WorldWideScience

Sample records for experimental human malaria

  1. Proteomic Studies on Human and Experimental Cerebral Malaria

    KAUST Repository

    Moussa, Ehab

    2012-07-01

    Cerebral malaria (CM) is a severe neurological complication of malaria infection that results from interrelated pathologies. Despite extensive research efforts, the mechanism of the disease is not completely understood. Clinical studies, postmortem analysis, and animal models have been the main research arenas in CM. In this thesis, shotgun proteomics approach was used to further understand the pathology of human and experimental CM. The mechanism by which CM turns fatal is yet to be identified. A clinical proteomics study was conducted on pooled plasma samples from children with reversible or fatal CM from the Gambia. The results show that depletion of coagulation factors and increased levels of circulating proteasomes are associated with fatal pediatric CM. This data suggests that the ongoing coagulation during CM might be a disseminated intravascular coagulation state that eventually causes depletion of the coagulation factors leading to petechial hemorrhages. In addition, the mechanism(s) by which blood transfusion benefits CM in children was investigated. To that end, the concentration and multimerization pattern of von-willebrand factor, and the concentration of haptoglobin in the plasma of children with CM who received blood transfusions were measured. In addition to clinical studies, experimental cerebral malaria (ECM) in mice has been long used as a model for the disease. A shotgun proteomics workflow was optimized to identify the proteomic signature of the brain tissue of mice with ECM.Because of the utmost importance of membrane proteins in the pathology of the disease, sample fractionation and filter aided sample preparation were used to recover them. The proteomic signature of the brains of mice infected with P. berghei ANKA that developed neurological syndrome, mice infected with P. berghei NK56 that developed severe malaria but without neurological signs, and non-infected mice, were compared to identify CM specific proteins. Among the differentially

  2. Cardiac complication after experimental human malaria infection: a case report

    Directory of Open Access Journals (Sweden)

    Druilhe Pierre

    2009-12-01

    Full Text Available Abstract A 20 year-old healthy female volunteer participated in a clinical Phase I and IIa safety and efficacy trial with candidate malaria vaccine PfLSA-3-rec adjuvanted with aluminium hydroxide. Eleven weeks after the third and last immunization she was experimentally infected by bites of Plasmodium falciparum-infected mosquitoes. When the thick blood smear became positive, at day 11, she was treated with artemether/lumefantrine according to protocol. On day 16 post-infection i.e. two days after completion of treatment, she woke up with retrosternal chest pain. She was diagnosed as acute coronary syndrome and treated accordingly. She recovered quickly and her follow-up was uneventful. Whether the event was related to the study procedures such as the preceding vaccinations, malaria infection or antimalarial drugs remains elusive. However, the relation in time with the experimental malaria infection and apparent absence of an underlying condition makes the infection the most probable trigger. This is in striking contrast, however, with the millions of malaria cases each year and the fact that such complication has never been reported in the literature. The rare occurrence of cardiac events with any of the preceding study procedures may even support a coincidental finding. Apart from acute coronary syndrome, myocarditis can be considered as a final diagnosis, but the true nature and patho-physiological explanation of the event remain unclear.

  3. Testing vaccines in human experimental malaria: statistical analysis of parasitemia measured by a quantitative real-time polymerase chain reaction.

    NARCIS (Netherlands)

    Hermsen, C.C.; Vlas, S.J. de; Gemert, G.J.A. van; Telgt, D.S.C.; Verhage, D.F.; Sauerwein, R.W.

    2004-01-01

    Clinical trials are an essential step in evaluation of safety and efficacy of malaria vaccines, and human experimental malaria infections have been used for evaluation of protective immunity of Plasmodium falciparum malaria. In this study, a quantitative real-time polymerase chain reaction was used

  4. Experimental human challenge infections can accelerate clinical malaria vaccine development

    NARCIS (Netherlands)

    Sauerwein, R.W.; Roestenberg, M.; Moorthy, V.S.

    2011-01-01

    Malaria is one of the most frequently occurring infectious diseases worldwide, with almost 1 million deaths and an estimated 243 million clinical cases annually. Several candidate malaria vaccines have reached Phase IIb clinical trials, but results have often been disappointing. As an alternative to

  5. PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria.

    Directory of Open Access Journals (Sweden)

    Lena Serghides

    2014-03-01

    Full Text Available Cerebral malaria (CM is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF and nerve growth factor (NGF in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.

  6. Longevity and composition of cellular immune responses following experimental Plasmodium falciparum malaria infection in humans.

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    Anne C Teirlinck

    2011-12-01

    Full Text Available Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz and asexual blood-stage (PfRBC malaria parasites in naïve human volunteers undergoing single (n = 5 or multiple (n = 10 experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2 responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only 'adaptive' but also 'innate' lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO(+ CD62L(- effector memory (EM phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ(+IL-2(+ EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P

  7. No hearing loss associated with the use of artemether-lumefantrine to treat experimental human malaria.

    NARCIS (Netherlands)

    McCall, M.B.B.; Beynon, A.J.; Mylanus, E.A.M.; Ven, A.J.A.M. van der; Sauerwein, R.W.

    2006-01-01

    Artemisinin derivatives are becoming the first-line treatment for uncomplicated malaria in areas with widespread resistance to chloroquine. Although generally safe and well tolerated, it has been suggested from animal experiments, and more recently from one human study with artemether-lumefantrine,

  8. Experimental asexual blood stage malaria immunity.

    Science.gov (United States)

    Amante, Fiona H; Engwerda, Christian R; Good, Michael F

    2011-04-01

    Immunity to asexual blood stages of malaria is complex, involving both humoral and cell-mediated immune mechanisms. The availability of murine models of malaria has greatly facilitated the analysis of immune mechanisms involved in resistance to the asexual blood stages. This unit details the materials and methods required for inducing protective immunity toward experimental blood stage malaria parasites by vaccination, repeated infection, and drug cure, as well as adoptive transfer of antigen-specific T cells.

  9. Malaria on the move: human population movement and malaria transmission.

    OpenAIRE

    Martens, P; Hall, L

    2000-01-01

    Reports of malaria are increasing in many countries and in areas thought free of the disease. One of the factors contributing to the reemergence of malaria is human migration. People move for a number of reasons, including environmental deterioration, economic necessity, conflicts, and natural disasters. These factors are most likely to affect the poor, many of whom live in or near malarious areas. Identifying and understanding the influence of these population movements can improve preventio...

  10. Molecular basis of human cerebral malaria development

    OpenAIRE

    Wah, Saw Thu; Hananantachai, Hathairad; Kerdpin, Usanee; Plabplueng, Chotiros; Prachayasittikul, Virapong; Nuchnoi, Pornlada

    2016-01-01

    Cerebral malaria is still a deleterious health problem in tropical countries. The wide spread of malarial drug resistance and the lack of an effective vaccine are obstacles for disease management and prevention. Parasite and human genetic factors play important roles in malaria susceptibility and disease severity. The malaria parasite exerted a potent selective signature on the human genome, which is apparent in the genetic polymorphism landscape of genes related to pathogenesis. Currently, m...

  11. Molecular basis of human cerebral malaria development.

    Science.gov (United States)

    Wah, Saw Thu; Hananantachai, Hathairad; Kerdpin, Usanee; Plabplueng, Chotiros; Prachayasittikul, Virapong; Nuchnoi, Pornlada

    2016-01-01

    Cerebral malaria is still a deleterious health problem in tropical countries. The wide spread of malarial drug resistance and the lack of an effective vaccine are obstacles for disease management and prevention. Parasite and human genetic factors play important roles in malaria susceptibility and disease severity. The malaria parasite exerted a potent selective signature on the human genome, which is apparent in the genetic polymorphism landscape of genes related to pathogenesis. Currently, much genomic data and a novel body of knowledge, including the identification of microRNAs, are being increasingly accumulated for the development of laboratory testing cassettes for cerebral malaria prevention. Therefore, understanding of the underlying complex molecular basis of cerebral malaria is important for the design of strategy for cerebral malaria treatment and control.

  12. Uncovering the role of IFNAR1 in Experimental Cerebral malaria

    OpenAIRE

    Ball, Elisabeth Ann

    2013-01-01

    Dissertation presented the Ph.D degree in Biology Cerebral malaria is a severe and fatal form of clinical Plasmodium falciparum infection, resulting in brain injury from a damaging cascade of vascular, inflammatory and immunological host responses. However progression to cerebral malaria can be modified by host genetic factors. This thesis work extensively reveals the role of Interferon type I receptor (IFNAR1) in the development of Experimental cerebral malaria, through ...

  13. The relevance of non-human primate and rodent malaria models for humans

    Directory of Open Access Journals (Sweden)

    Riley Eleanor

    2011-02-01

    Full Text Available Abstract At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host-Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models. Several speakers took the opportunity to demonstrate the similarities between findings in rodent models and human severe disease, as well as points of difference. The variety of malaria presentations in the different experimental models parallels the wide diversity of human malaria disease and, therefore, might be viewed as a strength. Many of the key features of human malaria can be replicated in a variety of nonhuman primate models, which are very under-utilized. The importance of animal models in the discovery of new anti-malarial drugs was emphasized. The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material.

  14. A quantitative brain map of experimental cerebral malaria pathology.

    Science.gov (United States)

    Strangward, Patrick; Haley, Michael J; Shaw, Tovah N; Schwartz, Jean-Marc; Greig, Rachel; Mironov, Aleksandr; de Souza, J Brian; Cruickshank, Sheena M; Craig, Alister G; Milner, Danny A; Allan, Stuart M; Couper, Kevin N

    2017-03-01

    The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.

  15. Host-seeking behaviors of mosquitoes experimentally infected with sympatric field isolates of the human malaria parasite Plasmodium falciparum: no evidence for host manipulation

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    Amélie eVantaux

    2015-08-01

    Full Text Available Previous studies have shown that Plasmodium parasites can manipulate mosquito feeding behaviours such as motivation and avidity to feed on vertebrate hosts, in ways that increase the probability of parasite transmission. These studies, however, have been mainly carried out on non-natural and/or laboratory based model systems and hence may not reflect what occurs in the field. We now need to move closer to the natural setting, if we are to fully capture the ecological and evolutionary consequences of these parasite-induced behavioral changes. As part of this effort, we conducted a series of experiments to investigate the long and short-range behavioural responses to human stimuli in the mosquito Anopheles coluzzii during different stages of infection with sympatric field isolates of the human malaria parasite Plasmodium falciparum in Burkina Faso. First, we used a dual-port olfactometer designed to take advantage of the whole body odor to gauge mosquito long-range host-seeking behaviors. Second, we used a locomotor activity monitor system to assess mosquito short-range behaviors. Compared to control uninfected mosquitoes, P. falciparum infection had no significant effect neither on long-range nor on short-range behaviors both at the immature and mature stages. This study, using a natural mosquito-malaria parasite association, indicates that manipulation of vector behavior may not be a general phenomenon. We speculate that the observed contrasting phenotypes with model systems might result from coevolution of the human parasite and its natural vector. Future experiments, using other sympatric malaria mosquito populations or species are required to test this hypothesis. In conclusion, our results highlight the importance of following up discoveries in laboratory model systems with studies on natural parasite–mosquito interactions to accurately predict the epidemiological, ecological and evolutionary consequences of parasite manipulation of vector

  16. Experimental models in vaccine research: malaria and leishmaniasis

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    C. Teixeira

    2013-02-01

    Full Text Available Animal models have a long history of being useful tools, not only to test and select vaccines, but also to help understand the elaborate details of the immune response that follows infection. Different models have been extensively used to investigate putative immunological correlates of protection against parasitic diseases that are important to reach a successful vaccine. The greatest challenge has been the improvement and adaptation of these models to reflect the reality of human disease and the screening of vaccine candidates capable of overcoming the challenge of natural transmission. This review will discuss the advantages and challenges of using experimental animal models for vaccine development and how the knowledge achieved can be extrapolated to human disease by looking into two important parasitic diseases: malaria and leishmaniasis.

  17. Experimental models in vaccine research: malaria and leishmaniasis.

    Science.gov (United States)

    Teixeira, C; Gomes, R

    2013-02-01

    Animal models have a long history of being useful tools, not only to test and select vaccines, but also to help understand the elaborate details of the immune response that follows infection. Different models have been extensively used to investigate putative immunological correlates of protection against parasitic diseases that are important to reach a successful vaccine. The greatest challenge has been the improvement and adaptation of these models to reflect the reality of human disease and the screening of vaccine candidates capable of overcoming the challenge of natural transmission. This review will discuss the advantages and challenges of using experimental animal models for vaccine development and how the knowledge achieved can be extrapolated to human disease by looking into two important parasitic diseases: malaria and leishmaniasis.

  18. Prevalence of malaria and human blood factors among patients in ...

    African Journals Online (AJOL)

    Background: Malaria has been and is still a major protozoan disease affecting the human population. Erythrocyte polymorphisms (mainly in blood groups and genotypes) influence the susceptibility to severe malaria. Aim: This study is aimed at assessing the prevalence malaria in relation to human blood factor and to ...

  19. Young Sprague Dawley rats infected by Plasmodium berghei: A relevant experimental model to study cerebral malaria.

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    Sokhna Keita Alassane

    Full Text Available Cerebral malaria (CM is the most severe manifestation of human malaria yet is still poorly understood. Mouse models have been developed to address the subject. However, their relevance to mimic human pathogenesis is largely debated. Here we study an alternative cerebral malaria model with an experimental Plasmodium berghei Keyberg 173 (K173 infection in Sprague Dawley rats. As in Human, not all infected subjects showed cerebral malaria, with 45% of the rats exhibiting Experimental Cerebral Malaria (ECM symptoms while the majority (55% of the remaining rats developed severe anemia and hyperparasitemia (NoECM. These results allow, within the same population, a comparison of the noxious effects of the infection between ECM and severe malaria without ECM. Among the ECM rats, 77.8% died between day 5 and day 12 post-infection, while the remaining rats were spontaneously cured of neurological signs within 24-48 hours. The clinical ECM signs observed were paresis quickly evolving to limb paralysis, global paralysis associated with respiratory distress, and coma. The red blood cell (RBC count remained normal but a drastic decrease of platelet count and an increase of white blood cell numbers were noted. ECM rats also showed a decrease of glucose and total CO2 levels and an increase of creatinine levels compared to control rats or rats with no ECM. Assessment of the blood-brain barrier revealed loss of integrity, and interestingly histopathological analysis highlighted cyto-adherence and sequestration of infected RBCs in brain vessels from ECM rats only. Overall, this ECM rat model showed numerous clinical and histopathological features similar to Human CM and appears to be a promising model to achieve further understanding the CM pathophysiology in Humans and to evaluate the activity of specific antimalarial drugs in avoiding/limiting cerebral damages from malaria.

  20. Young Sprague Dawley rats infected by Plasmodium berghei: A relevant experimental model to study cerebral malaria.

    Science.gov (United States)

    Keita Alassane, Sokhna; Nicolau-Travers, Marie-Laure; Menard, Sandie; Andreoletti, Olivier; Cambus, Jean-Pierre; Gaudre, Noémie; Wlodarczyk, Myriam; Blanchard, Nicolas; Berry, Antoine; Abbes, Sarah; Colongo, David; Faye, Babacar; Augereau, Jean-Michel; Lacroux, Caroline; Iriart, Xavier; Benoit-Vical, Françoise

    2017-01-01

    Cerebral malaria (CM) is the most severe manifestation of human malaria yet is still poorly understood. Mouse models have been developed to address the subject. However, their relevance to mimic human pathogenesis is largely debated. Here we study an alternative cerebral malaria model with an experimental Plasmodium berghei Keyberg 173 (K173) infection in Sprague Dawley rats. As in Human, not all infected subjects showed cerebral malaria, with 45% of the rats exhibiting Experimental Cerebral Malaria (ECM) symptoms while the majority (55%) of the remaining rats developed severe anemia and hyperparasitemia (NoECM). These results allow, within the same population, a comparison of the noxious effects of the infection between ECM and severe malaria without ECM. Among the ECM rats, 77.8% died between day 5 and day 12 post-infection, while the remaining rats were spontaneously cured of neurological signs within 24-48 hours. The clinical ECM signs observed were paresis quickly evolving to limb paralysis, global paralysis associated with respiratory distress, and coma. The red blood cell (RBC) count remained normal but a drastic decrease of platelet count and an increase of white blood cell numbers were noted. ECM rats also showed a decrease of glucose and total CO2 levels and an increase of creatinine levels compared to control rats or rats with no ECM. Assessment of the blood-brain barrier revealed loss of integrity, and interestingly histopathological analysis highlighted cyto-adherence and sequestration of infected RBCs in brain vessels from ECM rats only. Overall, this ECM rat model showed numerous clinical and histopathological features similar to Human CM and appears to be a promising model to achieve further understanding the CM pathophysiology in Humans and to evaluate the activity of specific antimalarial drugs in avoiding/limiting cerebral damages from malaria.

  1. Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model.

    Science.gov (United States)

    Dunachie, Susanna; Berthoud, Tamara; Hill, Adrian V S; Fletcher, Helen A

    2015-09-29

    The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination. We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model. Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects. These results represent novel insights into the immune repertoires involved in malaria vaccination. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection

    NARCIS (Netherlands)

    Coffeng, L.E.; Hermsen, C.C.; Sauerwein, R.W.; Vlas, S.J. de

    2017-01-01

    Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize

  3. The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection

    NARCIS (Netherlands)

    L.E. Coffeng (Luc); C.C. Hermsen (Cornelus); R.W. Sauerwein (Robert); S.J. de Vlas (Sake)

    2017-01-01

    textabstractControlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events.

  4. Inhibiting the Mammalian target of rapamycin blocks the development of experimental cerebral malaria.

    Science.gov (United States)

    Gordon, Emile B; Hart, Geoffrey T; Tran, Tuan M; Waisberg, Michael; Akkaya, Munir; Skinner, Jeff; Zinöcker, Severin; Pena, Mirna; Yazew, Takele; Qi, Chen-Feng; Miller, Louis H; Pierce, Susan K

    2015-06-02

    Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4(+) and CD8(+) T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection

  5. A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines.

    NARCIS (Netherlands)

    Laurens, M.B.; Duncan, C.J.; Epstein, J.E.; Hill, A.V.; Komisar, J.L.; Lyke, K.E.; Ockenhouse, C.F.; Richie, T.L.; Roestenberg, M.; Sauerwein, R.W.; Spring, M.D.; Talley, A.K.; Moorthy, V.S.

    2012-01-01

    Early clinical investigations of candidate malaria vaccines and antimalarial medications increasingly employ an established model of controlled human malaria infection (CHMI). Study results are used to guide further clinical development of vaccines and antimalarial medications as CHMI results to

  6. Pathogenicity of avian malaria in experimentally-infected Hawaii Amakihi

    Science.gov (United States)

    Atkinson, Carter T.; Dusek, Robert J.; Woods, K.L.; Iko, W.M.

    2000-01-01

    The introduction of avian malaria (Plasmodium relictum) and mosquitoes (Culex quinquefasciatus) to the Hawaiian Islands (USA) is believed to have played a major role in the decline and extinction of native Hawaiian honeycreepers (Drepanidinae). This introduced disease is thought to be one of the primary factors limiting recovery of honeycreepers at elevations below 1,200 m where native forest habitats are still relatively intact. One of the few remaining species of honeycreepers with a wide elevational distribution is the Hawaii Amakihi (Hernignathus virens). We measured morbidity and mortality in experimentally-infected Hawaii Amakihi that were captured in a high elevation, xeric habitat that is above the current range of the mosquito vector. Mortality among amakihi exposed to a single infective mosquito bite was 65% (13/20). All infected birds had significant declines in food consumption and a corresponding loss in body weight over the 60 day course of the experiment. Gross and microscopic lesions in birds that succumbed to malaria included enlargement and discoloration of the spleen and liver and parasitemias as high as 50% of circulating erythrocytes. Mortality in experimentally-infected amakihi was similar to that observed in Apapane (Himnatione sanguinea) and lower than that observed in Iiwi (Vestiaria coccinea) infected under similar conditions with the same parasite isolate. We conclude that the current elevational and geographic distribution of Hawaiian honeycreepers is determined by relative susceptibility to avian malaria.

  7. Prevalence and predictors of placental malaria in human ...

    African Journals Online (AJOL)

    2016-02-16

    Feb 16, 2016 ... Background: Human immunodeficiency virus (HIV)‑infected pregnant women have alterations in cellular and humoral immunity that increase the risks to placental malaria infection. Aim: This study aimed at determining the prevalence and predictors of placental malaria among HIV‑positive women.

  8. Prevalence and predictors of placental malaria in human ...

    African Journals Online (AJOL)

    Background: Human immunodeficiency virus (HIV)‑infected pregnant women have alterations in cellular and humoral immunity that increase the risks to placental malaria infection. Aim: This study aimed at determining the prevalence and predictors of placental malaria among HIV‑positive women in Nigeria. Materials and ...

  9. Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans

    Science.gov (United States)

    Cabrera-Mora, Monica; Garcia, AnaPatricia; Orkin, Jack; Strobert, Elizabeth; Barnwell, John W.; Galinski, Mary R.

    2013-01-01

    Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies. PMID:23509137

  10. An experimental vaccine cocktail for Plasmodium falciparum malaria.

    Science.gov (United States)

    Bathurst, I C; Gibson, H L; Kansopon, J; Hahm, B K; Green, K M; Chang, S P; Hui, G S; Siddiqui, W A; Inselburg, J; Millet, P

    1993-01-01

    Surface proteins from several different life-cycle stages of the malaria parasite Plasmodium falciparum were expressed at high levels in the yeast Saccharomyces cerevisiae. Purified proteins, both individually and in cocktails, were used to immunize mice and goats in conjunction with either Freund's adjuvant or a muramyl tripeptide-based adjuvant. Immune responses were measured by enzyme-linked immunosorbent assays and by the ability of antisera to inhibit (1) the invasion of hepatocytes by live sporozoites, (2) in vitro invasion of human erythrocytes by live merozoites, and (3) the development of oocytes in the mosquito vector. These results suggest that cocktails of different stage-specific antigens can provide the components necessary to block the development of the malaria parasite at multiple stages of its life cycle.

  11. Human movement data for malaria control and elimination strategic planning.

    Science.gov (United States)

    Pindolia, Deepa K; Garcia, Andres J; Wesolowski, Amy; Smith, David L; Buckee, Caroline O; Noor, Abdisalan M; Snow, Robert W; Tatem, Andrew J

    2012-06-18

    Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM) in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements.

  12. Human movement data for malaria control and elimination strategic planning

    Directory of Open Access Journals (Sweden)

    Pindolia Deepa K

    2012-06-01

    Full Text Available Abstract Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i discuss relevant types of HPM across spatial and temporal scales, (ii document where datasets exist to quantify HPM, (iii highlight where data gaps remain and (iv briefly put forward methods for integrating these datasets in a Geographic Information System (GIS framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements.

  13. Human malaria in the highlands of Yemen

    Science.gov (United States)

    AL-Mekhlafi, A M; AL-Mekhlafi, H M; Mahdy, M A K; Azazy, A A; Fong, M Y

    2011-01-01

    Between June 2008 and March 2009, a cross-sectional study of human malaria was carried out in four governorates of Yemen, two (Taiz and Hodiedah) representing the country’s highlands and the others (Dhamar and Raymah) the country’s coastal plains/foothills. The main aims were to determine the prevalences of Plasmodium infection among 455 febrile patients presenting for care at participating health facilities and to investigate the potential risk factors for such infection. Malarial infection was detected in 78 (17·1%) of the investigated patients and was more likely to be detected among the febrile patients from the highlands than among those presenting in the coastal plains/foothills (22·6% v.13·9%; χ2 = 10·102; P = 0·018). Binary logistic-regression models identified low household income [odds ratio (OR) = 13·52; 95% confidence interval (CI) = 2·62–69·67; P = 0·002], living in a household with access to a water pump (OR = 4·18; CI = 1·60–10·96; P = 0·004) and living in a household near a stream (OR = 4·43; CI = 1·35–14·56; P = 0·014) as significant risk factors for malarial infection in the highlands. Low household income was the only significant risk factor identified for such infection in the coastal plains and foothills (OR = 8·20; CI = 1·80–37·45; P = 0·007). It is unclear why febrile patients in the highlands of Yemen are much more likely to be found to have malarial infection than their counterparts from the coastal plains and foothills. Although it is possible that malarial transmission is relatively intense in the highlands, it seems more likely that, compared with those who live at lower altitudes, those who live in the highlands are less immune to malaria, and therefore more likely to develop febrile illness following malarial infection. Whatever the cause of the symptomatic malarial infection commonly found in the highlands of Yemen, it is a matter of serious

  14. malaria parasitaemia among febrile children infected with human

    African Journals Online (AJOL)

    2014-01-01

    Jan 1, 2014 ... MALARIA PARASITAEMIA AMONG FEBRILE CHILDREN INFECTED WITH. HUMAN IMMUNODEFICIENCY VIRUS IN THE CONTEXT OF PROPHYLACTIC. COTRIMOXAZOLE AS STANDARD OF CARE: A CROSS- SECTIONAL SURVEY. IN WESTERN KENYA. I. K. MARETE, M. MUTUGI, Z. LAGAT, ...

  15. Plasmodium falciparum histidine-rich protein II causes vascular leakage and exacerbates experimental cerebral malaria in mice.

    Science.gov (United States)

    Pal, Priya; Balaban, Amanda E; Diamond, Michael S; Sinnis, Photini; Klein, Robyn S; Goldberg, Daniel E

    2017-01-01

    A devastating complication of Plasmodium falciparum infection is cerebral malaria, in which vascular leakage and cerebral swelling lead to coma and often death. P. falciparum produces a protein called histidine-rich protein II (HRPII) that accumulates to high levels in the bloodstream of patients and serves as a diagnostic and prognostic marker for falciparum malaria. Using a human cerebral microvascular endothelial barrier model, we previously found that HRPII activates the endothelial cell inflammasome, resulting in decreased integrity of tight junctions and increased endothelial barrier permeability. Here, we report that intravenous administration of HRPII induced blood-brain barrier leakage in uninfected mice. Furthermore, HRPII infusion in P. berghei-infected mice increased early mortality from experimental cerebral malaria. These data support the hypothesis that HRPII is a virulence factor that contributes to cerebral malaria by compromising the integrity of the blood-brain barrier.

  16. BIOLOGY OF HUMAN MALARIA PLASMODIA INCLUDING PLASMODIUM KNOWLESI

    Directory of Open Access Journals (Sweden)

    Spinello Antinori

    2012-03-01

    Full Text Available Malaria is a vector-borne infection caused by unicellular parasite of the genus Plasmodium. Plasmodia are obligate intracellular parasites that in humans after a clinically silent replication phase in the liver are able to infect and replicate within the erythrocytes. Four species (P.falciparum, P.malariae, P.ovale and P.vivax are traditionally recognized as responsible of natural infection in human beings but the recent upsurge of P.knowlesi malaria in South-East Asia has led clinicians to consider it as the fifth human malaria parasite. Recent studies in wild-living apes in Africa have revealed that P.falciparum, the most deadly form of human malaria, is not only human-host restricted as previously believed and its phylogenetic lineage is much more complex with new species identified in gorilla, bonobo and chimpanzee. Although less impressive, new data on biology of P.malariae, P.ovale and P.vivax are also emerging and will be briefly discussed in this review.

  17. Identifying Malaria Transmission Foci for Elimination Using Human Mobility Data.

    Science.gov (United States)

    Ruktanonchai, Nick W; DeLeenheer, Patrick; Tatem, Andrew J; Alegana, Victor A; Caughlin, T Trevor; Zu Erbach-Schoenberg, Elisabeth; Lourenço, Christopher; Ruktanonchai, Corrine W; Smith, David L

    2016-04-01

    Humans move frequently and tend to carry parasites among areas with endemic malaria and into areas where local transmission is unsustainable. Human-mediated parasite mobility can thus sustain parasite populations in areas where they would otherwise be absent. Data describing human mobility and malaria epidemiology can help classify landscapes into parasite demographic sources and sinks, ecological concepts that have parallels in malaria control discussions of transmission foci. By linking transmission to parasite flow, it is possible to stratify landscapes for malaria control and elimination, as sources are disproportionately important to the regional persistence of malaria parasites. Here, we identify putative malaria sources and sinks for pre-elimination Namibia using malaria parasite rate (PR) maps and call data records from mobile phones, using a steady-state analysis of a malaria transmission model to infer where infections most likely occurred. We also examined how the landscape of transmission and burden changed from the pre-elimination setting by comparing the location and extent of predicted pre-elimination transmission foci with modeled incidence for 2009. This comparison suggests that while transmission was spatially focal pre-elimination, the spatial distribution of cases changed as burden declined. The changing spatial distribution of burden could be due to importation, with cases focused around importation hotspots, or due to heterogeneous application of elimination effort. While this framework is an important step towards understanding progressive changes in malaria distribution and the role of subnational transmission dynamics in a policy-relevant way, future work should account for international parasite movement, utilize real time surveillance data, and relax the steady state assumption required by the presented model.

  18. Seasonal changes in human immune responses to malaria

    DEFF Research Database (Denmark)

    Hviid, L; Theander, T G

    1993-01-01

    Cellular as well as humorol immune responses to malaria antigens fluctuate in time in individuals living in molono-endemic areas, particularly where malaria transmission is seasonal. The most pronounced changes are seen in association with clinical attacks, but osymptomatic infection can also lead...... to apparent immune depression. However, recent data have shown that seasonal variation in cellular immune responses may occur even in the absence of detectable porositaemia. Here, Lars Hviid and Thor G. Theonder review the seasonal variation in human immune responses to malaria, and discuss its possible...... causes and implications....

  19. Beer consumption increases human attractiveness to malaria mosquitoes.

    Directory of Open Access Journals (Sweden)

    Thierry Lefèvre

    2010-03-01

    Full Text Available Malaria and alcohol consumption both represent major public health problems. Alcohol consumption is rising in developing countries and, as efforts to manage malaria are expanded, understanding the links between malaria and alcohol consumption becomes crucial. Our aim was to ascertain the effect of beer consumption on human attractiveness to malaria mosquitoes in semi field conditions in Burkina Faso.We used a Y tube-olfactometer designed to take advantage of the whole body odour (breath and skin emanations as a stimulus to gauge human attractiveness to Anopheles gambiae (the primary African malaria vector before and after volunteers consumed either beer (n = 25 volunteers and a total of 2500 mosquitoes tested or water (n = 18 volunteers and a total of 1800 mosquitoes. Water consumption had no effect on human attractiveness to An. gambiae mosquitoes, but beer consumption increased volunteer attractiveness. Body odours of volunteers who consumed beer increased mosquito activation (proportion of mosquitoes engaging in take-off and up-wind flight and orientation (proportion of mosquitoes flying towards volunteers' odours. The level of exhaled carbon dioxide and body temperature had no effect on human attractiveness to mosquitoes. Despite individual volunteer variation, beer consumption consistently increased attractiveness to mosquitoes.These results suggest that beer consumption is a risk factor for malaria and needs to be integrated into public health policies for the design of control measures.

  20. Beer consumption increases human attractiveness to malaria mosquitoes.

    Science.gov (United States)

    Lefèvre, Thierry; Gouagna, Louis-Clément; Dabiré, Kounbobr Roch; Elguero, Eric; Fontenille, Didier; Renaud, François; Costantini, Carlo; Thomas, Frédéric

    2010-03-04

    Malaria and alcohol consumption both represent major public health problems. Alcohol consumption is rising in developing countries and, as efforts to manage malaria are expanded, understanding the links between malaria and alcohol consumption becomes crucial. Our aim was to ascertain the effect of beer consumption on human attractiveness to malaria mosquitoes in semi field conditions in Burkina Faso. We used a Y tube-olfactometer designed to take advantage of the whole body odour (breath and skin emanations) as a stimulus to gauge human attractiveness to Anopheles gambiae (the primary African malaria vector) before and after volunteers consumed either beer (n = 25 volunteers and a total of 2500 mosquitoes tested) or water (n = 18 volunteers and a total of 1800 mosquitoes). Water consumption had no effect on human attractiveness to An. gambiae mosquitoes, but beer consumption increased volunteer attractiveness. Body odours of volunteers who consumed beer increased mosquito activation (proportion of mosquitoes engaging in take-off and up-wind flight) and orientation (proportion of mosquitoes flying towards volunteers' odours). The level of exhaled carbon dioxide and body temperature had no effect on human attractiveness to mosquitoes. Despite individual volunteer variation, beer consumption consistently increased attractiveness to mosquitoes. These results suggest that beer consumption is a risk factor for malaria and needs to be integrated into public health policies for the design of control measures.

  1. Chloroquine-Chlorpheniramine Interaction In Human Malaria ...

    African Journals Online (AJOL)

    chlorpheniramine (CQ-CP) combination therapy on the efficacy and disposition of chloroquine (CQ) in acute uncomplicated malaria. A 3-day standard treatment with 25 mg CQ base per kilogram body weight alone or in combination with chlorpheniramine ...

  2. Mosquitoes as potential bridge vectors of malaria parasites from non-human primates to humans

    NARCIS (Netherlands)

    Verhulst, N.O.; Smallegange, R.C.; Takken, W.

    2012-01-01

    Malaria is caused by Plasmodium parasites which are transmitted by mosquitoes. Until recently, human malaria was considered to be caused by human-specific Plasmodium species. Studies on Plasmodium parasites in non-human primates (NHPs), however, have identified parasite species in gorillas and

  3. Controlled Human Malaria Infection: Applications, Advances, and Challenges.

    Science.gov (United States)

    Stanisic, Danielle I; McCarthy, James S; Good, Michael F

    2018-01-01

    Controlled human malaria infection (CHMI) entails deliberate infection with malaria parasites either by mosquito bite or by direct injection of sporozoites or parasitized erythrocytes. When required, the resulting blood-stage infection is curtailed by the administration of antimalarial drugs. Inducing a malaria infection via inoculation with infected blood was first used as a treatment (malariotherapy) for neurosyphilis in Europe and the United States in the early 1900s. More recently, CHMI has been applied to the fields of malaria vaccine and drug development, where it is used to evaluate products in well-controlled early-phase proof-of-concept clinical studies, thus facilitating progression of only the most promising candidates for further evaluation in areas where malaria is endemic. Controlled infections have also been used to immunize against malaria infection. Historically, CHMI studies have been restricted by the need for access to insectaries housing infected mosquitoes or suitable malaria-infected individuals. Evaluation of vaccine and drug candidates has been constrained in these studies by the availability of a limited number of Plasmodium falciparum isolates. Recent advances have included cryopreservation of sporozoites, the manufacture of well-characterized and genetically distinct cultured malaria cell banks for blood-stage infection, and the availability of Plasmodium vivax -specific reagents. These advances will help to accelerate malaria vaccine and drug development by making the reagents for CHMI more widely accessible and also enabling a more rigorous evaluation with multiple parasite strains and species. Here we discuss the different applications of CHMI, recent advances in the use of CHMI, and ongoing challenges for consideration. Copyright © 2017 American Society for Microbiology.

  4. Malaria.

    Science.gov (United States)

    Dupasquier, Isabelle

    1989-01-01

    Malaria, the greatest pandemia in the world, claims an estimated one million lives each year in Africa alone. While it may still be said that for the most part malaria is found in what is known as the world's poverty belt, cases are now frequently diagnosed in western countries. Due to resistant strains of malaria which have developed because of…

  5. Murine AIDS Protects Mice Against Experimental Cerebral Malaria: Down-Regulation by Interleukin 10 a T-Helper Type 1 CD4^+ Cell-Mediated Pathology

    Science.gov (United States)

    Eckwalanga, Michel; Marussig, Myriam; Dias Tavares, Marisa; Bouanga, Jean Claude; Hulier, Elisabeth; Henriette Pavlovitch, Jana; Minoprio, Paola; Portnoi, Denis; Renia, Laurent; Mazier, Dominique

    1994-08-01

    The retrovirus LP-BM5 murine leukemia virus induces murine AIDS in C57BL/6 mice that has many similarities with human AIDS; Plasmodium berghei ANKA causes experimental cerebral malaria in the same strain of mice. The outcome of malaria infection was studied in mice concurrently infected with the two pathogens. The retrovirus significantly reduced the gravity of the neurological manifestations associated with Plasmodium berghei ANKA infection. The protection against experimental cerebral malaria induced by murine AIDS increased with duration of viral infection and, hence, with the severity of the immunodeficiency. Interleukin 10, principally from splenic T cells, was shown to play a crucial role in this protection.

  6. Testing sex ratio theory with the malaria parasite Plasmodium mexicanum in natural and experimental infections.

    Science.gov (United States)

    Neal, Allison T; Schall, Jos J

    2014-04-01

    The malaria parasite (Plasmodium) life history accords well with the assumptions of local mate competition (LMC) of sex ratio theory. Within a single meal of the blood-feeding vector, sexually dimorphic gametocyte cells produce gametes (females produce one, males several) that mate and undergo sexual recombination. The theory posits several factors drive the Plasmodium sex ratio: male fecundity (gametes/male gametocyte), number and relative abundance of parasite clones, and gametocyte density. We measured these traits for the lizard malaria parasite, Plasmodium mexicanum, with a large sample of natural infections and infections from experiments that manipulated clonal diversity. Sex ratio in single-clone infections was slightly female-biased, but matched predictions of theory for this low-fecundity species. Sex ratio was less female-biased in clonally diverse infections as predicted by LMC for the experimental, but not natural infections. Gametocyte density was not positively related to sex ratio. These results are explained by the P. mexicanum life history of naturally low clonal diversity and high gametocyte production. This is the first study of a natural malaria system that examines all traits relevant to LMC in individual vertebrate hosts and suggests a striking example of sex ratio theory having significance for human public health. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

  7. P. falciparum Enhances HIV Replication in an Experimental Malaria Challenge System: e39000

    National Research Council Canada - National Science Library

    Marika Orlov; Florin Vaida; Olivia C Finney; David M Smith; Angela K Talley; Ruobing Wang; Stefan H Kappe; Qianqian Deng; Robert T Schooley; Patrick E Duffy

    2012-01-01

    ... naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial.PBMCs collected before the malaria challenge and at several time points post-infection were infected with HIV-1 and co-cultured with either P...

  8. Requirement for Tumor Necrosis Factor Receptor 2 Expression on Vascular Cells To Induce Experimental Cerebral Malaria

    OpenAIRE

    Stoelcker, Benjamin; Hehlgans, Thomas; Weigl, Karin; Bluethmann, Horst; Grau, Georges E.; Männel, Daniela N.

    2002-01-01

    Using tumor necrosis factor receptor type 2 (TNFR2)-deficient mice and generating bone marrow chimeras which express TNFR2 on either hematopoietic or nonhematopoietic cells, we demonstrated the requirement for TNFR2 expression on tissue cells to induce lethal cerebral malaria. Thus, TNFR2 on the brain vasculature mediates tumor necrosis factor-induced neurovascular lesions in experimental cerebral malaria.

  9. Experimental headache in humans

    DEFF Research Database (Denmark)

    Iversen, Helle Klingenberg

    1995-01-01

    The need for valid human experimental models of headache is obvious. Several compounds have been proposed as headache-inducing agents, but only the nitroglycerin (NTG) model has been validated. In healthy subjects, intravenous infusions of the nitric oxide (NO) donor NTG induce a dose-dependent h......The need for valid human experimental models of headache is obvious. Several compounds have been proposed as headache-inducing agents, but only the nitroglycerin (NTG) model has been validated. In healthy subjects, intravenous infusions of the nitric oxide (NO) donor NTG induce a dose...

  10. P. falciparum enhances HIV replication in an experimental malaria challenge system.

    Directory of Open Access Journals (Sweden)

    Marika Orlov

    Full Text Available Co-infection with HIV and P. falciparum worsens the prognosis of both infections; however, the mechanisms driving this adverse interaction are not fully delineated. To evaluate this, we studied HIV-1 and P. falciparum interactions in vitro using peripheral blood mononuclear cells (PBMCs from human malaria naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial. PBMCs collected before the malaria challenge and at several time points post-infection were infected with HIV-1 and co-cultured with either P. falciparum infected (iRBCs or uninfected (uRBCs red blood cells. HIV p24Ag and TNF-α, IFN-γ, IL-4, IL-6, IL-10, IL-17, and MIP-1α were quantified in the co-culture supernatants. In general, iRBCs stimulated more HIV p24Ag production by PBMCs than did uRBCs. HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs further increased during convalescence (days 35, 56, and 90 post-challenge. In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α than uRBCs, and production increased further during convalescence. Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.

  11. A controlled human malaria infection model enabling evaluation of transmission-blocking interventions.

    Science.gov (United States)

    Collins, Katharine A; Wang, Claire Yt; Adams, Matthew; Mitchell, Hayley; Rampton, Melanie; Elliott, Suzanne; Reuling, Isaie J; Bousema, Teun; Sauerwein, Robert; Chalon, Stephan; Möhrle, Jörg J; McCarthy, James S

    2018-02-01

    Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI). Seventeen healthy malaria-naïve volunteers underwent CHMI by intravenous inoculation of P. falciparum-infected erythrocytes to initiate blood-stage infection. Seven to eight days after inoculation participants received piperaquine (480 mg) to attenuate asexual parasite replication while allowing gametocytes to develop and mature. Primary endpoints were development of gametocytemia, the transmissibility of gametocytes from humans to mosquitoes, and the safety and tolerability of the CHMI transmission model. To investigate in-vivo gametocytocidal drug activity in this model, participants were either given an experimental antimalarial, artefenomel (500 mg), a known gametocytocidal drug, primaquine (15 mg), or remained untreated during the period of gametocyte carriage. Male and female gametocytes were detected in all participants, and transmission to mosquitoes was achieved from 8/11 (73%) participants evaluated. Compared to untreated controls (n = 7), primaquine (15 mg, n = 5) significantly reduced gametocyte burden (P = 0.01), while artefenomel (500 mg, n = 4) had no effect. Adverse events (AEs) were mostly mild or moderate. Three AEs were assessed as severe - fatigue, elevated alanine aminotransferase, and elevated aspartate aminotransferase - and were attributed to malaria infection. Transaminase elevations were transient, asymptomatic, and resolved without intervention. We report the safe and reproducible induction of P. falciparum gametocytes in healthy malaria-naïve volunteers at densities infectious to mosquitoes, thereby demonstrating the potential for

  12. Malaria

    Science.gov (United States)

    ... deadly type occurs in Africa south of the Sahara Desert. Malaria symptoms include chills, flu-like symptoms, fever, vomiting, diarrhea, and jaundice. A blood test can diagnose it. It can be life-threatening. However, you can treat malaria with drugs. ...

  13. ZOOPROPHYLAXIS WITH SPECIAL REFERENCE TO MALARIA IN HUMAN POPULATION

    Directory of Open Access Journals (Sweden)

    Abdul Hamid Jan, Manzoor Ahmad and Sana Ullah Khan

    2001-01-01

    Full Text Available To examine the possibility that domestic cattle kept in house courtyards might protect residents against malaria through zooprophylaxis. Prevalence of malaria was conducted from December 1995 to November, 1996 in human population of distract Karak (NWFP. The analysis showed that the overall incidence was higher (11.81 % among the population which reared cattle than among those which did not (6.53%. The overall incidence of the disease was higher in autumn in cattle keeping population. However, comparison of prevalence of both species of Plasmodium (P. vivax & P.falciparum revealed a positive correlation between parasite rates and the proportion of families owing cattle. This finding supports the prediction of the Sota-Mogi theoretical model that domestic animals can enhance rather than reduce malaria transmission when vectors are zoophilic. It can be concluded that alongwith other factors, cattle also play some role in spreading of the disease.

  14. Administrative Aspects of Human Experimentation.

    Science.gov (United States)

    Irvine, George W.

    1992-01-01

    The following administrative aspects of scientific experimentation with human subjects are discussed: the definition of human experimentation; the distinction between experimentation and treatment; investigator responsibility; documentation; the elements and principles of informed consent; and the administrator's role in establishing and…

  15. Malaria Vaccine Development: Are Bacterial Flagellin Fusion Proteins the Bridge between Mouse and Humans?

    Directory of Open Access Journals (Sweden)

    Daniel Y. Bargieri

    2011-01-01

    Full Text Available In the past 25 years, the development of an effective malaria vaccine has become one of the biggest riddles in the biomedical sciences. Experimental data using animal infection models demonstrated that it is possible to induce protective immunity against different stages of malaria parasites. Nonetheless, the vast body of knowledge has generated disappointments when submitted to clinical conditions and presently a single antigen formulation has progressed to the point where it may be translated into a human vaccine. In parallel, new means to increase the protective effects of antigens in general have been pursued and depicted, such as the use of bacterial flagellins as carriers/adjuvants. Flagellins activate pathways in the innate immune system of both mice and humans. The recent report of the first Phase I clinical trial of a vaccine containing a Salmonella flagellin as carrier/adjuvant may fuel the use of these proteins in vaccine formulations. Herein, we review the studies on the use of recombinant flagellins as vaccine adjuvants with malarial antigens in the light of the current state of the art of malaria vaccine development. The available information indicates that bacterial flagellins should be seriously considered for malaria vaccine formulations to the development of effective human vaccines.

  16. Testing Local Adaptation in a Natural Great Tit-Malaria System: An Experimental Approach.

    Directory of Open Access Journals (Sweden)

    Tania Jenkins

    Full Text Available Finding out whether Plasmodium spp. are coevolving with their vertebrate hosts is of both theoretical and applied interest and can influence our understanding of the effects and dynamics of malaria infection. In this study, we tested for local adaptation as a signature of coevolution between malaria blood parasites, Plasmodium spp. and its host, the great tit, Parus major. We conducted a reciprocal transplant experiment of birds in the field, where we exposed birds from two populations to Plasmodium parasites. This experimental set-up also provided a unique opportunity to study the natural history of malaria infection in the wild and to assess the effects of primary malaria infection on juvenile birds. We present three main findings: i there was no support for local adaptation; ii there was a male-biased infection rate; iii infection occurred towards the end of the summer and differed between sites. There were also site-specific effects of malaria infection on the hosts. Taken together, we present one of the few experimental studies of parasite-host local adaptation in a natural malaria system, and our results shed light on the effects of avian malaria infection in the wild.

  17. Pathogenic roles of CD14, galectin-3, and OX40 during experimental cerebral malaria in mice.

    Directory of Open Access Journals (Sweden)

    Miranda S Oakley

    Full Text Available An in-depth knowledge of the host molecules and biological pathways that contribute towards the pathogenesis of cerebral malaria would help guide the development of novel prognostics and therapeutics. Genome-wide transcriptional profiling of the brain tissue during experimental cerebral malaria (ECM caused by Plasmodium berghei ANKA parasites in mice, a well established surrogate of human cerebral malaria, has been useful in predicting the functional classes of genes involved and pathways altered during the course of disease. To further understand the contribution of individual genes to the pathogenesis of ECM, we examined the biological relevance of three molecules -- CD14, galectin-3, and OX40 that were previously shown to be overexpressed during ECM. We find that CD14 plays a predominant role in the induction of ECM and regulation of parasite density; deletion of the CD14 gene not only prevented the onset of disease in a majority of susceptible mice (only 21% of CD14-deficient compared to 80% of wildtype mice developed ECM, p<0.0004 but also had an ameliorating effect on parasitemia (a 2 fold reduction during the cerebral phase. Furthermore, deletion of the galectin-3 gene in susceptible C57BL/6 mice resulted in partial protection from ECM (47% of galectin-3-deficient versus 93% of wildtype mice developed ECM, p<0.0073. Subsequent adherence assays suggest that galectin-3 induced pathogenesis of ECM is not mediated by the recognition and binding of galectin-3 to P. berghei ANKA parasites. A previous study of ECM has demonstrated that brain infiltrating T cells are strongly activated and are CD44(+CD62L(- differentiated memory T cells [1]. We find that OX40, a marker of both T cell activation and memory, is selectively upregulated in the brain during ECM and its distribution among CD4(+ and CD8(+ T cells accumulated in the brain vasculature is approximately equal.

  18. Composition of human skin microbiota affects attractiveness to malaria mosquitoes.

    Directory of Open Access Journals (Sweden)

    Niels O Verhulst

    Full Text Available The African malaria mosquito Anopheles gambiae sensu stricto continues to play an important role in malaria transmission, which is aggravated by its high degree of anthropophily, making it among the foremost vectors of this disease. In the current study we set out to unravel the strong association between this mosquito species and human beings, as it is determined by odorant cues derived from the human skin. Microbial communities on the skin play key roles in the production of human body odour. We demonstrate that the composition of the skin microbiota affects the degree of attractiveness of human beings to this mosquito species. Bacterial plate counts and 16S rRNA sequencing revealed that individuals that are highly attractive to An. gambiae s.s. have a significantly higher abundance, but lower diversity of bacteria on their skin than individuals that are poorly attractive. Bacterial genera that are correlated with the relative degree of attractiveness to mosquitoes were identified. The discovery of the connection between skin microbial populations and attractiveness to mosquitoes may lead to the development of new mosquito attractants and personalized methods for protection against vectors of malaria and other infectious diseases.

  19. Plasmodium spp.: an experimental study on vertebrate host susceptibility to avian malaria.

    Science.gov (United States)

    Dimitrov, Dimitar; Palinauskas, Vaidas; Iezhova, Tatjana A; Bernotienė, Rasa; Ilgūnas, Mikas; Bukauskaitė, Dovile; Zehtindjiev, Pavel; Ilieva, Mihaela; Shapoval, Anatoly P; Bolshakov, Casimir V; Markovets, Mikhail Yu; Bensch, Staffan; Valkiūnas, Gediminas

    2015-01-01

    The interest in experimental studies on avian malaria caused by Plasmodium species has increased recently due to the need of direct information about host-parasite interactions. Numerous important issues (host susceptibility, development of infection, the resistance and tolerance to avian malaria) can be answered using experimental infections. However, specificity of genetically different lineages of malaria parasites and their isolates is largely unknown. This study reviews recent experimental studies and offers additional data about susceptibility of birds to several widespread cytochrome b (cyt b) lineages of Plasmodium species belonging to four subgenera. We exposed two domesticated avian hosts (canaries Serinus canaria and ducklings Anas platyrhynchos) and also 16 species of common wild European birds to malaria infections by intramuscular injection of infected blood and then tested them by microscopic examination and PCR-based methods. Our study confirms former field and experimental observations about low specificity and wide host-range of Plasmodium relictum (lineages SGS1 and GRW11) and P. circumflexum (lineage TURDUS1) belonging to the subgenera Haemamoeba and Giovannolaia, respectively. However, the specificity of different lineages and isolates of the same parasite lineage differed between species of exposed hosts. Several tested Novyella lineages were species specific, with a few cases of successful development in experimentally exposed birds. The majority of reported cases of mortality and high parasitaemia were observed during parasite co-infections. Canaries were susceptible mainly for the species of Haemamoeba and Giovannolaia, but were refractory to the majority of Novyella isolates. Ducklings were susceptible to three malaria infections (SGS1, TURDUS1 and COLL4), but parasitaemia was light (<0.01%) and transient in all exposed birds. This study provides novel information about susceptibility of avian hosts to a wide array of malaria parasite

  20. X-ray microscopy of human malaria

    Energy Technology Data Exchange (ETDEWEB)

    Magowan, C.; Brown, J.T.; Mohandas, N.; Meyer-Ilse, W. [Ernest Orlando Lawrence Berkeley National Lab., CA (United States)

    1997-04-01

    Associations between intracellular organisms and host cells are complex and particularly difficult to examine. X-ray microscopy provides transmission images of subcellular structures in intact cells at resolutions superior to available methodologies. The spatial resolution is 50-60nm with a 1 micron depth of focus, superior to anything achievable with light microscopy. Image contrast is generated by differences in photoelectric absorption by the atoms in different areas (i.e. subcellular structures) throughout the full thickness of the sample. Absorption due to carbon dominates among all the elements in the sample at 2.4 nm x-ray wavelength. Thus images show features or structures, in a way not usually seen by other types of microscopy. The authors used soft x-ray microscopy to investigate structural development of Plasmodium falciparum malaria parasites in normal and genetically abnormal erythrocytes, and in infected erythrocytes treated with compounds that have anti-malarial effects. X-ray microscopy showed newly elaborated structures in the cytosol of unstained, intact erythrocytes, redistribution of mass (carbon) in infected erythrocytes, and aberrant parasite morphology. Better understanding of the process of intracellular parasite maturation and the interactions between the parasite and its host erythrocyte can help define new approaches to the control of this deadly disease.

  1. Comparative genomics of the neglected human malaria parasite Plasmodium vivax

    Science.gov (United States)

    Carlton, Jane M.; Adams, John H.; Silva, Joana C.; Bidwell, Shelby L.; Lorenzi, Hernan; Caler, Elisabet; Crabtree, Jonathan; Angiuoli, Samuel V.; Merino, Emilio F.; Amedeo, Paolo; Cheng, Qin; Coulson, Richard M. R.; Crabb, Brendan S.; del Portillo, Hernando A.; Essien, Kobby; Feldblyum, Tamara V.; Fernandez-Becerra, Carmen; Gilson, Paul R.; Gueye, Amy H.; Guo, Xiang; Kang’a, Simon; Kooij, Taco W. A.; Korsinczky, Michael; Meyer, Esmeralda V.-S.; Nene, Vish; Paulsen, Ian; White, Owen; Ralph, Stuart A.; Ren, Qinghu; Sargeant, Tobias J.; Salzberg, Steven L.; Stoeckert, Christian J.; Sullivan, Steven A.; Yamamoto, Marcio Massao; Hoffman, Stephen L.; Wortman, Jennifer R.; Gardner, Malcolm J.; Galinski, Mary R.; Barnwell, John W.; Fraser-Liggett, Claire M.

    2008-01-01

    The human malaria parasite Plasmodium vivax is responsible for 25-40% of the ~515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated in the laboratory except in non-human primates. We determined the genome sequence of P. vivax in order to shed light on its distinctive biologic features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternate invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance scientific investigation into this neglected species. PMID:18843361

  2. Malaria.

    Science.gov (United States)

    Fletcher, Tom E; Beeching, N J

    2013-09-01

    Malaria is a life-threatening disease, with its largest impact being due to Plasmodium falciparum infection in Africa. Military populations continue to be at a high risk of malaria and reported case series have frequently revealed poor compliance with preventative measures. The symptoms of malaria are non-specific and its management depends on awareness of the diagnosis and early recognition and treatment. This is aided by new and simple rapid diagnostic tests, but these should not replace the examination of blood films if these are available. Artemisinin combination therapy provides a more rapid and dependable cure of uncomplicated P falciparum infection, with artesunate now being the drug of choice in severe infection.

  3. Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

    Directory of Open Access Journals (Sweden)

    Brandi D Freeman

    2016-03-01

    Full Text Available Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

  4. Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema.

    Science.gov (United States)

    Penet, Marie-France; Viola, Angèle; Confort-Gouny, Sylviane; Le Fur, Yann; Duhamel, Guillaume; Kober, Frank; Ibarrola, Danielle; Izquierdo, Marguerite; Coltel, Nicolas; Gharib, Bouchra; Grau, Georges E; Cozzone, Patrick J

    2005-08-10

    The first in vivo magnetic resonance study of experimental cerebral malaria is presented. Cerebral involvement is a lethal complication of malaria. To explore the brain of susceptible mice infected with Plasmodium berghei ANKA, multimodal magnetic resonance techniques were applied (imaging, diffusion, perfusion, angiography, spectroscopy). They reveal vascular damage including blood-brain barrier disruption and hemorrhages attributable to inflammatory processes. We provide the first in vivo demonstration for blood-brain barrier breakdown in cerebral malaria. Major edema formation as well as reduced brain perfusion was detected and is accompanied by an ischemic metabolic profile with reduction of high-energy phosphates and elevated brain lactate. In addition, angiography supplies compelling evidence for major hemodynamics dysfunction. Actually, edema further worsens ischemia by compressing cerebral arteries, which subsequently leads to a collapse of the blood flow that ultimately represents the cause of death. These findings demonstrate the coexistence of inflammatory and ischemic lesions and prove the preponderant role of edema in the fatal outcome of experimental cerebral malaria. They improve our understanding of the pathogenesis of cerebral malaria and may provide the necessary noninvasive surrogate markers for quantitative monitoring of treatment.

  5. CD19(+) B Cells Confer Protection against Experimental Cerebral Malaria in Semi-Immune Rodent Model

    OpenAIRE

    Lam Quoc Bao; Nguyen Tien Huy; Mihoko Kikuchi; Tetsuo Yanagi; Masachika Senba; Mohammed Nasir Shuaibu; Kiri Honma; Katsuyuki Yui; Kenji Hirayama

    2013-01-01

    In African endemic area, adults are less vulnerable to cerebral malaria than children probably because of acquired partial immunity or semi-immune status. Here, we developed an experimental cerebral malaria (ECM) model for semi-immune mice. C57BL/6 (B6) mice underwent one, two and three cycles of infection and radical treatment (1-cure, 2-cure and 3-cure, respectively) before being finally challenged with 10(4) Plasmodium berghei ANKA without treatment. Our results showed that 100% of naïve (...

  6. Glucagon-like peptide-1 analogue, liraglutide, in experimental cerebral malaria

    DEFF Research Database (Denmark)

    Della Valle, Brian William; Hempel, Casper; Staalsoe, Trine

    2016-01-01

    BACKGROUND: Cerebral malaria from Plasmodium falciparum infection is major cause of death in the tropics. The pathogenesis of the disease is complex and the contribution of reactive oxygen and nitrogen species (ROS/RNS) in the brain is incompletely understood. Insulinotropic glucagon-like peptide-1...... (GLP-1) mimetics have potent neuroprotective effects in animal models of neuropathology associated with ROS/RNS dysfunction. This study investigates the effect of the GLP-1 analogue, liraglutide against the clinical outcome of experimental cerebral malaria (ECM) and Plasmodium falciparum growth....... Furthermore the role of oxidative stress on ECM pathogenesis is evaluated. METHODS: ECM was induced in Plasmodium berghei ANKA-infected C57Bl/6j mice. Infected Balb/c (non-cerebral malaria) and uninfected C57Bl/6j mice were included as controls. Mice were treated twice-daily with vehicle or liraglutide (200...

  7. Reduction of Experimental Cerebral Malaria and Its Related Proinflammatory Responses by the Novel Liposome-Based β-Methasone Nanodrug

    Directory of Open Access Journals (Sweden)

    Jintao Guo

    2014-01-01

    Full Text Available Cerebral malaria (CM is a severe complication of and a leading cause of death due to Plasmodium falciparum infection. CM is likely the result of interrelated events, including mechanical obstruction due to parasite sequestration in the microvasculature, and upregulation of Th1 immune responses. In parallel, blood-brain-barrier (BBB breakdown and damage or death of microglia, astrocytes, and neurons occurs. We found that a novel formulation of a liposome-encapsulated glucocorticosteroid, β-methasone hemisuccinate (nSSL-BMS, prevents experimental cerebral malaria (ECM in a murine model and creates a survival time-window, enabling administration of an antiplasmodial drug before severe anemia develops. nSSL-BMS treatment leads to lower levels of cerebral inflammation, expressed by altered levels of corresponding cytokines and chemokines. The results indicate the role of integrated immune responses in ECM induction and show that the new steroidal nanodrug nSSL-BMS reverses the balance between the Th1 and Th2 responses in malaria-infected mice so that the proinflammatory processes leading to ECM are prevented. Overall, because of the immunopathological nature of CM, combined immunomodulator/antiplasmodial treatment should be considered for prevention/treatment of human CM and long-term cognitive damage.

  8. Kidney function status in Nigerian human malaria patients | Anionye ...

    African Journals Online (AJOL)

    Malaria is now known to affect over 500 million persons worldwide, killing about 1 to 3 million of them annually. Plasmodium falciparum is the species mostly implicated in the causation of severe malaria. This study was carried out to investigate the kidney function status of malaria patients in Benin metropolis, Southern ...

  9. The ten-thousand year fever: rethinking human and wild primate malarias

    National Research Council Canada - National Science Library

    Cormier, Loretta A

    2011-01-01

    ... relationships between culture and environment that shape the trajectory of a parasite. She argues against the entrenched distinction between human and non-human malarias, using ethnoprimatology to develop a new understanding of cross-species exchange...

  10. The ten-thousand year fever: rethinking human and wild primate malarias

    National Research Council Canada - National Science Library

    Cormier, Loretta A

    2011-01-01

    "Malaria is one of the oldest recorded diseases in human history, and its 10,000-year relationship to primates can teach us why it will be one of the most serious threats to humanity in the 21st century...

  11. Case Report: Severe and Complicated Cynomolgi Malaria in a Rhesus Macaque Resulted in Similar Histopathological Changes as Those Seen in Human Malaria.

    Science.gov (United States)

    J Joyner, Chester; Consortium, The MaHPIC; Wood, Jennifer S; Moreno, Alberto; Garcia, Anapatricia; Galinski, Mary R

    2017-08-01

    Histopathological data collected from patients with severe malaria have been instrumental for studying malaria pathogenesis. Animal models of malaria are critical to complement such studies. Here, the histopathological changes observed in a rhesus macaque with severe and complicated Plasmodium cynomolgi malaria are reported. The animal presented with thrombocytopenia, severe anemia, and hyperparasitemia during the acute infection. The macaque was given subcurative antimalarial treatment, fluid support, and a blood transfusion to treat the clinical complications, but at the time of transfusion, kidney function was compromised. These interventions did not restore kidney function, and the animal was euthanized due to irreversible renal failure. Gross pathological and histological examinations revealed that the lungs, kidneys, liver, spleen, and bone marrow exhibited abnormalities similar to those described in patients with malaria. Overall, this case report illustrates the similarities in the pathophysiological complications that can occur in human malaria and cynomolgi malaria in rhesus macaques.

