Among them, only five studies showed higher TNF-α levels in the cerebral malaria group compared to the severe malaria group. Methodological problems were identified regarding sample size, randomization and blindness, but no risk of bias was detected. CONCLUSION:Although the results suggested that that TNF-α level is associated with cerebral malaria, the evidence is inconsistent and imprecise. More observational studies evaluating the average TNF-alpha are needed.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Malaria transmission has recently fallen in many parts of Africa, but systematic descriptions of infection and disease across all age groups are rare. Here, an epidemiological investigation of parasite prevalence, the incidence of fevers associated with infection, severe hospitalized disease and mortality among children older than 6 months and adults on the Kenyan coast is presented. METHODS:A prospective fever surveillance was undertaken at 6 out-patients (OPD) health-facilities between March 2018 and February 2019. Four community-based, cross sectional surveys of fever history and infection prevalence were completed among randomly selected homestead members from the same communities. Paediatric and adult malaria at Kilifi county hospital was obtained for the 12 months period. Rapid Diagnostic Tests (CareStart™ RDT) to detect HRP2-specific to Plasmodium falciparum was used in the community and the OPD, and microscopy in the hospital. Crude and age-specific incidence rates were computed using Poisson regression. RESULTS:Parasite prevalence gradually increased from childhood, reaching 12% by 9 years of age then declining through adolescence into adulthood. The incidence rate of RDT positivity in the OPD followed a similar trend to that of infection prevalence in the community. The incidence of hospitalized malaria from the same community was concentrated among children aged 6 months to 4 years (i.e. 64% and 70% of all hospitalized and severe malaria during the 12 months of surveillance, respectively). Only 3.7% (12/316) of deaths were directly attributable to malaria. Malaria mortality was highest among children aged 6 months-4 years at 0.57 per 1000 person-years (95% CI 0.2, 1.2). Severe malaria and death from malaria was negligible above 15 years of age. CONCLUSION:Under conditions of low transmission intensity, immunity to disease and the fatal consequences of infection appear to continue to be acquired in childhood and faster than anti-parasitic immunity. There was no evidence of an emerging significant burden of severe malaria or malaria mortality among adults. This is contrary to current modelled approaches to disease burden estimation in Africa and has important implications for the targeting of infection prevention strategies based on chemoprevention or vector control.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:The drug combination atovaquone-proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone-proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb). CASE PRESENTATION:A 47-year-old female, native from Congo and resident in France, was admitted in hospital for uncomplicated falciparum malaria with parasitaemia of 0.5%, after travelling in Congo (Brazzaville and Pointe Noire). She was treated with atovaquone-proguanil (250 mg/100 mg) 4 tablets daily for 3 consecutive days. On day 5 after admission she was released home. However, many weeks after this episode, without having left France, she again experienced fever and intense weakness. On day 39 after the beginning of treatment, she consulted for fever, arthralgia, myalgia, photophobia, and blurred vision. She was hospitalized for uncomplicated falciparum malaria with a parasitaemia of 0.375% and treated effectively by piperaquine-artenimol (320 mg/40 mg) 3 tablets daily for 3 consecutive days. Resistance to atovaquone-proguanil was suspected. The Y268C mutation was detected in all of the isolates tested (D39, D42, D47). The genotyping of the pfdhfr gene showed a triple mutation (N51I, C59R, S108N) involved in cycloguanil resistance. CONCLUSION:This is the first observation of a late clinical failure of atovaquone-proguanil treatment of P. falciparum uncomplicated malaria associated with pfcytb 268 mutation in a traveller returning from Congo. These data confirm that the Y268C mutation is associated with delayed recrudescence 4 weeks or more after initial treatment. Although atovaquone-proguanil treatment failures remain rare, an increased surveillance is required. It is essential to declare and publish all well-documented cases of treatment failures because it is the only way to evaluate the level of resistance to atovaquone.

背景与目标：