  12. Human Gene Expression in Uncomplicated Plasmodium falciparum Malaria.

    Science.gov (United States)

    Colborn, James M; Ylöstalo, Joni H; Koita, Ousmane A; Cissé, Ousmane H; Krogstad, Donald J

    2015-01-01

    To examine human gene expression during uncomplicated P. falciparum malaria, we obtained three samples (acute illness, treatment, and recovery) from 10 subjects and utilized each subject's recovery sample as their baseline. At the time of acute illness (day 1), subjects had upregulation of innate immune response, cytokine, and inflammation-related genes (IL-1β, IL-6, TNF, and IFN-γ), which was more frequent with parasitemias >100,000 per μL and body temperatures ≥ 39°C. Apoptosis-related genes (Fas, BAX, and TP53) were upregulated acutely and for several days thereafter (days 1-3). In contrast, the expression of immune-modulatory (transcription factor 7, HLV-DOA, and CD6) and apoptosis inhibitory (c-myc, caspase 8, and Fas Ligand G) genes was downregulated initially and returned to normal with clinical recovery (days 7-10). These results indicate that the innate immune response, cytokine, and apoptosis pathways are upregulated acutely in uncomplicated malaria with concomitant downregulation of immune-modulatory and apoptosis inhibitory genes.

  13. A TCRβ Repertoire Signature Can Predict Experimental Cerebral Malaria.

    Directory of Open Access Journals (Sweden)

    Encarnita Mariotti-Ferrandiz

    Full Text Available Cerebral Malaria (CM is associated with a pathogenic T cell response. Mice infected by P. berghei ANKA clone 1.49 (PbA developing CM (CM+ present an altered PBL TCR repertoire, partly due to recurrently expanded T cell clones, as compared to non-infected and CM- infected mice. To analyse the relationship between repertoire alteration and CM, we performed a kinetic analysis of the TRBV repertoire during the course of the infection until CM-related death in PbA-infected mice. The repertoires of PBL, splenocytes and brain lymphocytes were compared between infected and non-infected mice using a high-throughput CDR3 spectratyping method. We observed a modification of the whole TCR repertoire in the spleen and blood of infected mice, from the fifth and the sixth day post-infection, respectively, while only three TRBV were significantly perturbed in the brain of infected mice. Using multivariate analysis and statistical modelling, we identified a unique TCRβ signature discriminating CM+ from CTR mice, enriched during the course of the infection in the spleen and the blood and predicting CM onset. These results highlight a dynamic modification and compartmentalization of the TCR diversity during the course of PbA infection, and provide a novel method to identify disease-associated TCRβ signature as diagnostic and prognostic biomarkers.

  14. Effects of human and mosquito migrations on the dynamical behavior of the spread of malaria

    Science.gov (United States)

    Beay, Lazarus Kalvein; Kasbawati, Toaha, Syamsuddin

    2017-03-01

    Malaria is one of infectious diseases which become the main public health problem especially in Indonesia. Mathematically, the spread of malaria can be modeled to predict the outbreak of the disease. This research studies about mathematical model of the spread of malaria which takes into consideration the migration of human and mosquito populations. By determining basic reproduction number of the model, we analyze effects of migration parameter with respect to the reduction of malaria outbreak. Sensitivity analysis of basic reproduction number shows that mosquito migration has greater effect in reducing the outbreak of malaria compared with human migration. Basic reproduction number of the model is monotonically decreasing as mosquito migration increasing. We then confirm the analytic result by doing numerical simulation. The results show that migrations in human and mosquito populations have big influences in eliminating and eradicating the disease from the system.

  15. An experimental hut study to quantify the effect of DDT and airborne pyrethroids on entomological parameters of malaria transmission

    Science.gov (United States)

    2014-01-01

    Background Current malaria vector control programmes rely on insecticides with rapid contact toxicity. However, spatial repellents can also be applied to reduce man-vector contact, which might ultimately impact malaria transmission. The aim of this study was to quantify effects of airborne pyrethroids from coils and DDT used an indoor residual spray (IRS) on entomological parameters that influence malaria transmission. Methods The effect of Transfluthrin and Metofluthrin coils compared to DDT on house entry, exit and indoor feeding behaviour of Anopheles gambiae sensu lato were measured in experimental huts in the field and in the semi-field. Outcomes were deterrence - reduction in house entry of mosquitoes; irritancy or excito-repellency – induced premature exit of mosquitoes; blood feeding inhibition and effect on mosquito fecundity. Results Transfluthrin coils, Metofluthrin coils and DDT reduced human vector contact through deterrence by 38%, 30% and 8%, respectively and induced half of the mosquitoes to leave huts before feeding (56%, 55% and 48%, respectively). Almost all mosquitoes inside huts with Metofluthrin and Transfluthrin coils and more than three quarters of mosquitoes in the DDT hut did not feed, almost none laid eggs and 67%, 72% and 70% of all mosquitoes collected from Transfluthrin, Metofluthrin and DDT huts, respectively had died after 24 hours. Conclusion This study highlights that airborne pyrethroids and DDT affect a range of anopheline mosquito behaviours that are important parameters in malaria transmission, namely deterrence, irritancy/excito-repellency and blood-feeding inhibition. These effects are in addition to significant toxicity and reduced mosquito fecundity that affect mosquito densities and, therefore, provide community protection against diseases for both users and non-users. Airborne insecticides and freshly applied DDT had similar effects on deterrence, irritancy and feeding inhibition. Therefore, it is suggested that

  16. Human skin emanations in the host-seeking behaviour of the malaria mosquito Anopheles gambiae

    NARCIS (Netherlands)

    Braks, M.

    1999-01-01

    Malaria is an infectious disease caused by a parasite ( Plasmodium spp.) that is transmitted between human individuals by mosquitoes, belonging to the order of insects, Diptera, family of Culicidae (mosquitoes) and genus of Anopheles (malaria

  17. Controlled Human Malaria Infection of Tanzanians by Intradermal Injection of Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites

    NARCIS (Netherlands)

    Shekalaghe, S.; Rutaihwa, M.; Billingsley, P.F.; Chemba, M.; Daubenberger, C.A.; James, E.R.; Mpina, M.; Juma, O. Ali; Schindler, T.; Huber, E.; Gunasekera, A.; Manoj, A.; Simon, B.; Saverino, E.; Church, L.W.; Hermsen, C.C.; Sauerwein, R.W.; Plowe, C.; Venkatesan, M.; Sasi, P.; Lweno, O.; Mutani, P.; Hamad, A.; Mohammed, A.; Urassa, A.; Mzee, T.; Padilla, D.; Ruben, A.; Sim, B.K.; Tanner, M.; Abdulla, S.; Hoffman, S.L.

    2014-01-01

    Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa.

  18. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening.

    Science.gov (United States)

    Cox-Singh, Janet; Davis, Timothy M E; Lee, Kim-Sung; Shamsul, Sunita S G; Matusop, Asmad; Ratnam, Shanmuga; Rahman, Hasan A; Conway, David J; Singh, Balbir

    2008-01-15

    Until recently, Plasmodium knowlesi malaria in humans was misdiagnosed as Plasmodium malariae malaria. The objectives of the present study were to determine the geographic distribution of P. knowlesi malaria in the human population in Malaysia and to investigate 4 suspected fatal cases. Sensitive and specific nested polymerase chain reaction was used to identify all Plasmodium species present in (1) blood samples obtained from 960 patients with malaria who were hospitalized in Sarawak, Malaysian Borneo, during 2001-2006; (2) 54 P. malariae archival blood films from 15 districts in Sabah, Malaysian Borneo (during 2003-2005), and 4 districts in Pahang, Peninsular Malaysia (during 2004-2005); and (3) 4 patients whose suspected cause of death was P. knowlesi malaria. For the 4 latter cases, available clinical and laboratory data were reviewed. P. knowlesi DNA was detected in 266 (27.7%) of 960 of the samples from Sarawak hospitals, 41 (83.7%) of 49 from Sabah, and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 patients who died. All were hyperparasitemic and developed marked hepatorenal dysfunction. Human infection with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 h, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for P. knowlesi malaria, we recommend that patients who reside in or have traveled to Southeast Asia and who have received a "P. malariae" hyperparasitemia diagnosis by microscopy receive intensive management as appropriate for severe falciparum malaria.

  19. Human leukocyte antigens and natural selection by malaria.

    Science.gov (United States)

    Hill, A V; Yates, S N; Allsopp, C E; Gupta, S; Gilbert, S C; Lalvani, A; Aidoo, M; Davenport, M; Plebanski, M

    1994-11-29

    The extraordinary polymorphism of human leukocyte antigens (HLA) poses a question as to how this remarkable diversity arose and is maintained. The explanation that infectious pathogens are largely responsible is theoretically attractive but clear and consistent associations between HLA alleles and major infectious diseases have rarely been identified. Large case-control studies of HLA types in African children with severe malaria indicate that HLA associations with this parasitic infection do exist and it is becoming possible to investigate the underlying mechanisms by identification of peptide epitopes in parasite antigens. Such analysis reveals how the magnitude and detectability of HLA associations may be influenced by numerous genetic and environmental factors. These complex interactions will give rise to variation over time and space in the selective pressures exerted by infectious diseases and this fluctuation may, in itself, contribute to the maintenance of HLA polymorphism.

  20. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study

    NARCIS (Netherlands)

    Roestenberg, M.; Teirlinck, A.C.; McCall, M.B.B.; Teelen, K.A.E.M.; Makamdop, K.; Wiersma, J.; Arens, T.; Beckers, P.; Gemert, G.J.A. van; Vegte-Bolmer, M.G. van de; Ven, A.J.A.M. van der; Luty, A.J.F.; Hermsen, C.C.; Sauerwein, R.W.

    2011-01-01

    BACKGROUND: We have shown that immunity to infection with Plasmodium falciparum can be induced experimentally in malaria-naive volunteers through immunisation by bites of infected mosquitoes while simultaneously preventing disease with chloroquine prophylaxis. This immunity was associated with

  1. Experimentation on humans and nonhumans.

    Science.gov (United States)

    Pluhar, Evelyn B

    2006-01-01

    In this article, I argue that it is wrong to conduct any experiment on a nonhuman which we would regard as immoral were it to be conducted on a human, because such experimentation violates the basic moral rights of sentient beings. After distinguishing the rights approach from the utilitarian approach, I delineate basic concepts. I then raise the classic "argument from marginal cases" against those who support experimentation on nonhumans but not on humans. After next replying to six important objections against that argument, I contend that moral agents are logically required to accord basic moral rights to every sentient being. I conclude by providing criteria for distinguishing ethical from unethical experimentation.

  2. The genome of the simian and human malaria parasite Plasmodium knowlesi

    DEFF Research Database (Denmark)

    Pain, A; Böhme, U; Berry, A E

    2008-01-01

    Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite...... species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood...... cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described...

  3. Azadirachta indica ethanolic extract protects neurons from apoptosis and mitigates brain swelling in experimental cerebral malaria.

    Science.gov (United States)

    Bedri, Selma; Khalil, Eltahir A; Khalid, Sami A; Alzohairy, Mohammad A; Mohieldein, Abdlmarouf; Aldebasi, Yousef H; Seke Etet, Paul Faustin; Farahna, Mohammed

    2013-08-29

    Cerebral malaria is a rapidly developing encephalopathy caused by the apicomplexan parasite Plasmodium falciparum. Drugs currently in use are associated with poor outcome in an increasing number of cases and new drugs are urgently needed. The potential of the medicinal plant Azadirachta indica (Neem) for the treatment of experimental cerebral malaria was evaluated in mice. Experimental cerebral malaria was induced in mice by infection with Plasmodium berghei ANKA. Infected mice were administered with Azadirachta indica ethanolic extract at doses of 300, 500, or 1000 mg/kg intraperitoneally (i.p.) in experimental groups, or with the anti-malarial drugs chloroquine (12 mg/kg, i.p.) or artemether (1.6 mg/kg, i.p.), in the positive control groups. Treatment was initiated at the onset of signs of brain involvement and pursued for five days on a daily basis. Mice brains were dissected out and processed for the study of the effects of the extract on pyramidal cells' fate and on markers of neuroinflammation and apoptosis, in the medial temporal lobe. Azadirachta indica ethanolic extract mitigated neuroinflammation, decreased the severity of brain oedema, and protected pyramidal neurons from apoptosis, particularly at the highest dose used, comparable to chloroquine and artemether. The present findings suggest that Azadirachta indica ethanolic extract has protective effects on neuronal populations in the inflamed central nervous system, and justify at least in part its use in African and Asian folk medicine and practices.

  4. Origin of the human malaria parasite Plasmodium falciparum in gorillas.

    Science.gov (United States)

    Liu, Weimin; Li, Yingying; Learn, Gerald H; Rudicell, Rebecca S; Robertson, Joel D; Keele, Brandon F; Ndjango, Jean-Bosco N; Sanz, Crickette M; Morgan, David B; Locatelli, Sabrina; Gonder, Mary K; Kranzusch, Philip J; Walsh, Peter D; Delaporte, Eric; Mpoudi-Ngole, Eitel; Georgiev, Alexander V; Muller, Martin N; Shaw, George M; Peeters, Martine; Sharp, Paul M; Rayner, Julian C; Hahn, Beatrice H

    2010-09-23

    Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin.

  5. Origin of the human malaria parasite Plasmodium falciparum in gorillas

    Science.gov (United States)

    Liu, Weimin; Li, Yingying; Learn, Gerald H.; Rudicell, Rebecca S.; Robertson, Joel D.; Keele, Brandon F.; Ndjango, Jean-Bosco N.; Sanz, Crickette M.; Morgan, David B.; Locatelli, Sabrina; Gonder, Mary K.; Kranzusch, Philip J.; Walsh, Peter D.; Delaporte, Eric; Mpoudi-Ngole, Eitel; Georgiev, Alexander V.; Muller, Martin N.; Shaw, George M.; Peeters, Martine; Sharp, Paul M.; Rayner, Julian C.; Hahn, Beatrice H.

    2010-01-01

    Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here, we developed a novel polymerase chain reaction based single genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in fecal samples of wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed, and almost always comprised of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas was comprised of parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla and not of chimpanzee, bonobo or ancient human origin. PMID:20864995

  6. Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara.

    Science.gov (United States)

    Webster, Daniel P; Dunachie, Susanna; Vuola, Jenni M; Berthoud, Tamara; Keating, Sheila; Laidlaw, Stephen M; McConkey, Samuel J; Poulton, Ian; Andrews, Laura; Andersen, Rikke F; Bejon, Philip; Butcher, Geoff; Sinden, Robert; Skinner, Michael A; Gilbert, Sarah C; Hill, Adrian V S

    2005-03-29

    Malaria is a major global health problem for which an effective vaccine is required urgently. Prime-boost vaccination regimes involving plasmid DNA and recombinant modified vaccinia virus Ankara-encoding liver-stage malaria antigens have been shown to be powerfully immunogenic for T cells and capable of inducing partial protection against experimental malaria challenge in humans, manifested as a delay in time to patent parasitemia. Here, we report that substitution of plasmid DNA as the priming vector with a specific attenuated recombinant fowlpox virus, FP9, vaccine in such prime-boost regimes can elicit complete sterile protection that can last for 20 months. Protection at 20 months was associated with persisting memory but not effector T cell responses. The protective efficacy of various immunization regimes correlated with the magnitude of induced immune responses, supporting the strategy of maximizing durable T cell immunogenicity to develop more effective liver-stage vaccines against Plasmodium falciparum malaria.

  7. The Historical Ecology of Human and Wild Primate Malarias in the New World

    Directory of Open Access Journals (Sweden)

    Loretta A. Cormier

    2010-02-01

    Full Text Available The origin and subsequent proliferation of malarias capable of infecting humans in South America remain unclear, particularly with respect to the role of Neotropical monkeys in the infectious chain. The evidence to date will be reviewed for Pre-Columbian human malaria, introduction with colonization, zoonotic transfer from cebid monkeys, and anthroponotic transfer to monkeys. Cultural behaviors (primate hunting and pet-keeping and ecological changes favorable to proliferation of mosquito vectors are also addressed.

  8. Cytokines and dysregulation of the immune response in human malaria

    Directory of Open Access Journals (Sweden)

    M. Fátima C. Alves

    1992-01-01

    Full Text Available The dysregulation of the immune response by malaria parasite has been considered as a possible constraint to the effectiveness of malaria vaccination. In spite of the important role interleukin-I (IL-1 in malaria are lacking. We found that only 2 out of 35 subjectswith acute malaria showed increased levels of serum IL-1 alpha by enzyme immunoassay. To assess whether IL-1 could interfere with T- lymphocyte responses, blood mononuclear cells from patients infected with Plasmodium falciparum, P. vivax, or healthy subjects were cultured with phytohemagglutinin, and lymphocyte proliferation measured 72h later by 3H-thymidine incorporation. Our data showed that T-lymphocyte responses are depressed both in P. falciparum (10,500 ñ 2,900 and P. vivax malaria (13,000 ñ 3,300, as compared to that of healthy individuals (27,000 ñ 3,000. Addition of IL-1 partially reserved depression of malaria lymphocytes, but had no effect on normal cells. On the other hand, T-lymphocytes from malaria infected-subjects presented a minimal decrease in proliferation, when cultured in the presence of exogenous PGE2. These data indicate the occurrence of two defects of immunoregulation in malaria: a deficiency of IL-1 production by monocytes/macrophages, and an increased resistance of lymphocytes to the antiproliferative effect of PGE2.

  9. An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials.

    Science.gov (United States)

    Steel, Ryan Wj; Kappe, Stefan Hi; Sack, Brandon K

    2016-12-01

    Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts.

  10. Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon

    Directory of Open Access Journals (Sweden)

    Albert Lalremruata

    2015-09-01

    Interpretation: This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts.

  11. Community-directed educational intervention for malaria elimination in Bhutan: quasi-experimental study in malaria endemic areas of Sarpang district.

    Science.gov (United States)

    Tobgay, Tashi; Pem, Deki; Dophu, Ugyen; Dumre, Shyam P; Na-Bangchang, Kesara; Torres, Cristina E

    2013-04-17

    As per the World Malaria Report 2011, there was a 17% reduction in morbidity and 26% reduction in mortality in 2010, compared to 2000. In Bhutan, there were only 194 malaria cases in 2011 as compared to 5,935 cases in 2000. As the country moves towards an elimination phase, educating the community and empowering them on malaria prevention and control is imperative. Hence, this study was conducted to elucidate the effectiveness of the community-directed educational intervention on malaria prevention and control in malaria-endemic areas of Sarpang district, Bhutan. This quasi-experimental study design was conducted using both qualitative and quantitative data collection methods. In-depth interviews and focus group discussions were carried out in addition to household survey using a structured questionnaire conducted before and after the intervention. Intervention was conducted using community action groups, who were provided with training and which then developed action plans for implementation of interventions within their communities. The study resulted in a significant improvement in knowledge and attitude in intervention as compared to control during the post-intervention survey (p Bhutan. Further studies are needed to see the long-term effect and sustainability of such interventions.

  12. Quantifying behavioural interactions between humans and mosquitoes: Evaluating the protective efficacy of insecticidal nets against malaria transmission in rural Tanzania

    Directory of Open Access Journals (Sweden)

    Mathenge Evan

    2006-11-01

    Full Text Available Abstract Background African malaria vectors bite predominantly indoors at night so sleeping under an Insecticide-Treated Net (ITN can greatly reduce malaria risk. Behavioural adaptation by mosquitoes to increasing ITN coverage could allow vector mosquitoes to bite outside of peak sleeping hours and undermine efficacy of this key malaria prevention measure. Methods High coverage with largely untreated nets has been achieved in the Kilombero Valley, southern Tanzania through social marketing programmes. Direct surveys of nightly biting activity by An. gambiae Giles were conducted in the area before (1997 and after (2004 implementation of ITN promotion. A novel analytical model was applied to estimate the effective protection provided by an ITN, based on published experimental hut trials combined with questionnaire surveys of human sleeping behaviour and recorded mosquito biting patterns. Results An. gambiae was predominantly endophagic and nocturnal in both surveys: Approximately 90% and 80% of exposure occurred indoors and during peak sleeping hours, respectively. ITNs consistently conferred >70% protection against exposure to malaria transmission for users relative to non-users. Conclusion As ITN coverage increases, behavioural adaptation by mosquitoes remains a future possibility. The approach described allows comparison of mosquito biting patterns and ITN efficacy at multiple study sites and times. Initial results indicate ITNs remain highly effective and should remain a top-priority intervention. Combined with recently developed transmission models, this approach allows rapid, informative and cost-effective preliminary comparison of diverse control strategies in terms of protection against exposure before more costly and intensive clinical trials.

  13. Comparison of clinical and parasitological data from controlled human malaria infection trials.

    Directory of Open Access Journals (Sweden)

    Meta Roestenberg

    Full Text Available BACKGROUND: Exposing healthy human volunteers to Plasmodium falciparum-infected mosquitoes is an accepted tool to evaluate preliminary efficacy of malaria vaccines. To accommodate the demand of the malaria vaccine pipeline, controlled infections are carried out in an increasing number of centers worldwide. We assessed their safety and reproducibility. METHODS: We reviewed safety and parasitological data from 128 malaria-naïve subjects participating in controlled malaria infection trials conducted at the University of Oxford, UK, and the Radboud University Nijmegen Medical Center, The Netherlands. Results were compared to a report from the US Military Malaria Vaccine Program. RESULTS: We show that controlled human malaria infection trials are safe and demonstrate a consistent safety profile with minor differences in the frequencies of arthralgia, fatigue, chills and fever between institutions. But prepatent periods show significant variation. Detailed analysis of Q-PCR data reveals highly synchronous blood stage parasite growth and multiplication rates. CONCLUSIONS: Procedural differences can lead to some variation in safety profile and parasite kinetics between institutions. Further harmonization and standardization of protocols will be useful for wider adoption of these cost-effective small-scale efficacy trials. Nevertheless, parasite growth rates are highly reproducible, illustrating the robustness of controlled infections as a valid tool for malaria vaccine development.

  14. Re-imagining malaria: heterogeneity of human and mosquito behaviour in relation to residual malaria transmission in Cambodia.

    Science.gov (United States)

    Gryseels, Charlotte; Durnez, Lies; Gerrets, René; Uk, Sambunny; Suon, Sokha; Set, Srun; Phoeuk, Pisen; Sluydts, Vincent; Heng, Somony; Sochantha, Tho; Coosemans, Marc; Peeters Grietens, Koen

    2015-04-24

    In certain regions in Southeast Asia, where malaria is reduced to forested regions populated by ethnic minorities dependent on slash-and-burn agriculture, malaria vector populations have developed a propensity to feed early and outdoors, limiting the effectiveness of long-lasting insecticide-treated nets (LLIN) and indoor residual spraying (IRS). The interplay between heterogeneous human, as well as mosquito behaviour, radically challenges malaria control in such residual transmission contexts. This study examines human behavioural patterns in relation to the vector behaviour. The anthropological research used a sequential mixed-methods study design in which quantitative survey research methods were used to complement findings from qualitative ethnographic research. The qualitative research existed of in-depth interviews and participant observation. For the entomological research, indoor and outdoor human landing collections were performed. All research was conducted in selected villages in Ratanakiri province, Cambodia. Variability in human behaviour resulted in variable exposure to outdoor and early biting vectors: (i) indigenous people were found to commute between farms in the forest, where malaria exposure is higher, and village homes; (ii) the indoor/outdoor biting distinction was less clear in forest housing often completely or partly open to the outside; (iii) reported sleeping times varied according to the context of economic activities, impacting on the proportion of infections that could be accounted for by early or nighttime biting; (iv) protection by LLINs may not be as high as self-reported survey data indicate, as observations showed around 40% (non-treated) market net use while (v) unprotected evening resting and deep forest activities impacted further on the suboptimal use of LLINs. The heterogeneity of human behaviour and the variation of vector densities and biting behaviours may lead to a considerable proportion of exposure occurring during

  15. CD19(+) B cells confer protection against experimental cerebral malaria in semi-immune rodent model.

    Science.gov (United States)

    Bao, Lam Quoc; Huy, Nguyen Tien; Kikuchi, Mihoko; Yanagi, Tetsuo; Senba, Masachika; Shuaibu, Mohammed Nasir; Honma, Kiri; Yui, Katsuyuki; Hirayama, Kenji

    2013-01-01

    In African endemic area, adults are less vulnerable to cerebral malaria than children probably because of acquired partial immunity or semi-immune status. Here, we developed an experimental cerebral malaria (ECM) model for semi-immune mice. C57BL/6 (B6) mice underwent one, two and three cycles of infection and radical treatment (1-cure, 2-cure and 3-cure, respectively) before being finally challenged with 10(4) Plasmodium berghei ANKA without treatment. Our results showed that 100% of naïve (0-cure), 67% of 1-cure, 37% of 2-cure and none of 3-cure mice succumbed to ECM within 10 days post challenge infection. In the protected 3-cure mice, significantly higher levels of plasma IL-10 and lower levels of IFN-γ than the others on day 7 post challenge infection were observed. Major increased lymphocyte subset of IL-10 positive cells in 3-cure mice was CD5(-)CD19(+) B cells. Passive transfer of splenic CD19(+) cells from 3-cure mice protected naïve mice from ECM. Additionally, aged 3-cure mice were also protected from ECM 12 and 20 months after the last challenge infection. In conclusion, mice became completely resistant to ECM after three exposures to malaria. CD19(+) B cells are determinants in protective mechanism of semi-immune mice against ECM possibly via modulatory IL-10 for pathogenic IFN-γ production.

  16. Malaria prevention and treatment

    African Journals Online (AJOL)

    malaria parasites into the blood. Four species of malaria parasites can infect humans and cause illness; only P. falci- parum malaria is potentially life-threat- ening. Most of the malaria found in Af- rica is of the falciparum species - this is the most dangerous species of malaria. Symptoms may develop as soon as seven days ...

  17. Targeting NAD+ metabolism in the human malaria parasite Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Jessica K O'Hara

    Full Text Available Nicotinamide adenine dinucleotide (NAD+ is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+ de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT, is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds.

  18. Multiplication rate variation in the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Murray, Lee; Stewart, Lindsay B; Tarr, Sarah J; Ahouidi, Ambroise D; Diakite, Mahamadou; Amambua-Ngwa, Alfred; Conway, David J

    2017-07-25

    It is important to understand intrinsic variation in asexual blood stage multiplication rates of the most virulent human malaria parasite, Plasmodium falciparum. Here, multiplication rates of long-term laboratory adapted parasite clones and new clinical isolates were measured, using a newly standardised assay of growth from low starting density in replicate parallel cultures with erythrocytes from multiple different donors, across multiple cycles. Multiplication rates of long-term established clones were between 7.6 and 10.5 fold per 48 hours, with clone Dd2 having a higher rate than others (clones 3D7, HB3 and D10). Parasite clone-specific growth was then analysed in co-culture assays with all possible heterologous pairwise combinations. This showed that co-culture of different parasites did not affect their replication rates, indicating that there were no suppressive interactions operating between parasites. Multiplication rates of eleven new clinical isolates were measured after a few weeks of culture, and showed a spectrum of replication rates between 2.3 and 6.0 fold per 48 hours, the entire range being lower than for the long-term laboratory adapted clones. Multiplication rate estimates remained stable over time for several isolates tested repeatedly up to three months after culture initiation, indicating considerable persistence of this important trait variation.

  19. The importance of human FcgammaRI in mediating protection to malaria.

    Directory of Open Access Journals (Sweden)

    Richard S McIntosh

    2007-05-01

    Full Text Available The success of passive immunization suggests that antibody-based therapies will be effective at controlling malaria. We describe the development of fully human antibodies specific for Plasmodium falciparum by antibody repertoire cloning from phage display libraries generated from immune Gambian adults. Although these novel reagents bind with strong affinity to malaria parasites, it remains unclear if in vitro assays are predictive of functional immunity in humans, due to the lack of suitable animal models permissive for P. falciparum. A potentially useful solution described herein allows the antimalarial efficacy of human antibodies to be determined using rodent malaria parasites transgenic for P. falciparum antigens in mice also transgenic for human Fc-receptors. These human IgG1s cured animals of an otherwise lethal malaria infection, and protection was crucially dependent on human FcgammaRI. This important finding documents the capacity of FcgammaRI to mediate potent antimalaria immunity and supports the development of FcgammaRI-directed therapy for human malaria.

  20. Human parallels to experimental myopia?

    DEFF Research Database (Denmark)

    Fledelius, Hans C; Goldschmidt, Ernst; Haargaard, Birgitte

    2014-01-01

    of the present PubMed literature-based review is to evaluate apparent similarities between experience from disturbed imaging in experimental laboratory science and varieties within the spectrum of childhood human myopia. So far, the main impression is that macroscopical optical deprivation appears absent...... in the prevalent types of human myopia, nor is myopia a regular sequel where early eye pathology has led to poor imaging and optical deprivation. Optical aberrations of a higher order are a relatively new issue in myopia research, and microstructural deprivation is only marginally dealt within the survey. Links...

  1. Relation between HLA genes, human skin volatiles and attractiveness of humans to malaria mosquitoes.

    Science.gov (United States)

    Verhulst, Niels O; Beijleveld, Hans; Qiu, Yu Tong; Maliepaard, Chris; Verduyn, Willem; Haasnoot, Geert W; Claas, Frans H J; Mumm, Roland; Bouwmeester, Harro J; Takken, Willem; van Loon, Joop J A; Smallegange, Renate C

    2013-08-01

    Chemical cues are considered to be the most important cues for mosquitoes to find their hosts and humans can be ranked for attractiveness to mosquitoes based on the chemical cues they emit. Human leukocyte antigen (HLA) genes are considered to be involved in the regulation of human body odor and may therefore affect human attractiveness to mosquitoes, and hence, affect the force of malaria transmission. In the present study the correlations between HLA profiles, human skin volatiles and human attractiveness to the malaria mosquito Anopheles gambiae Giles sensu stricto were examined. Skin emanations of 48 volunteers were collected by rubbing a foot over glass beads. Previously the attractiveness of these emanations to An. gambiae was determined. In this study, the chemical composition of these emanations was determined by gas chromatography-mass spectroscopy (GC-MS) and blood samples of all volunteers were taken for HLA analysis. Hierarchical cluster analysis (HCA), partial least squares discriminant analysis (PLS-DA), Fisher's exact test and random forest regression were used to test for correlations between individuals classified as either highly or poorly attractive to mosquitoes and their HLA profile and volatile composition. HLA profiling suggests that people carrying HLA gene Cw∗07 are more attractive to mosquitoes. GC-MS revealed that limonene, 2-phenylethanol and 2-ethyl-1-hexanol were associated with individuals that were poorly attractive to An.gambiae and lactic acid, 2-methylbutanoic acid, tetradecanoic acid and octanal with individuals that were highly attractive. Such compounds offer potential for disruption of mosquito behavior in malaria intervention programs. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Defining the protein interaction network of human malaria parasite Plasmodium falciparum

    KAUST Repository

    Ramaprasad, Abhinay

    2012-02-01

    Malaria, caused by the protozoan parasite Plasmodium falciparum, affects around 225. million people yearly and a huge international effort is directed towards combating this grave threat to world health and economic development. Considerable advances have been made in malaria research triggered by the sequencing of its genome in 2002, followed by several high-throughput studies defining the malaria transcriptome and proteome. A protein-protein interaction (PPI) network seeks to trace the dynamic interactions between proteins, thereby elucidating their local and global functional relationships. Experimentally derived PPI network from high-throughput methods such as yeast two hybrid (Y2H) screens are inherently noisy, but combining these independent datasets by computational methods tends to give a greater accuracy and coverage. This review aims to discuss the computational approaches used till date to construct a malaria protein interaction network and to catalog the functional predictions and biological inferences made from analysis of the PPI network. © 2011 Elsevier Inc.

  3. A human Phase I/IIa malaria challenge trial of a polyprotein malaria vaccine.

    Science.gov (United States)

    Porter, David W; Thompson, Fiona M; Berthoud, Tamara K; Hutchings, Claire L; Andrews, Laura; Biswas, Sumi; Poulton, Ian; Prieur, Eric; Correa, Simon; Rowland, Rosalind; Lang, Trudie; Williams, Jackie; Gilbert, Sarah C; Sinden, Robert E; Todryk, Stephen; Hill, Adrian V S

    2011-10-06

    We examined the safety, immunogenicity and efficacy of a prime-boost vaccination regime involving two poxvirus malaria subunit vaccines, FP9-PP and MVA-PP, expressing the same polyprotein consisting of six pre-erythrocytic antigens from Plasmodium falciparum. Following safety assessment of single doses, 15 volunteers received a heterologous prime-boost vaccination regime and underwent malaria sporozoite challenge. The vaccines were safe but interferon-γ ELISPOT responses were low compared to other poxvirus vectors, despite targeting multiple antigens. There was no vaccine efficacy as measured by delay in time to parasitaemia. A number of possible explanations are discussed, including the very large insert size of the polyprotein transgene. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites

    KAUST Repository

    Hunt, Paul

    2010-09-16

    Background: Classical and quantitative linkage analyses of genetic crosses have traditionally been used to map genes of interest, such as those conferring chloroquine or quinine resistance in malaria parasites. Next-generation sequencing technologies now present the possibility of determining genome-wide genetic variation at single base-pair resolution. Here, we combine in vivo experimental evolution, a rapid genetic strategy and whole genome re-sequencing to identify the precise genetic basis of artemisinin resistance in a lineage of the rodent malaria parasite, Plasmodium chabaudi. Such genetic markers will further the investigation of resistance and its control in natural infections of the human malaria, P. falciparum.Results: A lineage of isogenic in vivo drug-selected mutant P. chabaudi parasites was investigated. By measuring the artemisinin responses of these clones, the appearance of an in vivo artemisinin resistance phenotype within the lineage was defined. The underlying genetic locus was mapped to a region of chromosome 2 by Linkage Group Selection in two different genetic crosses. Whole-genome deep coverage short-read re-sequencing (IlluminaSolexa) defined the point mutations, insertions, deletions and copy-number variations arising in the lineage. Eight point mutations arise within the mutant lineage, only one of which appears on chromosome 2. This missense mutation arises contemporaneously with artemisinin resistance and maps to a gene encoding a de-ubiquitinating enzyme.Conclusions: This integrated approach facilitates the rapid identification of mutations conferring selectable phenotypes, without prior knowledge of biological and molecular mechanisms. For malaria, this model can identify candidate genes before resistant parasites are commonly observed in natural human malaria populations. 2010 Hunt et al; licensee BioMed Central Ltd.

  5. Characterizing Types of Human Mobility to Inform Differential and Targeted Malaria Elimination Strategies in Northeast Cambodia.

    Science.gov (United States)

    Peeters Grietens, Koen; Gryseels, Charlotte; Dierickx, Susan; Bannister-Tyrrell, Melanie; Trienekens, Suzan; Uk, Sambunny; Phoeuk, Pisen; Suon, Sokha; Set, Srun; Gerrets, René; Hoibak, Sarah; Muela Ribera, Joan; Hausmann-Muela, Susanna; Tho, Sochantha; Durnez, Lies; Sluydts, Vincent; d'Alessandro, Umberto; Coosemans, Marc; Erhart, Annette

    2015-11-23

    Human population movements currently challenge malaria elimination in low transmission foci in the Greater Mekong Subregion. Using a mixed-methods design, combining ethnography (n = 410 interviews), malariometric data (n = 4996) and population surveys (n = 824 indigenous populations; n = 704 Khmer migrants) malaria vulnerability among different types of mobile populations was researched in the remote province of Ratanakiri, Cambodia. Different structural types of human mobility were identified, showing differential risk and vulnerability. Among local indigenous populations, access to malaria testing and treatment through the VMW-system and LLIN coverage was high but control strategies failed to account for forest farmers' prolonged stays at forest farms/fields (61% during rainy season), increasing their exposure (p = 0.002). The Khmer migrants, with low acquired immunity, active on plantations and mines, represented a fundamentally different group not reached by LLIN-distribution campaigns since they were largely unregistered (79%) and unaware of the local VMW-system (95%) due to poor social integration. Khmer migrants therefore require control strategies including active detection, registration and immediate access to malaria prevention and control tools from which they are currently excluded. In conclusion, different types of mobility require different malaria elimination strategies. Targeting mobility without an in-depth understanding of malaria risk in each group challenges further progress towards elimination.

  6. Normocyte-binding protein required for human erythrocyte invasion by the zoonotic malaria parasitePlasmodium knowlesi

    KAUST Repository

    Moon, Robert W.

    2016-06-15

    The dominant cause of malaria in Malaysia is now Plasmodium knowlesi, a zoonotic parasite of cynomolgus macaque monkeys found throughout South East Asia. Comparative genomic analysis of parasites adapted to in vitro growth in either cynomolgus or human RBCs identified a genomic deletion that includes the gene encoding normocyte-binding protein Xa (NBPXa) in parasites growing in cynomolgus RBCs but not in human RBCs. Experimental deletion of the NBPXa gene in parasites adapted to growth in human RBCs (which retain the ability to grow in cynomolgus RBCs) restricted them to cynomolgus RBCs, demonstrating that this gene is selectively required for parasite multiplication and growth in human RBCs. NBPXa-null parasites could bind to human RBCs, but invasion of these cells was severely impaired. Therefore, NBPXa is identified as a key mediator of P. knowlesi human infection and may be a target for vaccine development against this emerging pathogen.

  7. Malaria overdiagnosis and subsequent overconsumption of antimalarial drugs in Angola: Consequences and effects on human health.

    Science.gov (United States)

    Manguin, Sylvie; Foumane, Vincent; Besnard, Patrick; Fortes, Filomeno; Carnevale, Pierre

    2017-07-01

    Microscopic blood smear examinations done in health centers of Angola demonstrated a large overdiagnosis of malaria cases with an average rate of errors as high as 85%. Overall 83% of patients who received Coartem ® had an inappropriate treatment. Overestimated malaria diagnosis was noticed even when specific symptoms were part of the clinical observation, antimalarial treatments being subsequently given. Then, malaria overdiagnosis has three main consequences, (i) the lack of data reliability is of great concern, impeding epidemiological records and evaluation of the actual influence of operations as scheduled by the National Malaria Control Programme; (ii) the large misuse of antimalarial drug can increase the selective pressure for resistant strain and can make a false consideration of drug resistant P. falciparum crisis; and (iii) the need of strengthening national health centers in term of human, with training in microscopy, and equipment resources to improve malaria diagnosis with a large scale use of rapid diagnostic tests associated with thick blood smears, backed up by a "quality control" developed by the national health authorities. Monitoring of malaria cases was done in three Angolan health centers of Alto Liro (Lobito town) and neighbor villages of Cambambi and Asseque (Benguéla Province) to evaluate the real burden of malaria. Carriers of Plasmodium among patients of newly-borne to 14 years old, with or without fever, were analyzed and compared to presumptive malaria cases diagnosed in these health centers. Presumptive malaria cases were diagnosed six times more than the positive thick blood smears done on the same children. In Alto Liro health center, the percentage of diagnosis error reached 98%, while in Cambambi and Asseque it was of 79% and 78% respectively. The percentage of confirmed malaria cases was significantly higher during the dry (20.2%) than the rainy (13.2%) season. These observations in three peripheral health centers confirmed what

  8. Are herders protected by their herds? An experimental analysis of zooprophylaxis against the malaria vector Anopheles arabiensis

    Directory of Open Access Journals (Sweden)

    Young Stephen

    2011-03-01

    Full Text Available Abstract Background The number of Anopheles arabiensis (Diptera: Culicidae and Anopheles pharoensis caught by human and cattle baits was investigated experimentally in the Arba Minch district of southern Ethiopia to determine if attraction to humans, indoors or outdoors, was affected by the presence or absence of cattle. Methods Field studies were made of the effect of a surrounding ring (10 m radius of 20 cattle on the numbers of mosquitoes collected by human-baited sampling methods (i inside or (ii outside a hut. Results The numbers of An. arabiensis caught outdoors by a human landing catch (HLC with or without a ring of cattle were not significantly different (2 × 2 Latin square comparisons: means = 24.8 and 37.2 mosquitoes/night, respectively; n = 12, P > 0.22, Tukey HSD, whereas, the numbers of An. pharoensis caught were significantly reduced (44% by a ring of cattle (4.9 vs. 8.7; n = 12, P An. arabiensis in human-baited traps (HBT was 25 times greater than in cattle-baited traps (CBT (34.0 vs. 1.3, n = 24; P An. pharoensis there was no significant difference. Furthermore, HBT and CBT catches were unaffected by a ring of cattle (4 × 4 Latin square comparison for either An. arabiensis (n = 48; P > 0.999 or An. pharoensis (n = 48, P > 0.870. The HLC catches indoors vs. outdoors were not significantly different for either An. arabiensis or An. pharoensis (n = 12, P > 0.969, but for An. arabiensis only, the indoor catch was reduced significantly by 49% when the hut was surrounded by cattle (Tukey HSD, n = 12, P > 0.01. Conclusions Outdoors, a preponderance of cattle (20:1, cattle:humans does not provide any material zooprophylactic effect against biting by An. arabiensis. For a human indoors, the presence of cattle outdoors nearly halved the catch. Unfortunately, this level of reduction would not have an appreciable impact on malaria incidence in an area with typically > 1 infective bite/person/night. For An. pharoensis, cattle significantly

  9. The ten-thousand year fever: rethinking human and wild primate malarias

    National Research Council Canada - National Science Library

    Cormier, Loretta A

    2011-01-01

    .... She also shows how current human-environment interactions, including deforestation and development, create the potential for new forms of malaria to threaten human populations. This book is a model of interdisciplinary integration that will be essential reading in fields from anthropology and biology to public health"--Provided by publisher.

  10. Plasmodium knowlesi malaria in humans is widely distributed and potentially life-threatening

    Science.gov (United States)

    Cox-Singh, Janet; Davis, Timothy M. E.; Lee, Kim-Sung; Shamsul, Sunita S. G.; Matusop, Asmad; Ratnam, Shanmuga; Rahman, Hasan A.; Conway, David J; Singh, Balbir

    2008-01-01

    Background Until recently, Plasmodium knowlesi malaria in humans was misdiagnosed as P. malariae. The present objectives were to determine the geographic distribution of P. knowlesi in the human population in Malaysia and to investigate four suspected fatal cases. Methods Sensitive and specific nested-PCR was used to identify all Plasmodium species present in blood from i) 960 patients with malaria hospitalized in Sarawak, Malaysian Borneo from 2001-2006, ii) 54 P. malariae archival blood-films from 15 districts in Sabah, Malaysian Borneo (2003–2005) and four districts in Pahang, Peninsular Malaysia (2004–2005), and iii) suspected knowlesi fatalities. In the four latter cases, available clinical and laboratory data were reviewed. Results P. knowlesi DNA was detected in 266 of 960 (27·7%) of the samples from Sarawak hospitals, 41 of 49 (83·7%) from Sabah and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 fatal cases. All were hyperparasitemic and developed marked hepatorenal dysfunction. Conclusions Human infections with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 hours, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for knowlesi malaria, we recommend that patients in, or who have travelled to, South-east Asia who are ill with a ‘P. malariae’ hyperparasitemia diagnosis by microscopy should receive intensive management as appropriate for severe falciparum malaria. PMID:18171245

  11. Malaria infected mosquitoes express enhanced attraction to human odor

    NARCIS (Netherlands)

    Smallegange, R.C.; Gemert, G.J.A. van; Vegte-Bolmer, M.G. van de; Gezan, S.; Takken, W.; Sauerwein, R.W.; Logan, J.G.

    2013-01-01

    There is much evidence that some pathogens manipulate the behaviour of their mosquito hosts to enhance pathogen transmission. However, it is unknown whether this phenomenon exists in the interaction of Anopheles gambiae sensu stricto with the malaria parasite, Plasmodium falciparum--one of the most

  12. Cytokine expression in malaria-infected non-human primate placentas

    Directory of Open Access Journals (Sweden)

    M.M. Gicheru

    2012-06-01

    Full Text Available Malaria parasites are known to mediate the induction of inflammatory immune responses at the maternal-foetal interface during placental malaria (PM leading to adverse consequences like pre-term deliveries and abortions. Immunological events that take place within the malaria-infected placental micro-environment leading to retarded foetal growth and disruption of pregnancies are among the critical parameters that are still in need of further elucidation. The establishment of more animal models for studying placental malaria can provide novel ways of circumventing problems experienced during placental malaria research in humans such as inaccurate estimation of gestational ages. Using the newly established olive baboon (Papio anubis-Plasmodium knowlesi (P. knowlesi H strain model of placental malaria, experiments were carried out to determine placental cytokine profiles underlying the immunopathogenesis of placental malaria. Four pregnant olive baboons were infected with blood stage P. knowlesi H strain parasites on the one fiftieth day of gestation while four other uninfected pregnant olive baboons were maintained as uninfected controls. After nine days of infection, placentas were extracted from all the eight baboons through cesarean surgery and used for the processing of placental plasma and sera samples for cytokine sandwich enzyme linked immunosorbent assays (ELISA. Results indicated that the occurrence of placental malaria was associated with elevated concentrations of tumour necrosis factor alpha (TNF-α and interleukin 12 (IL-12. Increased levels of IL-4, IL-6 and IL-10 and interferon gamma (IFN-γ levels were detected in uninfected placentas. These findings match previous reports regarding immunity during PM thereby demonstrating the reliability of the olive baboon-P. knowlesi model for use in further studies.

  13. Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon.

    Science.gov (United States)

    Lalremruata, Albert; Magris, Magda; Vivas-Martínez, Sarai; Koehler, Maike; Esen, Meral; Kempaiah, Prakasha; Jeyaraj, Sankarganesh; Perkins, Douglas Jay; Mordmüller, Benjamin; Metzger, Wolfram G

    2015-09-01

    The quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now. We investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing. Based on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys. This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts.

  14. A systematic review of the clinical presentation, treatment and relapse characteristics of human Plasmodium ovale malaria.

    Science.gov (United States)

    Groger, Mirjam; Fischer, Hannah S; Veletzky, Luzia; Lalremruata, Albert; Ramharter, Michael

    2017-03-11

    Despite increased efforts to control and ultimately eradicate human malaria, Plasmodium ovale malaria is for the most part outside the focus of research or public health programmes. Importantly, the understanding of P. ovale-nowadays regarded as the two distinct species P. ovale wallikeri and P. ovale curtisi-largely stems from case reports and case series lacking study designs providing high quality evidence. Consecutively, there is a lack of systematic evaluation of the clinical presentation, appropriate treatment and relapse characteristics of P. ovale malaria. The aim of this systematic review is to provide a systematic appraisal of the current evidence for severe manifestations, relapse characteristics and treatment options for human P. ovale malaria. This systematic review was performed according to the PRISMA guidelines and registered in the international prospective register for systematic reviews (PROSPERO 2016:CRD42016039214). P. ovale mono-infection was a strict inclusion criterion. Of 3454 articles identified by the literature search, 33 articles published between 1922 and 2015 met the inclusion criteria. These articles did not include randomized controlled trials. Five prospective uncontrolled clinical trials were performed on a total of 58 participants. P. ovale was sensitive to all tested drugs within the follow-up periods and on interpretable in vitro assays. Since its first description in 1922, only 18 relapsing cases of P. ovale with a total of 28 relapse events were identified in the scientific literature. There was however no molecular evidence for a causal relationship between dormant liver stages and subsequent relapses. A total of 22 severe cases of P. ovale malaria were published out of which five were fatal. Additionally, two cases of congenital P. ovale malaria were reported. Current knowledge of P. ovale malaria is based on small trials with minor impact, case reports and clinical observations. This systematic review highlights that P

  15. Pharmacology of human experimental anxiety

    Directory of Open Access Journals (Sweden)

    F.G. Graeff

    2003-04-01

    Full Text Available This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

  16. Serum urea and creatinine levels in Nigerian human malaria patients

    African Journals Online (AJOL)

    Serum urea and creatinine levels were determined in malaria patients infected with P. falciparum. Serum urea levels decreased significantly (P<0.05) in both mild (4.10 ±1.10 mmol/L) and moderate (4.40 ±1.40 mmol/L) parasitaemia when compared to control subjects (5.50 ±1.40 mmol/L). On the other hand, serum ...

  17. Cytometric quantification of singlet oxygen in the human malaria parasite Plasmodium falciparum

    NARCIS (Netherlands)

    Butzloff, Sabine; Groves, Matthew R; Wrenger, Carsten; Müller, Ingrid B

    The malaria parasite Plasmodium falciparum proliferates within human erythrocytes and is thereby exposed to a variety of reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyl radical, superoxide anion, and highly reactive singlet oxygen ((1)O(2)). While most ROS are already well studied

  18. Immune activation and induction of memory: lessons learned from controlled human malaria infection with Plasmodium falciparum

    NARCIS (Netherlands)

    Scholzen, A.; Sauerwein, R.W.

    2016-01-01

    Controlled human malaria infections (CHMIs) are a powerful tool to assess the efficacy of drugs and/or vaccine candidates, but also to study anti-malarial immune responses at well-defined time points after infection. In this review, we discuss the insights that CHMI trials have provided into early

  19. The human malaria parasite Pfs47 gene mediates evasion of the mosquito immune system

    NARCIS (Netherlands)

    Molina-Cruz, A.; Garver, L.S.; Alabaster, A.; Bangiolo, L.; Haile, A.; Winikor, J.; Ortega, C.; Schaijk, B.C.L. van; Sauerwein, R.W.; Taylor-Salmon, E.; Barillas-Mury, C.

    2013-01-01

    Plasmodium falciparum transmission by Anopheles gambiae mosquitoes is remarkably efficient, resulting in a very high prevalence of human malaria infection in sub-Saharan Africa. A combination of genetic mapping, linkage group selection, and functional genomics was used to identify Pfs47 as a P.

  20. Human Plasmodium knowlesi infection detected by rapid diagnostic tests for malaria

    NARCIS (Netherlands)

    J.J. van Hellemond (Jaap); M. Rutten (Martine); R. Koelewijn (Rob); A.M. Zeeman (Anne Marie); J. Verweij (Jaap); P.J. Wismans (Pieter); C.H. Kocken (Clemens); P.J.J. van Genderen (Perry)

    2009-01-01

    textabstractWe describe a PCR-confirmed case of Plasmodium knowlesi infection with a high parasitemia level and clinical signs of severe malaria in a migrant worker from Malaysian Borneo in the Netherlands. Investigations showed that commercially available rapid antigen tests for detection of human

  1. NF135.C10: a new Plasmodium falciparum clone for controlled human malaria infections

    NARCIS (Netherlands)

    Teirlinck, A.C.; Roestenberg, M.; Vegte-Bolmer, M.G. van de; Scholzen, A.; Heinrichs, M.J.; Siebelink-Stoter, R.; Graumans, W.; Gemert, G.J.A. van; Teelen, K.A.E.M.; Vos, M.W.; Nganou Makamdop, C.K.; Borrmann, S.; Rozier, Y.P.; Erkens, M.A.; Luty, A.J.F.; Hermsen, C.C.; Sim, B.K.; Lieshout, L. van; Hoffman, S.L.; Visser, L.G.; Sauerwein, R.W.

    2013-01-01

    We established a new field clone of Plasmodium falciparum for use in controlled human malaria infections and vaccine studies to complement the current small portfolio of P. falciparum strains, primarily based on NF54. The Cambodian clone NF135.C10 consistently produced gametocytes and generated

  2. Artemisinin-based combination therapy does not measurably reduce human infectiousness to vectors in a setting of intense malaria transmission

    NARCIS (Netherlands)

    Huho, Bernadette J.; Killeen, Gerard F.; Ferguson, Heather M.; Tami, Adriana; Lengeler, Christian; Charlwood, J. Derek; Kihonda, Aniset; Kihonda, Japhet; Kachur, S. Patrick; Smith, Thomas A.; Abdulla, Salim M. K.

    2012-01-01

    Background: Artemisinin-based combination therapy (ACT) for treating malaria has activity against immature gametocytes. In theory, this property may complement the effect of terminating otherwise lengthy malaria infections and reducing the parasite reservoir in the human population that can infect

  3. Impact of Sickle Cell Trait and Naturally Acquired Immunity on Uncomplicated Malaria after Controlled Human Malaria Infection in Adults in Gabon.

    Science.gov (United States)

    Lell, Bertrand; Mordmüller, Benjamin; Dejon Agobe, Jean-Claude; Honkpehedji, Josiane; Zinsou, Jeannot; Mengue, Juliana Boex; Loembe, Marguerite Massinga; Adegnika, Ayola Akim; Held, Jana; Lalremruata, Albert; Nguyen, The Trong; Esen, Meral; Kc, Natasha; Ruben, Adam J; Chakravarty, Sumana; Lee Sim, B Kim; Billingsley, Peter; James, Eric; Richie, Thomas L; Hoffman, Stephen L; Kremsner, Peter G

    2017-12-18

    Controlled human malaria infection (CHMI) by direct venous inoculation (DVI) with 3,200 cryopreserved Plasmodium falciparum sporozoites (PfSPZ) consistently leads to parasitemia and malaria symptoms in malaria-naive adults. We used CHMI by DVI to investigate infection rates, parasite kinetics, and malaria symptoms in lifelong malaria-exposed (semi-immune) Gabonese adults with and without sickle cell trait. Eleven semi-immune Gabonese with normal hemoglobin (IA), nine with sickle cell trait (IS), and five nonimmune European controls with normal hemoglobin (NI) received 3,200 PfSPZ by DVI and were followed 28 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction (qPCR) and for malaria symptoms. End points were time to parasitemia and parasitemia plus symptoms. PfSPZ Challenge was well tolerated and safe. Five of the five (100%) NI, 7/11 (64%) IA, and 5/9 (56%) IS volunteers developed parasitemia by TBS, and 5/5 (100%) NI, 9/11 (82%) IA, and 7/9 (78%) IS by qPCR, respectively. The time to parasitemia by TBS was longer in IA (geometric mean 16.9 days) and IS (19.1 days) than in NA (12.6 days) volunteers (P = 0.016, 0.021, respectively). Five of the five, 6/9, and 1/7 volunteers with parasitemia developed symptoms (P = 0.003, NI versus IS). Naturally acquired immunity (NAI) to malaria significantly prolonged the time to parasitemia. Sickle cell trait seemed to prolong it further. NAI plus sickle cell trait, but not NAI alone, significantly reduced symptom rate. Twenty percent (4/20) semi-immunes demonstrated sterile protective immunity. Standardized CHMI with PfSPZ Challenge is a powerful tool for dissecting the impact of innate and naturally acquired adaptive immunity on malaria.

  4. Experimental, therapeutic and natural transmission of Plasmodium vivax tertian malaria: scientific and anecdotal data on the history of Dutch malaria studies.

    Science.gov (United States)

    Verhave, Jan Peter

    2013-01-18

    When Plasmodium vivax tertian malaria was prevalent in The Netherlands, the use of therapeutic malaria for the treatment of neurosyphilis patients presented an opportunity for biological studies of the parasite's behaviour, in healthy volunteers. One unexplained phenomenon was the long latency between natural exposure to a single infected mosquito and the appearance of clinical signs (average 8 months). Dutch studies with volunteers and syphilis patients, suggested that hundreds of sporozoites transmitted by several mosquito bites were enough to provoke an early attack, known from tropical vivax-malaria. Sporozoites appeared to be programmed either to delay their pre-erythrocytic development or to proceed to an early attack within three weeks. The number of infectious bites also determined the relapse rate and the number of relapses after a primary attack. Analyses of primary cases and relapses from the previous year were used to predict the incidence for the next year. These historic findings fit well with recent studies on genotyping of blood stages during primary attacks and relapses. External factors (i.e. the milieu inside the human host) may trigger hypnozoites to reactivate, but predetermined periods of latency should also be considered.

  5. Experimental, therapeutic and natural transmission of Plasmodium vivax tertian malaria: scientific and anecdotal data on the history of Dutch malaria studies

    Directory of Open Access Journals (Sweden)

    Verhave Jan Peter

    2013-01-01

    Full Text Available Abstract When Plasmodium vivax tertian malaria was prevalent in The Netherlands, the use of therapeutic malaria for the treatment of neurosyphilis patients presented an opportunity for biological studies of the parasite’s behaviour, in healthy volunteers. One unexplained phenomenon was the long latency between natural exposure to a single infected mosquito and the appearance of clinical signs (average 8 months. Dutch studies with volunteers and syphilis patients, suggested that hundreds of sporozoites transmitted by several mosquito bites were enough to provoke an early attack, known from tropical vivax-malaria. Sporozoites appeared to be programmed either to delay their pre-erythrocytic development or to proceed to an early attack within three weeks. The number of infectious bites also determined the relapse rate and the number of relapses after a primary attack. Analyses of primary cases and relapses from the previous year were used to predict the incidence for the next year. These historic findings fit well with recent studies on genotyping of blood stages during primary attacks and relapses. External factors (i.e. the milieu inside the human host may trigger hypnozoites to reactivate, but predetermined periods of latency should also be considered.

  6. Predicting potential ranges of primary malaria vectors and malaria in northern South America based on projected changes in climate, land cover and human population.

    Science.gov (United States)

    Alimi, Temitope O; Fuller, Douglas O; Qualls, Whitney A; Herrera, Socrates V; Arevalo-Herrera, Myriam; Quinones, Martha L; Lacerda, Marcus V G; Beier, John C

    2015-08-20

    Changes in land use and land cover (LULC) as well as climate are likely to affect the geographic distribution of malaria vectors and parasites in the coming decades. At present, malaria transmission is concentrated mainly in the Amazon basin where extensive agriculture, mining, and logging activities have resulted in changes to local and regional hydrology, massive loss of forest cover, and increased contact between malaria vectors and hosts. Employing presence-only records, bioclimatic, topographic, hydrologic, LULC and human population data, we modeled the distribution of malaria and two of its dominant vectors, Anopheles darlingi, and Anopheles nuneztovari s.l. in northern South America using the species distribution modeling platform Maxent. Results from our land change modeling indicate that about 70,000 km(2) of forest land would be lost by 2050 and 78,000 km(2) by 2070 compared to 2010. The Maxent model predicted zones of relatively high habitat suitability for malaria and the vectors mainly within the Amazon and along coastlines. While areas with malaria are expected to decrease in line with current downward trends, both vectors are predicted to experience range expansions in the future. Elevation, annual precipitation and temperature were influential in all models both current and future. Human population mostly affected An. darlingi distribution while LULC changes influenced An. nuneztovari s.l. distribution. As the region tackles the challenge of malaria elimination, investigations such as this could be useful for planning and management purposes and aid in predicting and addressing potential impediments to elimination.

  7. Effect of deploying community health assistants on appropriate treatment for diarrhoea, malaria and pneumonia: quasi-experimental study in two districts of Zambia.

    Science.gov (United States)

    Biemba, Godfrey; Yeboah-Antwi, Kojo; Vosburg, Kathryn Bradford; Prust, Margaret L; Keller, Brett; Worku, Yekoyesew; Zulu, Happy; White, Emily; Hamer, Davidson H

    2016-08-01

    A critical shortage of human resources for health in Zambia remains a great challenge. In response, the Zambian Ministry of Health developed a national community health assistant (CHA) programme, aiming to create a well-trained and motivated community-based health workforce. This study assessed whether CHAs increased treatment rates for diarrhoea, confirmed malaria or pneumonia in the first programme year. This study used a quasi-experimental difference-in-difference design, comparing changes in the catchment areas of health posts with CHAs to those without. Baseline and end line household surveys were conducted to measure the proportion of children under 5 years treated for diarrhoea, malaria or pneumonia in the 2 weeks before the survey and immunisation rates and malaria rapid diagnostic test rates. We surveyed 2330 women with children under five from the intervention area and 2314 from comparison areas at baseline and end line. Treatment for diarrhoea, malaria or pneumonia increased by 18.0% (P < 0.01) and 23.5% (P < 0.01) in the intervention and comparison groups, respectively, but DID analysis was not significant (P = 0.27). The proportion of fully immunised children grew by 7.5% in the intervention, but shrank by 7.5% in the comparison group (DID: 0.14; 95% CI 0.12-0.16, P < 0.01). Although we observed no significant difference between the intervention and comparison groups in the DID estimates for the primary outcome, there were significant increases after one year in treatment for all three diseases in the intervention group from baseline to end line and in the proportion of fully immunised children. © 2016 John Wiley & Sons Ltd.

  8. Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum?

    Directory of Open Access Journals (Sweden)

    Raquel M Gonçalves

    Full Text Available BACKGROUND: The mechanisms by which humans regulate pro- and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Although Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma concentrations of seven cytokines and two soluble tumor necrosis factor (TNF-α receptors, and evaluated clinical and laboratory outcomes, in Brazilians with acute uncomplicated infections with P. vivax (n = 85, P. falciparum (n = 30, or both species (n = 12, and in 45 asymptomatic carriers of low-density P. vivax infection. Symptomatic vivax malaria patients, compared to those infected with P. falciparum or both species, had more intense paroxysms, but they had no clear association with a pro-inflammatory imbalance. To the contrary, these patients had higher levels of the regulatory cytokine interleukin (IL-10, which correlated positively with parasite density, and elevated IL-10/TNF-α, IL-10/interferon (IFN-γ, IL-10/IL-6 and sTNFRII/TNF-α ratios, compared to falciparum or mixed-species malaria patient groups. Vivax malaria patients had the highest levels of circulating soluble TNF-α receptor sTNFRII. Levels of regulatory cytokines returned to normal values 28 days after P. vivax clearance following chemotherapy. Finally, asymptomatic carriers of low P. vivax parasitemias had substantially lower levels of both inflammatory and regulatory cytokines than did patients with clinical malaria due to either species. CONCLUSIONS: Controlling fast-multiplying P. falciparum blood stages requires a strong inflammatory response to prevent fulminant infections, while reducing inflammation-related tissue damage with early regulatory cytokine responses may be a more cost-effective strategy in infections with the less virulent P. vivax parasite. The early induction

  9. Mitosis in the Human Malaria Parasite Plasmodium falciparum ▿

    Science.gov (United States)

    Gerald, Noel; Mahajan, Babita; Kumar, Sanjai

    2011-01-01

    Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa) that produce significant morbidity and mortality, mostly in developing countries. Plasmodium parasites have a complex life cycle that includes multiple stages in anopheline mosquito vectors and vertebrate hosts. During the life cycle, the parasites undergo several cycles of extreme population growth within a brief span, and this is critical for their continued transmission and a contributing factor for their pathogenesis in the host. As with other eukaryotes, successful mitosis is an essential requirement for Plasmodium reproduction; however, some aspects of Plasmodium mitosis are quite distinct and not fully understood. In this review, we will discuss the current understanding of the architecture and key events of mitosis in Plasmodium falciparum and related parasites and compare them with the traditional mitotic events described for other eukaryotes. PMID:21317311

  10. Changes in Serological Immunology Measures in UK and Kenyan Adults Post-Controlled Human Malaria Infection

    Directory of Open Access Journals (Sweden)

    Susanne Helena Hodgson

    2016-10-01

    Full Text Available Background: The timing of infection is closely determined in controlled human malaria infection (CHMI studies, and as such they provide a unique opportunity to dissect changes in immunological responses before and after a single infection. The first Kenyan Challenge Study (KCS (Pan African Clinical Trial Registry: PACTR20121100033272 was performed in 2013 with the aim of establishing the CHMI model in Kenya. This study used aseptic, cryopreserved, attenuated Plasmodium falciparum sporozoites administered by needle and syringe and was the first to evaluate parasite dynamics post-CHMI in individuals with varying degrees of prior exposure to malaria. Methods: We describe detailed serological and functional immunological responses pre- and post-CHMI for participants in the KCS and compare these with those from malaria-naïve UK volunteers who also underwent CHMI (VAC049 (ClinicalTrials.gov NCT01465048 using PfSPZ Challenge. We assessed antibody responses to three key blood-stage merozoite antigens (merozoite surface protein 1 (MSP1, apical membrane protein 1 (AMA1 and reticulocyte-binding protein homolog 5 (RH5 and functional activity using two candidate measures of anti-merozoite immunity; the growth inhibition activity (GIA assay and the antibody-dependent respiratory burst activity (ADRB assay. Results: Clear serological differences were observed pre- and post-CHMI by ELISA between malaria-naïve UK volunteers in VAC049, and Kenyan volunteers who had prior malaria exposure. Antibodies to AMA1 and schizont extract correlated with parasite multiplication rate (PMR post-CHMI in KCS. Serum from volunteer 110 in KCS, who demonstrated a dramatically reduced PMR in vivo, had no in vitro GIA prior to CHMI but the highest level of ADRB activity. A significant difference in ADRB activity was seen between KCS volunteers with minimal and definite prior exposure to malaria and significant increases were seen in ADRB activity post-CHMI in Kenyan volunteers

  11. Converging Human and Malaria Vector Diagnostics with Data Management towards an Integrated Holistic One Health Approach.

    Science.gov (United States)

    Mitsakakis, Konstantinos; Hin, Sebastian; Müller, Pie; Wipf, Nadja; Thomsen, Edward; Coleman, Michael; Zengerle, Roland; Vontas, John; Mavridis, Konstantinos

    2018-02-03

    Monitoring malaria prevalence in humans, as well as vector populations, for the presence of Plasmodium , is an integral component of effective malaria control, and eventually, elimination. In the field of human diagnostics, a major challenge is the ability to define, precisely, the causative agent of fever, thereby differentiating among several candidate (also non-malaria) febrile diseases. This requires genetic-based pathogen identification and multiplexed analysis, which, in combination, are hardly provided by the current gold standard diagnostic tools. In the field of vectors, an essential component of control programs is the detection of Plasmodium species within its mosquito vectors, particularly in the salivary glands, where the infective sporozoites reside. In addition, the identification of species composition and insecticide resistance alleles within vector populations is a primary task in routine monitoring activities, aiming to support control efforts. In this context, the use of converging diagnostics is highly desirable for providing comprehensive information, including differential fever diagnosis in humans, and mosquito species composition, infection status, and resistance to insecticides of vectors. Nevertheless, the two fields of human diagnostics and vector control are rarely combined, both at the diagnostic and at the data management end, resulting in fragmented data and mis- or non-communication between various stakeholders. To this direction, molecular technologies, their integration in automated platforms, and the co-assessment of data from multiple diagnostic sources through information and communication technologies are possible pathways towards a unified human vector approach.

  12. Re-imagining malaria: heterogeneity of human and mosquito behaviour in relation to residual malaria transmission in Cambodia

    NARCIS (Netherlands)

    Gryseels, C.; Durnez, L.; Gerrets, R.; Uk, S.; Suon, S.; Set, S.; Phoeuk, P.; Sluydts, V.; Heng, S.; Sochantha, T.; Coosemans, M.; Peeters Grietens, K.

    2015-01-01

    Background: In certain regions in Southeast Asia, where malaria is reduced to forested regions populated by ethnic minorities dependent on slash-and-burn agriculture, malaria vector populations have developed a propensity to feed early and outdoors, limiting the effectiveness of long-lasting

  13. Effect of acute Plasmodium falciparum malaria on reactivation and shedding of the eight human herpes viruses.

    Directory of Open Access Journals (Sweden)

    Arnaud Chêne

    Full Text Available Human herpes viruses (HHVs are widely distributed pathogens. In immuno-competent individuals their clinical outcomes are generally benign but in immuno-compromised hosts, primary infection or extensive viral reactivation can lead to critical diseases. Plasmodium falciparum malaria profoundly affects the host immune system. In this retrospective study, we evaluated the direct effect of acute P. falciparum infection on reactivation and shedding of all known human herpes viruses (HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8. We monitored their presence by real time PCR in plasma and saliva of Ugandan children with malaria at the day of admission to the hospital (day-0 and 14 days later (after treatment, or in children with mild infections unrelated to malaria. For each child screened in this study, at least one type of HHV was detected in the saliva. HHV-7 and HHV-6 were detected in more than 70% of the samples and CMV in approximately half. HSV-1, HSV-2, VZV and HHV-8 were detected at lower frequency. During salivary shedding the highest mean viral load was observed for HSV-1 followed by EBV, HHV-7, HHV-6, CMV and HHV-8. After anti-malarial treatment the salivary HSV-1 levels were profoundly diminished or totally cleared. Similarly, four children with malaria had high levels of circulating EBV at day-0, levels that were cleared after anti-malarial treatment confirming the association between P. falciparum infection and EBV reactivation. This study shows that acute P. falciparum infection can contribute to EBV reactivation in the blood and HSV-1 reactivation in the oral cavity. Taken together our results call for further studies investigating the potential clinical implications of HHVs reactivation in children suffering from malaria.

  14. The interaction between malaria and human immunodeficiency virus infection in severely anaemic Malawian children: a prospective longitudinal study.

    Science.gov (United States)

    Kyeyune, Francis X; Calis, Job C J; Phiri, Kamija S; Faragher, Brian; Kachala, David; Brabin, Bernard J; van Hensbroek, Michaël Boele

    2014-06-01

    Malaria and human immunodeficiency virus (HIV) infection are co-prevalent in sub-Saharan Africa and cause severe anaemia in children. Interactions between these infections occur in adults, although these are less clear in children. The aim of study was to determine their interaction in a cohort of severely anaemic children. Severely anaemic Malawian children were enrolled, tested for HIV and malaria, transfused and followed for 18 months for malaria incidence. Antiretrovirals were not widely available in Malawi during the study period. Of 381 children (haemoglobin <5 g/dl), 357 consented for HIV testing, 12.6% were HIV-infected, and 59.5% had malaria parasitaemia. At enrolment, HIV-infected children had similar malaria parasitaemia prevalence (59.1% vs. 58.7%; P = 0.96) and parasite density (geometric mean [parasites/μl] 6903 vs. 12417; P = 0.18) as HIV-negative children. There were no differences in mean CD4%, or prevalence of severe immunosuppression, between those with and without malaria parasitaemia. Plasma viral load correlated negatively with log parasitaemia (r = -0.78; P = 0.01). During follow-up, HIV-infected children did not experience more frequent parasitaemias or symptomatic malaria episodes. Adjusted risk estimates (95% CI) for malaria parasitaemia in HIV-infected children at 6 and 18 months follow-up were 0.39 (0.13-1.14) and 0.40 (0.11-1.51), respectively. Severely anaemic HIV-infected children showed no increased susceptibility to asymptomatic or symptomatic malaria during or following their anaemic episode, although all experienced lower parasite prevalence during follow-up. This contrasts with data in adults and may relate to the malaria immunity of young children which is insufficiently developed to be impaired by HIV. The negative correlation between viral load and malaria parasitaemia remains unexplained. © 2014 John Wiley & Sons Ltd.

  15. EDITORIAL MALARIA DIAGNOSIS Malaria remains the most ...

    African Journals Online (AJOL)

    hi-tech

    2005-03-02

    Mar 2, 2005 ... Malaria remains the most significant parasitic disease affecting man. Prompt and accurate diagnosis of malaria is the key to cost effective management (1). Since the identification of Plasmodium parasites in human blood in 1880, the diagnosis of malaria has remained a hot bed of scientific discussion.

  16. Contribution of Plasmodium knowlesi to Multispecies Human Malaria Infections in North Sumatera, Indonesia.

    Science.gov (United States)

    Lubis, Inke N D; Wijaya, Hendri; Lubis, Munar; Lubis, Chairuddin P; Divis, Paul C S; Beshir, Khalid B; Sutherland, Colin J

    2017-04-01

    As Indonesia works toward the goal of malaria elimination, information is lacking on malaria epidemiology from some western provinces. As a basis for studies of antimalarial efficacy, we set out to survey parasite carriage in 3 communities in North Sumatera Province. A combination of active and passive detection of infection was carried out among communities in Batubara, Langkat, and South Nias regencies. Finger-prick blood samples from consenting individuals of all ages provided blood films for microscopic examination and blood spots on filter paper. Plasmodium species were identified using nested polymerase chain reaction (PCR) of ribosomal RNA genes and a novel assay that amplifies a conserved sequence specific for the sicavar gene family of Plasmodium knowlesi. Of 3731 participants, 614 (16.5%) were positive for malaria parasites by microscopy. PCR detected parasite DNA in samples from 1169 individuals (31.3%). In total, 377 participants (11.8%) harbored P. knowlesi. Also present were Plasmodium vivax (14.3%), Plasmodium falciparum (10.5%) and Plasmodium malariae (3.4%). Amplification of sicavar is a specific and sensitive test for the presence of P. knowlesi DNA in humans. Subpatent and asymptomatic multispecies parasitemia is relatively common in North Sumatera, so PCR-based surveillance is required to support control and elimination activities.

  17. A study on the pathogenesis of human cerebral malaria and cerebral babesiosis

    Directory of Open Access Journals (Sweden)

    Masamichi Aikawa

    1992-01-01

    Full Text Available Cerebral complications are important, but poorly understood pathological features of infections caused by some species of Plasmodium and Babesia. Patients dying from P. falciparum were classified as cerebral or non-cerebral cases according to the cerebral malaria coma scale. Light microscopy revealed that cerebral microvessels of cerebral malaria patients were field with a mixture of parazited and unparazited erythrocytes, with 94% of the vessels showing parasitized red blood cell (PRBC sequestration. Some degree of PRBC sequestration was also found in non-cerebral malaria patients, but the percentage of microvessls with sequestered PRBC was only 13% Electron microscopy demonstrated knobs on the membrane of PRBC that formed focal junctions with the capillary endothelium. A number of host cell molecules such as CD36, thrombospondim (TSP and intracellular adhesion molecule I (ICAM-1 may function as endothelial cell surfacereports for P. falciparum-infected erythrocytes. Affinity labeling of CD36 and TSP to the PRBC surface showed these molecules specifically bind to the knobs. Babesia bovis infected erythrocytes procedure projections of the erythrocyte membrane that are similar to knobs. When brain tissue from B. bovis-infected cattle was examined, cerebral capillaries were packed with PRBC. Infected erythrocytes formed focal attachments with cerebral endothelial cells at the site of these knob-like projections. These findings indicate that cerebral pathology caused by B. bovis is similar to human cerebral malaria. A search for cytoadherence proteins in the endothelial cells may lead to a better understanding of the pathogenisis of cerebral babesiosis.

  18. Host-Parasite Interactions in Human Malaria: Clinical Implications of Basic Research.

    Science.gov (United States)

    Acharya, Pragyan; Garg, Manika; Kumar, Praveen; Munjal, Akshay; Raja, K D

    2017-01-01

    The malaria parasite, Plasmodium, is one of the oldest parasites documented to infect humans and has proven particularly hard to eradicate. One of the major hurdles in designing an effective subunit vaccine against the malaria parasite is the insufficient understanding of host-parasite interactions within the human host during infections. The success of the parasite lies in its ability to evade the human immune system and recruit host responses as physiological cues to regulate its life cycle, leading to rapid acclimatization of the parasite to its immediate host environment. Hence understanding the environmental niche of the parasite is crucial in developing strategies to combat this deadly infectious disease. It has been increasingly recognized that interactions between parasite proteins and host factors are essential to establishing infection and virulence at every stage of the parasite life cycle. This review reassesses all of these interactions and discusses their clinical importance in designing therapeutic approaches such as design of novel vaccines. The interactions have been followed from the initial stages of introduction of the parasite under the human dermis until asexual and sexual blood stages which are essential for transmission of malaria. We further classify the interactions as "direct" or "indirect" depending upon their demonstrated ability to mediate direct physical interactions of the parasite with host factors or their indirect manipulation of the host immune system since both forms of interactions are known to have a crucial role during infections. We also discuss the many ways in which this understanding has been taken to the field and the success of these strategies in controlling human malaria.

  19. Real-time imaging reveals the dynamics of leukocyte behaviour during experimental cerebral malaria pathogenesis.

    Directory of Open Access Journals (Sweden)

    Saparna Pai

    2014-07-01

    Full Text Available During experimental cerebral malaria (ECM mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. The precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. We developed a 2-photon intravital microscopy (2P-IVM-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ECM. Ly6C(hi monocytes, but not neutrophils, started to accumulate in the blood vessels of Plasmodium berghei ANKA (PbA-infected MacGreen mice, in which myeloid cells express GFP, one to two days prior to the onset of the neurological signs (NS. A decrease in the rolling speed of monocytes, a measure of endothelial cell activation, was associated with progressive worsening of clinical symptoms. Adoptive transfer experiments with defined immune cell subsets in recombinase activating gene (RAG-1-deficient mice showed that these changes were mediated by Plasmodium-specific CD8(+ T lymphocytes. A critical number of CD8(+ T effectors was required to induce disease and monocyte adherence to the vasculature. Depletion of monocytes at the onset of disease symptoms resulted in decreased lymphocyte accumulation, suggesting reciprocal effects of monocytes and T cells on their recruitment within the brain. Together, our studies define the real-time kinetics of leukocyte behaviour in the central nervous system during ECM, and reveal a significant role for Plasmodium-specific CD8(+ T lymphocytes in regulating vascular pathology in this disease.

  20. Real-Time Imaging Reveals the Dynamics of Leukocyte Behaviour during Experimental Cerebral Malaria Pathogenesis

    Science.gov (United States)

    Pai, Saparna; Qin, Jim; Cavanagh, Lois; Mitchell, Andrew; El-Assaad, Fatima; Jain, Rohit; Combes, Valery; Hunt, Nicholas H.; Grau, Georges E. R.; Weninger, Wolfgang

    2014-01-01

    During experimental cerebral malaria (ECM) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. The precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. We developed a 2-photon intravital microscopy (2P-IVM)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ECM. Ly6Chi monocytes, but not neutrophils, started to accumulate in the blood vessels of Plasmodium berghei ANKA (PbA)-infected MacGreen mice, in which myeloid cells express GFP, one to two days prior to the onset of the neurological signs (NS). A decrease in the rolling speed of monocytes, a measure of endothelial cell activation, was associated with progressive worsening of clinical symptoms. Adoptive transfer experiments with defined immune cell subsets in recombinase activating gene (RAG)-1-deficient mice showed that these changes were mediated by Plasmodium-specific CD8+ T lymphocytes. A critical number of CD8+ T effectors was required to induce disease and monocyte adherence to the vasculature. Depletion of monocytes at the onset of disease symptoms resulted in decreased lymphocyte accumulation, suggesting reciprocal effects of monocytes and T cells on their recruitment within the brain. Together, our studies define the real-time kinetics of leukocyte behaviour in the central nervous system during ECM, and reveal a significant role for Plasmodium-specific CD8+ T lymphocytes in regulating vascular pathology in this disease. PMID:25033406

  1. Phosphatidylinositol 3-Kinase γ is required for the development of experimental cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Norinne Lacerda-Queiroz

    Full Text Available Experimental cerebral malaria (ECM is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase γ (PI3Kγ is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ-/- and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA infection. Infected PI3Kγ-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kγ-/- mice. PI3Kγ deficiency also presented lower microglial activation (Iba-1+ reactive microglia and T cell cytotoxicity (Granzyme B expression in the brain. Additionally, on day 6 post-infection, CD3+CD8+ T cells were significantly reduced in the brain of infected PI3Kγ-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Kγ-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM.

  2. Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

    Science.gov (United States)

    Nacer, Adéla; Movila, Alexandru; Sohet, Fabien; Girgis, Natasha M.; Gundra, Uma Mahesh; Loke, P'ng; Daneman, Richard; Frevert, Ute

    2014-01-01

    Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8+ T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45hi CD8+ T cells, ICAM-1+ macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8+ T cells and ICAM+ macrophages, causes a severe restriction in

  3. Efficacy of Proveblue (Methylene Blue) in an Experimental Cerebral Malaria Murine Model

    OpenAIRE

    Dormoi, Jérome; Briolant, Sébastien; Desgrouas, Camille; Pradines, Bruno

    2013-01-01

    Although 100% of untreated mice infected with Plasmodium berghei died with specific signs of cerebral malaria and 100% of mice treated with 3 mg/kg dihydroartemisinin, the active metabolite of artesunate, which is used as the first-line treatment for severe malaria, also died but showed no specific signs of cerebral malaria, 78% of mice treated with 10 mg/kg Proveblue (methylene blue) and 78% of mice treated with a combination of 3 mg dihydroartemisinin and 10 mg/kg Proveblue survived and sho...

  4. Cloning, sequence and expression of the lactate dehydrogenase gene from the human malaria parasite, Plasmodium vivax.

    Science.gov (United States)

    Turgut-Balik, Dilek; Akbulut, Ekrem; Shoemark, Debbie K; Celik, Venhar; Moreton, Kathleen M; Sessions, Richard B; Holbrook, J John; Brady, R Leo

    2004-07-01

    Increased drug resistance to anti-malarials highlights the need for the development of new therapeutics for the treatment of malaria. To this end, the lactate dehydrogenase (LDH) gene was cloned and sequenced from genomic DNA of Plasmodium vivax ( PvLDH) Belem strain. The 316 amino acid protein-coding region of the PvLDH gene was inserted into the prokaryotic expression vector pKK223-3 and a 34 kDa protein with LDH activity was expressed in E. coli. Structural differences between human LDHs and PfLDH make the latter an attractive target for inhibitors leading to novel anti-malarial drugs. The sequence similarity between PvLDH and PfLDH (90% residue identity and no insertions or deletions) indicate that the same approach could be applied to Plasmodium vivax, the most common human malaria parasite in the world.

  5. Plasmodium berghei ANKA: erythropoietin activates neural stem cells in an experimental cerebral malaria model

    DEFF Research Database (Denmark)

    Core, Andrew; Hempel, Casper; Kurtzhals, Jørgen A L

    2011-01-01

    Cerebral malaria (CM) causes substantial mortality and neurological sequelae in survivors, and no neuroprotective regimens are currently available for this condition. Erythropoietin (EPO) reduces neuropathology and improves survival in murine CM. Using the Plasmodium berghei model of CM, we...

  6. Differential microRNA expression in experimental cerebral and noncerebral malaria

    DEFF Research Database (Denmark)

    El-Assaad, Fatima; Hempel, Casper; Combes, Valéry

    2011-01-01

    berghei ANKA (PbA), which causes cerebral malaria (CM), or Plasmodium berghei K173 (PbK), which causes severe malaria but without cerebral complications, termed non-CM. The differential expression profiles of selected miRNAs (let-7i, miR-27a, miR-150, miR-126, miR-210, and miR-155) were analyzed in mouse...... acute malaria. To investigate the involvement of let-7i, miR-27a, and miR-150 in CM-resistant mice, we assessed the expression levels in gamma interferon knockout (IFN-¿(-/-)) mice on a C57BL/6 genetic background. The expression of let-7i, miR-27a, and miR-150 was unchanged in both wild-type (WT...... a regulatory role in the pathogenesis of severe malaria....

  7. Malarial pathocoenosis: beneficial and deleterious interactions between malaria and other human diseases

    Directory of Open Access Journals (Sweden)

    Eric eFaure

    2014-11-01

    Full Text Available In nature, organisms are commonly infected by an assemblage of different parasite species or by genetically distinct parasite strains that interact in complex ways. Linked to co-infections, pathocoenosis, a term proposed by M. Grmek in 1969, refers to a pathological state arising from the interactions of diseases within a population and to the temporal and spatial dynamics of all of the diseases. In the long run, malaria was certainly one of the most important component of past pathocoenoses. Today this disease, which affects hundreds of millions of individuals and results in approximately one million deaths each year, is always highly endemic in over 20% of the world and is thus co-endemic with many other diseases. Therefore, the incidences of co-infections and possible direct and indirect interactions with Plasmodium parasites are very high. Both positive and negative interactions between malaria and other diseases caused by parasites belonging to numerous taxa have been described and in some cases, malaria may modify the process of another disease without being affected itself. Interactions include those observed during voluntary malarial infections intended to cure neuro-syphilis or during the enhanced activations of bacterial gastro-intestinal diseases and HIV infections. Complex relationships with multiple effects should also be considered, such as those observed during helminth infections. Moreover, reports dating back over 2000 years suggested that co- and multiple infections have generally deleterious consequences and analyses of historical texts indicated that malaria might exacerbate both plague and cholera, among other diseases. Possible biases affecting the research of etiological agents caused by the protean manifestations of malaria are discussed. A better understanding of the manner by which pathogens, particularly Plasmodium, modulate immune responses is particularly important for the diagnosis, cure and control of diseases in

  8. Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes

    KAUST Repository

    Moon, Robert

    2012-12-24

    Research into the aetiological agent of the most widespread form of severe malaria, Plasmodium falciparum, has benefitted enormously from the ability to culture and genetically manipulate blood-stage forms of the parasite in vitro. However, most malaria outside Africa is caused by a distinct Plasmodium species, Plasmodium vivax, and it has become increasingly apparent that zoonotic infection by the closely related simian parasite Plasmodium knowlesi is a frequent cause of life-threatening malaria in regions of southeast Asia. Neither of these important malarial species can be cultured in human cells in vitro, requiring access to primates with the associated ethical and practical constraints. We report the successful adaptation of P. knowlesi to continuous culture in human erythrocytes. Human-adapted P. knowlesi clones maintain their capacity to replicate in monkey erythrocytes and can be genetically modified with unprecedented efficiency, providing an important and unique model for studying conserved aspects of malarial biology as well as species-specific features of an emerging pathogen.

  9. Attributing Climate Conditions for Stable Malaria Transmission to Human Activity in sub-Saharan Africa

    Science.gov (United States)

    Sheldrake, L.; Mitchell, D.; Allen, M. R.

    2015-12-01

    Temperature and precipitation limit areas of stable malaria transmission, but the effects of climate change on the disease remain controversial. Previously, studies have not separated the influence of anthropogenic climate change and natural variability, despite being an essential step in the attribution of climate change impacts. Ensembles of 2900 simulations of regional climate in sub-Saharan Africa for the year 2013, one representing realistic conditions and the other how climate might have been in the absence of human influence, were used to force a P.falciparium climate suitability model developed by the Mapping Malaria Risk in Africa project. Strongest signals were detected in areas of unstable transmission, indicating their heightened sensitivity to climatic factors. Evidently, impacts of human-induced climate change were unevenly distributed: the probability of conditions being suitable for stable malaria transmission were substantially reduced (increased) in the Sahel (Greater Horn of Africa (GHOA), particularly in the Ethiopian and Kenyan highlands). The length of the transmission season was correspondingly shortened in the Sahel and extended in the GHOA, by 1 to 2 months, including in Kericho (Kenya), where the role of climate change in driving recent malaria occurrence is hotly contested. Human-induced warming was primarily responsible for positive anomalies in the GHOA, while reduced rainfall caused negative anomalies in the Sahel. The latter was associated with anthropogenic impacts on the West African Monsoon, but uncertainty in the RCM's ability to reproduce precipitation trends in the region weakens confidence in the result. That said, outputs correspond well with broad-scale changes in observed endemicity, implying a potentially important contribution of anthropogenic climate change to the malaria burden during the past century. Results support the health-framing of climate risk and help indicate hotspots of climate vulnerability, providing

  10. Experimental rabies vaccines for humans

    Science.gov (United States)

    McGettigan, James P

    2011-01-01

    Rabies remains a global public health threat that kills more than 55,000 people per year. Rabies disproportionately affects children and, therefore, is ranked the seventh most important infectious disease due to years lost. Prevention of human rabies is accomplished by controlling rabies in domestic and wild animals, including the use of vaccination programs. The usefulness of human rabies vaccines is hampered by high cost, complicated vaccination regimens and lack of compliance, especially in areas of Africa and Asia where human rabies infections are endemic. A single-dose vaccine would greatly benefit efforts to combat this global health threat. However, a single-dose vaccine based on current inactivated vaccines does not appear feasible and other approaches are needed. Technology has advanced since modern human rabies vaccines were developed over 40 years ago. In addition, our understanding of immunological principles that influence the outcome of vaccination has increased. This article describes the current status of inactivated rabies virus vaccines and recent developments arising from the use of reverse genetics technologies designed to develop replication-deficient or single-cycle live rabies virus-based vectors for use as a single-dose rabies vaccine for humans. PMID:20923268

  11. Proteins involved in invasion of human red blood cells by malaria parasites

    Directory of Open Access Journals (Sweden)

    Ewa Jaśkiewicz

    2010-11-01

    Full Text Available Malaria is a disease caused by parasites of Plasmodium species. It is responsible for around 1-2 million deaths annually, mainly children under the age of 5. It occurs mainly in tropical and subtropical areas.Malaria is caused by five Plasmodium species:[i] P. falciparum, P. malariae, P. vivax, P. knowlesi[/i] and [i]P. ovale[/i]. Mosquitoes spread the disease by biting humans. The malaria parasite has two stages of development: the human stage and the mosquito stage. The first stage occurs in the human body and is divided into two phases: the liver phase and the blood phase.The invasion of erythrocytes by [i]Plasmodium[/i] merozoites is a multistep process of specific protein interactions between the parasite and red blood cell. The first step is the reversible merozoite attachment to the erythrocyte followed by its apical reorientation, then formation of an irreversible “tight” junction and finally entry into the red cell in a parasitophorous vacuole.The blood phase is supported by a number of proteins produced by the parasite. The merozoite surface GPI-anchored proteins (MSP-1, 2, 4, 5, 8 and 10 assist in the process of recognition of susceptible erythrocytes, apical membrane antigen (AMA-1 may be directly responsible for apical reorientation of the merozoite and apical proteins which function in tight junction formation. These ligands are members of two families: Duffy binding-like (DBL and reticulocyte binding-like (RBL proteins. In [i]Plasmodium[/i] [i]falciparum[/i] the DBL family includes: EBA-175, EBA-140 (BAEBL, EBA-181 (JESEBL, EBA-165 (PEBL and EBL-1 ligands.To date, no effective antimalarial vaccine has been developed, but there are several studies for this purpose. Therefore, it is crucial to understand the molecular basis of host cells invasion by parasites. Major efforts are focused on developing a multiantigenic and multiepitope vaccine preventing all steps of [i]Plasmodium[/i] invasion.

  12. [Proteins involved in invasion of human red blood cells by malaria parasites].

    Science.gov (United States)

    Jaśkiewicz, Ewa; Graczyk, Jakub; Rydzak, Joanna

    2010-11-30

    Malaria is a disease caused by parasites of Plasmodium species. It is responsible for around 1-2 million deaths annually, mainly children under the age of 5. It occurs mainly in tropical and subtropical areas. Malaria is caused by five Plasmodium species: P. falciparum, P. malariae, P. vivax, P. knowlesi and P. ovale. Mosquitoes spread the disease by biting humans. The malaria parasite has two stages of development: the human stage and the mosquito stage. The first stage occurs in the human body and is divided into two phases: the liver phase and the blood phase. The invasion of erythrocytes by Plasmodium merozoites is a multistep process of specific protein interactions between the parasite and red blood cell. The first step is the reversible merozoite attachment to the erythrocyte followed by its apical reorientation, then formation of an irreversible "tight" junction and finally entry into the red cell in a parasitophorous vacuole. The blood phase is supported by a number of proteins produced by the parasite. The merozoite surface GPI-anchored proteins (MSP-1, 2, 4, 5, 8 and 10) assist in the process of recognition of susceptible erythrocytes, apical membrane antigen (AMA-1) may be directly responsible for apical reorientation of the merozoite and apical proteins which function in tight junction formation. These ligands are members of two families: Duffy binding-like (DBL) and reticulocyte binding-like (RBL) proteins. In Plasmodium falciparum the DBL family includes: EBA-175, EBA-140 (BAEBL), EBA-181 (JESEBL), EBA-165 (PEBL) and EBL-1 ligands. To date, no effective antimalarial vaccine has been developed, but there are several studies for this purpose. Therefore, it is crucial to understand the molecular basis of host cells invasion by parasites. Major efforts are focused on developing a multiantigenic and multiepitope vaccine preventing all steps of Plasmodium invasion.

  13. Molecular Detection of Plasmodium malariae/Plasmodium brasilianum in Non-Human Primates in Captivity in Costa Rica.

    Science.gov (United States)

    Fuentes-Ramírez, Alicia; Jiménez-Soto, Mauricio; Castro, Ruth; Romero-Zuñiga, Juan José; Dolz, Gaby

    2017-01-01

    One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium using thick blood smears, semi-nested multiplex polymerase chain reaction (SnM-PCR) for species differentiation, cloning and sequencing for confirmation. Using thick blood smears, two samples were determined to contain the Plasmodium malariae parasite, with SnM-PCR, a total of five (3.3%) samples were positive to P. malariae, cloning and sequencing confirmed both smear samples as P. malariae. One sample amplified a larger and conserved region of 18S rDNA for the genus Plasmodium and sequencing confirmed the results obtained microscopically and through SnM-PCR tests. Sequencing and construction of a phylogenetic tree of this sample revealed that the P. malariae/P. brasilianum parasite (GenBank KU999995) found in a howler monkey (Alouatta palliata) is identical to that recently reported in humans in Costa Rica. The SnM-PCR detected P. malariae/P. brasilianum parasite in different non-human primate species in captivity and in various regions of the southern Atlantic and Pacific coast of Costa Rica. The similarity of the sequences of parasites found in humans and a monkey suggests that monkeys may be acting as reservoirs of P.malariae/P. brasilianum, for which reason it is important, to include them in control and eradication programs.

  14. Medical practice, human experimentation and the sanctity of human ...

    African Journals Online (AJOL)

    ... human health and the sanctity of human life. In checkmating these dangers, the paper recommends and canvasses for the adoption of the ethical principles of the Nuremberg code of 1947 in properly regulating human experimentation so as to maximize its benefits and at the same time respect the sanctity of human life.

  15. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine.

    Science.gov (United States)

    Mordmüller, Benjamin; Surat, Güzin; Lagler, Heimo; Chakravarty, Sumana; Ishizuka, Andrew S; Lalremruata, Albert; Gmeiner, Markus; Campo, Joseph J; Esen, Meral; Ruben, Adam J; Held, Jana; Calle, Carlos Lamsfus; Mengue, Juliana B; Gebru, Tamirat; Ibáñez, Javier; Sulyok, Mihály; James, Eric R; Billingsley, Peter F; Natasha, K C; Manoj, Anita; Murshedkar, Tooba; Gunasekera, Anusha; Eappen, Abraham G; Li, Tao; Stafford, Richard E; Li, Minglin; Felgner, Phil L; Seder, Robert A; Richie, Thomas L; Sim, B Kim Lee; Hoffman, Stephen L; Kremsner, Peter G

    2017-02-23

    A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine'); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge') to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 10(4) PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 10(3) (group I) or 1.28 × 10(4) (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 10(4) PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.

  16. Relative roles of weather variables and change in human population in malaria: comparison over different states of India.

    Science.gov (United States)

    Goswami, Prashant; Murty, Upadhayula Suryanarayana; Mutheneni, Srinivasa Rao; Krishnan, Swathi Trithala

    2014-01-01

    Pro-active and effective control as well as quantitative assessment of impact of climate change on malaria requires identification of the major drivers of the epidemic. Malaria depends on vector abundance which, in turn, depends on a combination of weather variables. However, there remain several gaps in our understanding and assessment of malaria in a changing climate. Most of the studies have considered weekly or even monthly mean values of weather variables, while the malaria vector is sensitive to daily variations. Secondly, rarely all the relevant meteorological variables have been considered together. An important question is the relative roles of weather variables (vector abundance) and change in host (human) population, in the change in disease load. We consider the 28 states of India, characterized by diverse climatic zones and changing population as well as complex variability in malaria, as a natural test bed. An annual vector load for each of the 28 states is defined based on the number of vector genesis days computed using daily values of temperature, rainfall and humidity from NCEP daily Reanalysis; a prediction of potential malaria load is defined by taking into consideration changes in the human population and compared with the reported number of malaria cases. For most states, the number of malaria cases is very well correlated with the vector load calculated with the combined conditions of daily values of temperature, rainfall and humidity; no single weather variable has any significant association with the observed disease prevalence. The association between vector-load and daily values of weather variables is robust and holds for different climatic regions (states of India). Thus use of all the three weather variables provides a reliable means of pro-active and efficient vector sanitation and control as well as assessment of impact of climate change on malaria.

  17. Relative roles of weather variables and change in human population in malaria: comparison over different states of India.

    Directory of Open Access Journals (Sweden)

    Prashant Goswami

    Full Text Available Pro-active and effective control as well as quantitative assessment of impact of climate change on malaria requires identification of the major drivers of the epidemic. Malaria depends on vector abundance which, in turn, depends on a combination of weather variables. However, there remain several gaps in our understanding and assessment of malaria in a changing climate. Most of the studies have considered weekly or even monthly mean values of weather variables, while the malaria vector is sensitive to daily variations. Secondly, rarely all the relevant meteorological variables have been considered together. An important question is the relative roles of weather variables (vector abundance and change in host (human population, in the change in disease load.We consider the 28 states of India, characterized by diverse climatic zones and changing population as well as complex variability in malaria, as a natural test bed. An annual vector load for each of the 28 states is defined based on the number of vector genesis days computed using daily values of temperature, rainfall and humidity from NCEP daily Reanalysis; a prediction of potential malaria load is defined by taking into consideration changes in the human population and compared with the reported number of malaria cases.For most states, the number of malaria cases is very well correlated with the vector load calculated with the combined conditions of daily values of temperature, rainfall and humidity; no single weather variable has any significant association with the observed disease prevalence.The association between vector-load and daily values of weather variables is robust and holds for different climatic regions (states of India. Thus use of all the three weather variables provides a reliable means of pro-active and efficient vector sanitation and control as well as assessment of impact of climate change on malaria.

  18. An evolutionary perspective of how infection drives human genome diversity: the case of malaria.

    Science.gov (United States)

    Mangano, Valentina D; Modiano, David

    2014-10-01

    Infection with malaria parasites has imposed a strong selective pressure on the human genome, promoting the convergent evolution of a diverse range of genetic adaptations, many of which are harboured by the red blood cell, which hosts the pathogenic stage of the Plasmodium life cycle. Recent genome-wide and multi-centre association studies of severe malaria have consistently identified ATP2B4, encoding the major Ca(2+) pump of erythrocytes, as a novel resistance locus. Evidence is also accumulating that interaction occurs among resistance loci, the most recent example being negative epistasis among alpha-thalassemia and haptoglobin type 2. Finally, studies on the effect of haemoglobin S and C on parasite transmission to mosquitoes have suggested that protective variants could increase in frequency enhancing parasite fitness. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Specific depletion of Ly6C(hi inflammatory monocytes prevents immunopathology in experimental cerebral malaria.

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    Beatrix Schumak

    Full Text Available Plasmodium berghei ANKA (PbA infection of C57BL/6 mice leads to experimental cerebral malaria (ECM that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb, we depleted in vivo Ly6C(hi inflammatory monocytes (by anti-CCR2, Ly6G+ neutrophils (by anti-Ly6G or both cell types (by anti-Gr1 during infection with Ovalbumin-transgenic PbA parasites (PbTg. Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6C(hi inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6C(hi inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes.

  20. A malaria vaccine that elicits in humans antibodies able to kill Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available BACKGROUND: Plasmodium falciparum merozoite surface protein 3 is a malaria vaccine candidate that was identified, characterised, and developed based on a unique immuno-clinical approach. The vaccine construct was derived from regions fully conserved among various strains and containing B cell epitopes targeted by human antibodies (from malaria-immune adults that are able to mediate a monocyte-dependent parasite killing effect. The corresponding long synthetic peptide was administered to 36 volunteers, with either alum or Montanide ISA720 as adjuvant. METHODS AND FINDINGS: Both formulations induced cellular and humoral immune responses. With alum, the responses lasted up to 12 mo. The vaccine-induced antibodies were predominantly of cytophilic classes, i.e., able to cooperate with effector cells. In vitro, the antibodies induced an inhibition of the P. falciparum erythrocytic growth in a monocyte-dependent manner, which was in most instances as high as or greater than that induced by natural antibodies from immune African adults. In vivo transfer of the volunteers' sera into P. falciparum-infected humanized SCID mice profoundly reduced or abrogated parasitaemia. These inhibitory effects were related to the antibody reactivity with the parasite native protein, which was seen in 60% of the volunteers, and remained in samples taken 12 mo postimmunisation. CONCLUSION: This is the first malaria vaccine clinical trial to clearly demonstrate antiparasitic activity by vaccine-induced antibodies by both in vitro and in vivo methods. The results, showing the induction of long-lasting antibodies directed to a fully conserved polypeptide, also challenge current concepts about malaria vaccines, such as unavoidable polymorphism, low antigenicity, and poor induction of immune memory.

  1. The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

    Science.gov (United States)

    Fryauff, D J; Leksana, B; Masbar, S; Wiady, I; Sismadi, P; Susanti, A I; Nagesha, H S; Syafruddin; Atmosoedjono, S; Bangs, M J; Baird, J K

    2002-07-01

    Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene

  2. Controlled Human Malaria Infections by Intradermal Injection of Cryopreserved Plasmodium falciparum Sporozoites

    Science.gov (United States)

    Roestenberg, Meta; Bijker, Else M.; Sim, B. Kim Lee; Billingsley, Peter F.; James, Eric R.; Bastiaens, Guido J. H.; Teirlinck, Anne C.; Scholzen, Anja; Teelen, Karina; Arens, Theo; van der Ven, André J. A. M.; Gunasekera, Anusha; Chakravarty, Sumana; Velmurugan, Soundarapandian; Hermsen, Cornelus C.; Sauerwein, Robert W.; Hoffman, Stephen L.

    2013-01-01

    Controlled human malaria infection with sporozoites is a standardized and powerful tool for evaluation of malaria vaccine and drug efficacy but so far only applied by exposure to bites of Plasmodium falciparum (Pf)-infected mosquitoes. We assessed in an open label Phase 1 trial, infection after intradermal injection of respectively 2,500, 10,000, or 25,000 aseptic, purified, vialed, cryopreserved Pf sporozoites (PfSPZ) in three groups (N = 6/group) of healthy Dutch volunteers. Infection was safe and parasitemia developed in 15 of 18 volunteers (84%), 5 of 6 volunteers in each group. There were no differences between groups in time until parasitemia by microscopy or quantitative polymerase chain reaction, parasite kinetics, clinical symptoms, or laboratory values. This is the first successful infection by needle and syringe with PfSPZ manufactured in compliance with regulatory standards. After further optimization, the use of such PfSPZ may facilitate and accelerate clinical development of novel malaria drugs and vaccines. PMID:23149582

  3. Analysis of Antibodies Directed against Merozoite Surface Protein 1 of the Human Malaria Parasite Plasmodium falciparum

    Science.gov (United States)

    Woehlbier, Ute; Epp, Christian; Kauth, Christian W.; Lutz, Rolf; Long, Carole A.; Coulibaly, Boubacar; Kouyaté, Bocar; Arevalo-Herrera, Myriam; Herrera, Sócrates; Bujard, Hermann

    2006-01-01

    The 190-kDa merozoite surface protein 1 (MSP-1) of Plasmodium falciparum, an essential component in the parasite's life cycle, is a primary candidate for a malaria vaccine. Rabbit antibodies elicited by the heterologously produced MSP-1 processing products p83, p30, p38, and p42, derived from strain 3D7, were analyzed for the potential to inhibit in vitro erythrocyte invasion by the parasite and parasite growth. Our data show that (i) epitopes recognized by antibodies, which inhibit parasite replication, are distributed throughout the entire MSP-1 molecule; (ii) when combined, antibodies specific for different regions of MSP-1 inhibit in a strictly additive manner; (iii) anti-MSP-1 antibodies interfere with erythrocyte invasion as well as with the intraerythrocytic growth of the parasite; and (iv) antibodies raised against MSP-1 of strain 3D7 strongly cross-inhibit replication of the heterologous strain FCB-1. Accordingly, anti-MSP-1 antibodies appear to be capable of interfering with parasite multiplication at more than one level. Since the overall immunogenicity profile of MSP-1 in rabbits closely resembles that found in sera of Aotus monkeys immunized with parasite-derived MSP-1 and of humans semi-immune to malaria from whom highly inhibiting antigen-specific antibodies were recovered, we consider the findings reported here to be relevant for the development of MSP-1-based vaccines against malaria. PMID:16428781

  4. Genetics of Sub-Saharan African Human Population: Implications for HIV/AIDS, Tuberculosis, and Malaria

    Directory of Open Access Journals (Sweden)

    Gerald Mboowa

    2014-01-01

    Full Text Available Sub-Saharan Africa has continued leading in prevalence and incidence of major infectious disease killers such as HIV/AIDS, tuberculosis, and malaria. Epidemiological triad of infectious diseases includes susceptible host, pathogen, and environment. It is imperative that all aspects of vertices of the infectious disease triad are analysed to better understand why this is so. Studies done to address this intriguing reality though have mainly addressed pathogen and environmental components of the triad. Africa is the most genetically diverse region of the world as well as being the origin of modern humans. Malaria is relatively an ancient infection in this region as compared to TB and HIV/AIDS; from the evolutionary perspective, we would draw lessons that this ancestrally unique population now under three important infectious diseases both ancient and exotic will be skewed into increased genetic diversity; moreover, other evolutionary forces are also still at play. Host genetic diversity resulting from many years of malaria infection has been well documented in this population; we are yet to account for genetic diversity from the trio of these infections. Effect of host genetics on treatment outcome has been documented. Host genetics of sub-Saharan African population and its implication to infectious diseases are an important aspect that this review seeks to address.

  5. Misdiagnosis of cerebral malaria initially as acute psychotic disorder and later as human rabies: a case report.

    Science.gov (United States)

    Mudiyanselage, Meththananda Herath Herath; Weerasinghe, Nayani Prasangika; Pathirana, Kithsiri; Dias, Hasini

    2016-08-11

    Cerebral malaria is arguably one of the most common non-traumatic encephalopathies in the developing world. Unless the diagnosis of cerebral malaria is made promptly, the consequence could be disastrous. Even though the diagnosis of cerebral malaria can be made relatively easily in majority of cases atypical presentation can often lead to misdiagnosis or delayed diagnosis. We report a case of an uncommon presentation of Plasmodium falciparum infection in a 17-year-old school girl with altered sensorium, seizures and phobic spasms. A previously healthy 17-year-old school girl was admitted to our hospital with acute condition characterised by comatose state, recurrent seizures and phobic spasms. She initially presented to a local hospital with agitation and over talkativeness and was diagnosed as having an acute psychotic state. Few days later she became drowsy and developed recurrent seizures and marked phobic spasms which prompted the treating physician to diagnose human rabies. However, further investigations carried out in our unit (including rapid antigenic test for P. falciparum and peripheral blood smear) were positive for P. falciparum. She was treated as for cerebral malaria with intravenous quinine and discharge from hospital with no residual neurological deficit. Atypical presentation of cerebral malaria can often lead to misdiagnosis. This patient presented with encephalopathic illness with phobic spasms was initially misdiagnosed as human rabies. Therefore, the physicians in malarial endemic areas should be vigilant of similar presentations and should consider cerebral malaria as a possibility.

  6. Endothelial glycocalyx on brain endothelial cells is lost in experimental cerebral malaria

    DEFF Research Database (Denmark)

    Hempel, Casper; Hyttel, Poul; Kurtzhals, Jørgen Al

    2014-01-01

    electron microscopy and measured circulating glycosaminoglycans by dot blot and ELISA. The glycocalyx was degraded in brain vasculature in cerebral and to a lesser degree uncomplicated malaria. It was affected on both intact and apoptotic endothelial cells. Circulating glycosaminoglycan levels suggested...

  7. Differential attraction of malaria mosquitoes to volatile blends produced by human skin bacteria.

    Science.gov (United States)

    Verhulst, Niels O; Andriessen, Rob; Groenhagen, Ulrike; Bukovinszkiné Kiss, Gabriella; Schulz, Stefan; Takken, Willem; van Loon, Joop J A; Schraa, Gosse; Smallegange, Renate C

    2010-12-30

    The malaria mosquito Anopheles gambiae sensu stricto is mainly guided by human odour components to find its blood host. Skin bacteria play an important role in the production of human body odour and when grown in vitro, skin bacteria produce volatiles that are attractive to A. gambiae. The role of single skin bacterial species in the production of volatiles that mediate the host-seeking behaviour of mosquitoes has remained largely unknown and is the subject of the present study. Headspace samples were taken to identify volatiles that mediate this behaviour. These volatiles could be used as mosquito attractants or repellents. Five commonly occurring species of skin bacteria were tested in an olfactometer for the production of volatiles that attract A. gambiae. Odour blends produced by some bacterial species were more attractive than blends produced by other species. In contrast to odours from the other bacterial species tested, odours produced by Pseudomonas aeruginosa were not attractive to A. gambiae. Headspace analysis of bacterial volatiles in combination with behavioural assays led to the identification of six compounds that elicited a behavioural effect in A. gambiae. Our results provide, to our knowledge, the first evidence for a role of selected bacterial species, common on the human skin, in determining the attractiveness of humans to malaria mosquitoes. This information will be used in the further development of a blend of semiochemicals for the manipulation of mosquito behaviour.

  8. Accurate identification of the six human Plasmodium spp. causing imported malaria, including Plasmodium ovale wallikeri and Plasmodium knowlesi.

    Science.gov (United States)

    Calderaro, Adriana; Piccolo, Giovanna; Gorrini, Chiara; Rossi, Sabina; Montecchini, Sara; Dell'Anna, Maria Loretana; De Conto, Flora; Medici, Maria Cristina; Chezzi, Carlo; Arcangeletti, Maria Cristina

    2013-09-13

    Accurate identification of Plasmodium infections in non-endemic countries is of critical importance with regard to the administration of a targeted therapy having a positive impact on patient health and management and allowing the prevention of the risk of re-introduction of endemic malaria in such countries. Malaria is no longer endemic in Italy where it is the most commonly imported disease, with one of the highest rates of imported malaria among European non-endemic countries including France, the UK and Germany, and with a prevalence of 24.3% at the University Hospital of Parma. Molecular methods showed high sensitivity and specificity and changed the epidemiology of imported malaria in several non-endemic countries, highlighted a higher prevalence of Plasmodium ovale, Plasmodium vivax and Plasmodium malariae underestimated by microscopy and, not least, brought to light both the existence of two species of P. ovale (Plasmodium ovale curtisi and Plasmodium ovale wallikeri) and the infection in humans by Plasmodium knowlesi, otherwise not detectable by microscopy. In this retrospective study an evaluation of two real-time PCR assays able to identify P. ovale wallikeri, distinguishing it from P. ovale curtisi, and to detect P. knowlesi, respectively, was performed applying them on a subset of 398 blood samples belonging to patients with the clinical suspicion of malaria. These assays revealed an excellent analytical sensitivity and no cross-reactivity versus other Plasmodium spp. infecting humans, suggesting their usefulness for an accurate and complete diagnosis of imported malaria. Among the 128 patients with malaria, eight P. ovale curtisi and four P. ovale wallikeri infections were detected, while no cases of P. knowlesi infection were observed. Real-time PCR assays specific for P. ovale wallikeri and P. knowlesi were included in the panel currently used in the University Hospital of Parma for the diagnosis of imported malaria, accomplishing the goal of

  9. Successful human infection with P. falciparum using three aseptic Anopheles stephensi mosquitoes: a new model for controlled human malaria infection.

    Directory of Open Access Journals (Sweden)

    Matthew B Laurens

    Full Text Available Controlled human malaria infection (CHMI is a powerful method for assessing the efficacy of anti-malaria vaccines and drugs targeting pre-erythrocytic and erythrocytic stages of the parasite. CHMI has heretofore required the bites of 5 Plasmodium falciparum (Pf sporozoite (SPZ-infected mosquitoes to reliably induce Pf malaria. We reported that CHMI using the bites of 3 PfSPZ-infected mosquitoes reared aseptically in compliance with current good manufacturing practices (cGMP was successful in 6 participants. Here, we report results from a subsequent CHMI study using 3 PfSPZ-infected mosquitoes reared aseptically to validate the initial clinical trial. We also compare results of safety, tolerability, and transmission dynamics in participants undergoing CHMI using 3 PfSPZ-infected mosquitoes reared aseptically to published studies of CHMI using 5 mosquitoes. Nineteen adults aged 18-40 years were bitten by 3 Anopheles stephensi mosquitoes infected with the chloroquine-sensitive NF54 strain of Pf. All 19 participants developed malaria (100%; 12 of 19 (63% on Day 11. The mean pre-patent period was 258.3 hours (range 210.5-333.8. The geometric mean parasitemia at first diagnosis by microscopy was 9.5 parasites/µL (range 2-44. Quantitative polymerase chain reaction (qPCR detected parasites an average of 79.8 hours (range 43.8-116.7 before microscopy. The mosquitoes had a geometric mean of 37,894 PfSPZ/mosquito (range 3,500-152,200. Exposure to the bites of 3 aseptically-raised, PfSPZ-infected mosquitoes is a safe, effective procedure for CHMI in malaria-naïve adults. The aseptic model should be considered as a new standard for CHMI trials in non-endemic areas. Microscopy is the gold standard used for the diagnosis of Pf malaria after CHMI, but qPCR identifies parasites earlier. If qPCR continues to be shown to be highly specific, and can be made to be practical, rapid, and standardized, it should be considered as an alternative for diagnosis

  10. Human mobility and malaria risk in the Naya river basin of Colombia.

    Science.gov (United States)

    Sevilla-Casas, E

    1993-11-01

    This paper develops and tests a methodology for examining the manner and the extent to which human mobility can be associated with malaria risk within an endemic area. The paper presents entomological, epidemiological and mobility results obtained from macro data and micro data. Results indicate that malaria is concentrated in the delta zone of the Naya river basin where the circulation of people into this zone for economic reasons occurs at a time when vector densities are high. High human density combined with high vector density ensures continuous and intense transmission of malaria. In attempting to measure intensity of transmission, microscopic analysis of parasitaemia was found to underestimate prevalence showing it to be very low or negligible, whereas serological data collected during the same period of time reveal that prevalence is high, and similar for both sexes. Serological data also indicate that prevalence increases with age particularly from adolescence onwards. Since mobility for agricultural purposes involves able-bodied males and females, there seems ample justification for concluding that human mobility into certain areas increases the risk of infection for adults, particularly when such mobility coincides with peak rainfall and vector densities. Micro-level data are critical in pinpointing causation and small area variations in risk. Thus the beach area is a high risk area within the delta region, particularly for adults, and this is likely to be because of high vector biting rates in the beach environment. One conclusion is that micro analysis of behaviour, when linked to epidemiological data are particularly useful in defining and locating areas and groups at highest risk; using such information to achieve intensive coverage on a small scale may be more cost-effective than attempting to achieve vector or chemotherapeutic control over a wider area for all groups.

  11. Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes.

    Directory of Open Access Journals (Sweden)

    Ben C L van Schaijk

    Full Text Available Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium parasites. Immunizations with sporozoites that are attenuated by radiation (RAS can induce strong protective immunity both in humans and rodent models of malaria. Recently, in rodent parasites it has been shown that through the deletion of a single gene, sporozoites can also become attenuated in liver stage development and, importantly, immunization with these sporozoites results in immune responses identical to RAS. The promise of vaccination using these genetically attenuated sporozoites (GAS depends on translating the results in rodent malaria models to human malaria. In this study, we perform the first essential step in this transition by disrupting, p52, in P. falciparum an ortholog of the rodent parasite gene, p36p, which we had previously shown can confer long lasting protective immunity in mice. These P. falciparum P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes in vitro that is comparable to wild type sporozoites. However, inside the host hepatocyte development is arrested very soon after invasion. This study reveals, for the first time, that disrupting the equivalent gene in both P. falciparum and rodent malaria Plasmodium species generates parasites that become similarly arrested during liver stage development and these results pave the way for further development of GAS for human use.

  12. HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo.

    Directory of Open Access Journals (Sweden)

    Charlotte V Hobbs

    Full Text Available We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination, but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts.

  13. Monitoring of Plasmodium infection in humans and potential vectors of malaria in a newly emerged focus in southern Iran.

    Science.gov (United States)

    Kalantari, Mohsen; Soltani, Zahra; Ebrahimi, Mostafa; Yousefi, Masoud; Amin, Masoumeh; Shafiei, Ayda; Azizi, Kourosh

    2017-02-01

    Despite control programs, which aim to eliminate malaria from Iran by 2025, transmission of malaria has not been removed from the country. This study aimed to monitor malaria from asymptomatic parasitaemia and clinical cases from about one year of active case surveillance and potential vectors of malaria in the newly emerged focus of Mamasani and Rostam, southern Iran during 2014-2015. Samples were collected and their DNAs were extracted for Polymerase Chain Reaction (PCR) assay using specific primers for detection of Plasmodium species. The Annual Parasite Incidence rate (API) was three cases per 1,000 population from 2,000 individuals in three villages. Parasites species were detected in 9 out of the 4,000 blood smear samples among which, 6 cases were indigenous and had no history of travels to endemic areas of malaria. Also, the prevalence rate of asymptomatic parasites was about 0.3%. Overall, 1073 Anopheles spp. were caught from 9 villages. Totally, 512 female samples were checked by PCR, which indicated that none of them was infected with Plasmodium. Despite new malaria local transmission in humans in Mamasani and Rostam districts, no infection with Plasmodium was observed in Anopheles species. Because of neighboring of the studied area to the re-emerged focus in Fars province (Kazerun) and important endemic foci of malaria in other southern provinces, such as Hormozgan and Kerman, monitoring of the vectors and reservoir hosts of Plasmodium species would be unavoidable. Application of molecular methods, such as PCR, can simplify access to the highest level of accuracy in malaria researches.

  14. Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.

    Science.gov (United States)

    Reis, Patricia A; Comim, Clarissa M; Hermani, Fernanda; Silva, Bruno; Barichello, Tatiana; Portella, Aline C; Gomes, Flavia C A; Sab, Ive M; Frutuoso, Valber S; Oliveira, Marcus F; Bozza, Patricia T; Bozza, Fernando A; Dal-Pizzol, Felipe; Zimmerman, Guy A; Quevedo, João; Castro-Faria-Neto, Hugo C

    2010-06-24

    Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.

  15. Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.

    Directory of Open Access Journals (Sweden)

    Patricia A Reis

    2010-06-01

    Full Text Available Neurological impairments are frequently detected in children surviving cerebral malaria (CM, the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW mice with Plasmodium berghei ANKA (PbA or a lethal strain of Plasmodium yoelii XL (PyXL, respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.

  16. Cytokine expression in malaria-infected non-human primate placentas

    African Journals Online (AJOL)

    Malaria parasites are known to mediate the induction of inflammatory immune responses at the maternal-foetal interface during placental malaria (PM) leading to adverse consequences like pre-term deliveries and abortions. Immunological events that take place within the malaria-infected placental micro-environment ...

  17. Genome sequencing of chimpanzee malaria parasites reveals possible pathways of adaptation to human hosts

    KAUST Repository

    Otto, Thomas D.

    2014-09-09

    Plasmodium falciparum causes most human malaria deaths, having prehistorically evolved from parasites of African Great Apes. Here we explore the genomic basis of P. falciparum adaptation to human hosts by fully sequencing the genome of the closely related chimpanzee parasite species P. reichenowi, and obtaining partial sequence data from a more distantly related chimpanzee parasite (P. gaboni). The close relationship between P. reichenowi and P. falciparum is emphasized by almost complete conservation of genomic synteny, but against this strikingly conserved background we observe major differences at loci involved in erythrocyte invasion. The organization of most virulence-associated multigene families, including the hypervariable var genes, is broadly conserved, but P. falciparum has a smaller subset of rif and stevor genes whose products are expressed on the infected erythrocyte surface. Genome-wide analysis identifies other loci under recent positive selection, but a limited number of changes at the host–parasite interface may have mediated host switching.

  18. Experimental Evaluations of Two Strategies to Improve Reading Achievement in Kenya: Enhanced Literacy Instruction and Treatment of Malaria

    Science.gov (United States)

    Jukes, Matthew; Dubeck, Margaret; Brooker, Simon; Wolf, Sharon

    2012-01-01

    There is less quality evidence on how malaria may affect cognitive abilities and educational achievement or on how schools can tackle the problem of malaria among school children. A randomised trial among Sri Lankan children showed that weekly malaria chemoprophylaxis with chloroquine can improve school examination scores. The Health and Literacy…

  19. Controlled Human Malaria Infection of Tanzanians by Intradermal Injection of Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites

    Science.gov (United States)

    Shekalaghe, Seif; Rutaihwa, Mastidia; Billingsley, Peter F.; Chemba, Mwajuma; Daubenberger, Claudia A.; James, Eric R.; Mpina, Maximillian; Ali Juma, Omar; Schindler, Tobias; Huber, Eric; Gunasekera, Anusha; Manoj, Anita; Simon, Beatus; Saverino, Elizabeth; Church, L. W. Preston; Hermsen, Cornelus C.; Sauerwein, Robert W.; Plowe, Christopher; Venkatesan, Meera; Sasi, Philip; Lweno, Omar; Mutani, Paul; Hamad, Ali; Mohammed, Ali; Urassa, Alwisa; Mzee, Tutu; Padilla, Debbie; Ruben, Adam; Lee Sim, B. Kim; Tanner, Marcel; Abdulla, Salim; Hoffman, Stephen L.

    2014-01-01

    Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa. Aseptic, purified, cryopreserved Pf sporozoites, PfSPZ Challenge, were used to infect Dutch volunteers by intradermal injection. We conducted a double-blind, placebo-controlled trial to assess safety and infectivity of PfSPZ Challenge in adult male Tanzanians. Volunteers were injected intradermally with 10,000 (N = 12) or 25,000 (N = 12) PfSPZ or normal saline (N = 6). PfSPZ Challenge was well tolerated and safe. Eleven of 12 and 10 of 11 subjects, who received 10,000 and 25,000 PfSPZ respectively, developed parasitemia. In 10,000 versus 25,000 PfSPZ groups geometric mean days from injection to Pf positivity by thick blood film was 15.4 versus 13.5 (P = 0.023). Alpha-thalassemia heterozygosity had no apparent effect on infectivity. PfSPZ Challenge was safe, well tolerated, and infectious. PMID:25070995

  20. The protein-phosphatome of the human malaria parasite Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Doerig Christian

    2008-09-01

    Full Text Available Abstract Background Malaria, caused by the parasitic protist Plasmodium falciparum, represents a major public health problem in the developing world. The P. falciparum genome has been sequenced, which provides new opportunities for the identification of novel drug targets. We report an exhaustive analysis of the P. falciparum genomic database (PlasmoDB aimed at identifying and classifying all protein phosphatases (PP in this organism. Results Using a variety of bioinformatics tools, we identified 27 malarial putative PP sequences within the four major established PP families, plus 7 sequences that we predict to dephosphorylate "non-protein" substrates. We constructed phylogenetic trees to position these sequences relative to PPs from other organisms representing all major eukaryotic phyla except Cercozoans (for which no full genome sequence is available. Predominant observations were: (i P. falciparum possessed the smallest phosphatome of any of the organisms investigated in this study; (ii no malarial PP clustered with the tyrosine-specific subfamily of the PTP group (iii a cluster of 7 closely related members of the PPM/PP2C family is present, and (iv some P. falciparum protein phosphatases are present in clades lacking any human homologue. Conclusion The considerable phylogenetic distance between Apicomplexa and other Eukaryotes is reflected by profound divergences between the phosphatome of malaria parasites and those of representative organisms from all major eukaryotic phyla, which might be exploited in the context of efforts for the discovery of novel targets for antimalarial chemotherapy.

  1. Differential attractiveness of humans to the African malaria vector Anopheles gambiae Giles : effects of host characteristics and parasite infection

    NARCIS (Netherlands)

    Mukabana, W.R.

    2002-01-01

    The results of a series of studies designed to understand the principal factors that determine the differential attractiveness of humans to the malaria vector Anopheles

  2. Efficacy of preerythrocytic and blood-stage malaria vaccines can be assessed in small sporozoite challenge trials in human volunteers.

    NARCIS (Netherlands)

    Roestenberg, M.; Vlas, S.J. de; Nieman, A.E.; Sauerwein, R.W.; Hermsen, C.C.

    2012-01-01

    The development of a vaccine against malaria has public health priority. In a controlled setting, preliminary data on the efficacy of Plasmodium falciparum vaccine candidates can be obtained by exposing immunized human volunteers to the bites of laboratory-reared P. falciparum-infected mosquitoes.

  3. Experimental Campylobacter Jejuni Infection in Humans

    Science.gov (United States)

    1988-03-01

    Blaser MJI Black RE. Duncan DJ, Amer I. Campylobacter Clements ML, Robins-Brone R, Lim Y-L. Duration of jejuni -specific serum antibodies are elevated in...SUBTITLE 5 FUNDING •4UMBERS Experimental Campylobacter jejuni Infection 86PP6826 in Humans 61102A 30161102BS13 AB6. AUTHOR(S)DA328 Robert E. Black...SUPPLEMENTARY NOTES Contract Title: Studies of the Outer Membrane Proteins of Campylobacter Jejuni for Vaccine Development ൔa• DISTRIBUTION

  4. The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-saharan Africa

    NARCIS (Netherlands)

    ter Kuile, Feiko O.; Parise, Monica E.; Verhoeff, Francine H.; Udhayakumar, Venkatachalam; Newman, Robert D.; van Eijk, Anne M.; Rogerson, Stephen J.; Steketee, Richard W.

    2004-01-01

    In sub-Saharan Africa, human immunodeficiency virus (HIV) and malaria are among the leading causes of morbidity during pregnancy. We reviewed available information collected since the first report 15 years ago that HIV impaired the ability of pregnant women to control malaria parasitemia. Results

  5. Malaria: Epidemiology and Diagnostic

    Directory of Open Access Journals (Sweden)

    Lukman Hakim

    2011-12-01

    Full Text Available Malaria is an infectious disease caused by Plasmodium spp, are naturally trans­mitted by the mosquito Anopheles spp. Malaria transmission occurs because of interaction between the agent, the definitive host and intermediate hosts (humans. Therefore, the trans­mission of malaria is injluenced by the presence and fluctuations in vector populations (i.e transmitting mosquito Anopheles spp.Malaria diagnosis consists of clinical diagnosis and diagnosis based on laboratory examina­tion. Clinical diagnosis or clinical malaria diagnosis was presumptive diagnosis of malaria based on clinical examination of patients with symptoms include fever (periodical, heat, level of consciousness, dizziness, etc. as well as specific local typical symptoms. Experiences of medical personnel who perform precise diagnosis will determine whether or not the diag­nosis, so that clinical diagnosis cannot be the main reference in the treatment of malaria be­cause of high error rates.

  6. Clara Maass, yellow fever and human experimentation.

    Science.gov (United States)

    Chaves-Carballo, Enrique

    2013-05-01

    Clara Louise Maass, a 25-year-old American nurse, died of yellow fever on August 24, 1901, following experimental inoculation by infected mosquitoes in Havana, Cuba. The human yellow fever experiments were initially conducted by MAJ Walter Reed, who first used written informed consent and proved the validity of Finlay's mosquito-vector hypothesis. Despite informed consent form and an incentive of $100 in U.S. gold, human subjects were exposed to a deadly virus. The deaths of Clara Maass and two Spanish immigrants resulted in a public outcry and the immediate cessation of yellow fever human experiments in Cuba. Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.

  7. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria

    DEFF Research Database (Denmark)

    Wiese, Lothar; Hempel, Casper; Penkowa, Milena

    2008-01-01

    BACKGROUND: Cerebral malaria (CM) is an acute encephalopathy with increased pro-inflammatory cytokines, sequestration of parasitized erythrocytes and localized ischaemia. In children CM induces cognitive impairment in about 10% of the survivors. Erythropoietin (Epo) has - besides of its well known...... with recombinant human Epo (rhEpo; 50-5000 U/kg/OD, i.p.) at different time points. The effect on survival was measured. Brain pathology was investigated by TUNEL (Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick end labelling), as a marker of apoptosis. Gene...... expression in brain tissue was measured by real time PCR. RESULTS: Treatment with rhEpo increased survival in mice with CM in a dose- and time-dependent manner and reduced apoptotic cell death of neurons as well as the expression of pro-inflammatory cytokines in the brain. This neuroprotective effect...

  8. Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenases.

    Science.gov (United States)

    Bedingfield, Paul T P; Cowen, Deborah; Acklam, Paul; Cunningham, Fraser; Parsons, Mark R; McConkey, Glenn A; Fishwick, Colin W G; Johnson, A Peter

    2012-06-28

    The de novo pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase is an emerging drug target for the treatment of malaria. In this context a key property of Plasmodium falciparum DHODH (PfDHODH) is that it can be selectively inhibited over its human homologue (HsDHODH). However, HsDHODH is also a validated drug target for autoimmune diseases such as arthritis. Here a series of novel inhibitors is described that includes compounds that switch specificity between the two enzymes as a result of small alterations in chemical structure. Structure-activity relationship (SAR), crystallography, docking, and mutagenesis studies are used to examine the binding modes of the compounds within the two enzymes and to reveal structural changes induced by inhibitor binding. Within this series, compounds with therapeutically relevant HsDHODH activity are described and their binding modes characterized using X-ray crystallography, which reveals a novel conformational shift within the inhibitor binding site.

  9. Aspidosperma (Apocynaceae plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro

    Directory of Open Access Journals (Sweden)

    Anna CC Aguiar

    2015-11-01

    Full Text Available Several species of Aspidospermaplants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellowperoba, coffee-peroba andmatiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorumextracts, the plant activity against Plasmodium falciparumwas evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL; the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5 displayed high selectivity indexes (SI (= 56 and 113, respectively, whereas compounds 2 and 3 were toxic (SI < 10. The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium bergheiin mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.

  10. Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro.

    Science.gov (United States)

    Aguiar, Anna C C; Cunha, Ananda C; Ceravolo, Isabela Penna; Gonçalves, Regina A Correia; Oliveira, Arildo J B; Krettli, Antoniana Ursine

    2015-11-01

    Several species of Aspidosperma plants are used to treat diseases in the tropics, including Aspidosperma ramiflorum, which acts against leishmaniasis, an activity that is experimentally confirmed. The species, known as guatambu-yellow, yellow peroba, coffee-peroba and matiambu, grows in the Atlantic Forest of Brazil in the South to the Southeast regions. Through a guided biofractionation of A. ramiflorum extracts, the plant activity against Plasmodium falciparum was evaluated in vitro for toxicity towards human hepatoma G2 cells, normal monkey kidney cells and nonimmortalised human monocytes isolated from peripheral blood. Six of the seven extracts tested were active at low doses (half-maximal drug inhibitory concentration < 3.8 µg/mL); the aqueous extract was inactive. Overall, the plant extracts and the purified compounds displayed low toxicity in vitro. A nonsoluble extract fraction and one purified alkaloid isositsirikine (compound 5) displayed high selectivity indexes (SI) (= 56 and 113, respectively), whereas compounds 2 and 3 were toxic (SI < 10). The structure, activity and low toxicity of isositsirikine in vitro are described here for the first time in A. ramiflorum, but only the neutral and precipitate plant fractions were tested for activity, which caused up to 53% parasitaemia inhibition of Plasmodium berghei in mice with blood-induced malaria. This plant species is likely to be useful in the further development of an antimalarial drug, but its pharmacological evaluation is still required.

  11. Human Rights and the Global Fund to Fight AIDS, Tuberculosis and Malaria

    Science.gov (United States)

    Jürgens, Ralf; Lim, Hyeyoung; Timberlake, Susan; Smith, Matthew

    2017-01-01

    Abstract The Global Fund to Fight AIDS, Tuberculosis and Malaria was created to greatly expand access to basic services to address the three diseases in its name. From its beginnings, its governance embodied some human rights principles: civil society is represented on its board, and the country coordination mechanisms that oversee funding requests to the Global Fund include representatives of people affected by the diseases. The Global Fund’s core strategies recognize that the health services it supports would not be effective or cost-effective without efforts to reduce human rights-related barriers to access and utilization of health services, particularly those faced by socially marginalized and criminalized persons. Basic human rights elements were written into Global Fund grant agreements, and various technical support measures encouraged the inclusion in funding requests of programs to reduce human rights-related barriers. A five-year initiative to provide intensive technical and financial support for the scaling up of programs to reduce these barriers in 20 countries is ongoing. PMID:29302175

  12. Crystal structure of fructose-1,6-bisphosphate aldolase from the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Kim, H; Certa, U; Döbeli, H; Jakob, P; Hol, W G

    1998-03-31

    The structure of the glycolytic enzyme class I fructose-1, 6-bisphosphate aldolase from the human malaria parasite Plasmodium falciparum has been determined by X-ray crystallography. Homotetrameric P. falciparum aldolase (PfALDO) crystallizes in space group P3221 with one 80 kDa dimer per asymmetric unit. The final refined PfALDO model has an R-factor of 0.239 and an R-free of 0.329 with respect to data from 8 to 3.0 A resolution. PfALDO is potentially a target for antimalarial drug design as the intraerythrocytic merozoite lifestage of P. falciparum is completely dependent upon glycolysis for its ATP production. Thus, inhibitors directed against the glycolytic enzymes in P. falciparum may be effective in killing the parasite. The structure of PfALDO is compared with the previously determined structure of human aldolase in order to determine possible targets for the structure-based design of selective PfALDO ligands. The salient structural differences include a hydrophobic pocket on the surface of PfALDO, which results from some amino acid changes and a single residue deletion compared with human aldolase, and the overall quaternary structure of the PfALDO tetramer, which buries less surface area than human aldolase.

  13. A novel PCR-based system for the detection of four species of human malaria parasites and Plasmodium knowlesi

    Science.gov (United States)

    Komaki-Yasuda, Kanako; Vincent, Jeanne Perpétue; Nakatsu, Masami; Kato, Yasuyuki; Ohmagari, Norio

    2018-01-01

    A microscopy-based diagnosis is the gold standard for the detection and identification of malaria parasites in a patient’s blood. However, the detection of cases involving a low number of parasites and the differentiation of species sometimes requires a skilled microscopist. Although PCR-based diagnostic methods are already known to be very powerful tools, the time required to apply such methods is still much longer in comparison to traditional microscopic observation. Thus, improvements to PCR systems are sought to facilitate the more rapid and accurate detection of human malaria parasites Plasmodium falciparum, P. vivax, P. ovale, and P. malariae, as well as P. knowlesi, which is a simian malaria parasite that is currently widely distributed in Southeast Asia. A nested PCR that targets the small subunit ribosomal RNA genes of malaria parasites was performed using a “fast PCR enzyme”. In the first PCR, universal primers for all parasite species were used. In the second PCR, inner-specific primers, which targeted sequences from P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi, were used. The PCR reaction time was reduced with the use of the “fast PCR enzyme”, with only 65 minutes required to perform the first and second PCRs. The specific primers only reacted with the sequences of their targeted parasite species and never cross-reacted with sequences from other species under the defined PCR conditions. The diagnoses of 36 clinical samples that were obtained using this new PCR system were highly consistent with the microscopic diagnoses. PMID:29370297

  14. Plasmodium vivax sporozoite challenge in malaria-naïve and semi-immune Colombian volunteers

    DEFF Research Database (Denmark)

    Arévalo-Herrera, Myriam; Forero-Peña, David A.; Rubiano, Kelly

    2014-01-01

    Background: Significant progress has been recently achieved in the development of Plasmodium vivax challenge infections in humans, which are essential for vaccine and drug testing. With the goal of accelerating clinical development of malaria vaccines, the outcome of infections experimentally...

  15. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study.

    Science.gov (United States)

    Roestenberg, Meta; Teirlinck, Anne C; McCall, Matthew B B; Teelen, Karina; Makamdop, Krystelle Nganou; Wiersma, Jorien; Arens, Theo; Beckers, Pieter; van Gemert, GeertJan; van de Vegte-Bolmer, Marga; van der Ven, André J A M; Luty, Adrian J F; Hermsen, Cornelus C; Sauerwein, Robert W

    2011-05-21

    We have shown that immunity to infection with Plasmodium falciparum can be induced experimentally in malaria-naive volunteers through immunisation by bites of infected mosquitoes while simultaneously preventing disease with chloroquine prophylaxis. This immunity was associated with parasite-specific production of interferon γ and interleukin 2 by pluripotent effector memory cells in vitro. We aim to explore the persistence of protection and immune responses in the same volunteers. In an open-label study at the Radboud University Nijmegen Medical Centre (Nijmegen, Netherlands), from November to December, 2009, we rechallenged previously immune volunteers (28 months after immunisation) with the bites of five mosquitoes infected with P falciparum. Newly recruited malaria-naive volunteers served as infection controls. Our primary outcome was the detection of blood-stage parasitaemia by microscopy. We assessed the kinetics of parasitaemia with real-time quantitative PCR (rtPCR) and recorded clinical signs and symptoms. In-vitro production of interferon γ and interleukin 2 by effector memory T cells was studied after stimulation with sporozoites and red blood cells infected with P falciparum. Differences in cellular immune responses between the study groups were assessed with the Mann-Whitney test. This study is registered with ClinicalTrials.gov, number NCT00757887. Four of six immune volunteers were microscopically negative after rechallenge. rtPCR-based detection of blood-stage parasites in these individuals was negative throughout follow-up. Patent parasitaemia was delayed in the remaining two immunised volunteers. In-vitro assays showed the long-term persistence of parasite-specific pluripotent effector memory T-cell responses in protected volunteers. The four protected volunteers reported several mild to moderate adverse events, of which the most commonly reported symptom was headache (one to three episodes per volunteer). The two patients with delayed patency

  16. Advances in the management of cerebral malaria in adults

    DEFF Research Database (Denmark)

    Mishra, Saroj K; Wiese, Lothar

    2009-01-01

    PURPOSE OF REVIEW: Cerebral malaria continues to be a substantial cause of death and disability worldwide. Although many studies deal with cerebral malaria in children, only very few pertain to adults. Presence of multiorgan failure makes the prognosis poor. Various mechanisms in the pathogenesis...... of cerebral malaria and the role of adjuvant therapy will be discussed. RECENT FINDINGS: Artemisinin-based therapies have improved antiparasitic treatment, but in-hospital mortality still remains high, as do neurological sequelae. Several recent studies have given new insights in the pathophysiology...... of cerebral malaria particularly the role of immune mechanisms in disease progression. Recent findings have identified several potential candidates for adjuvant neuroprotective treatment. Recombinant human erythropoietin has shown beneficial effect in experimental cerebral malaria and will soon enter...

  17. Optimising Controlled Human Malaria Infection Studies Using Cryopreserved P. falciparum Parasites Administered by Needle and Syringe.

    Directory of Open Access Journals (Sweden)

    Susanne H Sheehy

    Full Text Available Controlled human malaria infection (CHMI studies have become a routine tool to evaluate efficacy of candidate anti-malarial drugs and vaccines. To date, CHMI trials have mostly been conducted using the bite of infected mosquitoes, restricting the number of trial sites that can perform CHMI studies. Aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge provide a potentially more accurate, reproducible and practical alternative, allowing a known number of sporozoites to be administered simply by injection.We sought to assess the infectivity of PfSPZ Challenge administered in different dosing regimens to malaria-naive healthy adults (n = 18. Six participants received 2,500 sporozoites intradermally (ID, six received 2,500 sporozoites intramuscularly (IM and six received 25,000 sporozoites IM.Five out of six participants receiving 2,500 sporozoites ID, 3/6 participants receiving 2,500 sporozoites IM and 6/6 participants receiving 25,000 sporozoites IM were successfully infected. The median time to diagnosis was 13.2, 17.8 and 12.7 days for 2,500 sporozoites ID, 2,500 sporozoites IM and 25,000 sporozoites IM respectively (Kaplan Meier method; p = 0.024 log rank test.2,500 sporozoites ID and 25,000 sporozoites IM have similar infectivities. Given the dose response in infectivity seen with IM administration, further work should evaluate increasing doses of PfSPZ Challenge IM to identify a dosing regimen that reliably infects 100% of participants.ClinicalTrials.gov NCT01465048.

  18. Malaria burden in irregular migrants returning to Sri Lanka from human smuggling operations in West Africa and implications for a country reaching malaria elimination.

    Science.gov (United States)

    Wickramage, K; Galappaththy, G N L

    2013-05-01

    The number of malaria cases among irregular migrants returning to Sri Lanka has not been investigated. In the first 6 months of 2012 we screened 287 irregular migrants returning from seven West African nations to Sri Lanka for malaria to ascertain the risk of infection during migration. Four men were diagnosed as having malaria: three with Plasmodium falciparum had travelled to Togo and one with P. vivax had travelled to Guinea. The risk of contracting malaria was 14 cases per 1000. Facilitating a safe return with selective screening for at-risk inbound migrants flows is desirable as Sri Lanka advances towards its goal of malaria elimination.

  19. Recognition of Human Erythrocyte Receptors by the Tryptophan-Rich Antigens of Monkey Malaria Parasite Plasmodium knowlesi.

    Directory of Open Access Journals (Sweden)

    Kriti Tyagi

    Full Text Available The monkey malaria parasite Plasmodium knowlesi also infect humans. There is a lack of information on the molecular mechanisms that take place between this simian parasite and its heterologous human host erythrocytes leading to this zoonotic disease. Therefore, we investigated here the binding ability of P. knowlesi tryptophan-rich antigens (PkTRAgs to the human erythrocytes and sharing of the erythrocyte receptors between them as well as with other commonly occurring human malaria parasites.Six PkTRAgs were cloned and expressed in E.coli as well as in mammalian CHO-K1 cell to determine their human erythrocyte binding activity by cell-ELISA, and in-vitro rosetting assay, respectively.Three of six PkTRAgs (PkTRAg38.3, PkTRAg40.1, and PkTRAg67.1 showed binding to human erythrocytes. Two of them (PkTRAg40.1 and PkTRAg38.3 showed cross-competition with each other as well as with the previously described P.vivax tryptophan-rich antigens (PvTRAgs for human erythrocyte receptors. However, the third protein (PkTRAg67.1 utilized the additional but different human erythrocyte receptor(s as it did not cross-compete for erythrocyte binding with either of these two PkTRAgs as well as with any of the PvTRAgs. These three PkTRAgs also inhibited the P.falciparum parasite growth in in-vitro culture, further indicating the sharing of human erythrocyte receptors by these parasite species and the biological significance of this receptor-ligand interaction between heterologous host and simian parasite.Recognition and sharing of human erythrocyte receptor(s by PkTRAgs with human parasite ligands could be part of the strategy adopted by the monkey malaria parasite to establish inside the heterologous human host.

  20. Recognition of Human Erythrocyte Receptors by the Tryptophan-Rich Antigens of Monkey Malaria Parasite Plasmodium knowlesi

    Science.gov (United States)

    Tyagi, Kriti; Gupta, Deepali; Saini, Ekta; Choudhary, Shilpa; Jamwal, Abhishek; Alam, Mohd. Shoeb; Zeeshan, Mohammad; Tyagi, Rupesh K.; Sharma, Yagya D.

    2015-01-01

    Background The monkey malaria parasite Plasmodium knowlesi also infect humans. There is a lack of information on the molecular mechanisms that take place between this simian parasite and its heterologous human host erythrocytes leading to this zoonotic disease. Therefore, we investigated here the binding ability of P. knowlesi tryptophan-rich antigens (PkTRAgs) to the human erythrocytes and sharing of the erythrocyte receptors between them as well as with other commonly occurring human malaria parasites. Methods Six PkTRAgs were cloned and expressed in E.coli as well as in mammalian CHO-K1 cell to determine their human erythrocyte binding activity by cell-ELISA, and in-vitro rosetting assay, respectively. Results Three of six PkTRAgs (PkTRAg38.3, PkTRAg40.1, and PkTRAg67.1) showed binding to human erythrocytes. Two of them (PkTRAg40.1 and PkTRAg38.3) showed cross-competition with each other as well as with the previously described P.vivax tryptophan-rich antigens (PvTRAgs) for human erythrocyte receptors. However, the third protein (PkTRAg67.1) utilized the additional but different human erythrocyte receptor(s) as it did not cross-compete for erythrocyte binding with either of these two PkTRAgs as well as with any of the PvTRAgs. These three PkTRAgs also inhibited the P.falciparum parasite growth in in-vitro culture, further indicating the sharing of human erythrocyte receptors by these parasite species and the biological significance of this receptor-ligand interaction between heterologous host and simian parasite. Conclusions Recognition and sharing of human erythrocyte receptor(s) by PkTRAgs with human parasite ligands could be part of the strategy adopted by the monkey malaria parasite to establish inside the heterologous human host. PMID:26393350

  1. Experimental evidence for evolved tolerance to avian malaria in a wild population of low elevation Hawai`i `Amakihi (Hemignathus virens)

    Science.gov (United States)

    Atkinson, Carter T.; Saili, Katerine S.; Utzurrum, Ruth B.; Jarvi, Susan I.

    2013-01-01

    Introduced vector-borne diseases, particularly avian malaria (Plasmodium relictum) and avian pox virus (Avipoxvirus spp.), continue to play significant roles in the decline and extinction of native forest birds in the Hawaiian Islands. Hawaiian honeycreepers are particularly susceptible to avian malaria and have survived into this century largely because of persistence of high elevation refugia on Kaua‘i, Maui, and Hawai‘i Islands, where transmission is limited by cool temperatures. The long term stability of these refugia is increasingly threatened by warming trends associated with global climate change. Since cost effective and practical methods of vector control in many of these remote, rugged areas are lacking, adaptation through processes of natural selection may be the best long-term hope for recovery of many of these species. We document emergence of tolerance rather than resistance to avian malaria in a recent, rapidly expanding low elevation population of Hawai‘i ‘Amakihi (Hemignathus virens) on the island of Hawai‘i. Experimentally infected low elevation birds had lower mortality, lower reticulocyte counts during recovery from acute infection, lower weight loss, and no declines in food consumption relative to experimentally infected high elevation Hawai‘i ‘Amakihi in spite of similar intensities of infection. Emergence of this population provides an exceptional opportunity for determining physiological mechanisms and genetic markers associated with malaria tolerance that can be used to evaluate whether other, more threatened species have the capacity to adapt to this disease.

  2. Ape malaria transmission and potential for ape-to-human transfers in Africa.

    Science.gov (United States)

    Makanga, Boris; Yangari, Patrick; Rahola, Nil; Rougeron, Virginie; Elguero, Eric; Boundenga, Larson; Moukodoum, Nancy Diamella; Okouga, Alain Prince; Arnathau, Céline; Durand, Patrick; Willaume, Eric; Ayala, Diego; Fontenille, Didier; Ayala, Francisco J; Renaud, François; Ollomo, Benjamin; Prugnolle, Franck; Paupy, Christophe

    2016-05-10

    Recent studies have highlighted the large diversity of malaria parasites infecting African great apes (subgenus Laverania) and their strong host specificity. Although the existence of genetic incompatibilities preventing the cross-species transfer may explain host specificity, the existence of vectors with a high preference for a determined host represents another possibility. To test this hypothesis, we undertook a 15-mo-long longitudinal entomological survey in two forest regions of Gabon, where wild apes live, at different heights under the canopy. More than 2,400 anopheline mosquitoes belonging to 18 species were collected. Among them, only three species of Anopheles were found infected with ape Plasmodium: Anopheles vinckei, Anopheles moucheti, and Anopheles marshallii Their role in transmission was confirmed by the detection of the parasites in their salivary glands. Among these species, An. vinckei showed significantly the highest prevalence of infection and was shown to be able to transmit parasites of both chimpanzees and gorillas. Transmission was also shown to be conditioned by seasonal factors and by the heights of capture under the canopy. Moreover, human landing catches of sylvan Anopheles demonstrated the propensity of these three vector species to feed on humans when available. Our results suggest therefore that the strong host specificity observed in the Laveranias is not linked to a specific association between the vertebrate host and the vector species and highlight the potential role of these vectors as bridge between apes and humans.

  3. Probability of Transmission of Malaria from Mosquito to Human Is Regulated by Mosquito Parasite Density in Naïve and Vaccinated Hosts.

    Directory of Open Access Journals (Sweden)

    Thomas S Churcher

    2017-01-01

    Full Text Available Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP, and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.

  4. A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

    DEFF Research Database (Denmark)

    Claessens, Antoine; Adams, Yvonne; Ghumra, Ashfaq

    2012-01-01

    Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human...... of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann-Whitney test, P = 0.......029) but not by antibodies from controls with uncomplicated malaria (Mann-Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria....

  5. Presence of IgE cells in human placenta is independent of malaria infection or chorioamnionitis

    DEFF Research Database (Denmark)

    Rindsjö, E; Hulthén Varli, I; Ofori, M F

    2006-01-01

    from Ghana with and without malaria parasites. The immunohistochemical staining pattern for IgE looked similar to our previous study, with the IgE located on Hofbauer-like cells. We could not find any difference in the amount or distribution of IgE(+) cells between malaria-infected and non...

  6. Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation.

    Science.gov (United States)

    Brasil, Patrícia; Zalis, Mariano Gustavo; de Pina-Costa, Anielle; Siqueira, Andre Machado; Júnior, Cesare Bianco; Silva, Sidnei; Areas, André Luiz Lisboa; Pelajo-Machado, Marcelo; de Alvarenga, Denise Anete Madureira; da Silva Santelli, Ana Carolina Faria; Albuquerque, Hermano Gomes; Cravo, Pedro; Santos de Abreu, Filipe Vieira; Peterka, Cassio Leonel; Zanini, Graziela Maria; Suárez Mutis, Martha Cecilia; Pissinatti, Alcides; Lourenço-de-Oliveira, Ricardo; de Brito, Cristiana Ferreira Alves; de Fátima Ferreira-da-Cruz, Maria; Culleton, Richard; Daniel-Ribeiro, Cláudio Tadeu

    2017-10-01

    Malaria was eliminated from southern and southeastern Brazil over 50 years ago. However, an increasing number of autochthonous episodes attributed to Plasmodium vivax have recently been reported from the Atlantic Forest region of Rio de Janeiro state. As the P vivax-like non-human primate malaria parasite species Plasmodium simium is locally enzootic, we performed a molecular epidemiological investigation to determine whether zoonotic malaria transmission is occurring. We examined blood samples from patients presenting with signs or symptoms suggestive of malaria as well as from local howler monkeys by microscopy and PCR. Samples were included from individuals if they had a history of travel to or resided in areas within the Rio de Janeiro Atlantic Forest, but not if they had malaria prophylaxis, blood transfusion or tissue or organ transplantation, or had travelled to known malaria endemic areas in the preceding year. Additionally, we developed a molecular assay based on sequencing of the parasite mitochondrial genome to distinguish between P vivax and P simium, and applied this assay to 33 cases from outbreaks that occurred in 2015, and 2016. A total of 49 autochthonous malaria cases were reported in 2015-16. Most patients were male, with a mean age of 44 years (SD 14·6), and 82% lived in urban areas of Rio de Janeiro state and had visited the Atlantic Forest for leisure or work-related activities. 33 cases were used for mitochondrial DNA sequencing. The assay was successfully performed for 28 samples, and all were shown to be P simium, indicative of zoonotic transmission of this species to human beings in this region. Sequencing of the whole mitochondrial genome of three of these cases showed that P simium is most closely related to P vivax parasites from South America. The malaria outbreaks in this region were caused by P simium, previously considered to be a monkey-specific malaria parasite, related to but distinct from P vivax, and which has never

  7. Plasmodium falciparum CS protein - prime malaria vaccine candidate: definition of the human CTL domain and analysis of its variation

    Directory of Open Access Journals (Sweden)

    Denise L. Doolan

    1992-01-01

    Full Text Available Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by citotoxic T lymphocytes (CTL specific for epitopes within the circumsporozoite (CS protein. Humans, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans ralies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL. against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.

  8. Of mice and women: rodent models of placental malaria

    DEFF Research Database (Denmark)

    Hviid, Lars; Marinho, Claudio R F; Staalsoe, Trine

    2010-01-01

    expressed in placental malaria (PM) and specific for chondroitin sulfate A (CSA). In Plasmodium falciparum, these VSA(PM) appear largely synonymous with the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family variant VAR2CSA. As rodent malaria parasites do not possess PfEMP1 homologs......, the usefulness of experimental mouse PM models remains controversial. However, many features of murine and human PM are similar, including involvement of VSAs analogous to PfEMP1. It thus appears that rodent model studies can further the understanding of VSA-dependent malaria pathogenesis and immunity....

  9. Rhinovirus genome evolution during experimental human infection.

    Directory of Open Access Journals (Sweden)

    Samuel Cordey

    Full Text Available Human rhinoviruses (HRVs evolve rapidly due in part to their error-prone RNA polymerase. Knowledge of the diversity of HRV populations emerging during the course of a natural infection is essential and represents a basis for the design of future potential vaccines and antiviral drugs. To evaluate HRV evolution in humans, nasal wash samples were collected daily for five days from 15 immunocompetent volunteers experimentally infected with a reference stock of HRV-39. In parallel, HeLa-OH cells were inoculated to compare HRV evolution in vitro. Nasal wash in vivo assessed by real-time PCR showed a viral load that peaked at 48-72 h. Ultra-deep sequencing was used to compare the low-frequency mutation populations present in the HRV-39 inoculum in two human subjects and one HeLa-OH supernatant collected 5 days post-infection. The analysis revealed hypervariable mutation locations in VP2, VP3, VP1, 2C and 3C genes and conserved regions in VP4, 2A, 2B, 3A, 3B and 3D genes. These results were confirmed by classical sequencing of additional samples, both from inoculated volunteers and independent cell infections, and suggest that HRV inter-host transmission is not associated with a strong bottleneck effect. A specific analysis of the VP1 capsid gene of 15 human cases confirmed the high mutation incidence in this capsid region, but not in the antiviral drug-binding pocket. We could also estimate a mutation frequency in vivo of 3.4x10(-4 mutations/nucleotides and 3.1x10(-4 over the entire ORF and VP1 gene, respectively. In vivo, HRV generate new variants rapidly during the course of an acute infection due to mutations that accumulate in hot spot regions located at the capsid level, as well as in 2C and 3C genes.

  10. Slow and continuous delivery of a low dose of nimodipine improves survival and electrocardiogram parameters in rescue therapy of mice with experimental cerebral malaria.

    Science.gov (United States)

    Martins, Yuri C; Clemmer, Leah; Orjuela-Sánchez, Pamela; Zanini, Graziela M; Ong, Peng Kai; Frangos, John A; Carvalho, Leonardo J M

    2013-04-24

    Human cerebral malaria (HCM) is a life-threatening complication caused by Plasmodium falciparum infection that continues to be a major global health problem despite optimal anti-malarial treatment. In the experimental model of cerebral malaria (ECM) by Plasmodium berghei ANKA, bolus administration of nimodipine at high doses together with artemether, increases survival of mice with ECM. However, the dose and administration route used is associated with cardiovascular side effects such as hypotension and bradycardia in humans and mice, which could preclude its potential use as adjunctive treatment in HCM. In the present study, alternative delivery systems for nimodipine during late-stage ECM in association with artesunate were searched to define optimal protocols to achieve maximum efficacy in increasing survival in rescue therapy while causing the least cardiac side effects. The baseline electrocardiogram (ECG) and arterial pressure characteristics of uninfected control animals and of mice with ECM and its response upon rescue treatment with artesunate associated or not with nimodipine is also analysed. Nimodipine, given at 0.5 mg/kg/day via a slow and continuous delivery system by osmotic pumps, increases survival of mice with ECM when used as adjunctive treatment to artesunate. Mice with ECM showed hypotension and ECG changes, including bradycardia and increases in PR, QRS, QTc and ST interval duration. ECM mice also show increased QTc dispersion, heart rate variability (HRV), RMSSD, low frequency (LF) and high frequency (HF) bands of the power spectrum. Both sympathetic and parasympathetic inputs to the heart were increased, but there was a predominance of sympathetic tone as demonstrated by an increased LF/HF ratio. Nimodipine potentiated bradycardia when given by bolus injection, but not when via osmotic pumps. In addition, nimodipine shortened PR duration and improved HRV, RMSSD, LF and HF powers in mice with ECM. In addition, nimodipine did not increased

  11. Experimental assessment of human corneal hysteresis.

    Science.gov (United States)

    Elsheikh, Ahmed; Wang, Defu; Rama, Paolo; Campanelli, Marino; Garway-Heath, David

    2008-03-01

    Hysteresis is a viscoelastic property characterized by the difference in behavior under loading and unloading. The aim of the study was to determine corneal hysteresis using experimental means. Twenty-nine human corneas with 50-95 year age were subjected to cycles of pressure loading and unloading. Two pressure application rates were adopted to approximate static and dynamic loading conditions. The behavior under both loading and unloading was found to stiffen with increased age. The unloading behavior appeared to be largely independent of the pressure level at which unloading started. The difference between the behavior patterns under loading and unloading was quantified and used as a measure of corneal hysteresis. The hysteresis area was significantly larger with faster loading and with decreased age. The trend for hysteresis to decrease with age is in agreement with previous clinical observations. Hysteresis was also found to increase with faster pressure application.

  12. Malaria Research

    Science.gov (United States)

    ... with facebook share with twitter share with linkedin Malaria Go to Information for Researchers ► Malaria is a ... for the disease. Why Is the Study of Malaria a Priority for NIAID? Roughly 3.2 billion ...

  13. MALARIA AMONG CHILDREN (1)

    African Journals Online (AJOL)

    BACKGROUND: Malaria is the most important parasitic disease of humans affecting more than half of the world population, majority of ... of this study was to describe patterns and trend of severe and complicated malaria cases, which could partly measure impact of .... Core body temperature >40°C. Hyperbilirubinemia.

  14. Plant-Mediated Effects on Mosquito Capacity to Transmit Human Malaria.

    Directory of Open Access Journals (Sweden)

    Domonbabele F D S Hien

    2016-08-01

    Full Text Available The ecological context in which mosquitoes and malaria parasites interact has received little attention, compared to the genetic and molecular aspects of malaria transmission. Plant nectar and fruits are important for the nutritional ecology of malaria vectors, but how the natural diversity of plant-derived sugar sources affects mosquito competence for malaria parasites is unclear. To test this, we infected Anopheles coluzzi, an important African malaria vector, with sympatric field isolates of Plasmodium falciparum, using direct membrane feeding assays. Through a series of experiments, we then examined the effects of sugar meals from Thevetia neriifolia and Barleria lupilina cuttings that included flowers, and fruit from Lannea microcarpa and Mangifera indica on parasite and mosquito traits that are key for determining the intensity of malaria transmission. We found that the source of plant sugar meal differentially affected infection prevalence and intensity, the development duration of the parasites, as well as the survival and fecundity of the vector. These effects are likely the result of complex interactions between toxic secondary metabolites and the nutritional quality of the plant sugar source, as well as of host resource availability and parasite growth. Using an epidemiological model, we show that plant sugar source can be a significant driver of malaria transmission dynamics, with some plant species exhibiting either transmission-reducing or -enhancing activities.

  15. Human IGF1 extends lifespan and enhances resistance to Plasmodium falciparum infection in the malaria vector Anopheles stephensi.

    Science.gov (United States)

    Drexler, Anna; Nuss, Andrew; Hauck, Eric; Glennon, Elizabeth; Cheung, Kong; Brown, Mark; Luckhart, Shirley

    2013-01-15

    The highly conserved insulin/insulin-like growth factor (IGF) signaling (IIS) pathway regulates metabolism, development, lifespan and immunity across a wide range of organisms. Previous studies have shown that human insulin ingested in the blood meal can activate mosquito IIS, resulting in attenuated lifespan and increased malaria parasite infection. Because human IGF1 is present at higher concentrations in blood than insulin and is functionally linked with lifespan and immune processes, we predicted that human IGF1 ingested in a blood meal would affect lifespan and malaria parasite infection in the mosquito Anopheles stephensi. Here we demonstrate that physiological levels of ingested IGF1, like insulin, can persist intact in the blood-filled midgut for up to 30 h and disseminate into the mosquito body, and that both peptides activate IIS in mosquito cells and midgut. At these same levels, ingested IGF1 alone extended average mosquito lifespan by 23% compared with controls and, more significantly, when ingested in infected blood meals, reduced the prevalence of Plasmodium falciparum-infected mosquitoes by >20% and parasite load by 35-50% compared with controls. Thus, the effects of ingested IGF1 on mosquito lifespan and immunity are opposite to those of ingested insulin. These results offer the first evidence that insect cells can functionally discriminate between mammalian insulin and IGF1. Further, in light of previous success in genetically targeting IIS to alter mosquito lifespan and malaria parasite transmission, this study indicates that a more complete understanding of the IIS-activating ligands in blood can be used to optimize transgenic strategies for malaria control.

  16. Application of the lumped age-class technique to studying the dynamics of malaria-mosquito-human interactions

    Directory of Open Access Journals (Sweden)

    Godfray H Charles J

    2007-07-01

    Full Text Available Abstract A series of models of malaria-mosquito-human interactions using the Lumped Age-Class technique of Gurney & Nisbet are developed. The models explicitly include sub-adult mosquito dynamics and assume that population regulation occurs at the larval stage. A challenge for modelling mosquito dynamics in continuous time is that the insect has discrete life-history stages (egg, larva, pupa & adult, the sub-adult stages of relatively fixed duration, which are subject to very different demographic rates. The Lumped Age-Class technique provides a natural way to treat this type of population structure. The resulting model, phrased as a system of delay-differential equations, is only slightly harder to analyse than traditional ordinary differential equations and much easier than the alternative partial differential equation approach. The Lumped Age-Class technique also allows the natural treatment of the relatively fixed time delay between the mosquito ingesting Plasmodium and it becoming infective. Three models are developed to illustrate the application of this approach: one including just the mosquito dynamics, the second including Plasmodium but no human dynamics, and the third including the interaction of the malaria pathogen and the human population (though only in a simple classical Ross-Macdonald manner. A range of epidemiological quantities used in studying malaria such as the vectorial capacity, the entomological inoculation rate and the basic reproductive number (R0 are derived, and examples given of the analysis and simulation of model dynamics. Assumptions and extensions are discussed. It is suggested that this modelling framework may be a natural and useful tool for exploring a variety of issues in malaria-vector epidemiology, especially in circumstances where a dynamic representation of mosquito recruitment is required.

  17. Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Dieudonnée Togbe

    Full Text Available BACKGROUND: TNF-related lymphotoxin alpha (LTalpha is essential for the development of Plasmodium berghei ANKA (PbA-induced experimental cerebral malaria (ECM. The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer. METHODOLOGY/PRINCIPAL FINDINGS: LTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+ CD8(+ T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM. CONCLUSIONS/SIGNIFICANCE: LTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.

  18. Changes in total and differential leukocyte counts during the clinically silent liver phase in a controlled human malaria infection in malaria-naïve Dutch volunteers.

    Science.gov (United States)

    van Wolfswinkel, Marlies E; Langenberg, Marijke C C; Wammes, Linda J; Sauerwein, Robert W; Koelewijn, Rob; Hermsen, Cornelus C; van Hellemond, Jaap J; van Genderen, Perry J

    2017-11-10

    Both in endemic countries and in imported malaria, changes in total and differential leukocyte count during Plasmodium falciparum infection have been described. To study the exact dynamics of differential leukocyte counts and their ratios, they were monitored in a group of healthy non-immune volunteers in two separate Controlled Human Malaria Infection (CHMI) studies. In two CHMI trials, CHMI-a and CHMI-b, 15 and 24 healthy malaria-naïve volunteers, respectively, were exposed to bites of infected mosquitoes, using the P. falciparum research strain NF54 and the novel clones NF135.C10 and NF166.C8. After mosquito bite exposure, twice-daily blood draws were taken to detect parasitaemia and to monitor the total and differential leukocyte counts. All subjects received a course of atovaquone-proguanil when meeting the treatment criteria. A total of 39 volunteers participated in the two trials. Thirty-five participants, all 15 participants in CHMI-a and 20 of the 24 volunteers in CHMI-b, developed parasitaemia. During liver stage development of the parasite, the median total leukocyte count increased from 5.5 to 6.1 × 10 9 leukocytes/L (p = 0.005), the median lymphocyte count from 1.9 to 2.2 (p = 0.001) and the monocyte count from 0.50 to 0.54 (p = 0.038). During the subsequent blood stage infection, significant changes in total and differential leukocyte counts lead to a leukocytopenia (nadir median 3.3 × 10 9 leukocytes/L, p = 0.0001), lymphocytopenia (nadir median 0.7 × 10 9 lymphocytes/L, p = 0.0001) and a borderline neutropenia (nadir median 1.5 × 10 9 neutrophils/L, p = 0.0001). The neutrophil to lymphocyte count ratio (NLCR) reached a maximum of 4.0. Significant correlations were found between parasite load and absolute lymphocyte count (p leukocyte count and differential lymphocytes and monocytes occurs. This finding has not been described previously. This increase is followed by the appearance of parasites in the peripheral blood after 2

  19. Comparing human T cell and NK cell responses in viral-based malaria vaccine trials.

    Science.gov (United States)

    Berthoud, Tamara K; Fletcher, Helen; Porter, David; Thompson, Fiona; Hill, Adrian V S; Todryk, Stephen M

    2009-12-10

    Vaccination with viral-based vaccines continues to hold promise for the prevention of malaria. Whilst antigen-specific T cell responses are considered a major aim of such an approach, a role for induced NK cells as anti-malarial effector cells, or in shaping T cell responses, has received less attention. In this study naïve human volunteers were vaccinated in a prime-boost vaccination regimen comprising recombinant viral vectors fowlpox (FP9) and modified vaccinia Ankara (MVA) encoding liver-stage antigens, or a virosome vaccine. Significant T cell responses specific for the vectored vaccine antigens were demonstrated by IFNgamma ELISPOT and intracellular cytokine staining (ICS) for IFNgamma and IL-2, the ICS being associated with increased time to parasitaemia following subsequent challenge. Numbers of CD56(bright) lymphocytes increased significantly following vaccination, as did CD3(+) CD56(+) lymphocytes, whilst CD56(dim) cells did not. No such increases were seen with the virosome vaccine. There was no significant correlation of these CD56(+) populations with the antigen-specific T cell responses nor time to parasitaemia. To investigate pathways of immune activation that could contribute to these lymphocyte responses, viral vectors were shown in vitro to efficiently infect APCs but not lymphocytes, and stimulated inflammatory cytokines such as type I interferons. In conclusion, measuring antigen-specific T cells is more meaningful than NK cells in these vaccination regimens.

  20. Autophagy-related Atg8 localizes to the apicoplast of the human malaria parasite Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Kei Kitamura

    Full Text Available Autophagy is a membrane-mediated degradation process, which is governed by sequential functions of Atg proteins. Although Atg proteins are highly conserved in eukaryotes, protozoa possess only a partial set of Atg proteins. Nonetheless, almost all protozoa have the complete factors belonging to the Atg8 conjugation system, namely, Atg3, Atg4, Atg7, and Atg8. Here, we report the biochemical properties and subcellular localization of the Atg8 protein of the human malaria parasite Plasmodium falciparum (PfAtg8. PfAtg8 is expressed during intra-erythrocytic development and associates with membranes likely as a lipid-conjugated form. Fluorescence microscopy and immunoelectron microscopy show that PfAtg8 localizes to the apicoplast, a four membrane-bound non-photosynthetic plastid. Autophagosome-like structures are not observed in the erythrocytic stages. These data suggest that, although Plasmodium parasites have lost most Atg proteins during evolution, they use the Atg8 conjugation system for the unique organelle, the apicoplast.

  1. The Clp Chaperones and Proteases of the Human Malaria Parasite Plasmodium falciparum

    Energy Technology Data Exchange (ETDEWEB)

    Bakkouri, Majida El; Pow, Andre; Mulichak, Anne; Cheung, Kevin L.Y.; Artz, Jennifer D.; Amani, Mehrnaz; Fell, Stuart; de Koning-Ward, Tania F.; Goodman, C. Dean; McFadden, Geoffrey I.; Ortega, Joaquin; Hui, Raymond; Houry, Walid A. (McMaster U.); (Melbourne); (Toronto); (Deakin); (HWMRI)

    2015-02-09

    The Clp chaperones and proteases play an important role in protein homeostasis in the cell. They are highly conserved across prokaryotes and found also in the mitochondria of eukaryotes and the chloroplasts of plants. They function mainly in the disaggregation, unfolding and degradation of native as well as misfolded proteins. Here, we provide a comprehensive analysis of the Clp chaperones and proteases in the human malaria parasite Plasmodium falciparum. The parasite contains four Clp ATPases, which we term PfClpB1, PfClpB2, PfClpC and PfClpM. One PfClpP, the proteolytic subunit, and one PfClpR, which is an inactive version of the protease, were also identified. Expression of all Clp chaperones and proteases was confirmed in blood-stage parasites. The proteins were localized to the apicoplast, a non-photosynthetic organelle that accommodates several important metabolic pathways in P. falciparum, with the exception of PfClpB2 (also known as Hsp101), which was found in the parasitophorous vacuole. Both PfClpP and PfClpR form mostly homoheptameric rings as observed by size-exclusion chromatography, analytical ultracentrifugation and electron microscopy. The X-ray structure of PfClpP showed the protein as a compacted tetradecamer similar to that observed for Streptococcus pneumoniae and Mycobacterium tuberculosis ClpPs. Our data suggest the presence of a ClpCRP complex in the apicoplast of P. falciparum.

  2. Characterization of human placental glycosaminoglycans and regional binding to VAR2CSA in malaria infected erythrocytes

    DEFF Research Database (Denmark)

    Beaudet, Julie M; Mansur, Leandra; Joo, Eun Ji

    2014-01-01

    Placental malaria is a serious problem in sub-Saharan Africa. Young women are particular susceptible to contracting this form of malaria during their first or second pregnancy despite previously acquired immunity from past infections. Placental malaria is caused by Plasmodium falciparum parasites...... expressing VAR2CSA on the erythrocyte surface. This protein adheres to a low-sulfated chondroitin sulfate-A found in placental tissue causing great harm to both mother and developing fetus. In rare cases, the localization of infected erythrocytes to the placenta can even result in the vertical transmission...... of malaria. In an effort to better understand this infection, chondroitin sulfate was isolated from the cotyledon part of the placenta, which should be accessible for parasite adhesion, as well as two non-accessible parts of the placenta to serve as controls. The placental chondroitin sulfate structures...

  3. Splenic CD11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.

    Science.gov (United States)

    Bao, Lam Q; Nhi, Dang M; Huy, Nguyen T; Kikuchi, Mihoko; Yanagi, Tetsuo; Hamano, Shinjiro; Hirayama, Kenji

    2015-01-28

    Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure ('three-cure') were required to protect mice against Plasmodium berghei (ANKA strain) infection. C57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia. The percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts. CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

  4. Early Phase Clinical Trials with Human Immunodeficiency Virus-1 and Malaria Vectored Vaccines in The Gambia: Frontline Challenges in Study Design and Implementation

    OpenAIRE

    Afolabi, Muhammed O; Adetifa, Jane U.; Imoukhuede, Egeruan B; Viebig, Nicola K; Kampmann, Beate; Bojang, Kalifa

    2014-01-01

    Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and malaria are among the most important infectious diseases in developing countries. Existing control strategies are unlikely to curtail these diseases in the absence of efficacious vaccines. Testing of HIV and malaria vaccines candidates start with early phase trials that are increasingly being conducted in developing countries where the burden of the diseases is high. Unique challenges, which affect planning and im...

  5. Knowledge of human social and behavioral factors essential for the success of community malaria control intervention programs: The case of Lomahasha in Swaziland.

    Science.gov (United States)

    Dlamini, Sabelo V; Liao, Chien-Wei; Dlamini, Zandile H; Siphepho, Jameson S; Cheng, Po-Ching; Chuang, Ting-Wu; Fan, Chia-Kwung

    2017-04-01

    Although malaria control programs have made rapid progress recently, they neglect important social and behavioral factors associated with the disease. Social, political, and cultural factors are involved in malaria control, and individuals in a community may be comfortable in behaving in ways that, to an outsider, may seem contrary to commonly held perceptions. Malaria control efforts can no longer afford to overlook the multidimensional human contexts that create and support varying notions of malaria and its prevention, treatment, and control. This study aimed to assess the knowledge and perceptions of malaria issues in the community, and to identify practices that support or hinder the progress of malaria control programs. A triangulation study involving individual interviews, focus group discussions, and observatory analysis between 2003 and 2010 at Lomahasha, a malarious community on the eastern border of Swaziland and Mozambique, was conducted. Results indicated that a high knowledge level and good perception of the disease were observed in the age group of malaria control are instituted. Copyright © 2015. Published by Elsevier B.V.

  6. Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.

    Directory of Open Access Journals (Sweden)

    Chloë R McDonald

    2015-09-01

    Full Text Available The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

  7. The flaws and human harms of animal experimentation.

    Science.gov (United States)

    Akhtar, Aysha

    2015-10-01

    Nonhuman animal ("animal") experimentation is typically defended by arguments that it is reliable, that animals provide sufficiently good models of human biology and diseases to yield relevant information, and that, consequently, its use provides major human health benefits. I demonstrate that a growing body of scientific literature critically assessing the validity of animal experimentation generally (and animal modeling specifically) raises important concerns about its reliability and predictive value for human outcomes and for understanding human physiology. The unreliability of animal experimentation across a wide range of areas undermines scientific arguments in favor of the practice. Additionally, I show how animal experimentation often significantly harms humans through misleading safety studies, potential abandonment of effective therapeutics, and direction of resources away from more effective testing methods. The resulting evidence suggests that the collective harms and costs to humans from animal experimentation outweigh potential benefits and that resources would be better invested in developing human-based testing methods.

  8. Quantifying the effects of temperature on mosquito and parasite traits that determine the transmission potential of human malaria.

    Directory of Open Access Journals (Sweden)

    Lillian L M Shapiro

    2017-10-01

    Full Text Available Malaria transmission is known to be strongly impacted by temperature. The current understanding of how temperature affects mosquito and parasite life history traits derives from a limited number of empirical studies. These studies, some dating back to the early part of last century, are often poorly controlled, have limited replication, explore a narrow range of temperatures, and use a mixture of parasite and mosquito species. Here, we use a single pairing of the Asian mosquito vector, An. stephensi and the human malaria parasite, P. falciparum to conduct a comprehensive evaluation of the thermal performance curves of a range of mosquito and parasite traits relevant to transmission. We show that biting rate, adult mortality rate, parasite development rate, and vector competence are temperature sensitive. Importantly, we find qualitative and quantitative differences to the assumed temperature-dependent relationships. To explore the overall implications of temperature for transmission, we first use a standard model of relative vectorial capacity. This approach suggests a temperature optimum for transmission of 29°C, with minimum and maximum temperatures of 12°C and 38°C, respectively. However, the robustness of the vectorial capacity approach is challenged by the fact that the empirical data violate several of the model's simplifying assumptions. Accordingly, we present an alternative model of relative force of infection that better captures the observed biology of the vector-parasite interaction. This model suggests a temperature optimum for transmission of 26°C, with a minimum and maximum of 17°C and 35°C, respectively. The differences between the models lead to potentially divergent predictions for the potential impacts of current and future climate change on malaria transmission. The study provides a framework for more detailed, system-specific studies that are essential to develop an improved understanding on the effects of temperature

  9. The Clp chaperones and proteases of the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    El Bakkouri, Majida; Pow, Andre; Mulichak, Anne; Cheung, Kevin L Y; Artz, Jennifer D; Amani, Mehrnaz; Fell, Stuart; de Koning-Ward, Tania F; Goodman, C Dean; McFadden, Geoffrey I; Ortega, Joaquin; Hui, Raymond; Houry, Walid A

    2010-12-03

    The Clp chaperones and proteases play an important role in protein homeostasis in the cell. They are highly conserved across prokaryotes and found also in the mitochondria of eukaryotes and the chloroplasts of plants. They function mainly in the disaggregation, unfolding and degradation of native as well as misfolded proteins. Here, we provide a comprehensive analysis of the Clp chaperones and proteases in the human malaria parasite Plasmodium falciparum. The parasite contains four Clp ATPases, which we term PfClpB1, PfClpB2, PfClpC and PfClpM. One PfClpP, the proteolytic subunit, and one PfClpR, which is an inactive version of the protease, were also identified. Expression of all Clp chaperones and proteases was confirmed in blood-stage parasites. The proteins were localized to the apicoplast, a non-photosynthetic organelle that accommodates several important metabolic pathways in P. falciparum, with the exception of PfClpB2 (also known as Hsp101), which was found in the parasitophorous vacuole. Both PfClpP and PfClpR form mostly homoheptameric rings as observed by size-exclusion chromatography, analytical ultracentrifugation and electron microscopy. The X-ray structure of PfClpP showed the protein as a compacted tetradecamer similar to that observed for Streptococcus pneumoniae and Mycobacterium tuberculosis ClpPs. Our data suggest the presence of a ClpCRP complex in the apicoplast of P. falciparum. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Optimization of an in vitro system to study the exo-erythrocytic stage of the human malaria parasite, Plasmodium falciparum

    CSIR Research Space (South Africa)

    Rossouw, C

    2010-02-01

    Full Text Available stream_source_info Rossouw_2010.pdf.txt stream_content_type text/plain stream_size 13329 Content-Encoding UTF-8 stream_name Rossouw_2010.pdf.txt Content-Type text/plain; charset=UTF-8 INTRODUCTION Much research remains... scaffold and harvesting cells via the temperature change is currently being scaled up and a prototype bioreactor has been developed. Optimization of an in vitro system to study the exo-erythrocytic stage of the human Malaria Parasite, Plasmodium...

  11. Plasmodium falciparum-like parasites infecting wild apes in southern Cameroon do not represent a recurrent source of human malaria

    Science.gov (United States)

    Sundararaman, Sesh A.; Liu, Weimin; Keele, Brandon F.; Learn, Gerald H.; Bittinger, Kyle; Mouacha, Fatima; Ahuka-Mundeke, Steve; Manske, Magnus; Sherrill-Mix, Scott; Li, Yingying; Malenke, Jordan A.; Delaporte, Eric; Laurent, Christian; Mpoudi Ngole, Eitel; Kwiatkowski, Dominic P.; Shaw, George M.; Rayner, Julian C.; Peeters, Martine; Sharp, Paul M.; Bushman, Frederic D.; Hahn, Beatrice H.

    2013-01-01

    Wild-living chimpanzees and gorillas harbor a multitude of Plasmodium species, including six of the subgenus Laverania, one of which served as the progenitor of Plasmodium falciparum. Despite the magnitude of this reservoir, it is unknown whether apes represent a source of human infections. Here, we used Plasmodium species-specific PCR, single-genome amplification, and 454 sequencing to screen humans from remote areas of southern Cameroon for ape Laverania infections. Among 1,402 blood samples, we found 1,000 to be Plasmodium mitochondrial DNA (mtDNA) positive, all of which contained human parasites as determined by sequencing and/or restriction enzyme digestion. To exclude low-abundance infections, we subjected 514 of these samples to 454 sequencing, targeting a region of the mtDNA genome that distinguishes ape from human Laverania species. Using algorithms specifically developed to differentiate rare Plasmodium variants from 454-sequencing error, we identified single and mixed-species infections with P. falciparum, Plasmodium malariae, and/or Plasmodium ovale. However, none of the human samples contained ape Laverania parasites, including the gorilla precursor of P. falciparum. To characterize further the diversity of P. falciparum in Cameroon, we used single-genome amplification to amplify 3.4-kb mtDNA fragments from 229 infected humans. Phylogenetic analysis identified 62 new variants, all of which clustered with extant P. falciparum, providing further evidence that P. falciparum emerged following a single gorilla-to-human transmission. Thus, unlike Plasmodium knowlesi-infected macaques in southeast Asia, African apes harboring Laverania parasites do not seem to serve as a recurrent source of human malaria, a finding of import to ongoing control and eradication measures. PMID:23569255

  12. Aotus infulatus monkey is susceptible to Plasmodium falciparum infection and may constitute an alternative experimental model for malaria

    Directory of Open Access Journals (Sweden)

    Carvalho Leonardo JM

    2000-01-01

    Full Text Available Aotus is one of the WHO-recommended primate models for studies in malaria, and several species can be infected with Plasmodium falciparum or P. vivax. Here we describe the successful infection of the species A. infulatus from eastern Amazon with blood stages of P. falciparum. Both intact and splenectomized animals were susceptible to infection; the intact ones were able to keep parasitemias at lower levels for several days, but developed complications such as severe anemia; splenectomized monkeys developed higher parasitemias but no major complications. We conclude that A. infulatus is susceptible to P. falciparum infection and may represent an alternative model for studies in malaria.

  13. Photoacoustic detection of hemozoin in human mononuclear cells as an early indicator of malaria infection

    Science.gov (United States)

    Custer, Jonathan R.; Kariuki, Michael; Beerntsen, Brenda T.; Viator, John A.

    2010-02-01

    Malaria is a blood borne infection affecting hundreds of millions of people worldwide2. The parasites reproduce within the blood cells, eventually causing their death and lysis. This process releases the parasites into the blood, continuing the cycle of infection. Usually, malaria is diagnosed only after a patient presents symptoms, including high fever, nausea, and, in advanced cases, coma and death. While invading the bloodstream of a host, malaria parasites convert hemoglobin into an insoluble crystal, known as hemozoin. These crystals, approximately several hundred nanometers in size, are contained within red blood cells and white blood cells that ingest free hemozoin in the blood. Thus, infected red blood cells and white blood cells contain a unique optical absorber that can be detected in blood samples using static photoacoustic detection methods. We separated the white blood cells from malaria infected blood and tested it in a photoacoustic set up using a tunable laser system consisting of an optical parametric oscillator pumped by an Nd:YAG laser with pulse duration of 5 ns. Our threshold of detection was 10 infected white blood cells per microliter, which is more sensitive than current diagnosis methods using microscopic analysis of blood.

  14. The Plasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections.

    Directory of Open Access Journals (Sweden)

    Greta E Weiss

    2010-05-01

    Full Text Available Immunity to Plasmodium falciparum (Pf malaria is only acquired after years of repeated infections and wanes rapidly without ongoing parasite exposure. Antibodies are central to malaria immunity, yet little is known about the B-cell biology that underlies the inefficient acquisition of Pf-specific humoral immunity. This year-long prospective study in Mali of 185 individuals aged 2 to 25 years shows that Pf-specific memory B-cells and antibodies are acquired gradually in a stepwise fashion over years of repeated Pf exposure. Both Pf-specific memory B cells and antibody titers increased after acute malaria and then, after six months of decreased Pf exposure, contracted to a point slightly higher than pre-infection levels. This inefficient, stepwise expansion of both the Pf-specific memory B-cell and long-lived antibody compartments depends on Pf exposure rather than age, based on the comparator response to tetanus vaccination that was efficient and stable. These observations lend new insights into the cellular basis of the delayed acquisition of malaria immunity.

  15. Anti-malaria drug mefloquine induces motor learning deficits in humans

    NARCIS (Netherlands)

    T.A. van Essen (T.); R.S. van der Giessen (Ruben Simon); S.K.E. Koekkoek (Bas); F. VanderWerf (Frans); C.I. de Zeeuw (Chris); P.J.J. van Genderen (Perry); D. Overbosch (David); M.T.G. de Jeu (Marcel)

    2010-01-01

    textabstractMefloquine (a marketed anti-malaria drug) prophylaxis has a high risk of causing adverse events. Interestingly, animal studies have shown that mefloquine imposes a major deficit in motor learning skills by affecting the connexin 36 gap junctions of the inferior olive. We were therefore

  16. Protein export marks the early phase of gametocytogenesis of the human malaria parasite Plasmodium falciparum.

    NARCIS (Netherlands)

    Silvestrini, F.; Lasonder, E.; Olivieri, A.; Camarda, G.; Schaijk, B.C.L. van; Sanchez, M.; Younis Younis, S.; Sauerwein, R.W.; Alano, P.

    2010-01-01

    Despite over a century of study of malaria parasites, parts of the Plasmodium falciparum life cycle remain virtually unknown. One of these is the early gametocyte stage, a round shaped cell morphologically similar to an asexual trophozoite in which major cellular transformations ensure subsequent

  17. Genome-wide diversity and differentiation in New World populations of the human malaria parasite Plasmodium vivax.

    Directory of Open Access Journals (Sweden)

    Thais C de Oliveira

    2017-07-01

    Full Text Available The Americas were the last continent colonized by humans carrying malaria parasites. Plasmodium falciparum from the New World shows very little genetic diversity and greater linkage disequilibrium, compared with its African counterparts, and is clearly subdivided into local, highly divergent populations. However, limited available data have revealed extensive genetic diversity in American populations of another major human malaria parasite, P. vivax.We used an improved sample preparation strategy and next-generation sequencing to characterize 9 high-quality P. vivax genome sequences from northwestern Brazil. These new data were compared with publicly available sequences from recently sampled clinical P. vivax isolates from Brazil (BRA, total n = 11 sequences, Peru (PER, n = 23, Colombia (COL, n = 31, and Mexico (MEX, n = 19.We found that New World populations of P. vivax are as diverse (nucleotide diversity π between 5.2 × 10-4 and 6.2 × 10-4 as P. vivax populations from Southeast Asia, where malaria transmission is substantially more intense. They display several non-synonymous nucleotide substitutions (some of them previously undescribed in genes known or suspected to be involved in antimalarial drug resistance, such as dhfr, dhps, mdr1, mrp1, and mrp-2, but not in the chloroquine resistance transporter ortholog (crt-o gene. Moreover, P. vivax in the Americas is much less geographically substructured than local P. falciparum populations, with relatively little between-population genome-wide differentiation (pairwise FST values ranging between 0.025 and 0.092. Finally, P. vivax populations show a rapid decline in linkage disequilibrium with increasing distance between pairs of polymorphic sites, consistent with very frequent outcrossing. We hypothesize that the high diversity of present-day P. vivax lineages in the Americas originated from successive migratory waves and subsequent admixture between parasite lineages from geographically

  18. Molecular identification of falciparum malaria and human tuberculosis co-infections in mummies from the Fayum depression (Lower Egypt.

    Directory of Open Access Journals (Sweden)

    Albert Lalremruata

    Full Text Available Due to the presence of the lake Quarun and to the particular nature of its irrigation system, it has been speculated that the Fayum, a large depression 80 kilometers south-west of modern Cairo, was exposed to the hazards of malaria in historic times. Similarly, it has been speculated that, in the same area, also human tuberculosis might have been far more widespread in the antiquity than in its recent past. If these hypotheses were confirmed, it would imply that frequent cases of co-infection between the two pathogens might have occurred in ancient populations. To substantiate those speculations, molecular analyses were carried out on sixteen mummified heads recovered from the necropolis of Abusir el Meleq (Fayum dating from the 3(rd Intermediate Period (1064-656 BC to the Roman Period (30 BC-300 AD. Soft tissue biopsies were used for DNA extractions and PCR amplifications using well-suited protocols. A partial 196-bp fragment of Plasmodium falciparum apical membrane antigen 1 gene and a 123-bp fragment of the Mycobacterium tuberculosis complex insertion sequence IS6110 were amplified and sequenced in six and five of the sixteen specimens, respectively. A 100% concordance rates between our sequences and those of P. falciparum and M. tuberculosis complex ones were obtained. Lastly, concomitant PCR amplification of P. falciparum and M. tuberculosis complex DNA specific fragments was obtained in four mummies, three of which are (14C dated to the Late and Graeco-Roman Periods. Our data confirm that the hydrography of Fayum was extremely conducive to the spread of malaria. They also support the notion that the agricultural boom and dense crowding occurred in this region, especially under the Ptolemies, highly increased the probability for the manifestation and spread of tuberculosis. Here we extend back-wards to ca. 800 BC new evidence for malaria tropica and human tuberculosis co-occurrence in ancient Lower Egypt.

  19. Human antibody responses to the Anopheles salivary gSG6-P1 peptide: a novel tool for evaluating the efficacy of ITNs in malaria vector control.

    Directory of Open Access Journals (Sweden)

    Papa Makhtar Drame

    Full Text Available To optimize malaria control, WHO has prioritised the need for new indicators to evaluate the efficacy of malaria vector control strategies. The gSG6-P1 peptide from gSG6 protein of Anopheles gambiae salivary glands was previously designed as a specific salivary sequence of malaria vector species. It was shown that the quantification of human antibody (Ab responses to Anopheles salivary proteins in general and especially to the gSG6-P1 peptide was a pertinent biomarker of human exposure to Anopheles. The present objective was to validate this indicator in the evaluation of the efficacy of Insecticide Treated Nets (ITNs. A longitudinal evaluation, including parasitological, entomological and immunological assessments, was conducted on children and adults from a malaria-endemic area before and after the introduction of ITNs. Significant decrease of anti-gSG6-P1 IgG response was observed just after the efficient ITNs use. Interestingly, specific IgG Ab level was especially pertinent to evaluate a short-time period of ITNs efficacy and at individual level. However, specific IgG rose back up within four months as correct ITN use waned. IgG responses to one salivary peptide could constitute a reliable biomarker for the evaluation of ITN efficacy, at short- and long-term use, and provide a valuable tool in malaria vector control based on a real measurement of human-vector contact.

  20. Human antibody responses to the Anopheles salivary gSG6-P1 peptide: a novel tool for evaluating the efficacy of ITNs in malaria vector control.

    Science.gov (United States)

    Drame, Papa Makhtar; Poinsignon, Anne; Besnard, Patrick; Cornelie, Sylvie; Le Mire, Jacques; Toto, Jean-Claude; Foumane, Vincent; Dos-Santos, Maria Adelaide; Sembène, Mbacké; Fortes, Filomeno; Simondon, Francois; Carnevale, Pierre; Remoue, Franck

    2010-12-14

    To optimize malaria control, WHO has prioritised the need for new indicators to evaluate the efficacy of malaria vector control strategies. The gSG6-P1 peptide from gSG6 protein of Anopheles gambiae salivary glands was previously designed as a specific salivary sequence of malaria vector species. It was shown that the quantification of human antibody (Ab) responses to Anopheles salivary proteins in general and especially to the gSG6-P1 peptide was a pertinent biomarker of human exposure to Anopheles. The present objective was to validate this indicator in the evaluation of the efficacy of Insecticide Treated Nets (ITNs). A longitudinal evaluation, including parasitological, entomological and immunological assessments, was conducted on children and adults from a malaria-endemic area before and after the introduction of ITNs. Significant decrease of anti-gSG6-P1 IgG response was observed just after the efficient ITNs use. Interestingly, specific IgG Ab level was especially pertinent to evaluate a short-time period of ITNs efficacy and at individual level. However, specific IgG rose back up within four months as correct ITN use waned. IgG responses to one salivary peptide could constitute a reliable biomarker for the evaluation of ITN efficacy, at short- and long-term use, and provide a valuable tool in malaria vector control based on a real measurement of human-vector contact.

  1. Human Antibody Responses to the Anopheles Salivary gSG6-P1 Peptide: A Novel Tool for Evaluating the Efficacy of ITNs in Malaria Vector Control

    Science.gov (United States)

    Drame, Papa Makhtar; Poinsignon, Anne; Besnard, Patrick; Cornelie, Sylvie; Le Mire, Jacques; Toto, Jean-Claude; Foumane, Vincent; Dos-Santos, Maria Adelaide; Sembène, Mbacké; Fortes, Filomeno; Simondon, Francois; Carnevale, Pierre; Remoue, Franck

    2010-01-01

    To optimize malaria control, WHO has prioritised the need for new indicators to evaluate the efficacy of malaria vector control strategies. The gSG6-P1 peptide from gSG6 protein of Anopheles gambiae salivary glands was previously designed as a specific salivary sequence of malaria vector species. It was shown that the quantification of human antibody (Ab) responses to Anopheles salivary proteins in general and especially to the gSG6-P1 peptide was a pertinent biomarker of human exposure to Anopheles. The present objective was to validate this indicator in the evaluation of the efficacy of Insecticide Treated Nets (ITNs). A longitudinal evaluation, including parasitological, entomological and immunological assessments, was conducted on children and adults from a malaria-endemic area before and after the introduction of ITNs. Significant decrease of anti-gSG6-P1 IgG response was observed just after the efficient ITNs use. Interestingly, specific IgG Ab level was especially pertinent to evaluate a short-time period of ITNs efficacy and at individual level. However, specific IgG rose back up within four months as correct ITN use waned. IgG responses to one salivary peptide could constitute a reliable biomarker for the evaluation of ITN efficacy, at short- and long-term use, and provide a valuable tool in malaria vector control based on a real measurement of human-vector contact. PMID:21179476

  2. Marine actinomycetes: a new source of compounds against the human malaria parasite.

    Directory of Open Access Journals (Sweden)

    Jacques Prudhomme

    2008-06-01

    Full Text Available Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and development. Throughout history, traditional herbal remedies or natural products have been a reliable source of antimalarial agents, e.g. quinine and artemisinin. Today, one emerging source of small molecule drug leads is the world's oceans. Included among the source of marine natural products are marine microorganisms such as the recently described actinomycete. Members of the genus Salinispora have yielded a wealth of new secondary metabolites including salinosporamide A, a molecule currently advancing through clinical trials as an anticancer agent. Because of the biological activity of metabolites being isolated from marine microorganisms, our group became interested in exploring the potential efficacy of these compounds against the malaria parasite.We screened 80 bacterial crude extracts for their activity against malaria growth. We established that the pure compound, salinosporamide A, produced by the marine actinomycete, Salinispora tropica, shows strong inhibitory activity against the erythrocytic stages of the parasite cycle. Biochemical experiments support the likely inhibition of the parasite 20S proteasome. Crystal structure modeling of salinosporamide A and the parasite catalytic 20S subunit further confirm this hypothesis. Ultimately we showed that salinosporamide A protected mice against deadly malaria infection when administered at an extremely low dosage.These findings underline the potential of secondary metabolites, derived from marine microorganisms, to inhibit Plasmodium growth. More specifically, we highlight the effect of proteasome inhibitors such as salinosporamide A on in vitro and in vivo parasite development. Salinosporamide A (NPI-0052 now

  3. Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations.

    Science.gov (United States)

    Ko, Wen-Ya; Kaercher, Kristin A; Giombini, Emanuela; Marcatili, Paolo; Froment, Alain; Ibrahim, Muntaser; Lema, Godfrey; Nyambo, Thomas B; Omar, Sabah A; Wambebe, Charles; Ranciaro, Alessia; Hirbo, Jibril B; Tishkoff, Sarah A

    2011-06-10

    Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geographically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3-4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  4. The dominant Anopheles vectors of human malaria in the Americas: occurrence data, distribution maps and bionomic précis.

    Science.gov (United States)

    Sinka, Marianne E; Rubio-Palis, Yasmin; Manguin, Sylvie; Patil, Anand P; Temperley, Will H; Gething, Peter W; Van Boeckel, Thomas; Kabaria, Caroline W; Harbach, Ralph E; Hay, Simon I

    2010-08-16

    An increasing knowledge of the global risk of malaria shows that the nations of the Americas have the lowest levels of Plasmodium falciparum and P. vivax endemicity worldwide, sustained, in part, by substantive integrated vector control. To help maintain and better target these efforts, knowledge of the contemporary distribution of each of the dominant vector species (DVS) of human malaria is needed, alongside a comprehensive understanding of the ecology and behaviour of each species. A database of contemporary occurrence data for 41 of the DVS of human malaria was compiled from intensive searches of the formal and informal literature. The results for the nine DVS of the Americas are described in detail here. Nearly 6000 occurrence records were gathered from 25 countries in the region and were complemented by a synthesis of published expert opinion range maps, refined further by a technical advisory group of medical entomologists. A suite of environmental and climate variables of suspected relevance to anopheline ecology were also compiled from open access sources. These three sets of data were then combined to produce predictive species range maps using the Boosted Regression Tree method. The predicted geographic extent for each of the following species (or species complex*) are provided: Anopheles (Nyssorhynchus) albimanus Wiedemann, 1820, An. (Nys.) albitarsis*, An. (Nys.) aquasalis Curry, 1932, An. (Nys.) darlingi Root, 1926, An. (Anopheles) freeborni Aitken, 1939, An. (Nys.) marajoara Galvão & Damasceno, 1942, An. (Nys.) nuneztovari*, An. (Ano.) pseudopunctipennis* and An. (Ano.) quadrimaculatus Say, 1824. A bionomics review summarising ecology and behaviour relevant to the control of each of these species was also compiled. The distribution maps and bionomics review should both be considered as a starting point in an ongoing process of (i) describing the distributions of these DVS (since the opportunistic sample of occurrence data assembled can be

  5. The dominant Anopheles vectors of human malaria in the Americas: occurrence data, distribution maps and bionomic précis

    Directory of Open Access Journals (Sweden)

    Sinka Marianne E

    2010-08-01

    Full Text Available Abstract Background An increasing knowledge of the global risk of malaria shows that the nations of the Americas have the lowest levels of Plasmodium falciparum and P. vivax endemicity worldwide, sustained, in part, by substantive integrated vector control. To help maintain and better target these efforts, knowledge of the contemporary distribution of each of the dominant vector species (DVS of human malaria is needed, alongside a comprehensive understanding of the ecology and behaviour of each species. Results A database of contemporary occurrence data for 41 of the DVS of human malaria was compiled from intensive searches of the formal and informal literature. The results for the nine DVS of the Americas are described in detail here. Nearly 6000 occurrence records were gathered from 25 countries in the region and were complemented by a synthesis of published expert opinion range maps, refined further by a technical advisory group of medical entomologists. A suite of environmental and climate variables of suspected relevance to anopheline ecology were also compiled from open access sources. These three sets of data were then combined to produce predictive species range maps using the Boosted Regression Tree method. The predicted geographic extent for each of the following species (or species complex* are provided: Anopheles (Nyssorhynchus albimanus Wiedemann, 1820, An. (Nys. albitarsis*, An. (Nys. aquasalis Curry, 1932, An. (Nys. darlingi Root, 1926, An. (Anopheles freeborni Aitken, 1939, An. (Nys. marajoara Galvão & Damasceno, 1942, An. (Nys. nuneztovari*, An. (Ano. pseudopunctipennis* and An. (Ano. quadrimaculatus Say, 1824. A bionomics review summarising ecology and behaviour relevant to the control of each of these species was also compiled. Conclusions The distribution maps and bionomics review should both be considered as a starting point in an ongoing process of (i describing the distributions of these DVS (since the opportunistic

  6. Human Experimentation: Impact on Health Education Research.

    Science.gov (United States)

    Vacalis, T. Demetri; Griffis, Kathleen

    1980-01-01

    The problems of the use of humans as subjects of medical research and the protection of their rights are discussed. Issues include the use of informed consent, the evaluation of risks and benefits, and the review of research plans by a committee. (JD)

  7. Gibberellin biosynthetic inhibitors make human malaria parasite Plasmodium falciparum cells swell and rupture to death.

    Directory of Open Access Journals (Sweden)

    Tomoko Toyama

    Full Text Available Malaria remains as one of the most devastating infectious disease, and continues to exact an enormous toll in medical cost and days of labor lost especially in the tropics. Effective malaria control and eventual eradication remain a huge challenge, with efficacious antimalarials as important intervention/management tool. Clearly new alternative drugs that are more affordable and with fewer side effects are desirable. After preliminary in vitro assays with plant growth regulators and inhibitors, here, we focus on biosynthetic inhibitors of gibberellin, a plant hormone with many important roles in plant growth, and show their inhibitory effect on the growth of both apicomplexa, Plasmodium falciparum and Toxoplasma gondii. Treatment of P. falciparum cultures with the gibberellin biosynthetic inhibitors resulted in marked morphological changes that can be reversed to a certain degree under hyperosmotic environment. These unique observations suggest that changes in the parasite membrane permeability may explain the pleiotropic effects observed within the intracellular parasites.

  8. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

    Science.gov (United States)

    Mok, Sachel; Ashley, Elizabeth A.; Ferreira, Pedro E.; Zhu, Lei; Lin, Zhaoting; Yeo, Tomas; Chotivanich, Kesinee; Imwong, Mallika; Pukrittayakamee, Sasithon; Dhorda, Mehul; Nguon, Chea; Lim, Pharath; Amaratunga, Chanaki; Suon, Seila; Hien, Tran Tinh; Htut, Ye; Faiz, M. Abul; Onyamboko, Marie A.; Mayxay, Mayfong; Newton, Paul N.; Tripura, Rupam; Woodrow, Charles J.; Miotto, Olivo; Kwiatkowski, Dominic P.; Nosten, François; Day, Nicholas P. J.; Preiser, Peter R.; White, Nicholas J.; Dondorp, Arjen M.; Fairhurst, Rick M.; Bozdech, Zbynek

    2017-01-01

    Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain–carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion. PMID:25502316

  9. Suppression of blood monocyte and neutrophil chemotaxis in acute human malaria

    DEFF Research Database (Denmark)

    Nielsen, H; Kharazmi, A; Theander, T G

    1986-01-01

    tested monocyte chemotactic responsiveness in 19 patients with acute primary attack malaria. In addition, the neutrophil chemotaxis was measured in 12 patients. Before the initiation of antimalarial treatment a significant depression of monocyte chemotaxis was observed in approximately half...... suppressed. The monocyte chemotaxis was followed in 14 of the patients, during treatment and after complete recovery. After 3 days of treatment the response had improved in most of the patients, and after 7 days all patients had a normal monocyte chemotaxis, which remained normal after one month....... No significant differences between P. falciparum and P. vivax/ovale malaria was observed with respect to blood monocyte chemotactic responsiveness. Neutrophil chemotaxis in patients with P. falciparum infections was similarly suppressed before treatment (54% of controls), was still defective after 3 days...

  10. Gibberellin Biosynthetic Inhibitors Make Human Malaria Parasite Plasmodium falciparum Cells Swell and Rupture to Death

    Science.gov (United States)

    Toyama, Tomoko; Tahara, Michiru; Nagamune, Kisaburo; Arimitsu, Kenji; Hamashima, Yoshio; Palacpac, Nirianne M. Q.; Kawaide, Hiroshi; Horii, Toshihiro; Tanabe, Kazuyuki

    2012-01-01

    Malaria remains as one of the most devastating infectious disease, and continues to exact an enormous toll in medical cost and days of labor lost especially in the tropics. Effective malaria control and eventual eradication remain a huge challenge, with efficacious antimalarials as important intervention/management tool. Clearly new alternative drugs that are more affordable and with fewer side effects are desirable. After preliminary in vitro assays with plant growth regulators and inhibitors, here, we focus on biosynthetic inhibitors of gibberellin, a plant hormone with many important roles in plant growth, and show their inhibitory effect on the growth of both apicomplexa, Plasmodium falciparum and Toxoplasma gondii. Treatment of P. falciparum cultures with the gibberellin biosynthetic inhibitors resulted in marked morphological changes that can be reversed to a certain degree under hyperosmotic environment. These unique observations suggest that changes in the parasite membrane permeability may explain the pleiotropic effects observed within the intracellular parasites. PMID:22412858

  11. Human Factors Experimental Design and Analysis Reference

    Science.gov (United States)

    2007-07-01

    8.75 83.36 8 =where, tObserved YPD = 53.75 YSD = 62.00 3.6.5. Within-Subjects t-Test (Cont’d) (Click in this red rectangle to see SAS calculations...expands computer experience into 3 levels, High, Medium , and Low, as compared to the original example that used only 2 levels of computer experience...High and Low. In this example, each of the 80 subjects who used the experimental text editor rated their computer experience as high, medium , or

  12. Ape malaria transmission and potential for ape-to-human transfers in Africa

    OpenAIRE

    Makanga, B; Yangari, P.; Rahola, N; Rougeron, V.; Elguero, E; Boundenga, L; Moukodoum, ND; Okouga, AP; Arnathau, C; Durand, P; Willaume, E.; Ayala, D; D. Fontenille; Ayala, FJ; Renaud, F.

    2016-01-01

    Recent studies have highlighted the large diversity of malaria parasites infecting African great apes (subgenus Laverania) and their strong host specificity. Although the existence of genetic incompatibilities preventing the cross-species transfer may explain host specificity, the existence of vectors with a high preference for a determined host represents another possibility. To test this hypothesis, we undertook a 15-mo-long longitudinal entomological survey in two forest regions of Gabon, ...

  13. The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

    OpenAIRE

    Syafruddin

    2002-01-01

    Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locall...

  14. Performance appraisal of rapid on-site malaria diagnosis (ICT malaria Pf/Pv test) in relation to human resources at village level in Myanmar.

    Science.gov (United States)

    Cho-Min-Naing; Gatton, M L

    2002-01-01

    Logistic, economic and technical factors limit rapid access to microscopic confirmation of symptomatic diagnosis of malaria in many rural areas in endemic countries such as Myanmar. A study was conducted to evaluate a rapid on-site immunochromatographic test (ICT Malaria Pf/Pv) for detection of Plasmodium falciparum and P. vivax in two villages in the Taikkyi region of Myanmar. The ICT Malaria tests were performed by a volunteer health worker (VHW) in Yae-Aye-San village and by a professionally trained midwife (MW) in Kankone village. A total of 1000 symptomatic patients participated in the study by providing blood samples for an ICT test and for microscopy. The ICT performance indices, relative to microscopy, were better for the trained MW compared with the less experienced VHW. For P. falciparum and/or P. vivax infections, the sensitivities were 82.7% for the VHW compared with 93.7% for the MW. For P. falciparum infections, the sensitivities were 82.2% for the VHW and 91.3% for the MW, while the corresponding values for P. vivax infections were 66.7 and 79%, respectively. Although the test kit appeared to perform better in more experienced hands, this study questions whether this difference is related to the use of the ICT Malaria Pf/Pv test kit, or related to other factors such as differences in the quality of blood slides prepared by the VHW and MW for microscopic examination. Overall, the results suggest that a rapid diagnostic assay such as the ICT Malaria Pf/Pv test kit can be used in rural settings by relatively inexperienced persons, such as VHWs, with a reasonable degree of sensitivity, thus providing on-site confirmation of symptomatic diagnosis of malaria.

  15. World Malaria Report: time to acknowledge Plasmodium knowlesi malaria.

    Science.gov (United States)

    Barber, Bridget E; Rajahram, Giri S; Grigg, Matthew J; William, Timothy; Anstey, Nicholas M

    2017-03-31

    The 2016 World Health Organization (WHO) World Malaria Report documents substantial progress towards control and elimination of malaria. However, major challenges remain. In some regions of Southeast Asia, the simian parasite Plasmodium knowlesi has emerged as an important cause of human malaria, and the authors believe this species warrants regular inclusion in the World Malaria Report. Plasmodium knowlesi is the most common cause of malaria in Malaysia, and cases have also been reported in nearly all countries of Southeast Asia. Outside of Malaysia, P. knowlesi is frequently misdiagnosed by microscopy as Plasmodium falciparum or Plasmodium vivax. Thus, P. knowlesi may be underdiagnosed in affected regions and its true incidence underestimated. Acknowledgement in the World Malaria Report of the regional importance of P. knowlesi will facilitate efforts to improve surveillance of this emerging parasite. Furthermore, increased recognition will likely lead to improved delivery of effective treatment for this potentially fatal infection, as has occurred in Malaysia where P. knowlesi case-fatality rates have fallen despite rising incidence. In a number of knowlesi-endemic countries, substantial progress has been made towards the elimination of P. vivax and P. falciparum. However, efforts to eliminate these human-only species should not preclude efforts to reduce human malaria from P. knowlesi. The regional importance of knowlesi malaria was recognized by the WHO with its recent Evidence Review Group meeting on knowlesi malaria to address strategies for prevention and mitigation. The WHO World Malaria Report has an appropriate focus on falciparum and vivax malaria, the major causes of global mortality and morbidity. However, the authors hope that in future years this important publication will also incorporate data on the progress and challenges in reducing knowlesi malaria in regions where transmission occurs.

  16. CD4+ natural regulatory T cells prevent experimental cerebral malaria via CTLA-4 when expanded in vivo.

    Directory of Open Access Journals (Sweden)

    Ashraful Haque

    Full Text Available Studies in malaria patients indicate that higher frequencies of peripheral blood CD4(+ Foxp3(+ CD25(+ regulatory T (Treg cells correlate with increased blood parasitemia. This observation implies that Treg cells impair pathogen clearance and thus may be detrimental to the host during infection. In C57BL/6 mice infected with Plasmodium berghei ANKA, depletion of Foxp3(+ cells did not improve parasite control or disease outcome. In contrast, elevating frequencies of natural Treg cells in vivo using IL-2/anti-IL-2 complexes resulted in complete protection against severe disease. This protection was entirely dependent upon Foxp3(+ cells and resulted in lower parasite biomass, impaired antigen-specific CD4(+ T and CD8(+ T cell responses that would normally promote parasite tissue sequestration in this model, and reduced recruitment of conventional T cells to the brain. Furthermore, Foxp3(+ cell-mediated protection was dependent upon CTLA-4 but not IL-10. These data show that T cell-mediated parasite tissue sequestration can be reduced by regulatory T cells in a mouse model of malaria, thereby limiting malaria-induced immune pathology.

  17. Wildlife disease and conservation in Hawaii: pathogenicity of avian malaria (Plasmodium relictum) in experimentally infected Iiwi (Vestiaria coccinea)

    Science.gov (United States)

    Atkinson, C.T.; Woods, K.L.; Dusek, Robert J.; Sileo, L.S.; Iko, W.M.

    1995-01-01

    Native Hawaiian forest birds are facing a major extinction crisis with more than 75% of species recorded in historical times either extinct or endangered. Reasons for this catastrophe include habitat destruction, competition with non-native species, and introduction of predators and avian diseases. We tested susceptibility of Iiwi (Vestiaria coccinea), a declining native species, and Nutmeg Mannikins (Lonchura punctulata), a common non-native species, to an isolate of Plasmodium relictum from the island of Hawaii. Food consumption, weight, and parasitaemia were monitored in juvenile Iiwi that were infected by either single (low-dose) or multiple (high-dose) mosquito bites. Mortality in both groups was significantly higher than in uninfected controls, reaching 100% of high-dose birds and 90% of low-dose birds. Significant declines in food consumption and a corresponding loss of body weight occurred in malaria-infected birds. Both sex and body weight had significant effects on survival time, with males more susceptible than females and birds with low initial weights more susceptible than those with higher initial weights. Gross and microscopic lesions in malaria fatalities included massive enlargement of the spleen and liver, hyperplasia of the reticuloendothelial system with extensive deposition of malarial pigment, and overwhelming anaemia in which over 30% of the circulating erythrocytes were parasitized. Nutmeg Mannikins, by contrast, were completely refractory to infection. Our findings support previous studies documenting high susceptibility of native Hawaiian forest birds to avian malaria. This disease continues to threaten remaining high elevation populations of endangered native birds.

  18. A human experimental model of episodic pain

    DEFF Research Database (Denmark)

    Petrini, Laura; Hennings, Kristian; Li, Xi

    2014-01-01

    were subjected to 45 min of intense painful cutaneous electrical stimulation (episodic pain session), using a stimulus paradigm that in animals has been shown to induce long-term potentiation. These electrical stimulations produced a verbal pain rating of approximately 85 on a 0-100 verbal rating scale......An experimental model of daily episodic pain was developed to investigate peripheral sensitization and cortical reorganization in healthy individuals. Two experiments (A and B) were conducted. Experiments A and B consisted of one and five consecutive days, respectively, in which the participants...... (VRS). Physiological (blood flow and axon flare reflex), psychophysical (perception threshold and verbal pain ratings) and electrophysiological (128 channels recorded somatosensory evoked potential (SEP)) measurements were recorded. The stimulation evoked a visible axon flare reflex and caused...

  19. Stress dependent infection cost of the human malaria agent Plasmodium falciparum on its natural vector Anopheles coluzzii.

    Science.gov (United States)

    Sangare, I; Dabire, R; Yameogo, B; Da, D F; Michalakis, Y; Cohuet, A

    2014-07-01

    Unraveling selective forces that shape vector-parasite interactions has critical implications for malaria control. However, it remains unclear whether Plasmodium infection induces a fitness cost to their natural mosquito vectors. Moreover, environmental conditions are known to affect infection outcome and may impact the effect of infection on mosquito fitness. We investigated in the laboratory the effects of exposition to and infection by field isolates of Plasmodium falciparum on fecundity and survival of a major vector in the field, Anopheles coluzzii under different conditions of access to sugar resources after blood feeding. The results evidenced fitness costs induced by exposition and infection. When sugar was available after blood meal, infected and exposed mosquitoes had either reduced or equal to survival to unexposed mosquitoes while fecundity was either increased or decreased depending on the blood donor. Under strong nutritional stress, survival was reduced for exposed and infected mosquitoes in all assays. We therefore provide here evidence of an environmental-dependant reduced survival in mosquitoes exposed to infection in a natural and one of the most important parasite-mosquito species associations for human malaria transmission. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  20. The response of the malaria mosquito, Anopheles gambiae, to two components of human sweat, ammonia and L-lactic acid, in an olfactometer

    NARCIS (Netherlands)

    Braks, M.A.H.; Meijerink, J.; Takken, W.

    2001-01-01

    In an olfactometer study on the response of the anthropophilic malaria mosquito Anopheles gambiae s.s. (Diptera, Culicidae) to human sweat it was found that freshly collected sweat, mostly of eccrine origin, was attractive, but that incubated sweat was significantly more attractive than fresh sweat.

  1. Bioinformatics approaches to malaria

    DEFF Research Database (Denmark)

    Hansen, Daniel Aaen

    Malaria is a life threatening disease found in tropical and subtropical regions of the world. Each year it kills 781 000 individuals; most of them are children under the age of five in sub-Saharan Africa. The most severe form of malaria in humans is caused by the parasite Plasmodium falciparum......, which is the subject of the first part of this thesis. The PfEMP1 protein which is encoded by the highly variablevargene family is important in the pathogenesis and immune evasion of malaria parasites. We analyzed and classified these genes based on the upstream sequence in seven......Plasmodium falciparumclones. We show that the amount of nucleotide diversity is just as big within each clone as it is between the clones. DNA methylation is an important epigenetic mark in many eukaryotic species. We are studying DNA methylation in the malaria parasitePlasmodium falciparum. The work is still in progress...

  2. Muscling out malaria

    DEFF Research Database (Denmark)

    Hughes, David Peter; Boomsma, Jacobus Jan

    2006-01-01

    ) [2] highlighted the back-to-back articles in Science 3 and 4 that demonstrated the potential biocontrol of malaria by targeting mosquitoes with entomopathogenic fungi (Metarhizium and Beauveria spp.). The wide impact of the original articles and the need to find alternatives to pesticidal control...... where malaria is endemic, humanity cannot afford shortcuts, because any failures owing to poor management or premature implementation will reduce local governmental support rather than enhance it (Andrew Read, pers. commun.). Therefore, if we are to ‘muscle out malaria', well...... of key importance, and the new focus on fungal biocontrol of malaria should therefore act as a catalyst for further research on the basic biology of fungal pathogens. Understanding morphological, biochemical or immune system-based resistance to insect pathogenic fungi will be easier if we know...

  3. Optimization of experimental human leukemia models (review

    Directory of Open Access Journals (Sweden)

    D. D. Pankov

    2012-01-01

    Full Text Available Actual problem of assessing immunotherapy prospects including antigenpecific cell therapy using animal models was covered in this review.Describe the various groups of currently existing animal models and methods of their creating – from different immunodeficient mice to severalvariants of tumor cells engraftment in them. The review addresses the possibility of tumor stem cells studying using mouse models for the leukemia treatment with adoptive cell therapy including WT1. Also issues of human leukemia cells migration and proliferation in a mice withdifferent immunodeficiency degree are discussed. To assess the potential immunotherapy efficacy comparison of immunodeficient mouse model with clinical situation in oncology patients after chemotherapy is proposed.

  4. Changes in total and differential leukocyte counts during the clinically silent liver phase in a controlled human malaria infection in malaria-naïve Dutch volunteers

    NARCIS (Netherlands)

    M.E. van Wolfswinkel (Marlies); Langenberg, M.C.C. (Marijke C. C.); L.J. Wammes (Linda); R.W. Sauerwein (Robert); R. Koelewijn (Rob); C.C. Hermsen (Cornelus); J.J. van Hellemond (Jaap); P.J.J. van Genderen (Perry)

    2017-01-01

    textabstractBackground: Both in endemic countries and in imported malaria, changes in total and differential leukocyte count during Plasmodium falciparum infection have been described. To study the exact dynamics of differential leukocyte counts and their ratios, they were monitored in a group of

  5. Changes in total and differential leukocyte counts during the clinically silent liver phase in a controlled human malaria infection in malaria-naive Dutch volunteers

    NARCIS (Netherlands)

    Wolfswinkel, M.E. van; Langenberg, M.C.; Wammes, L.J.; Sauerwein, R.W.; Koelewijn, R.; Hermsen, C.C.; Hellemond, J.J. van; Genderen, P.J. van

    2017-01-01

    BACKGROUND: Both in endemic countries and in imported malaria, changes in total and differential leukocyte count during Plasmodium falciparum infection have been described. To study the exact dynamics of differential leukocyte counts and their ratios, they were monitored in a group of healthy

  6. Early phase clinical trials with human immunodeficiency virus-1 and malaria vectored vaccines in The Gambia: frontline challenges in study design and implementation.

    Science.gov (United States)

    Afolabi, Muhammed O; Adetifa, Jane U; Imoukhuede, Egeruan B; Viebig, Nicola K; Kampmann, Beate; Bojang, Kalifa

    2014-05-01

    Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and malaria are among the most important infectious diseases in developing countries. Existing control strategies are unlikely to curtail these diseases in the absence of efficacious vaccines. Testing of HIV and malaria vaccines candidates start with early phase trials that are increasingly being conducted in developing countries where the burden of the diseases is high. Unique challenges, which affect planning and implementation of vaccine trials according to internationally accepted standards have thus been identified. In this review, we highlight specific challenges encountered during two early phase trials of novel HIV-1 and malaria vectored vaccine candidates conducted in The Gambia and how some of these issues were pragmatically addressed. We hope our experience will be useful for key study personnel involved in day-to-day running of similar clinical trials. It may also guide future design and implementation of vaccine trials in resource-constrained settings.

  7. Effects of experimental cerebral malaria in memory, brain-derived neurotrophic factor and acetylcholinesterase activity [correction for acitivity] in the hippocampus of survivor mice.

    Science.gov (United States)

    Comim, Clarissa M; Reis, Patrícia A; Frutuoso, Valber S; Fries, Gabriel R; Fraga, Daiane B; Kapczinski, Flávio; Zugno, Alexandra I; Barichello, Tatiana; Quevedo, João; Castro-Faria-Neto, Hugo C

    2012-08-15

    Malaria is the most important human parasitic disease and cerebral malaria (CM), its main neurological complication, is characterized by neurological and cognitive damage in both human and animal survivors. The brain-derived neurotrophic factor (BDNF) appears to be involved with activity-dependent synaptic plasticity. There is great interest regarding its role in learning and memory as well as acetylcholinesterase activity (AChE) that is implicated in many cognitive functions and probably plays important roles in neurodegenerative disorders. In the present work, we evaluated BDNF protein levels and AChE activity in the hippocampus and habituation in an animal model of CM using C57BL/6 mice after fifteen days of the induction. The results demonstrated that there was a decrease in BDNF levels in the hippocampus of C57BL/6 mice infected with PbA when compared with C57BL/6 non-infected mice and C57BL/6 non-infected mice that received treatment with chloroquine. However, no difference was observed in AChE activity in the hippocampus. When habituation was evaluated there was memory impairment in the C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). In conclusion, we believe that the decreased BDNF levels in the hippocampus may be related with memory impairment without alterations on AChE activity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  8. Prevalence of malaria and patients in Ethiope E alence of malaria ...

    African Journals Online (AJOL)

    McRoy

    2014-12-31

    Dec 31, 2014 ... Malaria and human blood factors. Int J Med Biomed Res 2014;3(3):191-201. 192. Human malaria is commonly caused by five plasmodiumspecies: Plasmodium vivax, P. malariae, P. falciparum, P. ovale and P. knowlesi each with their geographical location and varied incubation periods (IP), from infection ...

  9. Prevalence and Parasite Density of Asymptomatic Malaria ...

    African Journals Online (AJOL)

    effective use of insecticide treated nets and intermittent prophylaxis therapy for malaria during pregnancy. KEY WORDS: Asymptomatic malaria parasitemia, Nigeria, prevalence, unbooked paturients. INTRODUCTION. Malaria is a parasitic disease of humans especially in the sub‑Saharan Africa, where about 90% of deaths ...

  10. demographic factors associated factors associated with malaria ...

    African Journals Online (AJOL)

    userpc

    associated with malaria prevalence. Keywords: Malaria, Demographic, Plasmodiu. INTRODUCTION. Malaria is a parasitic disease,. Nigeria and many tropical and subtropic regions of the globe. It is caused by th protozoan parasite Plasmodium. Human malar is caused by four different species o. Plasmodium: P. falciparum ...

  11. Changes in microbiota during experimental human Rhinovirus infection

    NARCIS (Netherlands)

    Hofstra, J. J.; Matamoros, S.; van de Pol, M. A.; de Wever, B.; Tanck, M. W.; Wendt-Knol, H.; Deijs, M.; van der Hoek, L.; Wolthers, K. C.; Molenkamp, R.; Visser, C. E.; Sterk, P. J.; Lutter, R.; de Jong, M. D.

    2015-01-01

    Human Rhinovirus (HRV) is responsible for the majority of common colds and is frequently accompanied by secondary bacterial infections through poorly understood mechanisms. We investigated the effects of experimental human HRV serotype 16 infection on the upper respiratory tract microbiota. Six

  12. The GMZ2 malaria vaccine: from concept to efficacy in humans

    DEFF Research Database (Denmark)

    Theisen, Michael; Adu, Bright; Mordmueller, Benjamin

    2017-01-01

    Introduction: GMZ2 is a recombinant protein consisting of conserved domains of GLURP and MSP3, two asexual blood-stage antigens of Plasmodium falciparum, and is designed with the aim of mimicking naturally acquired anti-malarial immunity. The rationale for combining these two antigens is based...... on a series of immune epidemiological studies from geographically diverse malaria endemic regions; functional in vitro studies; and pre-clinical studies in rodents and New World monkeys. GMZ2 adjuvanted with alhydrogel® (alum) was well tolerated and immunogenic in three phase 1 studies. The recently concluded...

  13. Ethical aspects of malaria control and research

    OpenAIRE

    Jamrozik, Euzebiusz; de la Fuente-N??ez, V?nia; Reis, Andreas; Ringwald, Pascal; Selgelid, Michael J.

    2015-01-01

    Malaria currently causes more harm to human beings than any other parasitic disease, and disproportionally affects low-income populations. The ethical issues raised by efforts to control or eliminate malaria have received little explicit analysis, in comparison with other major diseases of poverty. While some ethical issues associated with malaria are similar to those that have been the subject of debate in the context of other infectious diseases, malaria also raises distinct ethical issues ...

  14. EXPERIMENTAL SEMIOTICS: AN ENGINE OF DISCOVERY FOR UNDERSTANDING HUMAN COMMUNICATION

    OpenAIRE

    BRUNO GALANTUCCI; GARETH ROBERTS

    2012-01-01

    The recent growth of Experimental Semiotics (ES) offers us a new option to investigate human communication. We briefly introduce ES, presenting results from three themes of research which emerged within it. Then we illustrate the contribution ES can make to the investigation of human communication systems, particularly in comparison with the other existing options. This comparison highlights how ES can provide an engine of discovery for understanding human communication. In fact, in complemen...

  15. In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria.

    Directory of Open Access Journals (Sweden)

    Henrique Borges da Silva

    2015-02-01

    Full Text Available Dendritic cells (DCs are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip, with Plasmodium chabaudi AS (Pc parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.

  16. Increased access to care and appropriateness of treatment at private sector drug shops with integrated management of malaria, pneumonia and diarrhoea: a quasi-experimental study in Uganda.

    Directory of Open Access Journals (Sweden)

    Phyllis Awor

    Full Text Available INTRODUCTION: Drug shops are a major source of care for children in low income countries but they provide sub-standard care. We assessed the feasibility and effect on quality of care of introducing diagnostics and pre-packaged paediatric-dosage drugs for malaria, pneumonia and diarrhoea at drug shops in Uganda. METHODS: We adopted and implemented the integrated community case management (iCCM intervention within registered drug shops. Attendants were trained to perform malaria rapid diagnostic tests (RDTs in each fever case and count respiratory rate in each case of cough with fast/difficult breathing, before dispensing recommended treatment. Using a quasi-experimental design in one intervention and one non-intervention district, we conducted before and after exit interviews for drug seller practices and household surveys for treatment-seeking practices in May-June 2011 and May-June 2012. Survey adjusted generalized linear models and difference-in-difference analysis was used. RESULTS: 3759 (1604 before/2155 after household interviews and 943 (163 before/780 after exit interviews were conducted with caretakers of children under-5. At baseline, no child at a drug shop received any diagnostic testing before treatment in both districts. After the intervention, while no child in the non-intervention district received a diagnostic test, 87.7% (95% CI 79.0-96.4 of children with fever at the intervention district drug shops had a parasitological diagnosis of malaria, prior to treatment. The prevalence ratios of the effect of the intervention on treatment of cough and fast breathing with amoxicillin and diarrhoea with ORS/zinc at the drug shop were 2.8 (2.0-3.9, and 12.8 (4.2-38.6 respectively. From the household survey, the prevalence ratio of the intervention effect on use of RDTs was 3.2 (1.9-5.4; Artemisinin Combination Therapy for malaria was 0.74 (0.65-0.84, and ORS/zinc for diarrhoea was 2.3 (1.2-4.7. CONCLUSION: iCCM can be utilized to improve

  17. A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration.

    Science.gov (United States)

    Mejia, Pedro; Treviño-Villarreal, J Humberto; Reynolds, Justin S; De Niz, Mariana; Thompson, Andrew; Marti, Matthias; Mitchell, James R

    2017-11-09

    Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.

  18. Biting behaviour of African malaria vectors: 1. where do the main vector species bite on the human body?

    Science.gov (United States)

    Braack, Leo; Hunt, Richard; Koekemoer, Lizette L; Gericke, Anton; Munhenga, Givemore; Haddow, Andrew D; Becker, Piet; Okia, Michael; Kimera, Isaac; Coetzee, Maureen

    2015-02-04

    Malaria control in Africa relies heavily on indoor vector management, primarily indoor residual spraying and insecticide treated bed nets. Little is known about outdoor biting behaviour or even the dynamics of indoor biting and infection risk of sleeping household occupants. In this paper we explore the preferred biting sites on the human body and some of the ramifications regarding infection risk and exposure management. We undertook whole-night human landing catches of Anopheles arabiensis in South Africa and Anopheles gambiae s.s. and Anopheles funestus in Uganda, for seated persons wearing short sleeve shirts, short pants, and bare legs, ankles and feet. Catches were kept separate for different body regions and capture sessions. All An. gambiae s.l. and An. funestus group individuals were identified to species level by PCR. Three of the main vectors of malaria in Africa (An. arabiensis, An. gambiae s.s. and An. funestus) all have a preference for feeding close to ground level, which is manifested as a strong propensity (77.3% - 100%) for biting on lower leg, ankles and feet of people seated either indoors or outdoors, but somewhat randomly along the lower edge of the body in contact with the surface when lying down. If the lower extremities of the legs (below mid-calf level) of seated people are protected and therefore exclude access to this body region, vector mosquitoes do not move higher up the body to feed at alternate body sites, instead resulting in a high (58.5% - 68.8%) reduction in biting intensity by these three species. Protecting the lower limbs of people outdoors at night can achieve a major reduction in biting intensity by malaria vector mosquitoes. Persons sleeping at floor level bear a disproportionate risk of being bitten at night because this is the preferred height for feeding by the primary vector species. Therefore it is critical to protect children sleeping at floor level (bednets; repellent-impregnated blankets or sheets, etc

  19. Experimental evaluation of the relationship between lethal or non-lethal virulence and transmission success in malaria parasite infections

    Directory of Open Access Journals (Sweden)

    Nithiuthai S

    2004-09-01

    Full Text Available Abstract Background Evolutionary theory suggests that the selection pressure on parasites to maximize their transmission determines their optimal host exploitation strategies and thus their virulence. Establishing the adaptive basis to parasite life history traits has important consequences for predicting parasite responses to public health interventions. In this study we examine the extent to which malaria parasites conform to the predicted adaptive trade-off between transmission and virulence, as defined by mortality. The majority of natural infections, however, result in sub-lethal virulent effects (e.g. anaemia and are often composed of many strains. Both sub-lethal effects and pathogen population structure have been theoretically shown to have important consequences for virulence evolution. Thus, we additionally examine the relationship between anaemia and transmission in single and mixed clone infections. Results Whereas there was a trade-off between transmission success and virulence as defined by host mortality, contradictory clone-specific patterns occurred when defining virulence by anaemia. A negative relationship between anaemia and transmission success was found for one of the parasite clones, whereas there was no relationship for the other. Notably the two parasite clones also differed in a transmission phenotype (gametocyte sex ratio that has previously been shown to respond adaptively to a changing blood environment. In addition, as predicted by evolutionary theory, mixed infections resulted in increased anaemia. The increased anaemia was, however, not correlated with any discernable parasite trait (e.g. parasite density or with increased transmission. Conclusions We found some evidence supporting the hypothesis that there is an adaptive basis correlating virulence (as defined by host mortality and transmission success in malaria parasites. This confirms the validity of applying evolutionary virulence theory to biomedical

  20. The Plasmodium PHIST and RESA-Like Protein Families of Human and Rodent Malaria Parasites.

    Directory of Open Access Journals (Sweden)

    Cristina K Moreira

    Full Text Available The phist gene family has members identified across the Plasmodium genus, defined by the presence of a domain of roughly 150 amino acids having conserved aromatic residues and an all alpha-helical structure. The family is highly amplified in P. falciparum, with 65 predicted genes in the genome of the 3D7 isolate. In contrast, in the rodent malaria parasite P. berghei 3 genes are identified, one of which is an apparent pseudogene. Transcripts of the P. berghei phist genes are predominant in schizonts, whereas in P. falciparum transcript profiles span different asexual blood stages and gametocytes. We pursued targeted disruption of P. berghei phist genes in order to characterize a simplistic model for the expanded phist gene repertoire in P. falciparum. Unsuccessful attempts to disrupt P. berghei PBANKA_114540 suggest that this phist gene is essential, while knockout of phist PBANKA_122900 shows an apparent normal progression and non-essential function throughout the life cycle. Epitope-tagging of P. falciparum and P. berghei phist genes confirmed protein export to the erythrocyte cytoplasm and localization with a punctate pattern. Three P. berghei PEXEL/HT-positive exported proteins exhibit at least partial co-localization, in support of a common vesicular compartment in the cytoplasm of erythrocytes infected with rodent malaria parasites.

  1. Malaria in pregnancy: ultrasound studies of fetal growth

    NARCIS (Netherlands)

    Rijken, M.J.

    2012-01-01

    Malaria has been a plague for human mankind. Each year roughly 125 million pregnancies are at risk for malaria infection. This thesis demonstrates the detrimental effects of malaria in pregnancy on the mother and the baby. To determine the effects of malaria in pregnancy on birth outcomes, accurate

  2. The development of human factors experimental evaluation techniques

    Energy Technology Data Exchange (ETDEWEB)

    Sim, Bong Shick; Oh, In Suk; Cha, Kyung Ho; Lee, Hyun Chul; Park, Geun Ok; Cheon, Se Woo; Suh, Sang Moon

    1997-07-01

    New human factors issues, such as evaluation of information navigation, the consideration of operator characteristics, and operator performance assessment, related to the HMI design based on VDUs are being risen. Thus, in order to solve these human factors issues, this project aims to establish the experimental technologies including the techniques for experimental design, experimental measurement, data collection and analysis, and to develop ITF (Integrated Test Facility) suitable for the experiment of HMI design evaluation. For the establish of the experimental data analysis and evaluation methodologies, we developed as the following: (1) a paradigm for human factors experimentation including experimental designs, procedures, and data analysis. (2) the methods for the assessment of operator`s mental workload (3) DAEXESS (data analysis and experiment evaluation supporting system). Also, we have established a experiment execution technologies through the preliminary experiments, such as the suitability evaluation of information display on a LSDP, the evaluation of information display on a LSDP, the evaluation of computerized operation procedure and an experiment of advanced alarm system (ADIOS). Finally, we developed the ITF including human machine simulator, telemetry system, an eye tracking system, an audio/video data measurement system, and three dimensional micro behaviour analysis system. (author). 81 refs., 68 tabs., 73 figs.

  3. Allomonal effect of breath contributes to differential attractiveness of humans to the African malaria vector Anopheles gambiae

    Directory of Open Access Journals (Sweden)

    Takken Willem

    2004-01-01

    Full Text Available Abstract Background Removal of exhaled air from total body emanations or artificially standardising carbon dioxide (CO2 outputs has previously been shown to eliminate differential attractiveness of humans to certain blackfly (Simuliidae and mosquito (Culicidae species. Whether or not breath contributes to between-person differences in relative attractiveness to the highly anthropophilic malaria vector Anopheles gambiae sensu stricto remains unknown and was the focus of the present study. Methods The contribution to and possible interaction of breath (BR and body odours (BO in the attraction of An. gambiae s.s. to humans was investigated by conducting dual choice tests using a recently developed olfactometer. Either one or two human subjects were used as bait. The single person experiments compared the attractiveness of a person's BR versus that person's BO or a control (empty tent with no odour. His BO and total emanations (TE = BR+BO were also compared with a control. The two-person experiments compared the relative attractiveness of their TE, BO or BR, and the TE of each person against the BO of the other. Results Experiments with one human subject (P1 as bait found that his BO and TE collected more mosquitoes than the control (P = 0.005 and P 1 attracted more mosquitoes than that of another person designated P8 (P 8 attracted more mosquitoes than the BR of P1 (P = 0.001. The attractiveness of the BO of P1 versus the BO of P8 did not differ (P = 0.346. The BO from either individual was consistently more attractive than the TE from the other (P Conclusions We demonstrated for the first time that human breath, although known to contain semiochemicals that elicit behavioural and/or electrophysiological responses (CO2, ammonia, fatty acids in An. gambiae also contains one or more constituents with allomonal (~repellent properties, which inhibit attraction and may serve as an important contributor to between-person differences in the relative

  4. Cerebral malaria Malaria cerebral

    Directory of Open Access Journals (Sweden)

    Silvia Blair Trujillo

    2003-03-01

    Full Text Available Is the most common complication of P. falciparum malaria; nearly 90% of people who have suffered CM can recover without neurological problems. Currently there are four hypotheses that explain pathogenesis of CM: cytoadherence and sequestering of parasitized red blood cells to cerebral capillaries; rosette formation and parasitized red blood cells agglutination; production of cytokines and activation of second messengers and opening of the blood-brain barrier. However the main question remains to be answered; how the host-parasite interaction in the vascular space interferes transiently with cerebral function? Recently, the beta amyloid precursor peptide has been employed as marker of neural injury in CM. It is expected that the beta amyloid precursor peptide will help to understand the pathogenesis of CM in complicated patients of endemic areas of Colombia. La malaria Cerebral (MC es la complicación más frecuente de la malaria por P. falciparum; aproximadamente el 90% de las personas que la han padecido se recuperan completamente sin secuelas neurológicas. Aún no se conoce con claridad su patogénesis pero se han postulado cuatro hipótesis o mecanismos posibles: 1 citoadherencia y secuestro de glóbulos rojos parasitados en la microvasculatura cerebral; 2 formación de rosetas y aglutinación de glóbulos rojos parasitados; 3 producción de citoquinas y activación de segundos mensajeros y, 4 apertura de la barrera hematoencefálica. Sin embargo, queda un interrogante sin resolver aún: ¿qué proceso se lleva a cabo para que el parásito, desde el espacio microvascular, pueda interferir transitoriamente con la función cerebral? Recientemente se ha utilizado el precursor de la proteína b-Amiloide como un marcador de daño neuronal en MC; este precursor será de gran ayuda en futuras investigaciones realizadas en nuestro medio que aporten información para comprender la patogénesis de la MC.

  5. Sex-Specific Biology of the Human Malaria Parasite Revealed from the Proteomes of Mature Male and Female Gametocytes.

    Science.gov (United States)

    Miao, Jun; Chen, Zhao; Wang, Zenglei; Shrestha, Sony; Li, Xiaolian; Li, Runze; Cui, Liwang

    2017-04-01

    The gametocytes of the malaria parasites are obligate for perpetuating the parasite's life cycle through mosquitoes, but the sex-specific biology of gametocytes is poorly understood. We generated a transgenic line in the human malaria parasite Plasmodium falciparum , which allowed us to accurately separate male and female gametocytes by flow cytometry. In-depth analysis of the proteomes by liquid chromatography-tandem mass spectrometry identified 1244 and 1387 proteins in mature male and female gametocytes, respectively. GFP-tagging of nine selected proteins confirmed their sex-partitions to be agreeable with the results from the proteomic analysis. The sex-specific proteomes showed significant differences that are consistent with the divergent functions of the two sexes. Although the male-specific proteome (119 proteins) is enriched in proteins associated with the flagella and genome replication, the female-specific proteome (262 proteins) is more abundant in proteins involved in metabolism, translation and organellar functions. Compared with the Plasmodium berghei sex-specific proteomes, this study revealed both extensive conservation and considerable divergence between these two species, which reflect the disparities between the two species in proteins involved in cytoskeleton, lipid metabolism and protein degradation. Comparison with three sex-specific proteomes allowed us to obtain high-confidence lists of 73 and 89 core male- and female-specific/biased proteins conserved in Plasmodium The identification of sex-specific/biased proteomes in Plasmodium lays a solid foundation for understanding the molecular mechanisms underlying the unique sex-specific biology in this early-branching eukaryote. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Malaria Matters

    Centers for Disease Control (CDC) Podcasts

    2008-04-18

    This podcast gives an overview of malaria, including prevention and treatment, and what CDC is doing to help control and prevent malaria globally.  Created: 4/18/2008 by National Center for Zoonotic, Vector-Borne, and Enteric Diseases (NCZVED).   Date Released: 4/18/2008.

  7. Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa

    National Research Council Canada - National Science Library

    Mamotte, Nicole; Wassenaar, Douglas; Koen, Jennifer; Essack, Zaynab

    2010-01-01

    .... In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine...

  8. Pathogenesis of Plasmodium berghei ANKA infection in the gerbil (Meriones unguiculatus as an experimental model for severe malaria

    Directory of Open Access Journals (Sweden)

    Junaid Quazim Olawale

    2017-01-01

    Full Text Available Background: As the quest to eradicate malaria continues, there remains a need to gain further understanding of the disease, particularly with regard to pathogenesis. This is facilitated, apart from in vitro and clinical studies, mainly via in vivo mouse model studies. However, there are few studies that have used gerbils (Meriones unguiculatus as animal models. Thus, this study is aimed at characterizing the effects of Plasmodium berghei ANKA (PbA infection in gerbils, as well as the underlying pathogenesis. Methods: Gerbils, 5-7 weeks old were infected by PbA via intraperitoneal injection of 1 × 106 (0.2 mL infected red blood cells. Parasitemia, weight gain/loss, hemoglobin concentration, red blood cell count and body temperature changes in both control and infected groups were monitored over a duration of 13 days. RNA was extracted from the brain, spleen and whole blood to assess the immune response to PbA infection. Organs including the brain, spleen, heart, liver, kidneys and lungs were removed aseptically for histopathology. Results: Gerbils were susceptible to PbA infection, showing significant decreases in the hemoglobin concentration, RBC counts, body weights and body temperature, over the course of the infection. There were no neurological signs observed. Both pro-inflammatory (IFNγ and TNF and anti-inflammatory (IL-10 cytokines were significantly elevated. Splenomegaly and hepatomegaly were also observed. PbA parasitized RBCs were observed in the organs, using routine light microscopy and in situ hybridization. Conclusion: Gerbils may serve as a good model for severe malaria to further understand its pathogenesis.

  9. Human antibody response to Anopheles gambiae saliva: an immuno-epidemiological biomarker to evaluate the efficacy of insecticide-treated nets in malaria vector control.

    Science.gov (United States)

    Drame, Papa M; Poinsignon, Anne; Besnard, Patrick; Le Mire, Jacques; Dos-Santos, Maria A; Sow, Cheikh S; Cornelie, Sylvie; Foumane, Vincent; Toto, Jean-Claude; Sembene, Mbacké; Boulanger, Denis; Simondon, François; Fortes, Filomeno; Carnevale, Pierre; Remoue, Franck

    2010-07-01

    For the fight against malaria, the World Health Organization (WHO) has emphasized the need for indicators to evaluate the efficacy of vector-control strategies. This study investigates a potential immunological marker, based on human antibody responses to Anopheles saliva, as a new indicator to evaluate the efficacy of insecticide-treated nets (ITNs). Parasitological, entomological, and immunological assessments were carried out in children and adults from a malaria-endemic region of Angola before and after the introduction of ITNs. Immunoglobulin G (IgG) levels to An. gambiae saliva were positively associated with the intensity of An. gambiae exposure and malaria infection. A significant decrease in the anti-saliva IgG response was observed after the introduction of ITNs, and this was associated with a drop in parasite load. This study represents the first stage in the development of a new indicator to evaluate the efficacy of malaria vector-control strategies, which could apply in other arthropod vector-borne diseases.

  10. Nocardia brasiliensis: from microbe to human and experimental infections.

    Science.gov (United States)

    Salinas-Carmona, M C

    2000-09-01

    Nocardia brasiliensis is a Gram-positive bacterium that lives as a saprophyte in soil. In this article the physical properties, chemical composition and taxonomic position of this species is reviewed. Human infections and an experimental model of actinomycetoma in BALB/c mice as well as the host-immune response is described.

  11. Pengendalian Malaria dalam Upaya Percepatan Pencapaian Target Millennium Development Goals

    Directory of Open Access Journals (Sweden)

    Tri Rini Puji Lestari

    2012-08-01

    health official Malaria Center, and community leaders who observe malaria. Retrieval of data time is 10 – 16 April 2011 by in-depth interviews. It was found that malaria control programs have been implemented by the Departement of Health North Maluku Province, but have not been able to effectively reduce malaria morbidity. This is because malaria control is performed is not comprehensive. Handling is more directed to break the chain transmission to human, their habitats have not been touched up. Key words: Control of malaria, millennium development goals, malaria morbidity

  12. Platelets alter gene expression profile in human brain endothelial cells in an in vitro model of cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Mathieu Barbier

    Full Text Available 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-, TGFβ-, death-receptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM.

  13. Tacrolimus prevents murine cerebral malaria.

    Science.gov (United States)

    Bao, Lam Quoc; Nhi, Dang My; Huy, Nguyen Tien; Hamano, Shinjiro; Hirayama, Kenji

    2017-02-01

    Tacrolimus and mycophenolate mofetil are immunosuppressants frequently used in human organ transplantation. Tacrolimus is also reported to inhibit Plasmodium falciparum growth in vitro. Here, we report that tacrolimus prevented the death from cerebral malaria of Plasmodium berghei ANKA-infected C57BL/6J mice, but not their death from malaria due to the high parasitaemia and severe anaemia. The mycophenolate mofetil-treated mice showed higher mortality from cerebral malaria and succumbed to malaria earlier than tacrolimus-treated littermates. Tacrolimus attenuated the infiltration of mononuclear cells including pathogenic CD8+ T cells into the brain. It appears to prevent murine cerebral malaria through the inhibition of cerebral infiltration of CD8+ T cells. © 2016 John Wiley & Sons Ltd.

  14. Malaria Treatment (United States)

    Science.gov (United States)

    ... a CDC Malaria Branch clinician. malaria@cdc.gov Malaria Treatment (United States) Recommend on Facebook Tweet Share Compartir Treatment of Malaria: Guidelines For Clinicians (United States) Download PDF version ...

  15. Malaria and Travelers

    Science.gov (United States)

    ... a CDC Malaria Branch clinician. malaria@cdc.gov Malaria and Travelers Recommend on Facebook Tweet Share Compartir ... may be at risk for infection. Determine if malaria transmission occurs at the destinations Obtain a detailed ...

  16. Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species.

    Directory of Open Access Journals (Sweden)

    Christian Mitri

    2009-09-01

    Full Text Available Genetically controlled resistance of Anopheles gambiae mosquitoes to Plasmodium falciparum is a common trait in the natural population, and a cluster of natural resistance loci were mapped to the Plasmodium-Resistance Island (PRI of the A. gambiae genome. The APL1 family of leucine-rich repeat (LRR proteins was highlighted by candidate gene studies in the PRI, and is comprised of paralogs APL1A, APL1B and APL1C that share > or =50% amino acid identity. Here, we present a functional analysis of the joint response of APL1 family members during mosquito infection with human and rodent Plasmodium species. Only paralog APL1A protected A. gambiae against infection with the human malaria parasite P. falciparum from both the field population and in vitro culture. In contrast, only paralog APL1C protected against the rodent malaria parasites P. berghei and P. yoelii. We show that anti-P. falciparum protection is mediated by the Imd/Rel2 pathway, while protection against P. berghei infection was shown to require Toll/Rel1 signaling. Further, only the short Rel2-S isoform and not the long Rel2-F isoform of Rel2 confers protection against P. falciparum. Protection correlates with the transcriptional regulation of APL1A by Rel2-S but not Rel2-F, suggesting that the Rel2-S anti-parasite phenotype results at least in part from its transcriptional control over APL1A. These results indicate that distinct members of the APL1 gene family display a mutually exclusive protective effect against different classes of Plasmodium parasites. It appears that a gene-for-pathogen-class system orients the appropriate host defenses against distinct categories of similar pathogens. It is known that insect innate immune pathways can distinguish between grossly different microbes such as Gram-positive bacteria, Gram-negative bacteria, or fungi, but the function of the APL1 paralogs reveals that mosquito innate immunity possesses a more fine-grained capacity to distinguish between

  17. Towards A Malaria Vaccine?

    Directory of Open Access Journals (Sweden)

    B S GARG

    1990-12-01

    Full Text Available The last few years have seen a marked change in the understanding of malaria mmunology.We have very little knowledge on immunity of Malaria based on experiments in humanbeings due to ethical reasons. Whatsoever our knowledge exists at present is based onexperimentas in mice and monkey. However it is clear that it is sporzoite or merozoitewhich is directly exposed to our immune system in the life cycle of Malaria parasite. On thebasis of human experiments we can draw inference that immunity to malaria is species.specific (on cross immunity, stage specific and strain specific as well acquired in the response to surface antigen and relapsed antigen although the parasite also demonstrates escape machanism to immune system.So the host system kills or elimi nate the parasite by means of (a Antbody to extracell~ular form of parasite with the help of mechanism of Block invasion, Agglutination or opsonization and/or (b Cellular machanism-either by phago-cytosis of parasite or by antibody dependent cellular cytotoxicity ABCC (? or by effects of mediators like tumor necrosis fJ.ctor (TNF in cerebaral malaria or crisis forming factor as found in sudan or by possible role of lysis mechanism.However, inspite of all these theories the parasite has been able to invade the immunesystem by virtue of its intracellular development stage specificity, sequestration in capillaries and also by its unusual characteristics of antigenic diversity and antigenic variation.

  18. Impact of acute malaria on pre-existing antibodies to viral and vaccine antigens in mice and humans.

    Directory of Open Access Journals (Sweden)

    Simran Banga

    Full Text Available Vaccine-induced immunity depends on long-lived plasma cells (LLPCs that maintain antibody levels. A recent mouse study showed that Plasmodium chaubaudi infection reduced pre-existing influenza-specific antibodies--raising concerns that malaria may compromise pre-existing vaccine responses. We extended these findings to P. yoelii infection, observing decreases in antibodies to model antigens in inbred mice and to influenza in outbred mice, associated with LLPC depletion and increased susceptibility to influenza rechallenge. We investigated the implications of these findings in Malian children by measuring vaccine-specific IgG (tetanus, measles, hepatitis B before and after the malaria-free 6-month dry season, 10 days after the first malaria episode of the malaria season, and after the subsequent dry season. On average, vaccine-specific IgG did not decrease following acute malaria. However, in some children malaria was associated with an accelerated decline in vaccine-specific IgG, underscoring the need to further investigate the impact of malaria on pre-existing vaccine-specific antibodies.

  19. Acculturating human experimentation: an empirical survey in France

    Science.gov (United States)

    Amiel, Philippe; Mathieu, Séverine; Fagot-Largeault, Anne

    2001-01-01

    Preliminary results of an empirical study of human experimentation practices are presented and contrasted with those of a survey conducted a hundred years ago when clinical research, although tolerated, was culturally deviant. Now that biomedical research is both authorized and controlled, its actors (sponsors, committees, investigators, subjects) come out with heterogeneous rationalities, and they appear to be engaged in a transactional process of negotiating their rationales with one another. In the European context “protective” of subjects, surprisingly the subjects we interviewed (and especially patient-subjects) were creative and revealed an aptitude for integrating experimental medicine into common culture. PMID:11445883

  20. Simultaneous genome-wide gene expression and transcript isoform profiling in the human malaria parasite.

    Science.gov (United States)

    Turnbull, Lindsey B; Siwo, Geoffrey H; Button-Simons, Katrina A; Tan, Asako; Checkley, Lisa A; Painter, Heather J; Llinás, Manuel; Ferdig, Michael T

    2017-01-01

    Gene expression DNA microarrays have been vital for characterizing whole-genome transcriptional profiles. Nevertheless, their effectiveness relies heavily on the accuracy of genome sequences, the annotation of gene structures, and the sequence-dependent performance of individual probes. Currently available gene expression arrays for the malaria parasite Plasmodium falciparum rely on an average of 2 probes per gene, usually positioned near the 3' end of genes; consequently, existing designs are prone to measurement bias and cannot capture complexities such as the occurrence of transcript isoforms arising from alternative splicing or alternative start/ stop sites. Here, we describe two novel gene expression arrays with exon-focused probes designed with an average of 12 and 20 probes spanning each gene. This high probe density minimizes signal noise inherent in probe-to-probe sequence-dependent hybridization intensity. We demonstrate that these exon arrays accurately profile genome-wide expression, comparing favorably to currently available arrays and RNA-seq profiling, and can detect alternatively spliced transcript isoforms as well as non-coding RNAs (ncRNAs). Of the 964 candidate alternate splicing events from published RNA-seq studies, 162 are confirmed using the exon array. Furthermore, the exon array predicted 330 previously unidentified alternate splicing events. Gene expression microarrays continue to offer a cost-effective alternative to RNA-seq for the simultaneous monitoring of gene expression and alternative splicing events. Microarrays may even be preferred in some cases due to their affordability and the rapid turn-around of results when hundreds of samples are required for fine-scale systems biology investigations, including the monitoring of the networks of gene co-expression in the emergence of drug resistance.

  1. Malaria Facts

    Science.gov (United States)

    ... 216 million clinical episodes, and 445,000 deaths. Biology, Pathology, Epidemiology Among the malaria species that infect ... Cinchona spp., South America, 17th century). Get Email Updates To receive email updates about this page, enter ...

  2. MalarImDB: an open-access literature-based malaria immunology database.

    Science.gov (United States)

    Deroost, Katrien; Opdenakker, Ghislain; Van den Steen, Philippe E

    2014-06-01

    The Malaria Immunology Database (MalarImDB, www.malarimdb.org) is a novel literature-based database of host mediators in blood-stage malaria. We designed this open-access online tool because intensive malaria research has resulted in a dazzling complexity of host mediators with pathogenic or protective functions. MalarImDB allows comparisons between expression levels in humans, expression levels in murine models, and functional data from experimental treatments in mice. The database is equipped with multiple search engines to retrieve information from many published studies. The search output is visualized schematically in tables, thereby revealing similarities and disparities. Thus, the primary aim of this database is to present a clear overview of the currently available data about malaria and to simplify literature searches. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Vaccines against malaria-still a long way to go.

    Science.gov (United States)

    Matuschewski, Kai

    2017-08-01

    Several species of Plasmodium cause a broad spectrum of human disease that range from nausea and fever to severe anemia, cerebral malaria, and multiorgan failure. In malaria-endemic countries, continuous exposure to Plasmodium sporozoite inoculations and subsequent blood infections elicit only partial and short-lived immunity, which gradually develops over many years of parasite exposure and multiple clinical episodes. The ambitious goal of malaria vaccinology over the past 70 years has been to develop an immunization strategy that mounts protection superior to naturally acquired immunity. Herein, three principal concepts in evidence-based malaria vaccine development are compared. Feasible leads are typically stand-alone subunit vaccine approaches that block Plasmodium parasite life cycle progression or parasite/host interactions, and they constitute the majority of candidates in preclinical research and early clinical testing. Integrated approaches incorporate malaria antigen(s) into licensed or emerging pediatric vaccine formulations. This strategy can complement the malaria control portfolio even if the antimalarial component is only partially effective and has led to the development of the only candidate vaccine to date, namely RTS,S-AS01. Experimental whole parasite vaccine approaches have been repeatedly shown to elicit sterile and lasting protection against identical parasite strains, but mass production, proof of broad protection against different parasite strains, and routes of vaccine delivery remain significant translational road blocks. Global access to an effective and affordable malaria vaccine will critically depend on innovative translational research that builds on a better molecular understanding of Plasmodium biology and host immunity. © 2017 Federation of European Biochemical Societies.

  4. Evaluations of training programs to improve human resource capacity for HIV, malaria, and TB control: a systematic scoping review of methods applied and outcomes assessed.

    Science.gov (United States)

    Wu, Shishi; Roychowdhury, Imara; Khan, Mishal

    2017-01-01

    Owing to the global health workforce crisis, more funding has been invested in strengthening human resources for health, particularly for HIV, tuberculosis, and malaria control; however, little is known about how these investments in training are evaluated. This paper examines how frequently HIV, malaria, and TB healthcare provider training programs have been scientifically evaluated, synthesizes information on the methods and outcome indicators used, and identifies evidence gaps for future evaluations to address. We conducted a systematic scoping review of publications evaluating postgraduate training programs, including in-service training programs, for HIV, tuberculosis, and malaria healthcare providers between 2000 and 2016. Using broad inclusion criteria, we searched three electronic databases and additional gray literature sources. After independent screening by two authors, data about the year, location, methodology, and outcomes assessed was extracted from eligible training program evaluation studies. Training outcomes evaluated were categorized into four levels (reaction, learning, behavior, and results) based on the Kirkpatrick model. Of 1473 unique publications identified, 87 were eligible for inclusion in the analysis. The number of published articles increased after 2006, with most (n = 57, 66%) conducted in African countries. The majority of training evaluations (n = 44, 51%) were based on HIV with fewer studies focused on malaria (n = 28, 32%) and TB (n = 23, 26%) related training. We found that quantitative survey of trainees was the most commonly used evaluation method (n = 29, 33%) and the most commonly assessed outcomes were knowledge acquisition (learning) of trainees (n = 44, 51%) and organizational impacts of the training programs (38, 44%). Behavior change and trainees' reaction to the training were evaluated less frequently and using less robust methods; costs of training were also rarely assessed. Our study found

  5. Hemozoin Differentially Regulates Proinflammatory Cytokine Production in Human Immunodeficiency Virus-Seropositive and -Seronegative Women with Placental Malaria

    Science.gov (United States)

    Moore, Julie M.; Chaisavaneeyakorn, Sujittra; Perkins, Douglas J.; Othoro, Caroline; Otieno, Juliana; Nahlen, Bernard L.; Shi, Ya Ping; Udhayakumar, Venkatachalam

    2004-01-01

    Pregnant women are at an increased risk for malarial infection. Plasmodium falciparum accumulates in the placenta and is associated with dysregulated immune function and poor birth outcomes. Malarial pigment (hemozoin) also accumulates in the placenta and may modulate local immune function. In this study, the impact of hemozoin on cytokine production by intervillous blood mononuclear cells from malaria-infected placentas was investigated. There was a dose-dependent, suppressive effect of hemozoin on production of gamma interferon (IFN-γ), with less of an effect on tumor necrosis factor alpha (TNF-α) and interleukin-10, in human immunodeficiency virus-seronegative (HIV−) women. In contrast, IFN-γ and TNF-α production tended to increase in HIV-seropositive women with increasing hemozoin levels. Production patterns of cytokines, especially IFN-γ in HIV− women, followed different trends as a function of parasite density and hemozoin level. The findings suggest that the influences of hemozoin accumulation and high-density parasitemia on placental cytokine production are not equivalent and may involve different mechanisms, all of which may operate differently in the context of HIV infection. Cytokine production dysregulated by accumulation of hemozoin or high-density parasitemia may induce pathology and impair protective immunity in HIV-infected and -uninfected women. PMID:15557625

  6. Encapsulation of metalloporphyrins improves their capacity to block the viability of the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Alves, Eduardo; Iglesias, Bernardo A; Deda, Daiana K; Budu, Alexandre; Matias, Tiago A; Bueno, Vânia B; Maluf, Fernando V; Guido, Rafael V C; Oliva, Glaucius; Catalani, Luiz H; Araki, Koiti; Garcia, Celia R S

    2015-02-01

    Several synthetic metallated protoporphyrins (M-PPIX) were tested for their ability to block the cell cycle of the lethal human malaria parasite Plasmodium falciparum. After encapsulating the porphyrin derivatives in micro- and nanocapsules of marine atelocollagen, their effects on cultures of red blood cells infected (RBC) with P. falciparum were verified. RBCs infected with synchronized P. falciparum incubated for 48 h showed a toxic effect over a micromolar range. Strikingly, the IC50 of encapsulated metalloporphyrins reached nanomolar concentrations, where Zn-PPIX showed the best antimalarial effect, with an IC50=330 nM. This value is an 80-fold increase in the antimalarial activity compared to the antimalarial effect of non-encapsulated Zn-PPIX. These findings reveal that the incubation of P. falciparum infected-RBCs with 20 μM Zn-PPIX reduced the size of hemozoin crystal by 34%, whereas a 28% reduction was noticed with chloroquine, confirming the importance of heme detoxification pathway in drug therapy. In this study, synthetic metalloporphyrins were tested as therapeutics that target Plasmodium falciparum. The IC50 of encapsulated metalloporphyrins was found to be in the nanomolar concentration range, with encapsulated Zn-PPIX showing an 80-fold increase in its antimalarial activity compared to the non-encapsulated form. Copyright © 2015. Published by Elsevier Inc.

  7. Opsonization of malaria-infected erythrocytes activates the inflammasome and enhances inflammatory cytokine secretion by human macrophages

    Directory of Open Access Journals (Sweden)

    Zhou Jingling

    2012-10-01

    Full Text Available Abstract Background Antibody opsonization of Plasmodium falciparum-infected erythrocytes (IE plays a crucial role in anti-malarial immunity by promoting clearance of blood-stage infection by monocytes and macrophages. The effects of phagocytosis of opsonized IE on macrophage pro-inflammatory cytokine responses are poorly understood. Methods Phagocytic clearance, cytokine response and intracellular signalling were measured using IFN-γ-primed human monocyte-derived macrophages (MDM incubated with opsonized and unopsonized trophozoite-stage CS2 IE, a chondroitin sulphate-binding malaria strain. Cytokine secretion was measured by bead array or ELISA, mRNA using quantitative PCR, and activation of NF-κB by Western blot and electrophoretic mobility shift assay. Data were analysed using the Mann–Whitney U test or the Wilcoxon signed rank test as appropriate. Results Unopsonized CS2 IE were not phagocytosed whereas IE opsonized with pooled patient immune serum (PPS were (Phagocytic index (PI=18.4, [SE 0.38] n=3. Unopsonized and opsonized IE induced expression of TNF, IL-1β and IL-6 mRNA by MDM and activated NF-κB to a similar extent. Unopsonized IE induced secretion of IL-6 (median= 622 pg/ml [IQR=1,250-240], n=9 but no IL-1β or TNF, whereas PPS-opsonized IE induced secretion of IL-1β (18.6 pg/mL [34.2-14.4] and TNF (113 pg/ml [421–17.0] and increased IL-6 secretion (2,195 pg/ml [4,658-1,095]. Opsonized, but not unopsonized, CS2 IE activated caspase-1 cleavage and enzymatic activity in MDM showing that Fc receptor-mediated phagocytosis activates the inflammasome. MDM attached to IgG-coated surfaces however secreted IL-1β in response to unopsonized IE, suggesting that internalization of IE is not absolutely required to activate the inflammasome and stimulate IL-1β secretion. Conclusions It is concluded that IL-6 secretion from MDM in response to CS2 IE does not require phagocytosis, whereas secretion of TNF and IL-1β is dependent on Fc

  8. Informed consent in human experimentation before the Nuremberg code.

    Science.gov (United States)

    Vollmann, J; Winau, R

    1996-12-07

    The issue of ethics with respect to medical experimentation in Germany during the 1930s and 1940s was crucial at the Nuremberg trials and related trials of doctors and public health officials. Those involved in horrible crimes attempted to excuse themselves by arguing that there were no explicit rules governing medical research on human beings in Germany during the period and that research practices in Germany were not different from those in allied countries. In this context the Nuremberg code of 1947 is generally regarded as the first document to set out ethical regulations in human experimentation based on informed consent. New research, however, indicates that ethical issues of informed consent in guidelines for human experimentation were recognised as early as the nineteenth century. These guidelines shed light on the still contentious issue of when the concepts of autonomy, informed consent, and therapeutic and non-therapeutic research first emerged. This issue assumes renewed importance in the context of current attempts to assess liability and responsibility for the abuse of people in various experiments conducted since the second world war in the United States, Canada, Russia, and other nations.

  9. Enhancing Malaria Vaccine Development by the Naval Medical Research Center

    National Research Council Canada - National Science Library

    Hile, David

    2001-01-01

    A priority of DoD is to develop effective vaccines for preventing malaria. Developing malaria vaccines is complicated by the complexity of the parasite and of the human host's response to the infection...

  10. Malaria Drug Protected Mouse Fetus from Zika: Study

    Science.gov (United States)

    ... 167128.html Malaria Drug Protected Mouse Fetus From Zika: Study More research is needed on effects in ... A malaria drug protected mice fetuses from the Zika virus, researchers report. In humans, Zika infection during ...

  11. Climate, environment and transmission of malaria.

    Science.gov (United States)

    Rossati, Antonella; Bargiacchi, Olivia; Kroumova, Vesselina; Zaramella, Marco; Caputo, Annamaria; Garavelli, Pietro Luigi

    2016-06-01

    Malaria, the most common parasitic disease in the world, is transmitted to the human host by mosquitoes of the genus Anopheles. The transmission of malaria requires the interaction between the host, the vector and the parasite.The four species of parasites responsible for human malaria are Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium vivax. Occasionally humans can be infected by several simian species, like Plasmodium knowlesi, recognised as a major cause of human malaria in South-East Asia since 2004. While P. falciparum is responsible for most malaria cases, about 8% of estimated cases globally are caused by P. vivax. The different Plasmodia are not uniformly distributed although there are areas of species overlap. The life cycle of all species of human malaria parasites is characterised by an exogenous sexual phase in which multiplication occurs in several species of Anopheles mosquitoes, and an endogenous asexual phase in the vertebrate host. The time span required for mature oocyst development in the salivary glands is quite variable (7-30 days), characteristic of each species and influenced by ambient temperature. The vector Anopheles includes 465 formally recognised species. Approximately 70 of these species have the capacity to transmit Plasmodium spp. to humans and 41 are considered as dominant vector capable of transmitting malaria. The intensity of transmission is dependent on the vectorial capacity and competence of local mosquitoes. An efficient system for malaria transmission needs strong interaction between humans, the ecosystem and infected vectors. Global warming induced by human activities has increased the risk of vector-borne diseases such as malaria. Recent decades have witnessed changes in the ecosystem and climate without precedent in human history although the emphasis in the role of temperature on the epidemiology of malaria has given way to predisposing conditions such as ecosystem changes, political

  12. Coadaptation and malaria control

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Tosta

    2007-06-01

    Full Text Available Malaria emerges from a disequilibrium of the system 'human-plasmodium-mosquito' (HPM. If the equilibrium is maintained, malaria does not ensue and the result is asymptomatic plasmodium infection. The relationships among the components of the system involve coadaptive linkages that lead to equilibrium. A vast body of evidence supports this assumption, including the strategies involved in the relationships between plasmodium and human and mosquito immune systems, and the emergence of resistance of plasmodia to antimalarial drugs and of mosquitoes to insecticides. Coadaptive strategies for malaria control are based on the following principles: (1 the system HPM is composed of three highly complex and dynamic components, whose interplay involves coadaptive linkages that tend to maintain the equilibrium of the system; (2 human and mosquito immune systems play a central role in the coadaptive interplay with plasmodium, and hence, in the mainten-ance of the system's equilibrium; the under- or overfunction of human immune system may result in malaria and influence its severity; (3 coadaptation depends on genetic and epigenetic phenomena occurring at the interfaces of the components of the system, and may involve exchange of infectrons (genes or gene fragments between the partners; (4 plasmodia and mosquitoes have been submitted to selective pressures, leading to adaptation, for an extremely long while and are, therefore, endowed with the capacity to circumvent both natural (immunity and artificial (drugs, insecticides, vaccines measures aiming at destroying them; (5 since malaria represents disequilibrium of the system HPM, its control should aim at maintaining or restoring this equilibrium; (6 the disequilibrium of integrated systems involves the disequilibrium of their components, therefore the maintenance or restoration of the system's equilibrium depend on the adoption of integrated and coordinated measures acting on all components, that means

  13. Characterization and application of multiple genetic markers for Plasmodium malariae

    OpenAIRE

    BRUCE, M. C.; Macheso, A.; Galinski, M.R.; Barnwell, J W

    2006-01-01

    Plasmodium malariae, a protozoan parasite that causes malaria in humans, has a global distribution in tropical and subtropical regions and is commonly found in sympatry with other Plasmodium species of humans. Little is known about the genetics or population structure of P. malariae. In the present study, we describe polymorphic genetic markers for P. malariae and present the first molecular epidemiological data for this parasite. Six microsatellite or minisatellite markers were validated usi...

  14. Boosting of DNA Vaccine-Elicited Gamma Interferon Responses in Humans by Exposure to Malaria Parasites

    National Research Council Canada - National Science Library

    Wang, Ruobing; Richie, Thomas L; Baraceros, Maria F; Rahardjo, Nancy; Gay, Tanya; Banania, Jo-Glenna; Charoenvit, Yupin; Epstein, Judith E; Luke, Thomas; Freilich, Daniel A; Norman, Jon; Hoffman, Stephen L

    2004-01-01

    A mixture of DNA plasmids expressing five Plasmodium falciparum pre-erythrocyte-stage antigens was administered with or without a DNA plasmid encoding human granulocyte-macrophage colony-stimulating factor (hGM-CSF...

  15. Human rights and the Global Fund to Fight AIDS, Tuberculosis, and Malaria

    National Research Council Canada - National Science Library

    Davis, Sara L M

    2014-01-01

    In recent years, multilateral and bilateral donors have begun engaging more actively in assessment and management of human rights risks that can either impact, or unintentionally result from, aid investments...

  16. CD8+ T cells and IFN-γ mediate the time-dependent accumulation of infected red blood cells in deep organs during experimental cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Carla Claser

    Full Text Available BACKGROUND: Infection with Plasmodium berghei ANKA (PbA in susceptible mice induces a syndrome called experimental cerebral malaria (ECM with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. Red blood cells infected with PbA parasites have been shown to accumulate in the brain and other tissues during infection. This accumulation is thought to be involved in PbA-induced pathologies, which mechanisms are poorly understood. METHODS AND FINDINGS: Using transgenic PbA parasites expressing the luciferase protein, we have assessed by real-time in vivo imaging the dynamic and temporal contribution of different immune factors in infected red blood cell (IRBC accumulation and distribution in different organs during PbA infection. Using deficient mice or depleting antibodies, we observed that CD8(+ T cells and IFN-γ drive the rapid increase in total parasite biomass and accumulation of IRBC in the brain and in different organs 6-12 days post-infection, at a time when mice develop ECM. Other cells types like CD4(+ T cells, monocytes or neutrophils or cytokines such as IL-12 and TNF-α did not influence the early increase of total parasite biomass and IRBC accumulation in different organs. CONCLUSIONS: CD8(+ T cells and IFN-γ are the major immune mediators controlling the time-dependent accumulation of P. berghei-infected red blood cells in tissues.

  17. Efficacy of Bendiocarb Used for Indoor Residual Spraying for Malaria Control in Madagascar: Results With Local Anopheles Species (Diptera: Culicidae) From Experimental Hut Trials.

    Science.gov (United States)

    Randriamaherijaona, Sanjiarizaha; Nepomichene, Thiery Nirina Jean Jose; Assoukpa, Jade; Madec, Yoann; Boyer, Sébastien

    2017-07-01

    To control malaria in Madagascar, two primary vector control interventions are being scaled up: insecticide-treated nets and indoor residual spraying of bendiocarb, which was implemented in the Malagasy Central Highlands in 2009. The current efficacy of bendiocarb against Anopheles species was evaluated in a small-scale field trial. An experimental hut trial comparing the effectiveness of bendiocarb sprayed on five substrates (cement, wood, tin, mud, and vegetative materials) was carried out against Anopheles species in two study sites located in the eastern foothills of Madagascar. No significant difference was detected in either exophily or blood-feeding rates between treated and untreated huts. The mortality rate was significantly greater in treated huts compared to untreated huts. Efficacy up to 80% was found for 5 mo posttreatment. Although effective, bendiocarb has been used for 7 yr, and therefore an alternative insecticide may be needed to avoid the emergence of resistance. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Ethical aspects of malaria control and research.

    Science.gov (United States)

    Jamrozik, Euzebiusz; de la Fuente-Núñez, Vânia; Reis, Andreas; Ringwald, Pascal; Selgelid, Michael J

    2015-12-22

    Malaria currently causes more harm to human beings than any other parasitic disease, and disproportionally affects low-income populations. The ethical issues raised by efforts to control or eliminate malaria have received little explicit analysis, in comparison with other major diseases of poverty. While some ethical issues associated with malaria are similar to those that have been the subject of debate in the context of other infectious diseases, malaria also raises distinct ethical issues in virtue of its unique history, epidemiology, and biology. This paper provides preliminary ethical analyses of the especially salient issues of: (i) global health justice, (ii) universal access to malaria control initiatives, (iii) multidrug resistance, including artemisinin-based combination therapy (ACT) resistance, (iv) mandatory screening, (v) mass drug administration, (vi) benefits and risks of primaquine, and (vii) malaria in the context of blood donation and transfusion. Several ethical issues are also raised by past, present and future malaria research initiatives, in particular: (i) controlled infection studies, (ii) human landing catches, (iii) transmission-blocking vaccines, and (iv) genetically-modified mosquitoes. This article maps the terrain of these major ethical issues surrounding malaria control and elimination. Its objective is to motivate further research and discussion of ethical issues associated with malaria--and to assist health workers, researchers, and policy makers in pursuit of ethically sound malaria control practice and policy.

  19. Experimental annotation of the human genome using microarray technology.

    Science.gov (United States)

    Shoemaker, D D; Schadt, E E; Armour, C D; He, Y D; Garrett-Engele, P; McDonagh, P D; Loerch, P M; Leonardson, A; Lum, P Y; Cavet, G; Wu, L F; Altschuler, S J; Edwards, S; King, J; Tsang, J S; Schimmack, G; Schelter, J M; Koch, J; Ziman, M; Marton, M J; Li, B; Cundiff, P; Ward, T; Castle, J; Krolewski, M; Meyer, M R; Mao, M; Burchard, J; Kidd, M J; Dai, H; Phillips, J W; Linsley, P S; Stoughton, R; Scherer, S; Boguski, M S

    2001-02-15

    The most important product of the sequencing of a genome is a complete, accurate catalogue of genes and their products, primarily messenger RNA transcripts and their cognate proteins. Such a catalogue cannot be constructed by computational annotation alone; it requires experimental validation on a genome scale. Using 'exon' and 'tiling' arrays fabricated by ink-jet oligonucleotide synthesis, we devised an experimental approach to validate and refine computational gene predictions and define full-length transcripts on the basis of co-regulated expression of their exons. These methods can provide more accurate gene numbers and allow the detection of mRNA splice variants and identification of the tissue- and disease-specific conditions under which genes are expressed. We apply our technique to chromosome 22q under 69 experimental condition pairs, and to the entire human genome under two experimental conditions. We discuss implications for more comprehensive, consistent and reliable genome annotation, more efficient, full-length complementary DNA cloning strategies and application to complex diseases.

  20. The history of 20th century malaria control in Peru.

    Science.gov (United States)

    Griffing, Sean M; Gamboa, Dionicia; Udhayakumar, Venkatachalam

    2013-08-30

    Malaria has been part of Peruvian life since at least the 1500s. While Peru gave the world quinine, one of the first treatments for malaria, its history is pockmarked with endemic malaria and occasional epidemics. In this review, major increases in Peruvian malaria incidence over the past hundred years are described, as well as the human factors that have facilitated these events, and concerted private and governmental efforts to control malaria. Political support for malaria control has varied and unexpected events like vector and parasite resistance have adversely impacted morbidity and mortality. Though the ready availability of novel insecticides like DDT and efficacious medications reduced malaria to very low levels for a decade after the post eradication era, malaria reemerged as an important modern day challenge to Peruvian public health. Its reemergence sparked collaboration between domestic and international partners towards the elimination of malaria in Peru.

  1. Report: Unsupervised identification of malaria parasites using computer vision.

    Science.gov (United States)

    Khan, Najeed Ahmed; Pervaz, Hassan; Latif, Arsalan; Musharaff, Ayesha

    2017-01-01

    Malaria in human is a serious and fatal tropical disease. This disease results from Anopheles mosquitoes that are infected by Plasmodium species. The clinical diagnosis of malaria based on the history, symptoms and clinical findings must always be confirmed by laboratory diagnosis. Laboratory diagnosis of malaria involves identification of malaria parasite or its antigen / products in the blood of the patient. Manual diagnosis of malaria parasite by the pathologists has proven to become cumbersome. Therefore, there is a need of automatic, efficient and accurate identification of malaria parasite. In this paper, we proposed a computer vision based approach to identify the malaria parasite from light microscopy images. This research deals with the challenges involved in the automatic detection of malaria parasite tissues. Our proposed method is based on the pixel-based approach. We used K-means clustering (unsupervised approach) for the segmentation to identify malaria parasite tissues.

  2. Experimental human pneumococcal carriage models for vaccine research.

    Science.gov (United States)

    Ferreira, Daniela M; Jambo, Kondwani C; Gordon, Stephen B

    2011-09-01

    Pneumococcal conjugate vaccines have had unprecedented success in controlling vaccine-type invasive pneumococcal disease. As serotype replacement and the complexity of designing vaccines to multiple capsular polysaccharides ultimately pose a threat to these vaccines, the development of alternative protein vaccines is important. Protein vaccines offer the promise of extended serotype coverage, reduced cost, and improved protection against otitis media and pneumococcal pneumonia. As placebo-controlled trials are not currently ethically justifiable, human pneumococcal challenge models using prevention of carriage as a test endpoint offer an attractive link between preclinical studies and clinical efficacy trials. Experimental human pneumococcal carriage studies offer a means of describing mechanisms of protection against carriage and a clinical tool to choose between vaccine candidates. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Experimental meningococcal sepsis in congenic transgenic mice expressing human transferrin.

    Directory of Open Access Journals (Sweden)

    Marek Szatanik

    Full Text Available Severe meningococcal sepsis is still of high morbidity and mortality. Its management may be improved by an experimental model allowing better understanding of its pathophysiology. We developed an animal model of meningococcal sepsis in transgenic BALB/c mice expressing human transferrin. We studied experimental meningococcal sepsis in congenic transgenic BALB/c mice expressing human transferrin by transcriptional profiling using microarray analysis of blood and brain samples. Genes encoding acute phase proteins, chemokines and cytokines constituted the largest strongly regulated groups. Dynamic bioluminescence imaging further showed high blood bacterial loads that were further enhanced after a primary viral infection by influenza A virus. Moreover, IL-1 receptor-associated kinase-3 (IRAK-3 was induced in infected mice. IRAK-3 is a negative regulator of Toll-dependant signaling and its induction may impair innate immunity and hence result in an immunocompromised state allowing bacterial survival and systemic spread during sepsis. This new approach should enable detailed analysis of the pathophysiology of meningococcal sepsis and its relationships with flu infection.

  4. Malaria ecology and climate change

    Science.gov (United States)

    McCord, G. C.

    2016-05-01

    Understanding the costs that climate change will exact on society is crucial to devising an appropriate policy response. One of the channels through while climate change will affect human society is through vector-borne diseases whose epidemiology is conditioned by ambient ecology. This paper introduces the literature on malaria, its cost on society, and the consequences of climate change to the physics community in hopes of inspiring synergistic research in the area of climate change and health. It then demonstrates the use of one ecological indicator of malaria suitability to provide an order-of-magnitude assessment of how climate change might affect the malaria burden. The average of Global Circulation Model end-of-century predictions implies a 47% average increase in the basic reproduction number of the disease in today's malarious areas, significantly complicating malaria elimination efforts.

  5. Antibody reactivities to glutamate-rich peptides of Plasmodium falciparum parasites in humans from areas of different malaria endemicity

    DEFF Research Database (Denmark)

    Jakobsen, P.H.; Theander, T.G.; Hvid, L

    1996-01-01

    Synthetic P. falciparum peptides were evaluated as tools in epidemiological investigations of malaria. Plasma IgM and IgG antibody reactivities against synthetic peptides covering sequences of glutamate-rich protein (GLURP) and acidic-basic repeat antigen (ABRA) were measured by ELISA in individu......Synthetic P. falciparum peptides were evaluated as tools in epidemiological investigations of malaria. Plasma IgM and IgG antibody reactivities against synthetic peptides covering sequences of glutamate-rich protein (GLURP) and acidic-basic repeat antigen (ABRA) were measured by ELISA...

  6. In vitro effect of chloroquine, mefloquine and quinine on human lymphocyte proliferative responses to malaria antigens and other antigens/mitogens

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Theander, T G; Andersen, B J

    1986-01-01

    The effect of 3 antimalarial quinoline derivatives, chloroquine, mefloquine and quinine on human blood mononuclear cells in vitro was studied. High concentrations profoundly suppressed the proliferation of mitogen- and antigen-stimulated lymphocytes, as indicated by decreased 14C...... of pokeweed mitogen) and antigens studied, including P. falciparum merozoites. The drugs' potential adverse effect on the immune system is discussed.......-thymidine incorporation. On a weight base, the most potent drug was mefloquine. At clinically relevant doses, chloroquine and mefloquine did not affect the response to malaria antigens, but mefloquine decreased the response to phytohaemagglutinin; quinine suppressed the response to all mitogens (with the exception...

  7. falciparum malaria?

    African Journals Online (AJOL)

    destruction by the reticulo-endothelial system.'·. Skudowitz er al. '7 have shown that thrombocytopenia in falciparum malaria is the result of excessive splenic pool- ing as well as decreased platelet survival. Unfortunately, platelet counts could not be measured in our study. In patients with systemic lupus erythemarosus a ...

  8. Kompliceret malaria

    DEFF Research Database (Denmark)

    Rønn, A M; Bygbjerg, Ib Christian; Jacobsen, E

    1989-01-01

    An increasing number of cases of malaria, imported to Denmark, are caused by Plasmodium falciparum and severe and complicated cases are more often seen. In the Department of Infectious Diseases, Rigshospitalet, 23 out of 32 cases, hospitalized from 1.1-30.6.1988, i.e. 72%, were caused by P...

  9. Is there an efficient trap or collection method for sampling Anopheles darlingi and other malaria vectors that can describe the essential parameters affecting transmission dynamics as effectively as human landing catches? - A Review

    Directory of Open Access Journals (Sweden)

    José Bento Pereira Lima

    2014-08-01

    Full Text Available Distribution, abundance, feeding behaviour, host preference, parity status and human-biting and infection rates are among the medical entomological parameters evaluated when determining the vector capacity of mosquito species. To evaluate these parameters, mosquitoes must be collected using an appropriate method. Malaria is primarily transmitted by anthropophilic and synanthropic anophelines. Thus, collection methods must result in the identification of the anthropophilic species and efficiently evaluate the parameters involved in malaria transmission dynamics. Consequently, human landing catches would be the most appropriate method if not for their inherent risk. The choice of alternative anopheline collection methods, such as traps, must consider their effectiveness in reproducing the efficiency of human attraction. Collection methods lure mosquitoes by using a mixture of olfactory, visual and thermal cues. Here, we reviewed, classified and compared the efficiency of anopheline collection methods, with an emphasis on Neotropical anthropophilic species, especially Anopheles darlingi, in distinct malaria epidemiological conditions in Brazil.

  10. Safety and comparability of controlled human Plasmodium falciparum infection by mosquito bite in malaria-naïve subjects at a new facility for sporozoite challenge.

    Directory of Open Access Journals (Sweden)

    Angela K Talley

    Full Text Available Controlled human malaria infection (CHMI studies which recapitulate mosquito-borne infection are a critical tool to identify protective vaccine and drug candidates for advancement to field trials. In partnership with the Walter Reed Army Institute of Research, the CHMI model was established at the Seattle Biomedical Research Institute's Malaria Clinical Trials Center (MCTC. Activities and reagents at both centers were aligned to ensure comparability and continued safety of the model. To demonstrate successful implementation, CHMI was performed in six healthy malaria-naïve volunteers.All volunteers received NF54 strain Plasmodium falciparum by the bite of five infected Anopheles stephensi mosquitoes under controlled conditions and were monitored for signs and symptoms of malaria and for parasitemia by peripheral blood smear. Subjects were treated upon diagnosis with chloroquine by directly observed therapy. Immunological (T cell and antibody and molecular diagnostic (real-time quantitative reverse transcriptase polymerase chain reaction [qRT-PCR] assessments were also performed.All six volunteers developed patent parasitemia and clinical malaria. No serious adverse events occurred during the study period or for six months post-infection. The mean prepatent period was 11.2 days (range 9-14 days, and geometric mean parasitemia upon diagnosis was 10.8 parasites/µL (range 2-69 by microscopy. qRT-PCR detected parasites an average of 3.7 days (range 2-4 days earlier than blood smears. All volunteers developed antibodies to the blood-stage antigen merozoite surface protein 1 (MSP-1, which persisted up to six months. Humoral and cellular responses to pre-erythrocytic antigens circumsporozoite protein (CSP and liver-stage antigen 1 (LSA-1 were limited.The CHMI model was safe, well tolerated and characterized by consistent prepatent periods, pre-symptomatic diagnosis in 3/6 subjects and adverse event profiles as reported at established centers. The MCTC

  11. Estimation of human body concentrations of DDT from indoor residual spraying for malaria control.

    Science.gov (United States)

    Gyalpo, Tenzing; Fritsche, Lukas; Bouwman, Henk; Bornman, Riana; Scheringer, Martin; Hungerbühler, Konrad

    2012-10-01

    Inhabitants of dwellings treated with DDT for indoor residual spraying show high DDT levels in blood and breast milk. This is of concern since mothers transfer lipid-soluble contaminants such as DDT via breastfeeding to their children. Focusing on DDT use in South Africa, we employ a pharmacokinetic model to estimate DDT levels in human lipid tissue over the lifetime of an individual to determine the amount of DDT transferred to children during breastfeeding, and to identify the dominant DDT uptake routes. In particular, the effects of breastfeeding duration, parity, and mother's age on DDT concentrations of mother and infant are investigated. Model results show that primiparous mothers have greater DDT concentrations than multiparous mothers, which causes higher DDT exposure of first-born children. DDT in the body mainly originates from diet. Generally, our modeled DDT levels reproduce levels found in South African biomonitoring data within a factor of 3. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Hysteresis in simulations of malaria transmission

    Science.gov (United States)

    Yamana, Teresa K.; Qiu, Xin; Eltahir, Elfatih A. B.

    2017-10-01

    Malaria transmission is a complex system and in many parts of the world is closely related to climate conditions. However, studies on environmental determinants of malaria generally consider only concurrent climate conditions and ignore the historical or initial conditions of the system. Here, we demonstrate the concept of hysteresis in malaria transmission, defined as non-uniqueness of the relationship between malaria prevalence and concurrent climate conditions. We show the dependence of simulated malaria transmission on initial prevalence and the initial level of human immunity in the population. Using realistic time series of environmental variables, we quantify the effect of hysteresis in a modeled population. In a set of numerical experiments using HYDREMATS, a field-tested mechanistic model of malaria transmission, the simulated maximum malaria prevalence depends on both the initial prevalence and the initial level of human immunity in the population. We found the effects of initial conditions to be of comparable magnitude to the effects of interannual variability in environmental conditions in determining malaria prevalence. The memory associated with this hysteresis effect is longer in high transmission settings than in low transmission settings. Our results show that efforts to simulate and forecast malaria transmission must consider the exposure history of a location as well as the concurrent environmental drivers.

  13. The march toward malaria vaccines.

    Science.gov (United States)

    Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L; Duffy, Patrick E

    2015-11-27

    In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of

  14. Human pregnancy-associated malaria-specific B cells target polymorphic, conformational epitopes in VAR2CSA

    DEFF Research Database (Denmark)

    Barfod, L.; Bernasconi, N. L.; Dahlback, M.

    2007-01-01

    Pregnancy-associated malaria (PAM) is caused by Plasmodium falciparum-infected erythrocytes (IEs) that bind to chondroitin sulphate A (CSA) in the placenta by PAM-associated clonally variant surface antigens (VSA). Pregnancy-specific VSA (VSA(PAM)), which include the PfEMP1 variant VAR2CSA...

  15. Symmetrical peripheral gangrene: A rare complication of plasmodium falciparum malaria

    OpenAIRE

    Rana, Atul; Singh, DP; Kaur, Gurdeep; Verma, SK; Mahur, Hemant

    2015-01-01

    Malaria, the most important of the parasitic diseases of humans, is transmitted in 108 countries containing 3 billion people and causes nearly 1 million deaths each year. With the re-emergence of malaria various life-threatening complications of malaria have been observed. Unarousable coma/cerebral malaria, severe normochromic, normocytic anemia, renal failure, pulmonary edema/adult respiratory distress syndrome, hypoglycemia, hypotension/shock, bleeding/disseminated intravascular coagulation...

  16. Rodent malaria parasites : genome organization & comparative genomics

    NARCIS (Netherlands)

    Kooij, Taco W.A.

    2006-01-01

    The aim of the studies described in this thesis was to investigate the genome organization of rodent malaria parasites (RMPs) and compare the organization and gene content of the genomes of RMPs and the human malaria parasite P. falciparum. The release of the complete genome sequence of P.

  17. New methods and software tools for high throughput CDR3 spectratyping. Application to T lymphocyte repertoire modifications during experimental malaria.

    Science.gov (United States)

    Collette, Alexis; Cazenave, Pierre-André; Pied, Sylviane; Six, Adrien

    2003-07-01

    Immune repertoires of T or B cells are very often studied by Complementary Determining Region 3 (CDR3) spectratyping. However, data obtained with this method is usually subject to a biased eye analysis. We developed recently the ISEApeaks software package to retrieve and handle peak data from automated sequencers, from which CDR3 spectratype data is obtained. We describe a general strategy for CDR3 spectratype analysis based on two new specific modules and multivariate statistics. The first module addresses the crucial problem of peak smoothing. The second is a toolbox for the analysis of CDR3 spectratypes, which includes perturbation computation, recurrent peak finding, expansion assessment and datamining. To illustrate our approach, we assessed the complex TCRB repertoire modifications induced by Plasmodium berghei ANKA (PbA) infection. This global and exhaustive repertoire analysis approach is of general interest for T- and B-lymphocyte repertoire studies and is currently used in human cohorts in various pathologies and during clinical trials.

  18. Mutations that Cause Human Disease: A Computational/Experimental Approach

    Energy Technology Data Exchange (ETDEWEB)

    Beernink, P; Barsky, D; Pesavento, B

    2006-01-11

    International genome sequencing projects have produced billions of nucleotides (letters) of DNA sequence data, including the complete genome sequences of 74 organisms. These genome sequences have created many new scientific opportunities, including the ability to identify sequence variations among individuals within a species. These genetic differences, which are known as single nucleotide polymorphisms (SNPs), are particularly important in understanding the genetic basis for disease susceptibility. Since the report of the complete human genome sequence, over two million human SNPs have been identified, including a large-scale comparison of an entire chromosome from twenty individuals. Of the protein coding SNPs (cSNPs), approximately half leads to a single amino acid change in the encoded protein (non-synonymous coding SNPs). Most of these changes are functionally silent, while the remainder negatively impact the protein and sometimes cause human disease. To date, over 550 SNPs have been found to cause single locus (monogenic) diseases and many others have been associated with polygenic diseases. SNPs have been linked to specific human diseases, including late-onset Parkinson disease, autism, rheumatoid arthritis and cancer. The ability to predict accurately the effects of these SNPs on protein function would represent a major advance toward understanding these diseases. To date several attempts have been made toward predicting the effects of such mutations. The most successful of these is a computational approach called ''Sorting Intolerant From Tolerant'' (SIFT). This method uses sequence conservation among many similar proteins to predict which residues in a protein are functionally important. However, this method suffers from several limitations. First, a query sequence must have a sufficient number of relatives to infer sequence conservation. Second, this method does not make use of or provide any information on protein structure, which

  19. Drug and Vaccine Evaluation in the Human Aotus Plasmodium Falciparum Model

    National Research Council Canada - National Science Library

    Obaldia

    2002-01-01

    The purpose of this report is to present data on the evaluation of drugs and vaccines in the human malaria/Aotus lemurinus lemurinus monkey model experimentally infected with Plasmodium falciparum or vivax...

  20. Prevalence of malaria parasites and Hepatitis-B virus in patients ...

    African Journals Online (AJOL)

    Malaria and Hepatitis-B virus (HBV) remain a threat to human health in many developing nations. Many regions with high malaria prevalence are also endemic for other infectious diseases which may predispose them to more of the malaria infection. Using thin and thick film preparations, malaria parasites were detected, ...

  1. Immunomodulation in human and experimental uveitis: Recent advances

    Directory of Open Access Journals (Sweden)

    Singh Vijay

    1999-01-01

    Full Text Available Experimental autoimmune uveitis (EAU is a T-cell mediated autoimmune disease that targets the neural retina and serves as a model of human uveitis. EAU can be induced against several retinal proteins in rats, mice, and subhuman primates. These include the S-antigen, a major protein in retinal photoreceptor cells; interphotoreceptor retinoid-binding protein (IRBP; and rhodopsin and other antigens of retinal origin. There are many similarities between clinical uveitis and EAU, but the latter differs in being self-limited, and needs adjuvant for disease induction. The experimental disease can be induced only in susceptible animal strains. Use of the EAU model has helped investigators understand the pathophysiology of the disease and to evaluate disease-modifying strategies, which could be applied in the clinic. There has been significant progress in this field during last decade, but much more understanding is needed before the knowledge can be transferred to clinical practice. A deeper understanding of the immune mechanisms involved in the EAU model may lead to the development of new therapeutic approaches targeted at various components of the immune response by immunomodulation to control uveitis. This review summarises the evidence from the EAU model, which could be of relevance to the clinical management of patients with uveitis.

  2. Experimental sleep restriction causes endothelial dysfunction in healthy humans.

    Science.gov (United States)

    Calvin, Andrew D; Covassin, Naima; Kremers, Walter K; Adachi, Taro; Macedo, Paula; Albuquerque, Felipe N; Bukartyk, Jan; Davison, Diane E; Levine, James A; Singh, Prachi; Wang, Shihan; Somers, Virend K

    2014-11-25

    Epidemiologic evidence suggests a link between short sleep duration and cardiovascular risk, although the nature of any relationship and mechanisms remain unclear. Short sleep duration has also been linked to an increase in cardiovascular events. Endothelial dysfunction has itself been implicated as a mediator of heightened cardiovascular risk. We sought to determine the effect of 8 days/8 nights of partial sleep restriction on endothelial function in healthy humans. Sixteen healthy volunteers underwent a randomized study of usual sleep versus sleep restriction of two-thirds normal sleep time for 8 days/8 nights in a hospital-based clinical research unit. The main outcome was endothelial function measured by flow-mediated brachial artery vasodilatation (FMD). Those randomized to sleep restriction slept 5.1 hours/night during the experimental period compared with 6.9 hours/night in the control group. Sleep restriction was associated with significant impairment in FMD (8.6±4.6% during the initial pre-randomization acclimation phase versus 5.2±3.4% during the randomized experimental phase, P=0.01) whereas no change was seen in the control group (5.0±3.0 during the acclimation phase versus 6.73±2.9% during the experimental phase, P=0.10) for a between-groups difference of -4.40% (95% CI -7.00 to -1.81%, P=0.003). No change was seen in non-flow mediated vasodilatation (NFMD) in either group. In healthy individuals, moderate sleep restriction causes endothelial dysfunction. ClinicalTrials.gov. Unique identifier: NCT01334788. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  3. Heritability of Malaria in Africa.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available BACKGROUND: While many individual genes have been identified that confer protection against malaria, the overall impact of host genetics on malarial risk remains unknown. METHODS AND FINDINGS: We have used pedigree-based genetic variance component analysis to determine the relative contributions of genetic and other factors to the variability in incidence of malaria and other infectious diseases in two cohorts of children living on the coast of Kenya. In the first, we monitored the incidence of mild clinical malaria and other febrile diseases through active surveillance of 640 children 10 y old or younger, living in 77 different households for an average of 2.7 y. In the second, we recorded hospital admissions with malaria and other infectious diseases in a birth cohort of 2,914 children for an average of 4.1 y. Mean annual incidence rates for mild and hospital-admitted malaria were 1.6 and 0.054 episodes per person per year, respectively. Twenty-four percent and 25% of the total variation in these outcomes was explained by additively acting host genes, and household explained a further 29% and 14%, respectively. The haemoglobin S gene explained only 2% of the total variation. For nonmalarial infections, additive genetics explained 39% and 13% of the variability in fevers and hospital-admitted infections, while household explained a further 9% and 30%, respectively. CONCLUSION: Genetic and unidentified household factors each accounted for around one quarter of the total variability in malaria incidence in our study population. The genetic effect was well beyond that explained by the anticipated effects of the haemoglobinopathies alone, suggesting the existence of many protective genes, each individually resulting in small population effects. While studying these genes may well provide insights into pathogenesis and resistance in human malaria, identifying and tackling the household effects must be the more efficient route to reducing the burden

  4. Primate malarias: Diversity, distribution and insights for zoonotic Plasmodium.

    Science.gov (United States)

    Faust, Christina; Dobson, Andrew P

    2015-12-01

    Protozoans within the genus Plasmodium are well-known as the causative agents of malaria in humans. Numerous Plasmodium species parasites also infect a wide range of non-human primate hosts in tropical and sub-tropical regions worldwide. Studying this diversity can provide critical insight into our understanding of human malarias, as several human malaria species are a result of host switches from non-human primates. Current spillover of a monkey malaria, Plasmodium knowlesi, in Southeast Asia highlights the permeability of species barriers in Plasmodium. Also recently, surveys of apes in Africa uncovered a previously undescribed diversity of Plasmodium in chimpanzees and gorillas. Therefore, we carried out a meta-analysis to quantify the global distribution, host range, and diversity of known non-human primate malaria species. We used published records of Plasmodium parasites found in non-human primates to estimate the total diversity of non-human primate malarias globally. We estimate that at least three undescribed primate malaria species exist in sampled primates, and many more likely exist in unstudied species. The diversity of malaria parasites is especially uncertain in regions of low sampling such as Madagascar, and taxonomic groups such as African Old World Monkeys and gibbons. Presence-absence data of malaria across primates enables us to highlight the close association of forested regions and non-human primate malarias. This distribution potentially reflects a long coevolution of primates, forest-adapted mosquitoes, and malaria parasites. The diversity and distribution of primate malaria are an essential prerequisite to understanding the mechanisms and circumstances that allow Plasmodium to jump species barriers, both in the evolution of malaria parasites and current cases of spillover into humans.

  5. Primate malarias: Diversity, distribution and insights for zoonotic Plasmodium

    Directory of Open Access Journals (Sweden)

    Christina Faust

    2015-12-01

    Full Text Available Protozoans within the genus Plasmodium are well-known as the causative agents of malaria in humans. Numerous Plasmodium species parasites also infect a wide range of non-human primate hosts in tropical and sub-tropical regions worldwide. Studying this diversity can provide critical insight into our understanding of human malarias, as several human malaria species are a result of host switches from non-human primates. Current spillover of a monkey malaria, Plasmodium knowlesi, in Southeast Asia highlights the permeability of species barriers in Plasmodium. Also recently, surveys of apes in Africa uncovered a previously undescribed diversity of Plasmodium in chimpanzees and gorillas. Therefore, we carried out a meta-analysis to quantify the global distribution, host range, and diversity of known non-human primate malaria species. We used published records of Plasmodium parasites found in non-human primates to estimate the total diversity of non-human primate malarias globally. We estimate that at least three undescribed primate malaria species exist in sampled primates, and many more likely exist in unstudied species. The diversity of malaria parasites is especially uncertain in regions of low sampling such as Madagascar, and taxonomic groups such as African Old World Monkeys and gibbons. Presence–absence data of malaria across primates enables us to highlight the close association of forested regions and non-human primate malarias. This distribution potentially reflects a long coevolution of primates, forest-adapted mosquitoes, and malaria parasites. The diversity and distribution of primate malaria are an essential prerequisite to understanding the mechanisms and circumstances that allow Plasmodium to jump species barriers, both in the evolution of malaria parasites and current cases of spillover into humans.

  6. Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease

    OpenAIRE

    1991-01-01

    Hemoglobin is an important nutrient source for intraerythrocytic malaria organisms. Its catabolism occurs in an acidic digestive vacuole. Our previous studies suggested that an aspartic protease plays a key role in the degradative process. We have now isolated this enzyme and defined its role in the hemoglobinolytic pathway. Laser desorption mass spectrometry was used to analyze the proteolytic action of the purified protease. The enzyme has a remarkably stringent specificity towards native h...

  7. The behaviour of mosquitoes in relation to humans under holed bednets: the evidence from experimental huts

    Directory of Open Access Journals (Sweden)

    Seth R Irish

    2014-11-01

    Full Text Available The physical integrity of bednets is a concern of national malaria control programs, as it is a key factor in determining the rate of replacement of bednets. It is largely assumed that increased numbers of holes will result in a loss of protection of sleepers from potentially infective bites. Experimental hut studies are valuable in understanding mosquito behaviour indoors, particularly as it relates to blood feeding and mortality. This review summarises findings from experimental hut studies, focusing on two issues: (i the effect of different numbers or sizes of holes in bednets and (ii feeding behaviour and mortality with holed nets as compared with unholed nets. As might be expected, increasing numbers and area of holes resulted in increased blood feeding by mosquitoes on sleepers. However, the presence of holes did not generally have a large effect on the mortality of mosquitoes. Successfully entering a holed mosquito net does not necessarily mean that mosquitoes spend less time in contact with the net, which could explain the lack in differences in mortality. Further behavioural studies are necessary to understand mosquito behaviour around nets and the importance of holed nets on malaria transmission.

  8. Towards eliminating malaria in high endemic countries: the roles of community health workers and related cadres and their challenges in integrated community case management for malaria: a systematic review.

    Science.gov (United States)

    Sunguya, Bruno F; Mlunde, Linda B; Ayer, Rakesh; Jimba, Masamine

    2017-01-03

    Human resource for health crisis has impaired global efforts against malaria in highly endemic countries. To address this, the World Health Organization (WHO) recommended scaling-up of community health workers (CHWs) and related cadres owing to their documented success in malaria and other disease prevention and management. Evidence is inconsistent on the roles and challenges they encounter in malaria interventions. This systematic review aims to summarize evidence on roles and challenges of CHWs and related cadres in integrated community case management for malaria (iCCM). This systematic review retrieved evidence from PubMed, CINAHL, ISI Web of Knowledge, and WHO regional databases. Terms extracted from the Boolean phrase used for PubMed were also used in other databases. The review included studies with Randomized Control Trial, Quasi-experimental, Pre-post interventional, Longitudinal and cohort, Cross-sectional, Case study, and Secondary data analysis. Because of heterogeneity, only narrative synthesis was conducted for this review. A total of 66 articles were eligible for analysis out of 1380 studies retrieved. CHWs and related cadre roles in malaria interventions included: malaria case management, prevention including health surveillance and health promotion specific to malaria. Despite their documented success, CHWs and related cadres succumb to health system challenges. These are poor and unsustainable finance for iCCM, workforce related challenges, lack of and unsustainable supply of medicines and diagnostics, lack of information and research, service delivery and leadership challenges. Community health workers and related cadres had important preventive, case management and promotive roles in malaria interventions. To enable their effective integration into the health systems, the identified challenges should be addressed. They include: introducing sustainable financing on iCCM programmes, tailoring their training to address the identified gaps

  9. An experimental investigation of the combustion performance of human faeces.

    Science.gov (United States)

    Onabanjo, Tosin; Kolios, Athanasios J; Patchigolla, Kumar; Wagland, Stuart T; Fidalgo, Beatriz; Jurado, Nelia; Hanak, Dawid P; Manovic, Vasilije; Parker, Alison; McAdam, Ewan; Williams, Leon; Tyrrel, Sean; Cartmell, Elise

    2016-11-15

    Poor sanitation is one of the major hindrances to the global sustainable development goals. The Reinvent the Toilet Challenge of the Bill and Melinda Gates Foundation is set to develop affordable, next-generation sanitary systems that can ensure safe treatment and wide accessibility without compromise on sustainable use of natural resources and the environment. Energy recovery from human excreta is likely to be a cornerstone of future sustainable sanitary systems. Faeces combustion was investigated using a bench-scale downdraft combustor test rig, alongside with wood biomass and simulant faeces. Parameters such as air flow rate, fuel pellet size, bed height, and fuel ignition mode were varied to establish the combustion operating range of the test rig and the optimum conditions for converting the faecal biomass to energy. The experimental results show that the dry human faeces had a higher energy content (∼25 MJ/kg) than wood biomass. At equivalence ratio between 0.86 and 1.12, the combustion temperature and fuel burn rate ranged from 431 to 558 °C and 1.53 to 2.30 g/min respectively. Preliminary results for the simulant faeces show that a minimum combustion bed temperature of 600 ± 10 °C can handle faeces up to 60 wt.% moisture at optimum air-to-fuel ratio. Further investigation is required to establish the appropriate trade-off limits for drying and energy recovery, considering different stool types, moisture content and drying characteristics. This is important for the design and further development of a self-sustained energy conversion and recovery systems for the NMT and similar sanitary solutions.

  10. IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection.

    Directory of Open Access Journals (Sweden)

    Catherine Q Nie

    2009-04-01

    Full Text Available Plasmodium falciparum malaria causes 660 million clinical cases with over 2 million deaths each year. Acquired host immunity limits the clinical impact of malaria infection and provides protection against parasite replication. Experimental evidence indicates that cell-mediated immune responses also result in detrimental inflammation and contribute to severe disease induction. In both humans and mice, the spleen is a crucial organ involved in blood stage malaria clearance, while organ-specific disease appears to be associated with sequestration of parasitized erythrocytes in vascular beds and subsequent recruitment of inflammatory leukocytes. Using a rodent model of cerebral malaria, we have previously found that the majority of T lymphocytes in intravascular infiltrates of cerebral malaria-affected mice express the chemokine receptor CXCR3. Here we investigated the effect of IP-10 blockade in the development of experimental cerebral malaria and the induction of splenic anti-parasite immunity. We found that specific neutralization of IP-10 over the course of infection and genetic deletion of this chemokine in knockout mice reduces cerebral intravascular inflammation and is sufficient to protect P. berghei ANKA-infected mice from fatality. Furthermore, our results demonstrate that lack of IP-10 during infection significantly reduces peripheral parasitemia. The increased resistance to infection observed in the absence of IP-10-mediated cell trafficking was associated with retention and subsequent expansion of parasite-specific T cells in spleens of infected animals, which appears to be advantageous for the control of parasite burden. Thus, our results demonstrate that modulating homing of cellular immune responses to malaria is critical for reaching a balance between protective immunity and immunopathogenesis.

  11. Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

    Directory of Open Access Journals (Sweden)

    Ana Paula Morais Martins Almeida

    2011-08-01

    Full Text Available The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures, has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject.

  12. Malaria (For Parents)

    Science.gov (United States)

    ... in others. Proper treatment can cure malaria. What Causes Malaria? Malaria is caused by parasites carried by mosquitoes. ... seen a lot, doctors often treat people for malaria who have a fever with no obvious cause without getting lab tests to prove the person ...

  13. Artemisia vulgaris L. ethanolic leaf extract reverses thrombocytopenia/thrombocytosis and averts end-stage disease of experimental severe Plasmodium berghei murine malaria.

    Science.gov (United States)

    Bamunuarachchi, Gayan S; Ratnasooriya, Wanigasekara D; Premakumara, Sirimal; Udagama, Preethi V

    2014-12-01

    Artemisinin isolated from Artemisia annua is the most potent antimalarial against chloroquine resistant Plasmodium falciparum malaria. We previously reported that the ethanolic leaf extract of Artemisia vulgaris, an invasive weed and the only Artemisia species in Sri Lanka, possess both potent and safe antimalarial activity (in terms of antiparasitic properties) in a P. berghei murine malaria model. We report here a prototype study that investigated antidisease activities of A. vulgaris ethanolic leaf extract (AVELE) in a P. berghei ANKA murine malaria model that elicit pathogenesis similar to falciparum malaria. Profound thrombocytosis and thrombocytopenia in mice were detected in early-stage (Day 3), and at a later stage of infection (Day 6), respectively. Plasmodium berghei infected mice, 7 or 8 days post-infection reached end-stage disease with rapid drop in body temperature and usually die within 24 h, as a consequence of cerebral malaria. Three doses of the AVELE (500, 750 and 1000 mg/kg) were used to assess antidisease activity of A. vulgaris in terms of survival, effects on thrombocyte related pathology and end-stage disease, antipyretic activity, and antinociception, using standard methodology. The 1000 mg/kg dose of AVELE significantly increased survival, reversed the profound thrombocytopenia/ thrombocytosis (p ≤0.01), altered the end-stage disease (p ≤0.05), and manifested significant antipyretic and antinociceptive (p ≤0.05) activities. We conclude that a crude ethanolic leaf extract of A. vulgaris, showed potent antimalarial properties, in terms of antidisease activities; antipyretic activity, peripheral and central antinociception, increased survival, averted end-stage disease and reversed thrombocytopenia/thrombocytosis.

  14. Mast cells in human and experimental cardiometabolic diseases.

    Science.gov (United States)

    Shi, Guo-Ping; Bot, Ilze; Kovanen, Petri T

    2015-11-01

    Mast cells, like many other types of inflammatory cell, perform pleiotropic roles in cardiometabolic diseases such as atherosclerosis, abdominal aortic aneurysms, obesity, and diabetes mellitus, as well as complications associated with these diseases. Low numbers of mast cells are present in the heart, aorta, and adipose tissue of healthy humans, but patients with cardiometabolic diseases and animals with experimentally-induced cardiometabolic pathologies have high numbers of mast cells with increased activity in the affected tissues. Mediators released by the activated mast cells, such as chemokines, cytokines, growth factors, heparin, histamine, and proteases, not only function as biomarkers of cardiometabolic diseases, but might also directly contribute to the pathogenesis of such diseases. Mast-cell mediators impede the functions of vascular cells, the integrity of the extracellular matrix, and the activity of other inflammatory cells, thereby contributing to the pathobiology of the conditions at multiple levels. In mouse models, mast-cell activation aggravates the progression of various cardiometabolic pathologies, whereas a genetic deficiency or pharmacological stabilization of mast cells, or depletion or inhibition of specific mast-cell mediators, tends to delay the progression of such conditions. Pharmacological inhibition of mast-cell activation or their targeted effector functions offers potential novel therapeutic strategies for patients with cardiometabolic disorders.

  15. Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia.

    Directory of Open Access Journals (Sweden)

    Stan de Kleijn

    Full Text Available Polymorphonuclear cells (neutrophils play an important role in the systemic inflammatory response syndrome and the development of sepsis. These cells are essential for the defense against microorganisms, but may also cause tissue damage. Therefore, neutrophil numbers and activity are considered to be tightly regulated. Previous studies have investigated gene transcription during experimental endotoxemia in whole blood and peripheral blood mononuclear cells. However, the gene transcription response of the circulating pool of neutrophils to systemic inflammatory stimulation in vivo is currently unclear. We examined neutrophil gene transcription kinetics in healthy human subjects (n = 4 administered a single dose of endotoxin (LPS, 2 ng/kg iv. In addition, freshly isolated neutrophils were stimulated ex vivo with LPS, TNFα, G-CSF and GM-CSF to identify stimulus-specific gene transcription responses. Whole transcriptome microarray analysis of circulating neutrophils at 2, 4 and 6 hours after LPS infusion revealed activation of inflammatory networks which are involved in signaling of TNFα and IL-1α and IL-1β. The transcriptome profile of inflammatory activated neutrophils in vivo reflects extended survival and regulation of inflammatory responses. These changes in neutrophil transcriptome suggest a combination of early activation of circulating neutrophils by TNFα and G-CSF and a mobilization of young neutrophils from the bone marrow.

  16. Simian malaria at two sites in the Brazilian Amazon: I-The infection rates of Plasmodium brasilianum in non-human primates

    Directory of Open Access Journals (Sweden)

    Ricardo Lourenço-de-Oliveira

    1995-06-01

    Full Text Available The parasite that causes simian malaria in the Brazilian Amazon, Plasmodium brasilianum, is infective to man. In this region, where humans live within and in close proximity to the forest, it was suspected that this parasite could be the cause of a zoonosis. A study was performed in the areas surrounding two hydroelectric plants in the Amazon, Balbina and Samuel, aiming at determining the zoonotic potential of this parasite. P. brasilianum was detected in, respectively, 15.8% and 9.9% of 126 and 252 primates belonging to seven and eight species examined from Balbina and Samuel. The highest malaria infection rates were found among the red-howler monkey Alouatta seniculus straminea (32.3%, the bearded-saki Chiropotes satanas chiropotes (50% and the spider-monkey Ateles paniscus paniscus (2[1+] from Balbina and in the squirrel-monkey Saimiri ustus (21% and the black-faced-spider-monkey Ateles paniscus chamek (28.6% from Samuel.

  17. Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa.

    Science.gov (United States)

    Mamotte, Nicole; Wassenaar, Douglas; Koen, Jennifer; Essack, Zaynab

    2010-03-09

    Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB) and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges. In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009. Key cross cutting ethical issues were prioritized during the consultation as community engagement; ancillary care obligations; care and treatment; informed consent; and resource sharing. The consultation revealed that while there have been few attempts to find convergence on ethical issues between HIV/AIDS, TB and malaria vaccine trial fields to date, there is much common ground and scope for convergence work between stakeholders in the three fields.

  18. Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa

    Directory of Open Access Journals (Sweden)

    Essack Zaynab

    2010-03-01

    Full Text Available Abstract Background Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges. Methods In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009. Results Key cross cutting ethical issues were prioritized during the consultation as community engagement; ancillary care obligations; care and treatment; informed consent; and resource sharing. Conclusion The consultation revealed that while there have been few attempts to find convergence on ethical issues between HIV/AIDS, TB and malaria vaccine trial fields to date, there is much common ground and scope for convergence work between stakeholders in the three fields.

  19. Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa

    Science.gov (United States)

    2010-01-01

    Background Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB) and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges. Methods In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009. Results Key cross cutting ethical issues were prioritized during the consultation as community engagement; ancillary care obligations; care and treatment; informed consent; and resource sharing. Conclusion The consultation revealed that while there have been few attempts to find convergence on ethical issues between HIV/AIDS, TB and malaria vaccine trial fields to date, there is much common ground and scope for convergence work between stakeholders in the three fields. PMID:20211030

  20. NNDSS - Table II. Legionellosis to Malaria

    Data.gov (United States)

    U.S. Department of Health & Human Services — NNDSS - Table II. Legionellosis to Malaria - 2017. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the preceding...

  1. NNDSS - Table II. Legionellosis to Malaria

    Data.gov (United States)

    U.S. Department of Health & Human Services — NNDSS - Table II. Legionellosis to Malaria - 2018. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the preceding...

  2. Health education and caregivers' management of Malaria among ...

    African Journals Online (AJOL)

    Results revealed that the respondents had good knowledge of how malaria was transmitted- 75.8% in the experimental group and 73.3% in the control group. Their knowledge about the indirect causes of malaria was poor- 39.2% in experimental group and 41.7% in control group respectively. Knowledge scores on signs ...

  3. Malaria in the Greater Mekong Subregion: heterogeneity and complexity.

    Science.gov (United States)

    Cui, Liwang; Yan, Guiyun; Sattabongkot, Jetsumon; Cao, Yaming; Chen, Bin; Chen, Xiaoguang; Fan, Qi; Fang, Qiang; Jongwutiwes, Somchai; Parker, Daniel; Sirichaisinthop, Jeeraphat; Kyaw, Myat Phone; Su, Xin-zhuan; Yang, Henglin; Yang, Zhaoqing; Wang, Baomin; Xu, Jianwei; Zheng, Bin; Zhong, Daibin; Zhou, Guofa

    2012-03-01

    The Greater Mekong Subregion (GMS), comprised of six countries including Cambodia, China's Yunnan Province, Lao PDR, Myanmar (Burma), Thailand and Vietnam, is one of the most threatening foci of malaria. Since the initiation of the WHO's Mekong Malaria Program a decade ago, malaria situation in the GMS has greatly improved, reflected in the continuous decline in annual malaria incidence and deaths. However, as many nations are moving towards malaria elimination, the GMS nations still face great challenges. Malaria epidemiology in this region exhibits enormous geographical heterogeneity with Myanmar and Cambodia remaining high-burden countries. Within each country, malaria distribution is also patchy, exemplified by 'border malaria' and 'forest malaria' with high transmission occurring along international borders and in forests or forest fringes, respectively. 'Border malaria' is extremely difficult to monitor, and frequent malaria introductions by migratory human populations constitute a major threat to neighboring, malaria-eliminating countries. Therefore, coordination between neighboring countries is essential for malaria elimination from the entire region. In addition to these operational difficulties, malaria control in the GMS also encounters several technological challenges. Contemporary malaria control measures rely heavily on effective chemotherapy and insecticide control of vector mosquitoes. However, the spread of multidrug resistance and potential emergence of artemisinin resistance in Plasmodium falciparum make resistance management a high priority in the GMS. This situation is further worsened by the circulation of counterfeit and substandard artemisinin-related drugs. In most endemic areas of the GMS, P. falciparum and Plasmodium vivax coexist, and in recent malaria control history, P. vivax has demonstrated remarkable resilience to control measures. Deployment of the only registered drug (primaquine) for the radical cure of vivax malaria is severely

  4. Impact of malaria and helminth infections on immunogenicity of the human papillomavirus-16/18 AS04-adjuvanted vaccine in Tanzania.

    Science.gov (United States)

    Brown, Joelle; Baisley, Kathy; Kavishe, Bazil; Changalucha, John; Andreasen, Aura; Mayaud, Philippe; Gumodoka, Balthazar; Kapiga, Saidi; Hayes, Richard; Watson-Jones, Deborah

    2014-01-23

    Endemic malaria and helminth infections in sub-Saharan Africa can act as immunological modulators and impact responses to standard immunizations. We conducted a cohort study to measure the influence of malaria and helminth infections on the immunogenicity of the bivalent HPV-16/18 vaccine. We evaluated the association between malaria and helminth infections, and HPV-16/18 antibody responses among 298 Tanzanian females aged 10-25 years enrolled in a randomized controlled trial of the HPV-16/18 vaccine. Malaria parasitaemia was diagnosed by examination of blood smears, and helminth infections were diagnosed by examination of urine and stool samples, respectively. Geometric mean antibody titres (GMT) against HPV-16/18 antibodies were measured by enzyme-linked immunosorbent assay. Parasitic infections were common; one-third (30.4%) of participants had a helminth infection and 10.2% had malaria parasitaemia. Overall, the vaccine induced high HPV-16/18 GMTs, and there was no evidence of a reduction in HPV-16 or HPV-18 GMT at Month 7 or Month 12 follow-up visits among participants with helminths or malaria. There was some evidence that participants with malaria had increased GMTs compared to those without malaria. The data show high HPV immunogenicity regardless of the presence of malaria and helminth infections. The mechanism and significance for the increase in GMT in those with malaria is unknown. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Melatonin-Induced Temporal Up-Regulation of Gene Expression Related to Ubiquitin/Proteasome System (UPS in the Human Malaria Parasite Plasmodium falciparum

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    Fernanda C. Koyama

    2014-12-01

    Full Text Available There is an increasing understanding that melatonin and the ubiquitin/ proteasome system (UPS interact to regulate multiple cellular functions. Post-translational modifications such as ubiquitination are important modulators of signaling processes, cell cycle and many other cellular functions. Previously, we reported a melatonin-induced upregulation of gene expression related to ubiquitin/proteasome system (UPS in Plasmodium falciparum, the human malaria parasite, and that P. falciparum protein kinase 7 influences this process. This implies a role of melatonin, an indolamine, in modulating intraerythrocytic development of the parasite. In this report we demonstrate by qPCR analysis, that melatonin induces gene upregulation in nine out of fourteen genes of the UPS, consisting of the same set of genes previously reported, between 4 to 5 h after melatonin treatment. We demonstrate that melatonin causes a temporally controlled gene expression of UPS members.

  6. Melatonin-induced temporal up-regulation of gene expression related to ubiquitin/proteasome system (UPS) in the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Koyama, Fernanda C; Azevedo, Mauro F; Budu, Alexandre; Chakrabarti, Debopam; Garcia, Célia R S

    2014-12-03

    There is an increasing understanding that melatonin and the ubiquitin/ proteasome system (UPS) interact to regulate multiple cellular functions. Post-translational modifications such as ubiquitination are important modulators of signaling processes, cell cycle and many other cellular functions. Previously, we reported a melatonin-induced upregulation of gene expression related to ubiquitin/proteasome system (UPS) in Plasmodium falciparum, the human malaria parasite, and that P. falciparum protein kinase 7 influences this process. This implies a role of melatonin, an indolamine, in modulating intraerythrocytic development of the parasite. In this report we demonstrate by qPCR analysis, that melatonin induces gene upregulation in nine out of fourteen genes of the UPS, consisting of the same set of genes previously reported, between 4 to 5 h after melatonin treatment. We demonstrate that melatonin causes a temporally controlled gene expression of UPS members.

  7. The vertical dispersión of Anopheles (Kerteszia cruzi in a forest in southern Brazil suggests that human cases of malaria of simian origin might be expected

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    Leonidas M. Deane

    1984-12-01

    Full Text Available By staining females of Anopheles cruzi with fluorescent coloured powders in a forest in the State of Santa Catarina, we showed that they move from canopy to ground and vice-versa to feed. This suggests that in areas where this mosquito is a vector of human and simian malarias sporadic infections of man with monkey plasmodia might be expected.Pintando fêmeas de Anopheles cruzi com pós fluorescentes coloridos, numa floresta de Santa Catarina, mostramos que elas movimentam-se da copa ao solo e vice-versa para se alimentar de sangue. Isso sugere que em áreas onde esse mosquito for tansmissor das malárias humana e simiana pode-se esperar que ocorram infecções humanas esporádicas por plasmódios de macacos.

  8. A supervised land cover classification of a western Kenya lowland endemic for human malaria: associations of land cover with larval Anopheles habitats.

    Science.gov (United States)

    Mutuku, F M; Bayoh, M N; Hightower, A W; Vulule, J M; Gimnig, J E; Mueke, J M; Amimo, F A; Walker, E D

    2009-04-16

    A supervised land cover classification was developed from very high resolution IKONOS satellite data and extensive ground truth sampling of a ca. 10 sq km malaria-endemic lowland in western Kenya. The classification was then applied to an investigation of distribution of larval Anopheles habitats. The hypothesis was that the distribution and abundance of aquatic habitats of larvae of various species of mosquitoes in the genus Anopheles is associated with identifiable landscape features. The classification resulted in 7 distinguishable land cover types, each with a distinguishable vegetation pattern, was highly accurate (89%, Kappa statistic = 0.86), and had a low rate of omission and commission errors. A total of 1,198 habitats and 19,776 Anopheles larvae of 9 species were quantified in samples from a rainy season, and 184 habitats and 582 larvae from a dry season. Anopheles gambiae s.l. was the dominant species complex (51% of total) and A. arabiensis the dominant species. Agricultural land covers (mature maize fields, newly cultivated fields, and pastured grasslands) were positively associated with presence of larval habitats, and were located relatively close to stream channels; whilst nonagricultural land covers (short shrubs, medium shrubs, tall shrubs, and bare soil around residences) were negatively associated with presence of larval habitats and were more distant from stream channels. Number of larval habitats declined exponentially with distance from streams. IKONOS imagery was not useful in direct detection of larval habitats because they were small and turbid (resembling bare soil), but was useful in localization of them through statistical associations with specific land covers. A supervised classification of land cover types in rural, lowland, western Kenya revealed a largely human-modified and fragmented landscape consisting of agricultural and domestic land uses. Within it, larval habitats of Anopheles vectors of human malaria were associated with

  9. Expression and Evaluation of Recombinant Plasmodium knowlesi Merozoite Surface Protein-3 (MSP-3 for Detection of Human Malaria.

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    Jeremy Ryan De Silva

    Full Text Available Malaria remains a major health threat in many parts of the globe and causes high mortality and morbidity with 214 million cases of malaria occurring globally in 2015. Recent studies have outlined potential diagnostic markers and vaccine candidates one of which is the merozoite surface protein (MSP-3. In this study, novel recombinant Plasmodium knowlesi MSP-3 was cloned, expressed and purified in an Escherichia coli system. Subsequently, the recombinant protein was evaluated for its sensitivity and specificity. The recombinant pkMSP-3 protein reacted with sera from patients with P. knowlesi infection in both Western blot (61% and ELISA (100%. Specificity-wise, pkMSP-3 did not react with healthy donor sera in either assay and only reacted with a few non-malarial parasitic patient sera in the ELISA assay (3 of 49. In conclusion, sensitivity and specificity of pkMSP-3 was found to be high in the ELISA and Western Blot assay and thus utilising both assays in tandem would provide the best sero-diagnostic result for P. knowlesi infection.

  10. The complexities of malaria disease manifestations with a focus on asymptomatic malaria

    Science.gov (United States)

    2012-01-01

    Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted. PMID:22289302

  11. Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

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    Annett Eitner

    2017-11-01

    Full Text Available Pain due to osteoarthritis (OA is one of the most frequent causes of chronic pain. However, the mechanisms of OA pain are poorly understood. This review addresses the mechanisms which are thought to be involved in OA pain, derived from studies on pain mechanisms in humans and in experimental models of OA. Three areas will be considered, namely local processes in the joint associated with OA pain, neuronal mechanisms involved in OA pain, and general factors which influence OA pain. Except the cartilage all structures of the joints are innervated by nociceptors. Although the hallmark of OA is the degradation of the cartilage, OA joints show multiple structural alterations of cartilage, bone and synovial tissue. In particular synovitis and bone marrow lesions have been proposed to determine OA pain whereas the contribution of the other pathologies to pain generation has been studied less. Concerning the peripheral neuronal mechanisms of OA pain, peripheral nociceptive sensitization was shown, and neuropathic mechanisms may be involved at some stages. Structural changes of joint innervation such as local loss and/or sprouting of nerve fibers were shown. In addition, central sensitization, reduction of descending inhibition, descending excitation and cortical atrophies were observed in OA. The combination of different neuronal mechanisms may define the particular pain phenotype in an OA patient. Among mediators involved in OA pain, nerve growth factor (NGF is in the focus because antibodies against NGF significantly reduce OA pain. Several studies show that neutralization of interleukin-1β and TNF may reduce OA pain. Many patients with OA exhibit comorbidities such as obesity, low grade systemic inflammation and diabetes mellitus. These comorbidities can significantly influence the course of OA, and pain research just began to study the significance of such factors in pain generation. In addition, psychologic and socioeconomic factors may aggravate

  12. Severe Flooding and Malaria Transmission in the Western Ugandan Highlands: Implications for Disease Control in an Era of Global Climate Change.

    Science.gov (United States)

    Boyce, Ross; Reyes, Raquel; Matte, Michael; Ntaro, Moses; Mulogo, Edgar; Metlay, Joshua P; Band, Lawrence; Siedner, Mark J

    2016-11-01

     There are several mechanisms by which global climate change may impact malaria transmission. We sought to assess how the increased frequency of extreme precipitation events associated with global climate change will influence malaria transmission in highland areas of East Africa.  We used a differences-in-differences, quasi-experimental design to examine spatial variability in the incidence rate of laboratory-confirmed malaria cases and malaria-related hospitalizations between villages (1) at high versus low elevations, (2) with versus without rivers, and (3) upstream versus downstream before and after severe flooding that occurred in Kasese District, Western Region, Uganda, in May 2013.  During the study period, 7596 diagnostic tests were performed, and 1285 patients were admitted with a diagnosis of malaria. We observed that extreme flooding resulted in an increase of approximately 30% in the risk of an individual having a positive result of a malaria diagnostic test in the postflood period in villages bordering a flood-affected river, compared with villages farther from a river, with a larger relative impact on upstream versus downstream villages (adjusted rate ratio, 1.91 vs 1.33).  Extreme precipitation such as the flooding described here may pose significant challenges to malaria control programs and will demand timely responses to mitigate deleterious impacts on human health. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  13. Cerebral malaria: insights from host-parasite protein-protein interactions

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    Bulusu Gopalakrishnan

    2010-06-01

    Full Text Available Abstract Background Cerebral malaria is a form of human malaria wherein Plasmodium falciparum-infected red blood cells adhere to the blood capillaries in the brain, potentially leading to coma and death. Interactions between parasite and host proteins are important in understanding the pathogenesis of this deadly form of malaria. It is, therefore, necessary to study available protein-protein interactions to identify lesser known interactions that could throw light on key events of cerebral malaria. Methods Sequestration, haemostasis dysfunction, systemic inflammation and neuronal damage are key processes of cerebral malaria. Key events were identified from literature as being crucial to these processes. An integrated interactome was created using available experimental and predicted datasets as well as from literature. Interactions from this interactome were filtered based on Gene Ontology and tissue-specific annotations, and further analysed for relevance to the key events. Results PfEMP1 presentation, platelet activation and astrocyte dysfunction were identified as the key events influencing the disease. 48896 host-parasite along with other host-parasite, host-host and parasite-parasite protein-protein interactions obtained from a disease-specific corpus were combined to form an integrated interactome. Filtering of the interactome resulted in five host-parasite PPI, six parasite-parasite and two host-host PPI. The analysis of these interactions revealed the potential significance of apolipoproteins and temperature/Hsp expression on efficient PfEMP1 presentation; role of MSP-1 in platelet activation; effect of parasite proteins in TGF-β regulation and the role of albumin in astrocyte dysfunction. Conclusions This work links key host-parasite, parasite-parasite and host-host protein-protein interactions to key processes of cerebral malaria and generates hypotheses for disease pathogenesis based on a filtered interaction dataset. These

  14. Plasmodium vivax sporozoite challenge in malaria-naïve and semi-immune Colombian volunteers.

    Science.gov (United States)

    Arévalo-Herrera, Myriam; Forero-Peña, David A; Rubiano, Kelly; Gómez-Hincapie, José; Martínez, Nora L; Lopez-Perez, Mary; Castellanos, Angélica; Céspedes, Nora; Palacios, Ricardo; Oñate, José Millán; Herrera, Sócrates

    2014-01-01

    Significant progress has been recently achieved in the development of Plasmodium vivax challenge infections in humans, which are essential for vaccine and drug testing. With the goal of accelerating clinical development of malaria vaccines, the outcome of infections experimentally induced in naïve and semi-immune volunteers by infected mosquito bites was compared. Seven malaria-naïve and nine semi-immune Colombian adults (n = 16) were subjected to the bites of 2-4 P. vivax sporozoite-infected Anopheles mosquitoes. Parasitemia levels, malaria clinical manifestations, and immune responses were assessed and compared. All volunteers developed infections as confirmed by microscopy and RT-qPCR. No significant difference in the pre-patent period (mean 12.5 and 12.8 days for malaria-naïve and malaria-exposed, respectively) was observed but naïve volunteers developed classical malaria signs and symptoms, while semi-immune volunteers displayed minor or no symptoms at the day of diagnosis. A malaria-naïve volunteer developed a transient low submicroscopic parasitemia that cured spontaneously. Infection induced an increase in specific antibody levels in both groups. Sporozoite infectious challenge was safe and reproducible in semi-immune and naïve volunteers. This model will provide information for simultaneous comparison of the protective efficacy of P. vivax vaccines in naïve and semi-immune volunteers under controlled conditions and would accelerate P. vivax vaccine development. clinicaltrials.gov NCT01585077.

  15. Plasmodium vivax sporozoite challenge in malaria-naïve and semi-immune Colombian volunteers.

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    Myriam Arévalo-Herrera

    Full Text Available Significant progress has been recently achieved in the development of Plasmodium vivax challenge infections in humans, which are essential for vaccine and drug testing. With the goal of accelerating clinical development of malaria vaccines, the outcome of infections experimentally induced in naïve and semi-immune volunteers by infected mosquito bites was compared.Seven malaria-naïve and nine semi-immune Colombian adults (n = 16 were subjected to the bites of 2-4 P. vivax sporozoite-infected Anopheles mosquitoes. Parasitemia levels, malaria clinical manifestations, and immune responses were assessed and compared.All volunteers developed infections as confirmed by microscopy and RT-qPCR. No significant difference in the pre-patent period (mean 12.5 and 12.8 days for malaria-naïve and malaria-exposed, respectively was observed but naïve volunteers developed classical malaria signs and symptoms, while semi-immune volunteers displayed minor or no symptoms at the day of diagnosis. A malaria-naïve volunteer developed a transient low submicroscopic parasitemia that cured spontaneously. Infection induced an increase in specific antibody levels in both groups.Sporozoite infectious challenge was safe and reproducible in semi-immune and naïve volunteers. This model will provide information for simultaneous comparison of the protective efficacy of P. vivax vaccines in naïve and semi-immune volunteers under controlled conditions and would accelerate P. vivax vaccine development.clinicaltrials.gov NCT01585077.

  16. The role of activins in hepcidin regulation during malaria

    DEFF Research Database (Denmark)

    Spottiswoode, Natasha; Armitage, Andrew E; Williams, Andrew R

    2017-01-01

    Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships......, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP...... A increased in parallel with hepcidin in serum from malaria-naïve volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins...

  17. Role of Activins in Hepcidin Regulation during Malaria

    DEFF Research Database (Denmark)

    Spottiswoode, Natasha; Armitage, Andrew E; Williams, Andrew R

    2017-01-01

    Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships......, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP...... A increased in parallel with hepcidin in serum from malaria-naïve volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins...

  18. Comparative efficacy of pre-erythrocytic whole organism vaccine strategies against the malaria parasite.

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    Friesen, Johannes; Matuschewski, Kai

    2011-09-16

    Despite major efforts over the past 50 years to develop a malaria vaccine, no product has been licensed yet. Irradiated sporozoites are the benchmark for an experimental live-attenuated malaria vaccine that induces potent protection against re-infection in humans and animal models. Lasting protection can also be elicited by parasite attenuation via tailored genetic modification or drug cover leading to renewed interest in whole-organism vaccination strategies. In this study, we systematically compared the protective efficacy of different whole-organism vaccination approaches in the Plasmodium berghei/C57bl/6 rodent malaria model. We applied blood stage parasitemia and quantitative RT-PCR of liver parasite loads as two complementary primary endpoints of a malaria challenge infection. We were able to demonstrate similar potency of genetic attenuation, i.e., uis3(-) and p36p(-) parasites, and prophylactic drug cover, i.e., azithromycin, pyrimethamine, primaquine and chloroquine, during sporozoite exposure in comparison to irradiated sporozoites. Importantly, when animals were covered with the antibiotic azithromycin during sporozoite exposure we observed superior protection. On the other end, immunizations with heat-killed and over-irradiated sporozoites failed to confer any detectable protection. Together, we show that systematic pre-clinical evaluation and quantification of vaccine efficacy is vital for identification of the most potent whole organism anti-malaria vaccine strategy. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates.

    Science.gov (United States)

    Hobbs, Charlotte V; Dixit, Saurabh; Penzak, Scott R; Sahu, Tejram; Orr-Gonzalez, Sachy; Lambert, Lynn; Zeleski, Katie; Chen, Jingyang; Neal, Jillian; Borkowsky, William; Wu, Yimin; Duffy, Patrick E

    2014-01-01

    Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.

  20. Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates.

    Directory of Open Access Journals (Sweden)

    Charlotte V Hobbs

    Full Text Available Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.

  1. Malaria in three epidemiological strata in Mauritania.

    Science.gov (United States)

    Ouldabdallahi Moukah, Mohamed; Ba, Ousmane; Ba, Hampaté; Ould Khairy, Mohamed Lemine; Faye, Ousmane; Bogreau, Hervé; Simard, Frédéric; Basco, Leonardo K

    2016-04-12

    Malaria epidemiology in Mauritania has been characterized on the basis of epidemiological strata, defined by climatic and geographic features, which divide the country into three zones: Sahelian zone, Sahelo-Saharan transition zone, and Saharan zone. The association between geographic stratification and malaria transmission was assessed through a series of parasitological and entomological surveys. Surveys were conducted during the 'cool' dry season in 2011, 'hot' dry season in 2012, and rainy season in 2013 in a total of 12 sentinel sites. Finger-prick capillary blood samples were collected from children aged 2-9 years old in randomly selected households for microscopic examination and rapid diagnostic test for malaria. Adult mosquitoes were sampled by pyrethrum spray catch and CDC light traps and identified using morphological keys and molecular tools. Of 3445 children included, 143 (4.15 %) were infected with malaria parasites including Plasmodium falciparum (n = 71, 2.06 %), Plasmodium vivax (57, 1.65 %), P. falciparum-P. vivax (2, 0.06 %), Plasmodium ovale (12, 0.35 %), and Plasmodium malariae (1, 0.03 %). A large majority of P. falciparum infections were observed in the Sahelo-Saharan zone. Malaria prevalence (P strata during the 'cool' dry season in 2011 but was absent in all study sites, except for Teyarett district in Nouakchott, during the 'hot' dry season in 2012. During the rainy season in 2013, An. gambiae, Anopheles arabiensis, Anopheles pharoensis, and Anopheles rufipes were abundant in different zones. The results of the present study support the stratification of malaria in Mauritania. However, the Sahelian zone had the lowest malaria prevalence, while the Sahelo-Saharan zone had the highest malaria burden. Local changes due to anthropogenic factors (i.e., human migration, urbanization, malaria interventions) should be considered in order to optimize the control strategy.

  2. Wide cross-reactivity between Anopheles gambiae and Anopheles funestus SG6 salivary proteins supports exploitation of gSG6 as a marker of human exposure to major malaria vectors in tropical Africa

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    Petrarca Vincenzo

    2011-07-01

    Full Text Available Abstract Background The Anopheles gambiae gSG6 is an anopheline-specific salivary protein which helps female mosquitoes to efficiently feed on blood. Besides its role in haematophagy, gSG6 is immunogenic and elicits in exposed individuals an IgG response, which may be used as indicator of exposure to the main African malaria vector A. gambiae. However, malaria transmission in tropical Africa is sustained by three main vectors (A. gambiae, Anopheles arabiensis and Anopheles funestus and a general marker, reflecting exposure to at least these three species, would be especially valuable. The SG6 protein is highly conserved within the A. gambiae species complex whereas the A. funestus homologue, fSG6, is more divergent (80% identity with gSG6. The aim of this study was to evaluate cross-reactivity of human sera to gSG6 and fSG6. Methods The A. funestus SG6 protein was expressed/purified and the humoral response to gSG6, fSG6 and a combination of the two antigens was compared in a population from a malaria hyperendemic area of Burkina Faso where both vectors were present, although with a large A. gambiae prevalence (>75%. Sera collected at the beginning and at the end of the high transmission/rainy season, as well as during the following low transmission/dry season, were analysed. Results According to previous observations, both anti-SG6 IgG level and prevalence decreased during the low transmission/dry season and showed a typical age-dependent pattern. No significant difference in the response to the two antigens was found, although their combined use yielded in most cases higher IgG level. Conclusions Comparative analysis of gSG6 and fSG6 immunogenicity to humans suggests the occurrence of a wide cross-reactivity, even though the two proteins carry species-specific epitopes. This study supports the use of gSG6 as reliable indicator of exposure to the three main African malaria vectors, a marker which may be useful to monitor malaria transmission

  3. Deoxyhypusine hydroxylase from Plasmodium vivax, the neglected human malaria parasite: molecular cloning, expression and specific inhibition by the 5-LOX inhibitor zileuton.

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    Veronika Anyigoh Atemnkeng

    Full Text Available Primaquine, an 8-aminoquinoline, is the only drug which cures the dormant hypnozoites of persistent liver stages from P. vivax. Increasing resistance needs the discovery of alternative pathways as drug targets to develop novel drug entities. Deoxyhypusine hydroxylase (DOHH completes hypusine biosynthesis in eukaryotic initiation factor (eIF-5A which is the only cellular protein known to contain the unusual amino acid hypusine. Modified EIF-5A is important for proliferation of the malaria parasite. Here, we present the first successful cloning and expression of DOHH from P. vivax causing tertiary malaria. The nucleic acid sequence of 1041 bp encodes an open reading frame of 346 amino acids. Histidine tagged expression of P. vivax DOHH detected a protein of 39.01 kDa in E. coli. The DOHH protein from P. vivax shares significant amino acid identity to the simian orthologues from P. knowlesi and P. yoelii strain H. In contrast to P. falciparum only four E-Z-type HEAT-like repeats are present in P. vivax DOHH with different homology to phycocyanin lyase subunits from cyanobacteria and in proteins participating in energy metabolism of Archaea and Halobacteria. However, phycocyanin lyase activity is absent in P. vivax DOHH. The dohh gene is present as a single copy gene and transcribed throughout the whole erythrocytic cycle. Specific inhibition of recombinant P. vivax DOHH is possible by complexing the ferrous iron with zileuton, an inhibitor of mammalian 5-lipoxygenase (5-LOX. Ferrous iron in the active site of 5-LOX is coordinated by three conserved histidines and the carboxylate of isoleucine(673. Zileuton inhibited the P. vivax DOHH protein with an IC50 of 12,5 nmol determined by a relative quantification by GC/MS. By contrast, the human orthologue is only less affected with an IC50 of 90 nmol suggesting a selective iron-complexing strategy for the parasitic enzyme.

  4. Pfnek-1, a NIMA-related kinase from the human malaria parasite Plasmodium falciparum Biochemical properties and possible involvement in MAPK regulation.

    Science.gov (United States)

    Dorin, D; Le Roch, K; Sallicandro, P; Alano, P; Parzy, D; Poullet, P; Meijer, L; Doerig, C

    2001-05-01

    We have cloned Pfnek-1, a gene encoding a novel protein kinase from the human malaria parasite Plasmodium falciparum. This enzyme displays maximal homology to the never-in-mitosis/Aspergillus (NIMA)/NIMA-like kinase (Nek) family of protein kinases, whose members are involved in eukaryotic cell division processes. Similar to other P. falciparum protein kinases and many enzymes of the NIMA/Nek family, Pfnek-1 possesses a large C-terminal extension in addition to the catalytic domain. Bacterially expressed recombinant Pfnek-1 protein is able to autophosphorylate and phosphorylate a panel of protein substrates with a specificity that is similar to that displayed by other members of the NIMA/Nek family. However, the FXXT motif usually found in NIMA/Nek protein kinases is substituted in Pfnek-1 by a SMAHS motif, which is reminiscent of a MAP/ERK kinase (MEK) activation site. Mutational analysis indicates that only one of the serine residues in this motif is essential for Pfnek-1 kinase activity in vitro. We show (a) that recombinant Pfnek-1 is able to specifically phosphorylate Pfmap-2, an atypical P. falciparum MAPK homologue, in vitro, and (b) that coincubation of Pfnek-1 and Pfmap-2 results in a synergistic increase in exogenous substrate labelling. This suggests that Pfnek-1 may be involved in the modulation of MAPK pathway output in malaria parasites. Finally, we demonstrate that recombinant Pfnek-1 can be used in inhibition assays to monitor the effect of kinase inhibitors, which opens the way to the screening of chemical libraries aimed at identifying potential new antimalarials.

  5. Malaria Surveillance - United States, 2014.

    Science.gov (United States)

    Mace, Kimberly E; Arguin, Paul M

    2017-05-26

    Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. This report summarizes cases in persons with onset of illness in 2014 and trends during previous years. Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments by health care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System, National Notifiable Diseases Surveillance System, or direct CDC consultations. CDC conducts antimalarial drug resistance marker testing on blood samples submitted by health care providers or local or state health departments. Data from these reporting systems serve as the basis for this report. CDC received reports of 1,724 confirmed malaria cases, including one congenital case and two cryptic cases, with onset of symptoms in 2014 among persons in the United States. The number of confirmed cases in 2014 is consistent with the number of confirmed cases reported in 2013 (n = 1,741; this number has been updated from a previous publication to account for delayed reporting for persons with symptom onset occurring in late 2013). Plasmodium falciparum, P. vivax, P. ovale, and P. malariae were identified in 66.1%, 13.3%, 5.2%, and 2.7% of cases, respectively

  6. Assessment of knowledge, attitude and practices on Malaria ...

    African Journals Online (AJOL)

    INTRODUCTION Malaria is a parasitic disease of humans caused by a protozoon of Plasmodium species. Malaria remains to be a life threatening condition and a public health problem in much of Sub-Saharan Africa, it is the most important parasitic disease affecting humans, causing about 1-3 million deaths per year and ...

  7. Ethical dilemmas in malaria vector research in Africa: Making the ...

    African Journals Online (AJOL)

    Malaria vector research presents several dilemmas relating to the various ways in which humans are used in the malaria vector research enterprise. A review of the past and present practices reveals much about the prevailing attitudes and assumptions with regard to the ethical conduct of research involving humans.

  8. STATUS HEMATOLOGI PENDERITA MALARIA SEREBRAL

    Directory of Open Access Journals (Sweden)

    Nurhayati Nurhayati

    2009-05-01

    Full Text Available AbstrakMalaria masih merupakan masalah kesehatan masyarakat dunia. Berdasarkan klasifikasi klinis, malaria dibedakan atas malaria berat dan malaria tanpa komplikasi. Malaria serebral merupakan komplikasi terberat dari malaria falsiparum.Telah dilakukan penelitian seksi silang terhadap penderita malaria falciparum yang dirawat inap di Bangsal Penyakit Dalam RS. Perjan. Dr. M. Djamil Padang dari bulan Juni 2002 sampai Juni 2006. Pada penelitian ini didapatkan jumlah sampel sebanyak 60 orang, terdiri dari 16 orang penderita malaria serebral dan 44 orang penderita malaria tanpa komplikasi.Data penelitian menunjukan terdapat perbedaan bermakna nilai hematokrit (p<0,05 dan jumlah leukosit (p<0,05 antara penderita malaria serebral dengan penderita malaria tanpa komplikasi. Dan terdapat korelasi positif antara nilai hemoglobin dengan hematokrit (r=0,864; p<0,05 pada penderita malaria falsiparum.Kata kunci: malaria serebral, malaria tanpa komplikasi, malaria falsiparumAbstract Malaria is still a problem of health of world society. Based on the clinical classification, are distinguished on severe malaria and uncomplicated malaria. Cerebral malaria is the worst complication of falciparum malaria. Cross section of the research done at the Hospital Dr. M. Djamil Padang againts medical record of malaria patients who are hospitalized in the Internal Medicine from June 2002 until June 2004. In this study, a total sample of 60 people, consisting of 16 cerebral malaria and 44 uncomplicated malaria. Data showed there were significant differences for hematocrit values (p <0.05 and total leukocytes values (p <0.05 between cerebral malaria and uncomplicated malaria patients. There is a positive correlation between hemoglobin with hematocrit values (r = 0.864; p <0.05 of falciparum malaria patients. Keywords: cerebral malaria, uncomplicated malaria, falciparum malaria

  9. De behandeling van malaria

    NARCIS (Netherlands)

    Kager, P. A.; Zijlmans, C. W.; Boele van Hensbroek, M.; Wetsteyn, J. C.

    1997-01-01

    The diagnosis of malaria should include the species involved and in case of P. falciparum infection the parasitaemia index: the percentage of the infected red cells. P. vivax, ovale and malariae infection are treated with chloroquine, in case of P. vivax and ovale malaria followed by primaquine.

  10. Use of insecticide-impregnated mosquito nets and other impregnated materials for malaria control in the Americas

    Directory of Open Access Journals (Sweden)

    R. H. Zimmerman

    1997-07-01

    Full Text Available This article reviews the current status of the use of insecticide-impregnated mosquito nets and other impregnated materials in the Americas. Studies from Brazil, Colombia, Ecuador, Guatemala, Peru, Suriname, and Venezuela are examined. It is concluded that most studies have suffered from experimental design errors, short duration problems, and/or inadequate measurement of health indicators. The review brings out the great difficulty of conducting scientific studies that attempt to measure the impact of insecticide-treated materials on malaria incidence. In particular, the low incidence of malaria in the Americas, the high prevalences of P. vivax and relapsing cases, and the relationship between human activity patterns and the crepuscular biting patterns of certain malaria vectors stand in the way of easy experimental design and execution. The utilization of impregnated mosquito nets or other impregnated materials as a major component of an integrated malaria control program would be premature at this time. However, it is recommended that well-conceived large-scale trials and interventions be considered when they are based on a thorough understanding of the dynamics of malaria transmission in the area of study.

  11. Use of insecticide-impregnated mosquito nets and other impregnated materials for malaria control in the Americas.

    Science.gov (United States)

    Zimmerman, R H; Voorham, J

    1997-07-01

    This article reviews the current status of the use of insecticide-impregnated mosquito nets and other impregnated materials in the Americas. Studies from Brazil, Colombia, Ecuador, Guatemala, Peru, Suriname, and Venezuela are examined. It is concluded that most studies have suffered from experimental design errors, short duration problems, and/or inadequate measurement of health indicators. The review brings out the great difficulty of conducting scientific studies that attempt to measure the impact of insecticide-treated materials on malaria incidence. In particular, the low incidence of malaria in the Americas, the high prevalences of P. vivax and relapsing cases, and the relationship between human activity patterns and the crepuscular biting patterns of certain malaria vectors stand in the way of easy experimental design and execution. The utilization of impregnated mosquito nets or other impregnated materials as a major component of an integrated malaria control program would be premature at this time. However, it is recommended that well-conceived large-scale trials and interventions be considered when they are based on a thorough understanding of the dynamics of malaria transmission in the area of study.

  12. 40 CFR 158.2083 - Experimental use permit biochemical pesticides human health assessment data requirements table.

    Science.gov (United States)

    2010-07-01

    ... pesticides human health assessment data requirements table. 158.2083 Section 158.2083 Protection of... Biochemical Pesticides § 158.2083 Experimental use permit biochemical pesticides human health assessment data... determine the human health assessment data requirements for a particular biochemical pesticide product. (2...

  13. A research agenda for malaria eradication: drugs.

    Science.gov (United States)

    2011-01-25

    Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission.

  14. Using Satellite Images in Determination of Malaria Outbreaks Potential Region

    OpenAIRE

    Abolfazl Ahmadian Marj; Mohammad Reza Mobasheri; Mohammad Javad Valadanzouje; Yousef Rezaie; Mohammad Reza Abaie

    2008-01-01

    Malaria outbreaks are affecting nearly 40 percent of the earth's population most of whom are living in tropical and subtropical zones. Malaria is an infectious disease that is being transferred by the female mosquito of the species Anopheles. The life cycle of the malaria parasite develops in the anopheline and in the human body. These parasites require suitable environmental parameters in order to complete their development cycles within the mosquito. These parameters are temperature, h...

  15. Recombinant vacuolar iron transporter family homologue PfVIT from human malaria-causing Plasmodium falciparum is a Fe2+/H+exchanger.

    Science.gov (United States)

    Labarbuta, Paola; Duckett, Katie; Botting, Catherine H; Chahrour, Osama; Malone, John; Dalton, John P; Law, Christopher J

    2017-02-15

    Vacuolar iron transporters (VITs) are a poorly understood family of integral membrane proteins that can function in iron homeostasis via sequestration of labile Fe2+ into vacuolar compartments. Here we report on the heterologous overexpression and purification of PfVIT, a vacuolar iron transporter homologue from the human malaria-causing parasite Plasmodium falciparum. Use of synthetic, codon-optimised DNA enabled overexpression of functional PfVIT in the inner membrane of Escherichia coli which, in turn, conferred iron tolerance to the bacterial cells. Cells that expressed PfVIT had decreased levels of total cellular iron compared with cells that did not express the protein. Qualitative transport assays performed on inverted vesicles enriched with PfVIT revealed that the transporter catalysed Fe2+/H+ exchange driven by the proton electrochemical gradient. Furthermore, the PfVIT transport function in this system did not require the presence of any Plasmodium-specific factor such as post-translational phosphorylation. PfVIT purified as a monomer and, as measured by intrinsic protein fluorescence quenching, bound Fe2+ in detergent solution with low micromolar affinity. This study of PfVIT provides material for future detailed biochemical, biophysical and structural studies to advance understanding of the vacuolar iron transporter family of membrane proteins from important human pathogens.

  16. Malaria in Children.

    Science.gov (United States)

    Cohee, Lauren M; Laufer, Miriam K

    2017-08-01

    Malaria is a leading cause of morbidity and mortality in endemic areas, leading to an estimated 438,000 deaths in 2015. Malaria is also an important health threat to travelers to endemic countries and should be considered in evaluation of any traveler returning from a malaria-endemic area who develops fever. Considering the diagnosis of malaria in patients with potential exposure is critical. Prompt provision of effective treatment limits the complications of malaria and can be life-saving. Understanding Plasmodium species variation, epidemiology, and drug-resistance patterns in the geographic area where infection was acquired is important for determining treatment choices. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Healthy malaria control.

    Science.gov (United States)

    Mathen, K

    1998-01-01

    According to an article in the May 27, 1998, issue of the Times of India, Dr. Menno Jan Bouma, an epidemiologist from the London School of Hygiene and Tropical Medicine, has suggested spraying India's cows, goats, and buffaloes with insecticide in a bid to combat malaria. This strategy, however, fails to fully consider what is currently known about insect behavior, insecticides' modes of action, and the interaction between the two in the environment. A population of insects can ultimately develop resistance and adapt to the repeated onslaught of insecticides. Furthermore, each type of insecticide which could potentially be used has its own set of problems with regard to the environment, the products into which they break down, and how they affect wildlife and humans. The once commonplace spraying of livestock in the West led to Mad Cow Disease, Chicken Flu, and other problems. India's meat and dairy products will definitely be contaminated should the country's livestock be sprayed with insecticides. In the long-term interest of humankind, efforts must be made to contain, not eradicate, mosquitoes and malaria.

  18. Coordination Mechanisms in Fast Human Movement. Experimental and Modelling Studies.

    Science.gov (United States)

    1984-07-15

    INTRODUCTION Whether the performance task involves the total body as in gymnastics , or only a part of the body as in playing a piano, skilled performance is...Human stretch reflexes (SRs) are often too weak and ineffectual to provide adequate postural regulation or rhythmic movement boosting (e.g. in ankle

  19. An Experimental Study of the Emergence of Human Communication Systems

    Science.gov (United States)

    Galantucci, Bruno

    2005-01-01

    The emergence of human communication systems is typically investigated via 2 approaches with complementary strengths and weaknesses: naturalistic studies and computer simulations. This study was conducted with a method that combines these approaches. Pairs of participants played video games requiring communication. Members of a pair were…

  20. Signatures of malaria vaccine efficacy in ageing murine immune memory

    NARCIS (Netherlands)

    Haussig, J.M.; Burgold, J.; Hafalla, J.C.; Matuschewski, K.; Kooij, T.W.A.

    2014-01-01

    Malaria transmission occurs by mosquito bite. Thereafter, Plasmodium sporozoites specifically invade the liver, where they develop into thousands of merozoites that initiate blood-stage infection and clinical malaria. The pre-erythrocytic phase of a Plasmodium infection is the target of experimental

  1. Simultaneous presence of DDT and pyrethroid residues in human breast milk from a malaria endemic area in South Africa

    Energy Technology Data Exchange (ETDEWEB)

    Bouwman, H. [School for Environmental Sciences and Development, North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom 2520 (South Africa)]. E-mail: drkhb@puk.ac.za; Sereda, B. [Agricultural Research Council, Plant Protection Research Institute, Private Bag X134 Queenswood, Pretoria 0121 (South Africa); Meinhardt, H.M. [South African Bureau of Standards, Testing and Conformity Services (Pty) Ltd, Private Bag X191, Pretoria 0001 (South Africa)

    2006-12-15

    DDT and pyrethroids were determined in 152 breast-milk samples from three towns in KwaZulu-Natal, South Africa, one of which had no need for DDT for malaria control. All compounds were found present in breast milk. Primiparae from one town had the highest mean {sigma}DDT whole milk levels (238.23 {mu}g/l), and multiparae from the same town had the highest means for permethrin (14.51 {mu}g/l), cyfluthrin (41.74 {mu}g/l), cypermethrin (4.24 {mu}g/l), deltamethrin (8.39 {mu}g/l), and {sigma}pyrethroid (31.5 {mu}g/l), most likely derived from agriculture. The ADI for DDT was only exceeded by infants from one town, but the ADI for pyrethroids was not exceeded. Since the ADI for DDT was recently reduced from 20 to 10 {mu}g/kg/bw, we suggest that this aspect be treated with concern. We therefore raise a concern based on toxicant interactions, due to the presence of four different pyrethroids and DDT. Breastfeeding however, remains safe under prevailing conditions. - The simultaneous presence of DDT and pyrethroid residues in breast milk raises the question of infant exposure and safety.

  2. Malaria in the Greater Mekong Subregion: Heterogeneity and Complexity

    Science.gov (United States)

    Cui, Liwang; Yan, Guiyun; Sattabongkot, Jetsumon; Cao, Yaming; Chen, Bin; Chen, Xiaoguang; Fan, Qi; Fang, Qiang; Jongwutiwes, Somchai; Parker, Daniel; Sirichaisinthop, Jeeraphat; Kyaw, Myat Phone; Su, Xin-zhuan; Yang, Henglin; Yang, Zhaoqing; Wang, Baomin; Xu, Jianwei; Zheng, Bin; Zhong, Daibin; Zhou, Guofa

    2011-01-01

    The Greater Mekong Subregion (GMS), comprised of six countries including Cambodia, China's Yunnan Province, Lao PDR, Myanmar (Burma), Thailand and Vietnam, is one of the most threatening foci of malaria. Since the initiation of the WHO's Mekong Malaria Program a decade ago, malaria situation in the GMS has greatly improved, reflected in the continuous decline in annual malaria incidence and deaths. However, as many nations are moving towards malaria elimination, the GMS nations still face great challenges. Malaria epidemiology in this region exhibits enormous geographical heterogeneity with Myanmar and Cambodia remaining high-burden countries. Within each country, malaria distribution is also patchy, exemplified by ‘border malaria’ and ‘forest malaria’ with high transmission occurring along international borders and in forests or forest fringes, respectively. ‘Border malaria’ is extremely difficult to monitor, and frequent malaria introductions by migratory human populations constitute a major threat to neighboring, malaria-eliminating countries. Therefore, coordination between neighboring countries is essential for malaria elimination from the entire region. In addition to these operational difficulties, malaria control in the GMS also encounters several technological challenges. Contemporary malaria control measures rely heavily on effective chemotherapy and insecticide control of vector mosquitoes. However, the spread of multidrug resistance and potential emergence of artemisinin resistance in Plasmodium falciparum make resistance management a high priority in the GMS. This situation is further worsened by the circulation of counterfeit and substandard artemisinin-related drugs. In most endemic areas of the GMS, P. falciparum and P. vivax coexist, and in recent malaria control history, P. vivax has demonstrated remarkable resilience to control measures. Deployment of the only registered drug (primaquine) for the radical cure of vivax malaria is

  3. Malaria og graviditet

    DEFF Research Database (Denmark)

    Hoffmann, A L; Rønn, A M; Langhoff-Roos, J

    1992-01-01

    In regions where malaria is endemism, the disease is a recognised cause of complications of pregnancy such as spontaneous abortion, premature delivery, intrauterine growth retardation and foetal death. Malaria is seldom seen in pregnant women in Denmark but, during the past two years, the authors...... the patients but also their practitioners were unaware that malaria can occur several years after exposure. Three out of the four patients had employed malaria prophylaxis. As resistance to malarial prophylactics in current use is increasing steadily, chemoprophylaxis should be supplemented by mechanical...... protection against malaria and insect repellents. As a rule, malaria is treated with chloroquine. In cases of Falciparum malaria in whom chloroquine resistance is suspected, treatment with mefloquine may be employed although this should only be employed in cases of dire necessity in pregnant patients during...

  4. Epidemiology of Plasmodium vivax Malaria in Peru

    Science.gov (United States)

    Rosas-Aguirre, Angel; Gamboa, Dionicia; Manrique, Paulo; Conn, Jan E.; Moreno, Marta; Lescano, Andres G.; Sanchez, Juan F.; Rodriguez, Hugo; Silva, Hermann; Llanos-Cuentas, Alejandro; Vinetz, Joseph M.

    2016-01-01

    Malaria in Peru, dominated by Plasmodium vivax, remains a public health problem. The 1990s saw newly epidemic malaria emerge, primarily in the Loreto Department in the Amazon region, including areas near to Iquitos, the capital city, but sporadic malaria transmission also occurred in the 1990s–2000s in both north-coastal Peru and the gold mining regions of southeastern Peru. Although a Global Fund-supported intervention (PAMAFRO, 2005–2010) was temporally associated with a decrease of malaria transmission, from 2012 to the present, both P. vivax and Plasmodium falciparum malaria cases have rapidly increased. The Peruvian Ministry of Health continues to provide artemesinin-based combination therapy for microscopy-confirmed cases of P. falciparum and chloroquine–primaquine for P. vivax. Malaria transmission continues in remote areas nonetheless, where the mobility of humans and parasites facilitates continued reintroduction outside of ongoing surveillance activities, which is critical to address for future malaria control and elimination efforts. Ongoing P. vivax research gaps in Peru include the following: identification of asymptomatic parasitemics, quantification of the contribution of patent and subpatent parasitemics to mosquito transmission, diagnosis of nonparasitemic hypnozoite carriers, and implementation of surveillance for potential emergence of chloroquine- and 8-aminoquinoline-resistant P. vivax. Clinical trials of tafenoquine in Peru have been promising, and glucose-6-phosphate dehydrogenase deficiency in the region has not been observed to be a limitation to its use. Larger-scale challenges for P. vivax (and malaria in general) in Peru include logistical difficulties in accessing remote riverine populations, consequences of government policy and poverty trends, and obtaining international funding for malaria control and elimination. PMID:27799639

  5. Epidemiology of Plasmodium vivax Malaria in Peru.

    Science.gov (United States)

    Rosas-Aguirre, Angel; Gamboa, Dionicia; Manrique, Paulo; Conn, Jan E; Moreno, Marta; Lescano, Andres G; Sanchez, Juan F; Rodriguez, Hugo; Silva, Hermann; Llanos-Cuentas, Alejandro; Vinetz, Joseph M

    2016-12-28

    Malaria in Peru, dominated by Plasmodium vivax, remains a public health problem. The 1990s saw newly epidemic malaria emerge, primarily in the Loreto Department in the Amazon region, including areas near to Iquitos, the capital city, but sporadic malaria transmission also occurred in the 1990s-2000s in both north-coastal Peru and the gold mining regions of southeastern Peru. Although a Global Fund-supported intervention (PAMAFRO, 2005-2010) was temporally associated with a decrease of malaria transmission, from 2012 to the present, both P. vivax and Plasmodium falciparum malaria cases have rapidly increased. The Peruvian Ministry of Health continues to provide artemesinin-based combination therapy for microscopy-confirmed cases of P. falciparum and chloroquine-primaquine for P. vivax Malaria transmission continues in remote areas nonetheless, where the mobility of humans and parasites facilitates continued reintroduction outside of ongoing surveillance activities, which is critical to address for future malaria control and elimination efforts. Ongoing P. vivax research gaps in Peru include the following: identification of asymptomatic parasitemics, quantification of the contribution of patent and subpatent parasitemics to mosquito transmission, diagnosis of nonparasitemic hypnozoite carriers, and implementation of surveillance for potential emergence of chloroquine- and 8-aminoquinoline-resistant P. vivax Clinical trials of tafenoquine in Peru have been promising, and glucose-6-phosphate dehydrogenase deficiency in the region has not been observed to be a limitation to its use. Larger-scale challenges for P. vivax (and malaria in general) in Peru include logistical difficulties in accessing remote riverine populations, consequences of government policy and poverty trends, and obtaining international funding for malaria control and elimination. © The American Society of Tropical Medicine and Hygiene.

  6. Development of replication-deficient adenovirus malaria vaccines.

    Science.gov (United States)

    Hollingdale, Michael R; Sedegah, Martha; Limbach, Keith

    2017-03-01

    Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.

  7. Numerical modeling of experimental human fibrous cap delamination.

    Science.gov (United States)

    Leng, Xiaochang; Davis, Lindsey A; Deng, Xiaomin; Sutton, Michael A; Lessner, Susan M

    2016-06-01

    Fibrous cap delamination is a critical process during the rupture of atherosclerotic plaque, which often leads to severe life-threatening clinical consequences such as myocardial infarction or stroke. In this study a finite element modeling and simulation approach is presented that enables the study of fibrous cap delamination experiments for the purpose of understanding the fibrous cap delamination process. A cohesive zone model (CZM) approach is applied to simulate delamination of the fibrous cap from the underlying plaque tissue. A viscoelastic anisotropic (VA) model for the bulk arterial material behavior is extended from existing studies so that the hysteresis phenomenon observed in the fibrous cap delamination experiments can be captured. A finite element model is developed for the fibrous cap delamination experiments, in which arterial layers (including the fibrous cap and the underlying plaque tissue) are represented by solid elements based on the VA model and the fibrous cap-underlying plaque tissue interface is characterized by interfacial CZM elements. In the CZM, the delamination process is governed by an exponential traction-separation law which utilizes critical energy release rates obtained directly from the fibrous cap delamination experiments. A set of VA model parameter values and CZM parameter values is determined based on values suggested in the literature and through matching simulation predictions of the load vs. load-point displacement curve with one set of experimental measurements. Using this set of parameter values, simulation predictions for other sets of experimental measurements are obtained and good agreement between simulation predictions and experimental measurements is observed. Results of this study demonstrate the applicability of the viscoelastic anisotropic model and the CZM approach for the simulation of diseased arterial tissue failure processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. An experimental cyst model established from human unkeratinized vaginal mucosa.

    Science.gov (United States)

    Thompson, I O; van Wyk, C W

    1996-12-01

    Because of the scarcity of sizeable specimens of normal oral mucosa and the availability of human vaginal mucosa, which resembles the lining mucosa of the mouth, we used the latter to establish a human cyst model. Fragments of vaginal mucosa, removed during corrective procedures, were sutured around 2 mm glass balls and implanted into the flanks of nude mice. Thirty-seven specimens were implanted and 31 harvested after 3, 6, 9 and 12 weeks. At 6 weeks the wall of the implanted cyst consisted of recognizable unkeratinized vaginal mucosa but had not healed completely at the sutured edges. From 9 weeks the cyst cavities were healed and the lumens lined by unkeratinized stratified squamous vaginal epithelium. The enclosing connective tissue had retained the characteristics of the lamina propria of the vaginal mucosa and could be distinguished from mouse tissue.

  9. [From Nuremberg to the ethics committees in human experimentation].

    Science.gov (United States)

    Demarez, Jean-Paul

    2008-02-01

    During the Nuremberg trials, the accusation prompted the creation of an ad hoc committee to advise on human experiments carried out on prisoners during wartime in the USA. Precisely a charge that had been brought against Karl Brandt and his colleagues. This committee was the forerunner of the Independent Committees, to which the Declaration of Helsinki assigned a role in analysing the ethics of research projects in humans. From 1980 onwards, in industrialised countries, the legislation regarding clinical trials began to incorporate similar structures, IRBs in the United States of America, Ethics Committees elsewhere, and the ''Committee for the Protection of Persons" in France. However, at that time, in spite of the misleading words, we went from ethics to law, from rules of conduct intended for researchers to legal regulations organising relations between sponsors, investigators and persons participating in biomedical research, which is not the same thing.

  10. Enzymatic Characterization of Recombinant Food Vacuole Plasmepsin 4 from the Rodent Malaria Parasite Plasmodium berghei.

    Science.gov (United States)

    Liu, Peng; Robbins, Arthur H; Marzahn, Melissa R; McClung, Scott H; Yowell, Charles A; Stevens, Stanley M; Dame, John B; Dunn, Ben M

    2015-01-01

    The rodent malaria parasite Plasmodium berghei is a practical model organism for experimental studies of human malaria. Plasmepsins are a class of aspartic proteinase isoforms that exert multiple pathological effects in malaria parasites. Plasmepsins residing in the food vacuole (FV) of the parasite hydrolyze hemoglobin in red blood cells. In this study, we cloned PbPM4, the FV plasmepsin gene of P. berghei that encoded an N-terminally truncated pro-segment and the mature enzyme from genomic DNA. We over-expressed this PbPM4 zymogen as inclusion bodies (IB) in Escherichia coli, and purified the protein following in vitro IB refolding. Auto-maturation of the PbPM4 zymogen to mature enzyme was carried out at pH 4.5, 5.0, and 5.5. Interestingly, we found that the PbPM4 zymogen exhibited catalytic activity regardless of the presence of the pro-segment. We determined the optimal catalytic conditions for PbPM4 and studied enzyme kinetics on substrates and inhibitors of aspartic proteinases. Using combinatorial chemistry-based peptide libraries, we studied the active site preferences of PbPM4 at subsites S1, S2, S3, S1', S2' and S3'. Based on these results, we designed and synthesized a selective peptidomimetic compound and tested its inhibition of PbPM4, seven FV plasmepsins from human malaria parasites, and human cathepsin D (hcatD). We showed that this compound exhibited a >10-fold selectivity to PbPM4 and human malaria parasite plasmepsin 4 orthologs versus hcatD. Data from this study furthesr our understanding of enzymatic characteristics of the plasmepsin family and provides leads for anti-malarial drug design.

  11. Enzymatic Characterization of Recombinant Food Vacuole Plasmepsin 4 from the Rodent Malaria Parasite Plasmodium berghei.

    Directory of Open Access Journals (Sweden)

    Peng Liu

    Full Text Available The rodent malaria parasite Plasmodium berghei is a practical model organism for experimental studies of human malaria. Plasmepsins are a class of aspartic proteinase isoforms that exert multiple pathological effects in malaria parasites. Plasmepsins residing in the food vacuole (FV of the parasite hydrolyze hemoglobin in red blood cells. In this study, we cloned PbPM4, the FV plasmepsin gene of P. berghei that encoded an N-terminally truncated pro-segment and the mature enzyme from genomic DNA. We over-expressed this PbPM4 zymogen as inclusion bodies (IB in Escherichia coli, and purified the protein following in vitro IB refolding. Auto-maturation of the PbPM4 zymogen to mature enzyme was carried out at pH 4.5, 5.0, and 5.5. Interestingly, we found that the PbPM4 zymogen exhibited catalytic activity regardless of the presence of the pro-segment. We determined the optimal catalytic conditions for PbPM4 and studied enzyme kinetics on substrates and inhibitors of aspartic proteinases. Using combinatorial chemistry-based peptide libraries, we studied the active site preferences of PbPM4 at subsites S1, S2, S3, S1', S2' and S3'. Based on these results, we designed and synthesized a selective peptidomimetic compound and tested its inhibition of PbPM4, seven FV plasmepsins from human malaria parasites, and human cathepsin D (hcatD. We showed that this compound exhibited a >10-fold selectivity to PbPM4 and human malaria parasite plasmepsin 4 orthologs versus hcatD. Data from this study furthesr our understanding of enzymatic characteristics of the plasmepsin family and provides leads for anti-malarial drug design.

  12. Protective CD8+ T cell responses against the pre-erythrocytic stages of malaria parasites: an overview

    Directory of Open Access Journals (Sweden)

    Oliveira-Ferreira J

    2001-01-01

    Full Text Available CD8+ T cells have been implicated as critical effector cells in protection against the pre-erythrocytic stage of malaria in mice and humans following irradiated sporozoite immunization. Immunization experiments in animal models by several investigators have suggested different strategies for vaccination against malaria and many of the targets from liver stage malaria antigens have been shown to be immunogenic and to protect mice from the sporozoite challenge. Several prime/boost protocols with replicating vectors, such as vaccinia/influenza, with non-replicating vectors, such as recombinant particles derived from yeast transposon (Ty-particles and modified vaccinia virus Ankara, and DNA, significantly enhanced CD8+ T cell immunogenicity and also the protective efficacy against the circumsporosoite protein of Plasmodium berghei and P. yeti. Based on these experimental results the development of a CD8+ T cell inducing vaccine has moved forward from epitope identification to planning stages of safety and immunogenicity trials of candidate vaccines.

  13. Brief historical perspectives of malaria in Iran.

    Science.gov (United States)

    Azizi, Mohammad Hossein; Bahadori, Moslem

    2013-02-01

    The history of malaria as a serious human disease dates back to ancient times. For centuries, malaria has been a deadly disease with high morbidity and mortality that profoundly impacted the socioeconomic status of endemic countries. However, its causative agent remained unidentified until the last decades of the nineteenth century. There were no effective synthetic anti-malarial agents until the mid-twentieth century. Currently malaria has been eliminated or pre-eliminated in numerous countries; however, this preventable and curable disease remains a significant global health problem. A major concern is drug resistance. Presented here, is a brief look at the history of malaria in Iran and the rest of the world, particularly during the nineteenth and twentieth centuries.

  14. KEMUNGKINAN MALARIA PRIMATA SEBAGAI MASALAH ZOONOSIS

    Directory of Open Access Journals (Sweden)

    Shinta Shinta

    2012-09-01

    Full Text Available Until today, four species of Plasmodium are pedicular to inan {Plasmodium falciparum, P. vivax, P. malariae, and P. ovale and at least five species are common in simian: Plasmodium inue, P. cynomolgy, P. knowlesi, P. brasilianum and P. simium. There is little doubts that simian Plasmodium can infect man, it is known as zoonosis. Number of cases of zoonosis infection of simian Plasmodium have been reported from several countries; P. knowlesi (1965, in America, P. simium (1966 in Brazilia, P. inui (1971 in Pahang Malaysia, P. cynomolgi (1973 in America and P. Brazilianum in Sao Paulo (1966, 1995. While pro and contra about zoonotic malaria still not clearly discussed, the new cases have occurred. This give an indication that this zoor >tic malaria will probably be in Indonesia where human, primate, Plasmodium (agents and vector live in the same ecosystem. This paper will discuss the simian Plasmodium and its possibility to be a zoonotic malaria.

  15. Consistently high estimates for the proportion of human exposure to malaria vector populations occurring indoors in rural Africa

    National Research Council Canada - National Science Library

    Huho, Bernadette; Briët, Olivier; Seyoum, Aklilu; Sikaala, Chadwick; Bayoh, Nabie; Gimnig, John; Okumu, Fredros; Diallo, Diadier; Abdulla, Salim; Smith, Thomas; Killeen, Gerry

    2013-01-01

    .... funestus group, usually prefer biting humans indoors at night. Matched surveys of mosquito and human behaviour from six rural sites in Burkina Faso, Tanzania, Zambia, and Kenya, with ITN use ranging from 0.2% to 82.5...

  16. Experimental rhinovirus infection in human volunteers exposed to ozone

    Energy Technology Data Exchange (ETDEWEB)

    Henderson, F.W.; Dubovi, E.J.; Harder, S.; Seal, E. Jr.; Graham, D.

    1988-05-01

    We studied 24 young adult male volunteers experimentally inoculated with type 39 rhinovirus to determine whether the course of viral infection was modified by exposure to moderate levels of ozone (0.3 ppm for 6 h per day) over the 5 days after virus inoculation. No differences in rhinovirus titers in nasal secretions, recruitment of neutrophils into nasal secretions, levels of interferon in nasal lavage fluid, in vitro lymphocyte proliferative responses to rhinovirus antigen, or levels of convalescent serum neutralizing antibody to type 39 rhinovirus were demonstrated in relation to ozone exposure. The level and pattern of ozone exposure used in this experiment had no demonstrable adverse effects on the immune responses necessary to limit and terminate rhinovirus infection of the upper respiratory tract.

  17. Experimental rhinovirus infection in human volunteers exposed to ozone.

    Science.gov (United States)

    Henderson, F W; Dubovi, E J; Harder, S; Seal, E; Graham, D

    1988-05-01

    We studied 24 young adult male volunteers experimentally inoculated with type 39 rhinovirus to determine whether the course of viral infection was modified by exposure to moderate levels of ozone (0.3 ppm for 6 h per day) over the 5 days after virus inoculation. No differences in rhinovirus titers in nasal secretions, recruitment of neutrophils into nasal secretions, levels of interferon in nasal lavage fluid, in vitro lymphocyte proliferative responses to rhinovirus antigen, or levels of convalescent serum neutralizing antibody to type 39 rhinovirus were demonstrated in relation to ozone exposure. The level and pattern of ozone exposure used in this experiment had no demonstrable adverse effects on the immune responses necessary to limit and terminate rhinovirus infection of the upper respiratory tract.

  18. Malaria in South Asia: Prevalence and control

    Science.gov (United States)

    Kumar, Ashwani; Chery, Laura; Biswas, Chinmoy; Dubhashi, Nagesh; Dutta, Prafulla; Dua, Virendra Kumar; Kacchap, Mridula; Kakati, Sanjeeb; Khandeparkar, Anar; Kour, Dalip; Mahajanj, Satish N.; Maji, Ardhendu; Majumder, Partha; Mohanta, Jagadish; Mohapatra, Pradyumna K.; Narayanasamy, Krishnamoorthy; Roy, Krishnangshu; Shastri, Jayanthi; Valecha, Neena; Vikash, Rana; Wani, Reena; White, John; Rathod, Pradipsinh K

    2013-01-01

    The “Malaria Evolution in South Asia” (MESA) program project is an International Center of Excellence for Malaria Research (ICEMR) sponsored by the US National Institutes of Health. This US–India collaborative program will study the origin of genetic diversity of malaria parasites and their selection on the Indian subcontinent. This knowledge should contribute to a better understanding of unexpected disease outbreaks and unpredictable disease presentations from Plasmodium falciparum and Plasmodium vivax infections. In this first of two reviews, we highlight malaria prevalence in India. In particular, we draw attention to variations in distribution of different human-parasites and different vectors, variation in drug resistance traits, and multiple forms of clinical presentations. Uneven malaria severity in India is often attributed to large discrepancies in health care accessibility as well as human migrations within the country and across neighboring borders. Poor access to health care goes hand in hand with poor reporting from some of the same areas, combining to possibly distort disease prevalence and death from malaria in some parts of India. Corrections are underway in the form of increased resources for disease control, greater engagement of village-level health workers for early diagnosis and treatment, and possibly new public–private partnerships activities accompanying traditional national malaria control programs in the most severely affected areas. A second accompanying review raises the possibility that, beyond uneven health care, evolutionary pressures may alter malaria parasites in ways that contribute to severe disease in India, particularly in the NE corridor of India bordering Myanmar Narayanasamy et al., 2012. PMID:22248528

  19. Landscape Ecology and Epidemiology of Malaria Associated with Rubber Plantations in Thailand: Integrated Approaches to Malaria Ecotoping

    Directory of Open Access Journals (Sweden)

    Wuthichai Kaewwaen

    2015-01-01

    Full Text Available The agricultural land use changes that are human-induced changes in agroforestry ecosystems and in physical environmental conditions contribute substantially to the potential risks for malaria transmission in receptive areas. Due to the pattern and extent of land use change, the risks or negatively ecosystemic outcomes are the results of the dynamics of malaria transmission, the susceptibility of human populations, and the geographical distribution of malaria vectors. This review focused basically on what are the potential effects of agricultural land use change as a result of the expansion of rubber plantations in Thailand and how significant the ecotopes of malaria-associated rubber plantations (MRP are. More profoundly, this review synthesized the novel concepts and perspectives on applied landscape ecology and epidemiology of malaria, as well as approaches to determine the degree to which an MRP ecotope as fundamental landscape scale can establish malaria infection pocket(s. Malaria ecotoping encompasses the integrated approaches and tools applied to or used in modeling malaria transmission. The scalability of MRP ecotope depends upon its unique landscape structure as it is geographically associated with the infestation or reinfestation of Anopheles vectors, along with the attributes that are epidemiologically linked with the infections. The MRP ecotope can be depicted as the hotspot such that malaria transmission is modeled upon the MRP factors underlying human settlements and movement activities, health behaviors, land use/land cover change, malaria vector population dynamics, and agrienvironmental and climatic conditions. The systemic and uniform approaches to malaria ecotoping underpin the stratification of the potential risks for malaria transmission by making use of remotely sensed satellite imagery or landscape aerial photography using unmanned aerial vehicle (UAV, global positioning systems (GPS, and geographical information systems

  20. A simulation model of African Anopheles ecology and population dynamics for the analysis of malaria transmission

    NARCIS (Netherlands)

    Depinay, J.M.O.; Mbogo, C.M.; Killeen, G.; Knols, B.G.J.; Beier, J.; Carlson, J.; Dushoff, J.; Billingsley, P.; Mwambi, H.; Githure, J.; Toure, A.M.; McKenzie, F.E.

    2004-01-01

    Background: Malaria is one of the oldest and deadliest infectious diseases in humans. Many mathematical models of malaria have been developed during the past century, and applied to potential interventions. However, malaria remains uncontrolled and is increasing in many areas, as are vector and

  1. Sri Lanka Malaria Maps

    Directory of Open Access Journals (Sweden)

    van der Hoek Wim

    2003-07-01

    Full Text Available Abstract Background Despite a relatively good national case reporting system in Sri Lanka, detailed maps of malaria distribution have not been publicly available. Methods In this study, monthly records over the period 1995 – 2000 of microscopically confirmed malaria parasite positive blood film readings, at sub-district spatial resolution, were used to produce maps of malaria distribution across the island. Also, annual malaria trends at district resolution were displayed for the period 1995 – 2002. Results The maps show that Plasmodium vivax malaria incidence has a marked variation in distribution over the island. The incidence of Plasmodium falciparum malaria follows a similar spatial pattern but is generally much lower than that of P. vivax. In the north, malaria shows one seasonal peak in the beginning of the year, whereas towards the south a second peak around June is more pronounced. Conclusion This paper provides the first publicly available maps of both P. vivax and P. falciparum malaria incidence distribution on the island of Sri Lanka at sub-district resolution, which may be useful to health professionals, travellers and travel medicine professionals in their assessment of malaria risk in Sri Lanka. As incidence of malaria changes over time, regular updates of these maps are necessary.

  2. Spatial and temporal distribution of falciparum malaria in China

    Directory of Open Access Journals (Sweden)

    Lin Hualiang

    2009-06-01

    Full Text Available Abstract Background Falciparum malaria is the most deadly among the four main types of human malaria. Although great success has been achieved since the launch of the National Malaria Control Programme in 1955, malaria remains a serious public health problem in China. This paper aimed to analyse the geographic distribution, demographic patterns and time trends of falciparum malaria in China. Methods The annual numbers of falciparum malaria cases during 1992–2003 and the individual case reports of each clinical falciparum malaria during 2004–2005 were extracted from communicable disease information systems in China Center for Diseases Control and Prevention. The annual number of cases and the annual incidence were mapped by matching them to corresponding province- and county-level administrative units in a geographic information system. The distribution of falciparum malaria by age, gender and origin of infection was analysed. Time-series analysis was conducted to investigate the relationship between the falciparum malaria in the endemic provinces and the imported falciparum malaria in non-endemic provinces. Results Falciparum malaria was endemic in two provinces of China during 2004–05. Imported malaria was reported in 26 non-endemic provinces. Annual incidence of falciparum malaria was mapped at county level in the two endemic provinces of China: Yunnan and Hainan. The sex ratio (male vs. female for the number of cases in Yunnan was 1.6 in the children of 0–15 years and it reached 5.7 in the adults over 15 years of age. The number of malaria cases in Yunnan was positively correlated with the imported malaria of concurrent months in the non-endemic provinces. Conclusion The endemic area of falciparum malaria in China has remained restricted to two provinces, Yunnan and Hainan. Stable transmission occurs in the bordering region of Yunnan and the hilly-forested south of Hainan. The age and gender distribution in the endemic area is

  3. Vaccine candidate discovery for the next generation of malaria vaccines.

    Science.gov (United States)

    Tuju, James; Kamuyu, Gathoni; Murungi, Linda M; Osier, Faith H A

    2017-10-01

    Although epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre- to post-genomic era. Probing of genomic and cDNA libraries with antibodies of defined specificities or functional activity predominated the former, whereas reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite data sets is the mainstay of the latter. Antibody-guided vaccine design spanned both eras but currently benefits from technological advances facilitating high-throughput screening and downstream applications. We make the case that although we have exponentially increased our ability to identify numerous potential vaccine candidates in a relatively short space of time, a significant bottleneck remains in their validation and prioritization for evaluation in clinical trials. Longitudinal cohort studies provide supportive evidence but results are often conflicting between studies. Demonstration of antigen-specific antibody function is valuable but the relative importance of one mechanism over another with regards to protection remains undetermined. Animal models offer useful insights but may not accurately reflect human disease. Challenge studies in humans are preferable but prohibitively expensive. In the absence of reliable correlates of protection, suitable animal models or a better understanding of the mechanisms underlying protective immunity in humans, vaccine candidate discovery per se may not be sufficient to provide the paradigm shift necessary to develop the next generation of highly effective subunit malaria vaccines. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  4. Development of the BG-Malaria trap as an alternative to human-landing catches for the capture of Anopheles darlingi

    Directory of Open Access Journals (Sweden)

    Renata Antonaci Gama

    2013-09-01

    Full Text Available Although the human-landing catch (HLC method is the most effective for collecting anthropophilic anophelines, it has been increasingly abandoned, primarily for ethical considerations. The objective of the present study was to develop a new trap for the collection of Anopheles darlingi . The initial trials were conducted using the BG-Sentinel trap as a standard for further trap development based on colour, airflow direction and illumination. The performance of the trap was then compared with those of the CDC, Fay-Prince, counterflow geometry trap (CFG and HLC. All trials were conducted outdoors between 06:00 pm-08:00 pm. Female specimens of An. darlingi were dissected to determine their parity. A total of 8,334 anophelines were captured, of which 4,945 were identified as An. darlingi . The best trap configuration was an all-white version, with an upward airflow and no required light source. This configuration was subsequently named BG-Malaria (BGM. The BGM captured significantly more anophelines than any of the other traps tested and was similar to HLC with respect to the number and parity of anophelines. The BGM trap can be used as an alternative to HLC for collecting anophelines.

  5. Use of reward-penalty structures in human experimentation

    Science.gov (United States)

    Stein, A. C.; Allen, R. W.; Schwartz, S. H.

    1978-01-01

    The use of motivational techniques in human performance research is reviewed and an example study employing a reward-penalty structure to simulate the motivations inherent in a real-world situation is presented. Driver behavior in a decision-making driving scenario was studied. The task involved control of an instrumented car on a cooperative test course. Subjects were penalized monetarily for tickets and accidents and rewarded for saving driving time. Two groups were assigned different ticket penalties. The group with the highest penalties tended to drive more conservatively. However, the average total payoff to each group was the same, as the conservative drivers traded off slower driving times with lower ticket penalties.

  6. Tuskegee redux: evolution of legal mandates for human experimentation.

    Science.gov (United States)

    Levine, Robert S; Williams, Jamila C; Kilbourne, Barbara A; Juarez, Paul D

    2012-11-01

    Human health experiments systematically expose people to conditions beyond the boundaries of medical evidence. Such experiments have included legal-medical collaboration, exemplified in the U.S. by the Public Health Service (PHS) Syphilis Study (Tuskegee). That medical experiment was legal, conforming to segregationist protocols and specific legislative authorization which excluded a selected group of African Americans from any medical protection from syphilis. Subsequent corrective action outlawed unethical medical experiments but did not address other forms of collaboration, including PHS submission to laws which may have placed African American women at increased risk from AIDS and breast cancer. Today, anti-lobbying law makes it a felony for PHS workers to openly challenge legally anointed suspension of medical evidence. African Americans and other vulnerable populations may thereby face excess risks-not only from cancer, but also from motor vehicle crashes, firearm assault, end stage renal disease, and other problems-with PHS workers as silent partners.

  7. Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer

    Science.gov (United States)

    Ding, Lin; El Zaatari, Mohamad

    2017-01-01

    Overview Gastric cancer has been traditionally defined by the Correa paradigm as a progression of sequential pathological events that begins with chronic inflammation [1]. Infection with Helicobacter pylori (H. pylori) is the typical explanation for why the stomach becomes chronically inflamed. Acute gastric inflammation then leads to chronic gastritis, atrophy particularly of acid-secreting parietal cells, metaplasia due to mucous neck cell expansion from trans-differentiation of zymogenic cells to dysplasia and eventually carcinoma [2]. The chapter contains an overview of gastric anatomy and physiology to set the stage for signaling pathways that play a role in gastric tumorigenesis. Finally, the major known mouse models of gastric transformation are critiqued in terms of the rationale behind their generation and contribution to our understanding of human cancer subtypes. PMID:27573785

  8. Designing malaria vaccines to circumvent antigen variability✩

    Science.gov (United States)

    Ouattara, Amed; Barry, Alyssa E.; Dutta, Sheetij; Remarque, Edmond J.; Beeson, James G.; Plowe, Christopher V.

    2016-01-01

    Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines. PMID:26475447

  9. Designing malaria vaccines to circumvent antigen variability.

    Science.gov (United States)

    Ouattara, Amed; Barry, Alyssa E; Dutta, Sheetij; Remarque, Edmond J; Beeson, James G; Plowe, Christopher V

    2015-12-22

    Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines. Copyright © 2015. Published by Elsevier Ltd.

  10. Effect of Lemongrass Aroma on Experimental Anxiety in Humans.

    Science.gov (United States)

    Goes, Tiago Costa; Ursulino, Fábio Reis Carvalho; Almeida-Souza, Thiago Henrique; Alves, Péricles Barreto; Teixeira-Silva, Flavia

    2015-12-01

    The objective of this study was to evaluate the potential anxiolytic effect of lemongrass (Cymbopogon citratus) aroma in healthy volunteers submitted to an anxiogenic situation. Forty male volunteers were allocated to four different groups for the inhalation of lemongrass essential oil (test aroma: three or six drops), tea tree essential oil (control aroma: three drops), or distilled water (nonaromatic control: three drops). Immediately after inhalation, each volunteer was submitted to an experimental model of anxiety, the video-monitored version of the Stroop Color-Word Test (SCWT). Psychologic parameters (state anxiety, subjective tension, tranquilization, and sedation) and physiologic parameters (heart rate and gastrocnemius electromyogram activity) were evaluated before the inhalation period and before, during, and after the SCWT. Individuals exposed to the test aroma (three and six drops), unlike the control groups, presented a reduction in state anxiety and subjective tension, immediately after treatment administration. In addition, although they presented an anxious response to the task, they completely recovered from it in 5 min, unlike the control groups. Physiologic alterations along the test were not prevented by any treatment, in the same way as has previously been observed for diazepam. Although more investigations are necessary to clarify the clinical relevance of lemongrass essential oil as an anxiety treatment, this work shows that very brief exposure to this aroma has some perceived anxiolytic effects.

  11. Experimental human endotoxemia enhances brain activity during social cognition.

    Science.gov (United States)

    Kullmann, Jennifer S; Grigoleit, Jan-Sebastian; Wolf, Oliver T; Engler, Harald; Oberbeck, Reiner; Elsenbruch, Sigrid; Forsting, Michael; Schedlowski, Manfred; Gizewski, Elke R

    2014-06-01

    Acute peripheral inflammation with corresponding increases in peripheral cytokines affects neuropsychological functions and induces depression-like symptoms. However, possible effects of increased immune responses on social cognition remain unknown. Therefore, this study investigated the effects of experimentally induced acute inflammation on performance and neural responses during a social cognition task assessing Theory of Mind (ToM) ability. In this double-blind randomized crossover functional magnetic resonance imaging study, 18 healthy right-handed male volunteers received an injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline, respectively. Plasma levels of pro- and anti-inflammatory cytokines as well as mood ratings were analyzed together with brain activation during a validated ToM task (i.e. Reading the Mind in the Eyes Test). LPS administration induced pronounced transient increases in pro- (IL-6, TNF-α) and anti-inflammatory (IL-10, IL-1ra) cytokines as well as decreases in mood. Social cognition performance was not affected by acute inflammation. However, altered neural activity was observed during the ToM task after LPS administration, reflected by increased responses in the fusiform gyrus, temporo-parietal junction, superior temporal gyrus and precuneus. The increased task-related neural responses in the LPS condition may reflect a compensatory strategy or a greater social cognitive processing as a function of sickness. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  12. Experimental forearm immobilization in humans induces cold and mechanical hyperalgesia.

    Science.gov (United States)

    Terkelsen, Astrid J; Bach, Flemming W; Jensen, Troels S

    2008-08-01

    Complex regional pain syndrome is a painful condition of unknown etiology. Clinical and experimental observations suggest that limb immobilization may induce symptoms and signs characteristic of complex regional pain syndrome. This study examined the effect of forearm immobilization on regional sensory and autonomic functions in healthy subjects. Thermal and mechanical sensitivity, skin temperature, and vasoconstrictor responses were measured in 30 healthy subjects before and 0, 3, and 28 days after scaphoid cast immobilization. Fifteen subjects served as nonimmobilized controls. At cast removal, 27 subjects experienced pain at joint movement. Cast immobilization induced cold hyperalgesia in glabrous and hairy skin on the immobilized hand and induced significant skin temperature differences between the control and the immobilized hand at cast removal and after 3 days. Immobilization also reduced pain threshold at skin fold testing at all time points after cast removal. All measures except pain threshold at skin fold testing were normalized after 28 days. Immobilization did not affect thermal detection, heat pain, and pressure pain thresholds; resting skin perfusion; or vasoconstrictor responses induced by mental stress or deep inspirations. Four weeks of forearm immobilization caused transient changes in skin temperature, mechanosensitivity, and thermosensitivity, without alteration in the sympathetically mediated vascular tone.

  13. An affordable, quality-assured community-based system for high-resolution entomological surveillance of vector mosquitoes that reflects human malaria infection risk patterns

    Directory of Open Access Journals (Sweden)

    Chaki Prosper P

    2012-05-01

    Full Text Available Abstract Background More sensitive and scalable entomological surveillance tools are required to monitor low levels of transmission that are increasingly common across the tropics, particularly where vector control has been successful. A large-scale larviciding programme in urban Dar es Salaam, Tanzania is supported by a community-based (CB system for trapping adult mosquito densities to monitor programme performance. Methodology An intensive and extensive CB system for routine, longitudinal, programmatic surveillance of malaria vectors and other mosquitoes using the Ifakara Tent Trap (ITT-C was developed in Urban Dar es Salaam, Tanzania, and validated by comparison with quality assurance (QA surveys using either ITT-C or human landing catches (HLC, as well as a cross-sectional survey of malaria parasite prevalence in the same housing compounds. Results Community-based ITT-C had much lower sensitivity per person-night of sampling than HLC (Relative Rate (RR [95% Confidence Interval (CI] = 0.079 [0.051, 0.121], P Anopheles gambiae s.l. and 0.153 [0.137, 0.171], P An. gambiae or Culex respectively. Despite the poor sensitivity of the ITT per night of sampling, when CB-ITT was compared with QA-HLC, it proved at least comparably sensitive in absolute terms (171 versus 169 primary vectors caught and cost-effective (153US$ versus 187US$ per An. gambiae caught because it allowed more spatially extensive and temporally intensive sampling (4284 versus 335 trap nights distributed over 615 versus 240 locations with a mean number of samples per year of 143 versus 141. Despite the very low vectors densities (Annual estimate of about 170 An gambiae s.l bites per person per year, CB-ITT was the only entomological predictor of parasite infection risk (Odds Ratio [95% CI] = 4.43[3.027,7. 454] per An. gambiae or Anopheles funestus caught per night, P =0.0373. Discussion and conclusion CB trapping approaches could be improved with more sensitive traps

  14. Knowledge About Malaria, and Coverage and Utilization Pattern of ...

    African Journals Online (AJOL)

    Interruption of contact between humans and mosquitoes through the use of insecticide-treated mosquito nets (ITNs) is an encouraging approach to protect people from malaria infection. This paper reflects on how people in an area of seasonal malaria, perceive the cause and transmission of the disease, and also assesses ...

  15. Protection against a malaria challenge by sporozoite inoculation.

    NARCIS (Netherlands)

    Roestenberg, M.; McCall, M.B.B.; Hopman, J.C.W.; Wiersma, J.; Luty, A.J.F.; Gemert, G.J.A. van; Vegte-Bolmer, M.G. van de; Schaijk, B.C.L. van; Teelen, K.A.E.M.; Arens, T.; Spaarman, L.; Mast, Q. de; Roeffen, W.F.G.; Snounou, G.; Renia, L.; Ven, A.J.A.M. van der; Hermsen, C.C.; Sauerwein, R.W.

    2009-01-01

    BACKGROUND: An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites.

  16. Malaria in the UK: past, present, and future

    OpenAIRE

    Chin, T; Welsby, P

    2004-01-01

    There is strong evidence that malaria was once indigenous to the UK, that global warming is occurring, and that human activity is contributing to global warming. Global warming will have a variety of effects, one of which will probably be the return of indigenous malaria.

  17. Congenital Malaria in China

    Science.gov (United States)

    Liu, Xue; Culleton, Richard; Tao, Li; Xia, Hui; Gao, Qi

    2014-01-01

    Abstract Background Congenital malaria, in which infants are directly infected with malaria parasites from their mother prior to or during birth, is a potentially life-threatening condition that occurs at relatively low rates in malaria-endemic regions. It is recognized as a serious problem in Plasmodium falciparum–endemic sub-Saharan Africa, where recent data suggests that it is more common than previously believed. In such regions where malaria transmission is high, neonates may be protected from disease caused by congenital malaria through the transfer of maternal antibodies against the parasite. However, in low P. vivax–endemic regions, immunity to vivax malaria is low; thus, there is the likelihood that congenital vivax malaria poses a more significant threat to newborn health. Malaria had previously been a major parasitic disease in China, and congenital malaria case reports in Chinese offer valuable information for understanding the risks posed by congenital malaria to neonatal health. As most of the literature documenting congenital malaria cases in China are written in Chinese and therefore are not easily accessible to the global malaria research community, we have undertaken an extensive review of the Chinese literature on this subject. Methods/Principal Findings Here, we reviewed congenital malaria cases from three major searchable Chinese journal databases, concentrating on data from 1915 through 2011. Following extensive screening, a total of 104 cases of congenital malaria were identified. These cases were distributed mainly in the eastern, central, and southern regions of China, as well as in the low-lying region of southwest China. The dominant species was P. vivax (92.50%), reflecting the malaria parasite species distribution in China. The leading clinical presentation was fever, and other clinical presentations were anaemia, jaundice, paleness, diarrhoea, vomiting, and general weakness. With the exception of two cases, all patients were cured

  18. HEW Proposed Policy on the Protection of Human Subjects: Experimentation and the Institutionalized Mentally Disabled

    Science.gov (United States)

    Washington University Law Quarterly, 1975

    1975-01-01

    Underlying bases for federal interest in experimentation on human subjects, including abuses of investigative processes and efforts at regulation, are explored. Focus is on recent HEW rules on the protection of human subjects, which will have a significant impact on many research institutions. (LBH)

  19. Experimental model of human corpus cavernosum smooth muscle relaxation

    Directory of Open Access Journals (Sweden)

    Rommel P. Regadas

    2010-08-01

    Full Text Available PURPOSE: To describe a technique for en bloc harvesting of the corpus cavernosum, cavernous artery and urethra from transplant organ donors and contraction-relaxation experiments with corpus cavernosum smooth muscle. MATERIALS AND METHODS: The corpus cavernosum was dissected to the point of attachment with the crus penis. A 3 cm segment (corpus cavernosum and urethra was isolated and placed in ice-cold sterile transportation buffer. Under magnification, the cavernous artery was dissected. Thus, 2 cm fragments of cavernous artery and corpus cavernosum were obtained. Strips measuring 3 x 3 x 8 mm3 were then mounted vertically in an isolated organ bath device. Contractions were measured isometrically with a Narco-Biosystems force displacement transducer (model F-60, Narco-Biosystems, Houston, TX, USA and recorded on a 4-channel Narco-Biosystems desk model polygraph. RESULTS: Phenylephrine (1µM was used to induce tonic contractions in the corpus cavernosum (3 - 5 g tension and cavernous artery (0.5 - 1g tension until reaching a plateau. After precontraction, smooth muscle relaxants were used to produce relaxation-response curves (10-12M to 10-4 M. Sodium nitroprusside was used as a relaxation control. CONCLUSION: The harvesting technique and the smooth muscle contraction-relaxation model described in this study were shown to be useful instruments in the search for new drugs for the treatment of human erectile dysfunction.

  20. Experimental model of human corpus cavernosum smooth muscle relaxation.

    Science.gov (United States)

    Regadas, Rommel P; Moraes, Maria E A; Mesquita, Francisco J C; Cerqueira, Joao B G; Gonzaga-Silva, Lucio F

    2010-01-01

    To describe a technique for en bloc harvesting of the corpus cavernosum, cavernous artery and urethra from transplant organ donors and contraction-relaxation experiments with corpus cavernosum smooth muscle. The corpus cavernosum was dissected to the point of attachment with the crus penis. A 3 cm segment (corpus cavernosum and urethra) was isolated and placed in ice-cold sterile transportation buffer. Under magnification, the cavernous artery was dissected. Thus, 2 cm fragments of cavernous artery and corpus cavernosum were obtained. Strips measuring 3 x 3 x 8 mm(3) were then mounted vertically in an isolated organ bath device. Contractions were measured isometrically with a Narco-Biosystems force displacement transducer (model F-60, Narco-Biosystems, Houston, TX, USA) and recorded on a 4-channel Narco-Biosystems desk model polygraph. Phenylephrine (1 microM) was used to induce tonic contractions in the corpus cavernosum (3-5 g tension) and cavernous artery (0.5-1 g tension) until reaching a plateau. After precontraction, smooth muscle relaxants were used to produce relaxation-response curves (10(-12) M to 10(-4) M). Sodium nitroprusside was used as a relaxation control. The harvesting technique and the smooth muscle contraction-relaxation model described in this study were shown to be useful instruments in the search for new drugs for the treatment of human erectile dysfunction.

  1. Cultured skin microbiota attracts malaria mosquitoes

    NARCIS (Netherlands)

    Verhulst, Niels O.; Beijleveld, Hans; Knols, Bart Gj; Takken, Willem; Schraa, Gosse; Bouwmeester, Harro J.; Smallegange, Renate C.

    2009-01-01

    Host-seeking of the African malaria mosquito, Anopheles gambiae sensu stricto, is guided by human odours. The precise nature of the odours, and the composition of attractive blends of volatiles, remains largely unknown. Skin microbiota plays an important role in the production of human body odours.

  2. Cultured skin microbiota attracts malaria mosquitoes

    NARCIS (Netherlands)

    Verhulst, N.O.; Beijleveld, H.; Knols, B.G.J.; Takken, W.; Schraa, G.; Bouwmeester, H.J.; Smallegange, R.C.

    2009-01-01

    Background: Host-seeking of the African malaria mosquito, Anopheles gambiae sensu stricto, is guided by human odours. The precise nature of the odours, and the composition of attractive blends of volatiles, remains largely unknown. Skin microbiota plays an important role in the production of human

  3. Cultured skin microbiota attracts malaria mosquitoes

    NARCIS (Netherlands)

    Verhulst, N.O.; Beijleveld, H.; Knols, B.G.J.; Takken, W.; Schraa, G.; Bouwmeester, H.J.; Smallegange, R.C.

    2009-01-01

    Background - Host-seeking of the African malaria mosquito, Anopheles gambiae sensu stricto, is guided by human odours. The precise nature of the odours, and the composition of attractive blends of volatiles, remains largely unknown. Skin microbiota plays an important role in the production of human

  4. HIV AND MALARIA

    Directory of Open Access Journals (Sweden)

    Ririek Parwitasari

    2014-01-01

    Full Text Available IV/AIDS is a global problem involving industrialized and developing country including Indonesia. Malaria has killed millions ofhuman beings almost 3 million people each year, whereas since 1999, nearly 36 million people in the world infected with HIV and 3 million more have died (Kakilaya, 2006. HIV infection increases the risk and aggravate malaria. In Africa in the area of malaria transmission intensities high and low, HIVaggravate malaria and improve case fatality at any age (Eline 2006. HIVis an RNA viruses whose hallmark is the reverse transcriptation ofits genomic. Malaria is a protozoan disease transmitted by the bite ofinfected anopheles mosquito. Infection malaria can stimulate HIV replication and may cause faster progression ofHIV disease.

  5. Behavioural and electrophysiological responses of the malaria mosquito Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) to human emanations

    NARCIS (Netherlands)

    Qiu, Y.T.; Smallegange, R.C.; Hoppe, S.; Loon, van J.J.A.; Bakker, E.J.; Takken, W.

    2004-01-01

    Behavioural and electrophysiological responses of Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) to human skin emanations collected on glass beads were studied using a dual-port olfactometer and electroantannography. Glass beads to which skin emanations from human hands had been

  6. Pathways to human experimentation, 1933-1945: Germany, Japan, and the United States.

    Science.gov (United States)

    Baader, Gerhard; Lederer, Susan E; Low, Morris; Schmaltz, Florian; Schwerin, Alexander V

    2005-01-01

    The history of human experimentation in the twelve years between Hitler's rise to power and the end of the Second World War is notorious in the annals of the twentieth century. The horrific experiments conducted at Dachau, Auschwitz, Ravensbrueck, Birkenau, and other National Socialist concentration camps reflected an extreme indifference to human life and human suffering. Unfortunately, they do not reflect the extent and complexity of the human experiments undertaken in the years between 1933 and 1945. Following the prosecution of twenty-three high-ranking National Socialist physicians and medical administrators for war crimes and crimes against humanity in the Nuremberg Medical Trial (United States v. Karl Brandt et al.), scholars have rightly focused attention on the nightmarish researches conducted by a small group of investigators on concentration camp inmates. Less well known are alternative pathways that brought investigators to undertake human experimentation in other laboratories, settings, and nations.

  7. Colorectal carcinogenesis: Review of human and experimental animal studies

    Directory of Open Access Journals (Sweden)

    Tanaka Takuji

    2009-01-01

    Full Text Available This review gives a comprehensive overview of cancer development and links it to the current understanding of tumorigenesis and malignant progression in colorectal cancer. The focus is on human and murine colorectal carcinogenesis and the histogenesis of this malignant disorder. A summary of a model of colitis-associated colon tumorigenesis (an AOM/DSS model will also be presented. The earliest phases of colorectal oncogenesis occur in the normal mucosa, with a disorder of cell replication. The large majority of colorectal malignancies develop from an adenomatous polyp (adenoma. These can be defined as well-demarcated masses of epithelial dysplasia, with uncontrolled crypt cell proliferation. When neoplastic cells pass through the muscularis mucosa and infiltrate the submucosa, they are malignant. Carcinomas usually originate from pre-existing adenomas, but this does not imply that all polyps undergo malignant changes and does not exclude de novo oncogenesis. Besides adenomas, there are other types of pre-neoplasia, which include hyperplastic polyps, serrated adenomas, flat adenomas and dysplasia that occurs in the inflamed colon in associated with inflammatory bowel disease. Colorectal neoplasms cover a wide range of pre-malignant and malignant lesions, many of which can easily be removed during endoscopy if they are small. Colorectal neoplasms and/or pre-neoplasms can be prevented by interfering with the various steps of oncogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas and eventually evolves into malignancy. The knowledge described herein will help to reduce and prevent this malignancy, which is one of the most frequent neoplasms in some Western and developed countries.

  8. Malaria in Suriname: a new era : impact of modified intervention strategies on Anopheles darlingi populations and malaria incidence

    NARCIS (Netherlands)

    Hiwat-van Laar, H.

    2011-01-01

    Malaria is an infectious disease caused by Plasmodiumblood parasites which live inside the human host and are spread by Anopheles mosquitoes.Every year an estimated 225 million new cases and near 800.000 malaria deaths are reported. Control of the disease is a formidable task involving all three

  9. Malaria and Tropical Travel

    Centers for Disease Control (CDC) Podcasts

    2008-05-15

    Malaria is a serious mosquito-borne disease that can lead to death. This podcast discusses malaria risk when traveling to tropical areas, as well as how to protect yourself and your family from malaria infection.  Created: 5/15/2008 by National Center for Zoonotic, Vector-Borne, and Enteric Diseases (NCZVED).   Date Released: 5/29/2008.

  10. Malaria vaccines and their potential role in the elimination of malaria

    Directory of Open Access Journals (Sweden)

    Greenwood Brian M

    2008-12-01

    Full Text Available Abstract Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely. The feature of the life-cycles of human malarias that presents the greatest challenge to an elimination programme is the persistence of parasites as asymptomatic infections. These are an important source from which transmission to mosquitoes can occur. Consequently, an elimination strategy requires a community-based approach covering all individuals and not just those who are susceptible to clinical malaria. The progress that has been made in development of candidate malaria vaccines is reviewed. It is unlikely that many of these will have the efficacy required for complete elimination of parasites, though they may have an important role to play as part of future integrated control programmes. Vaccines for elimination must have a high level of efficacy in order to stop transmission to mosquitoes. This might be achieved with some pre-erythrocytic stage candidate vaccines or by targeting the sexual stages directly with transmission-blocking vaccines. An expanded malaria vaccine programme with such objectives is now a priority.

  11. Vaccines against malaria.

    Science.gov (United States)

    Ouattara, Amed; Laurens, Matthew B

    2015-03-15

    Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Control of Disease Tolerance to Malaria by Nitric Oxide and Carbon Monoxide

    Directory of Open Access Journals (Sweden)

    Viktória Jeney

    2014-07-01

    Full Text Available Nitric oxide (NO and carbon monoxide (CO are gasotransmitters that suppress the development of severe forms of malaria associated with Plasmodium infection. Here, we addressed the mechanism underlying their protective effect against experimental cerebral malaria (ECM, a severe form of malaria that develops in Plasmodium-infected mice, which resembles, in many aspects, human cerebral malaria (CM. NO suppresses the pathogenesis of ECM via a mechanism involving (1 the transcription factor nuclear factor erythroid 2-related factor 2 (NRF-2, (2 induction of heme oxygenase-1 (HO-1, and (3 CO production via heme catabolism by HO-1. The protection afforded by NO is associated with inhibition of CD4+ T helper (TH and CD8+ cytotoxic (TC T cell activation in response to Plasmodium infection via a mechanism involving HO-1 and CO. The protective effect of NO and CO is not associated with modulation of host pathogen load, suggesting that these gasotransmitters establish a crosstalk-conferring disease tolerance to Plasmodium infection.

  13. Scientific misconduct and unethical human experimentation: historic parallels and moral implications.

    Science.gov (United States)

    Lefor, Alan T

    2005-01-01

    Although a great deal of human experimentation has been performed to elucidate information otherwise not obtainable, there are many recorded instances of unethical human experimentation. There is also a history of crimes that were committed and disguised as human experiments, best exemplified by the activities of some physicians in Nazi Germany from 1933 until 1945. As a direct result of these activities, a war-crimes trial after World War II resulted in the creation of the Nuremberg Code, to guide future human experimentation. Despite this, unethical experiments were conducted at major academic institutions in the United States in the years after World War II by otherwise normal physicians who did not feel that the Nuremberg Code applied to them personally. There are several possible explanations for such activities, but the desire for personal advancement is prominent among these. Episodes of scientific misconduct such as falsification of experimental data or of personal qualifications seem to be more commonly reported recently and have also been described in the popular press. This activity may also be motivated by desire for personal advancement, giving it a parallel to the conduct of unethical human experimentation. Education may be the best way to prevent these activities that may have similar motivating factors.

  14. Mapping malaria transmission in West and Central Africa.

    Science.gov (United States)

    Gemperli, Armin; Sogoba, Nafomon; Fondjo, Etienne; Mabaso, Musawenkosi; Bagayoko, Magaran; Briët, Olivier J T; Anderegg, Dan; Liebe, Jens; Smith, Tom; Vounatsou, Penelope

    2006-07-01

    We have produced maps of Plasmodium falciparum malaria transmission in West and Central Africa using the Mapping Malaria Risk in Africa (MARA) database comprising all malaria prevalence surveys in these regions that could be geolocated. The 1846 malaria surveys analysed were carried out during different seasons, and were reported using different age groupings of the human population. To allow comparison between these, we used the Garki malaria transmission model to convert the malaria prevalence data at each of the 976 locations sampled to a single estimate of transmission intensity E, making use of a seasonality model based on Normalized Difference Vegetation Index (NDVI), temperature and rainfall data. We fitted a Bayesian geostatistical model to E using further environmental covariates and applied Bayesian kriging to obtain smooth maps of E and hence of age-specific prevalence. The product is the first detailed empirical map of variations in malaria transmission intensity that includes Central Africa. It has been validated by expert opinion and in general confirms known patterns of malaria transmission, providing a baseline against which interventions such as insecticide-treated nets programmes and trends in drug resistance can be evaluated. There is considerable geographical variation in the precision of the model estimates and, in some parts of West Africa, the predictions differ substantially from those of other risk maps. The consequent uncertainties indicate zones where further survey data are needed most urgently. Malaria risk maps based on compilations of heterogeneous survey data are highly sensitive to the analytical methodology.

  15. Malaria Control and Elimination,1 Venezuela, 1800s–1970s

    Science.gov (United States)

    Villegas, Leopoldo; Udhayakumar, Venkatachalam

    2014-01-01

    Venezuela had the highest number of human malaria cases in Latin American before 1936. During 1891–1920, malaria was endemic to >600,000 km2 of this country; malaria death rates led to major population decreases during 1891–1920. No pathogen, including the influenza virus that caused the 1918 pandemic, caused more deaths than malaria during 1905–1945. Early reports of malaria eradication in Venezuela helped spark the world’s interest in global eradication. We describe early approaches to malaria epidemiology in Venezuela and how this country developed an efficient control program and an approach to eradication. Arnoldo Gabaldón was a key policy maker during this development process. He directed malaria control in Venezuela from the late 1930s to the end of the 1970s and contributed to malaria program planning of the World Health Organization. We discuss how his efforts helped reduce the incidence of malaria in Venezuela and how his approach diverged from World Health Organization guidelines.

  16. Malaria control and elimination, Venezuela, 1800s –1970s.

    Science.gov (United States)

    Griffing, Sean M; Villegas, Leopoldo; Udhayakumar, Venkatachalam

    2014-10-01

    Venezuela had the highest number of human malaria cases in Latin American before 1936. During 1891–1920,malaria was endemic to >600,000 km2 of this country; malaria death rates led to major population decreases during 1891–1920. No pathogen, including the influenza virus that caused the 1918 pandemic, caused more deaths than malaria during 1905–1945. Early reports of malaria eradication in Venezuela helped spark the world's interest in global eradication. We describe early approaches to malaria epidemiology in Venezuela and how this country developed an efficient control program and an approach to eradication.Arnoldo Gabaldón was a key policy maker during this development process. He directed malaria control in Venezuela from the late 1930s to the end of the 1970s and contributed to malaria program planning of the World Health Organization.We discuss how his efforts helped reduce the incidence of malaria in Venezuela and how his approach diverged from World Health Organization guidelines.

  17. Forecasting paediatric malaria admissions on the Kenya Coast using rainfall.

    Science.gov (United States)

    Karuri, Stella Wanjugu; Snow, Robert W

    2016-01-01

    Malaria is a vector-borne disease which, despite recent scaled-up efforts to achieve control in Africa, continues to pose a major threat to child survival. The disease is caused by the protozoan parasite Plasmodium and requires mosquitoes and humans for transmission. Rainfall is a major factor in seasonal and secular patterns of malaria transmission along the East African coast. The goal of the study was to develop a model to reliably forecast incidences of paediatric malaria admissions to Kilifi District Hospital (KDH). In this article, we apply several statistical models to look at the temporal association between monthly paediatric malaria hospital admissions, rainfall, and Indian Ocean sea surface temperatures. Trend and seasonally adjusted, marginal and multivariate, time-series models for hospital admissions were applied to a unique data set to examine the role of climate, seasonality, and long-term anomalies in predicting malaria hospital admission rates and whether these might become more or less predictable with increasing vector control. The proportion of paediatric admissions to KDH that have malaria as a cause of admission can be forecast by a model which depends on the proportion of malaria admissions in the previous 2 months. This model is improved by incorporating either the previous month's Indian Ocean Dipole information or the previous 2 months' rainfall. Surveillance data can help build time-series prediction models which can be used to anticipate seasonal variations in clinical burdens of malaria in stable transmission areas and aid the timing of malaria vector control.

  18. Malaria control by commodities without practical malariology.

    Science.gov (United States)

    Kevin Baird, J

    2017-06-21

    Malaria remains a serious clinical and public health problem, the object of an ongoing technological and humanitarian struggle to abate the very substantial harm done. The manner by which humanity approached malaria control changed abruptly and profoundly after 1945 with the advent of the insecticide DDT. Malariologists in the first half of the twentieth century conceived precise modifications to natural or man-made environments aimed at making those less hospitable to specific anopheline mosquito vector species. This practical malariology achieved very significant reductions in burdens of morbidity and mortality, but the revolutionary insecticide eliminated the need for its specialized knowledge and diverse practices. By 1970 mosquito resistance to DDT and perceived environmental concerns precipitated the collapse of what had been a vigorous global campaign to eradicate malaria. Humanity did not then revitalize practical malariology but turned to another commodity as the foundation of control strategy, the war-spurred suite of synthetic antimalarial drugs developed in the 1940s and 1950s. When those drugs became lost to parasite resistance in the latter twentieth century, malaria resurged globally. Since 2005, tens of billions of dollars mobilized new commodities to control malaria: point-of-care diagnostics, effective artemisinin-based treatments, and longer-lasting insecticide treated bed nets. The know-how of practical malariology is not part of that ongoing commodities-based strategy. This article examines contemporary malaria control in the broad strokes of a strategy mitigating the consequences of infection contrasted to that of the abandoned practical malariology strategy of prevention. The inherent risks and limitations of over-reliance upon commodities in striving to control malaria may prompt consideration of a strategic posture inclusive of the proven methods of practical malariology.

  19. Thrombocytopenia in pregnant women with Plasmodium falciparum malaria in an area of unstable malaria transmission in eastern Sudan

    Directory of Open Access Journals (Sweden)

    Adam Mayyada B

    2012-08-01

    Full Text Available Abstract Background Blood platelet levels are being evaluated as predictive and prognostic indicators of the severity of malaria infections in humans. However, there are few studies on platelets and Plasmodium falciparum malaria during pregnancy. Methods A case–control study was conducted at Gadarif Hospital in Eastern Sudan, an area characterized by unstable malaria transmission. The aim of the study was to investigate thrombocytopenia in pregnant women with P. falciparum malaria (cases and healthy pregnant women (controls. Results The median (interquartile platelet counts were significantly lower in patients with malaria (N = 60 than in the controls (N = 60, 61, 000 (43,000–85,000 vs. 249,000 (204,000–300,000/μL, respectively, p P. falciparum malaria (N = 12 compared with those patients with uncomplicated P. falciparum malaria (N = 48, 68, 000 (33,000-88,000/μL vs. 61, 000 (45,000–85,000/μL, respectively, p = 0.8. While none of the control group had thrombocytopenia (platelet count p P. falciparum malaria, compared with the pregnant healthy control group, were at higher risk (OR = 10.1, 95% CI = 4.1–25.18; p  Conclusion P. falciparum malaria is associated with thrombocytopenia in pregnant women in this setting. More research is needed.

  20. Bacteraemia in cerebral malaria

    NARCIS (Netherlands)

    Enwere, G.; van Hensbroek, M. B.; Adegbola, R.; Palmer, A.; Onyiora, E.; Weber, M.; Greenwood, B.

    1998-01-01

    As part of a treatment trial of cerebral malaria, blood cultures were done in 276 Gambian children, aged between 1 and 9 years, with cerebral malaria. Fourteen (5%) of these were positive. The organisms isolated were Staphylococcus aureus (6), coliforms (4), Pseudomonas spp. (2), Salmonella spp. (1)

  1. Changing the Malaria Environment

    African Journals Online (AJOL)

    tega

    Changing the Malaria Environment. On Friday, 21st ... that malaria exerts a great burden in Africa, but even the World Health Organization (WHO) acknowledges the difficulty of counting ... Although selectivity and resistance also limits the deployment of biological control mechanisms, they represent local technologies.

  2. Malaria at Johannesburg Hospital

    African Journals Online (AJOL)

    AGE GROUPS. There were 43 positive blood smears from 32 male and 11 female patients (median age 30 years; range 3 - 66 years). The incidence of malaria in the different age groups is shown in. Table I. Over the last 10 - 15 years the deterioration in the incidence of malaria in Mrica has been partly due to the increasing ...

  3. Fighting malaria without DDT

    International Development Research Centre (IDRC) Digital Library (Canada)

    Nancy Minogue

    The women are part of a successful Mexican initiative that is fighting malaria on many fronts. Through community involve- ment in control strategies, improved surveillance and treatment, and the use of new household spraying techniques, Mexico has dramatically reduced malaria transmission. In 2001 there were just 4,996 ...

  4. Asexual populations of the human malaria parasite, Plasmodium falciparum, use a two-step genomic strategy to acquire accurate, beneficial DNA amplifications.

    Directory of Open Access Journals (Sweden)

    Jennifer L Guler

    Full Text Available Malaria drug resistance contributes to up to a million annual deaths. Judicious deployment of new antimalarials and vaccines could benefit from an understanding of early molecular events that promote the evolution of parasites. Continuous in vitro challenge of Plasmodium falciparum parasites with a novel dihydroorotate dehydrogenase (DHODH inhibitor reproducibly selected for resistant parasites. Genome-wide analysis of independently-derived resistant clones revealed a two-step strategy to evolutionary success. Some haploid blood-stage parasites first survive antimalarial pressure through fortuitous DNA duplications that always included the DHODH gene. Independently-selected parasites had different sized amplification units but they were always flanked by distant A/T tracks. Higher level amplification and resistance was attained using a second, more efficient and more accurate, mechanism for head-to-tail expansion of the founder unit. This second homology-based process could faithfully tune DNA copy numbers in either direction, always retaining the unique DNA amplification sequence from the original A/T-mediated duplication for that parasite line. Pseudo-polyploidy at relevant genomic loci sets the stage for gaining additional mutations at the locus of interest. Overall, we reveal a population-based genomic strategy for mutagenesis that operates in human stages of P. falciparum to efficiently yield resistance-causing genetic changes at the correct locus in a successful parasite. Importantly, these founding events arise with precision; no other new amplifications are seen in the resistant haploid blood stage parasite. This minimizes the need for meiotic genetic cleansing that can only occur in sexual stage development of the parasite in mosquitoes.

  5. Asexual populations of the human malaria parasite, Plasmodium falciparum, use a two-step genomic strategy to acquire accurate, beneficial DNA amplifications.

    Science.gov (United States)

    Guler, Jennifer L; Freeman, Daniel L; Ahyong, Vida; Patrapuvich, Rapatbhorn; White, John; Gujjar, Ramesh; Phillips, Margaret A; DeRisi, Joseph; Rathod, Pradipsinh K

    2013-01-01

    Malaria drug resistance contributes to up to a million annual deaths. Judicious deployment of new antimalarials and vaccines could benefit from an understanding of early molecular events that promote the evolution of parasites. Continuous in vitro challenge of Plasmodium falciparum parasites with a novel dihydroorotate dehydrogenase (DHODH) inhibitor reproducibly selected for resistant parasites. Genome-wide analysis of independently-derived resistant clones revealed a two-step strategy to evolutionary success. Some haploid blood-stage parasites first survive antimalarial pressure through fortuitous DNA duplications that always included the DHODH gene. Independently-selected parasites had different sized amplification units but they were always flanked by distant A/T tracks. Higher level amplification and resistance was attained using a second, more efficient and more accurate, mechanism for head-to-tail expansion of the founder unit. This second homology-based process could faithfully tune DNA copy numbers in either direction, always retaining the unique DNA amplification sequence from the original A/T-mediated duplication for that parasite line. Pseudo-polyploidy at relevant genomic loci sets the stage for gaining additional mutations at the locus of interest. Overall, we reveal a population-based genomic strategy for mutagenesis that operates in human stages of P. falciparum to efficiently yield resistance-causing genetic changes at the correct locus in a successful parasite. Importantly, these founding events arise with precision; no other new amplifications are seen in the resistant haploid blood stage parasite. This minimizes the need for meiotic genetic cleansing that can only occur in sexual stage development of the parasite in mosquitoes.

  6. Metabolomics in the fight against malaria.

    Science.gov (United States)

    Salinas, Jorge L; Kissinger, Jessica C; Jones, Dean P; Galinski, Mary R

    2014-08-01

    Metabolomics uses high-resolution mass spectrometry to provide a chemical fingerprint of thousands of metabolites present in cells, tissues or body fluids. Such metabolic phenotyping has been successfully used to study various biologic processes and disease states. High-resolution metabolomics can shed new light on the intricacies of host-parasite interactions in each stage of the Plasmodium life cycle and the downstream ramifications on the host's metabolism, pathogenesis and disease. Such data can become integrated with other large datasets generated using top-down systems biology approaches and be utilised by computational biologists to develop and enhance models of malaria pathogenesis relevant for identifying new drug targets or intervention strategies. Here, we focus on the promise of metabolomics to complement systems biology approaches in the quest for novel interventions in the fight against malaria. We introduce the Malaria Host-Pathogen Interaction Center (MaHPIC), a new systems biology research coalition. A primary goal of the MaHPIC is to generate systems biology datasets relating to human and non-human primate (NHP) malaria parasites and their hosts making these openly available from an online relational database. Metabolomic data from NHP infections and clinical malaria infections from around the world will comprise a unique global resource.

  7. Metabolomics in the fight against malaria

    Directory of Open Access Journals (Sweden)

    Jorge L Salinas

    2014-08-01

    Full Text Available Metabolomics uses high-resolution mass spectrometry to provide a chemical fingerprint of thousands of metabolites present in cells, tissues or body fluids. Such metabolic phenotyping has been successfully used to study various biologic processes and disease states. High-resolution metabolomics can shed new light on the intricacies of host-parasite interactions in each stage of the Plasmodium life cycle and the downstream ramifications on the host’s metabolism, pathogenesis and disease. Such data can become integrated with other large datasets generated using top-down systems biology approaches and be utilised by computational biologists to develop and enhance models of malaria pathogenesis relevant for identifying new drug targets or intervention strategies. Here, we focus on the promise of metabolomics to complement systems biology approaches in the quest for novel interventions in the fight against malaria. We introduce the Malaria Host-Pathogen Interaction Center (MaHPIC, a new systems biology research coalition. A primary goal of the MaHPIC is to generate systems biology datasets relating to human and non-human primate (NHP malaria parasites and their hosts making these openly available from an online relational database. Metabolomic data from NHP infections and clinical malaria infections from around the world will comprise a unique global resource.

  8. MALARIA DI PURWOREJO

    Directory of Open Access Journals (Sweden)

    Harijani A. Marwoto

    2012-10-01

    Full Text Available Dalam 5 tahun terakhir banyak laporan tentang adanya peningkatan  angka penyakit yang dapat menimbulkan wabah di Jawa Tengah, terutama malaria. Angka malaria/API (Annual Parasite Incidence meningkat > 16 kali lipat, di mana 65% diantaranya berasal dari Purworejo. Masalah malaria tinggi meliputi 11 kecamatan, dengan jumlah desa HCI (High Case Incidence mencapai 171 buah. Masalah malaria tersebut meluas ke daerah pegunungan Menoreh (Magelang,    Wonosobo, Kebumen dan Banyumas. Bahkan sejak tahun 1999 mulai masuk wilayah Kota Purworejo.Sejak tahun 1999 telah dilakukan penelitian kerjasama antara Badan Penelitian dan Pengem­bangan Kesehatan (BPPK - Naval Medical Reseach Unit 2 (Namru 2 - Dinas Kesehatan Ka­bupaten (DKK Purworejo dalam berbagai aspek untuk penanggulangan malaria setempat.

  9. Severe malaria in Europe

    DEFF Research Database (Denmark)

    Kurth, Florian; Develoux, Michel; Mechain, Matthieu

    2017-01-01

    BACKGROUND: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria. METHODS: The European Network for Tropical Medicine and Travel Health (Trop......Net) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre...... for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria. RESULTS: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections...

  10. A longitudinal study of human antibody responses to Plasmodium falciparum rhoptry-associated protein 1 in a region of seasonal and unstable malaria transmission

    DEFF Research Database (Denmark)

    Fonjungo, P N; Elhassan, I M; Cavanagh, D R

    1999-01-01

    Rhoptry-associated protein 1 (RAP1) of Plasmodium falciparum is a nonpolymorphic merozoite antigen that is considered a potential candidate for a malaria vaccine against asexual blood stages. In this longitudinal study, recombinant RAP1 (rRAP1) proteins with antigenicity similar to that of P...... detectable with at least one rRAP1 protein. However, the anti-RAP1 antibody responses were detected only during or shortly after clinical malarial infections. RAP1 antibody levels declined rapidly (within 1 to 2 months) following drug treatment of the infections. No anti-RAP1 antibodies were usually detected....... falciparum-derived RAP1 were used to analyze antibody responses to RAP1 over a period of 4 years (1991 to 1995) of 53 individuals naturally exposed to P. falciparum malaria. In any 1 year during the study, between 23 and 39% of individuals who had malaria developed immunoglobulin G (IgG) antibodies...

  11. Translational repression in malaria sporozoites

    Directory of Open Access Journals (Sweden)

    Oliver Turque

    2016-04-01

    Full Text Available Malaria is a mosquito-borne infectious disease of humans and other animals. It is caused by the parasitic protozoan, Plasmodium. Sporozoites, the infectious form of malaria parasites, are quiescent when they remain in the salivary glands of the Anopheles mosquito until transmission into a mammalian host. Metamorphosis of the dormant sporozoite to its active form in the liver stage requires transcriptional and translational regulations. Here, we summarize recent advances in the translational repression of gene expression in the malaria sporozoite. In sporozoites, many mRNAs that are required for liver stage development are translationally repressed. Phosphorylation of eukaryotic Initiation Factor 2α (eIF2α leads to a global translational repression in sporozoites. The eIF2α kinase, known as Upregulated in Infectious Sporozoite 1 (UIS1, is dominant in the sporozoite. The eIF2α phosphatase, UIS2, is translationally repressed by the Pumilio protein Puf2. This translational repression is alleviated when sporozoites are delivered into the mammalian host.

  12. Implication of the mosquito midgut microbiota in the defense against malaria parasites

    National Research Council Canada - National Science Library

    Dong, Yuemei; Manfredini, Fabio; Dimopoulos, George

    2009-01-01

    .... We have undertaken a comprehensive functional genomic approach to elucidate the molecular interplay between the bacterial co-infection and the development of the human malaria parasite Plasmodium...

  13. Ethical regulation or regulating ethics? The need for both internal and external governance of human experimentation.

    Science.gov (United States)

    Tomossy, George F

    2002-10-01

    Research regulation is a timely topic for discussions in bioethics and public health policy. This response to articles in the previous special issue of the Monash Bioethics Review emphasises the importance of having both internal and external controls on human experimentation. Unless both elements are incorporated into research ethics governance frameworks, they will ultimately fail to achieve what should be their primary goal: human subject protection.

  14. Myxoma Virus Is a Novel Oncolytic Virus with Significant Antitumor Activity against Experimental Human Gliomas

    OpenAIRE

    Lun, Xueqing; Yang, Wenqing; Alain, Tommy; Shi, Zhong-Qiao; Muzik, Huong; Barrett, John W.; McFadden, Grant; Bell, John; Hamilton, Mark G.; Senger, Donna L.; Forsyth, Peter A.

    2005-01-01

    Myxoma virus, a poxvirus previously considered rabbit specific, can replicate productively in a variety of human tumor cells in culture. The purpose of this study was to determine if there was efficacy or toxicities of this oncolytic virus against experimental models of human malignant gliomas in vitro, in vivo, and ex vivo in malignant glioma specimens. In vitro, the majority of glioma cell lines tested (7 of 8, 87.5%) were fully permissive for myxoma virus replication and killed by infectio...

  15. Malaria control in the African Region: perceptions and viewspoints on proceedings of the Africa Leaders Malaria Alliance (ALMA).

    Science.gov (United States)

    Sambo, Luis Gomes; Ki-Zerbo, Georges; Kirigia, Joses Muthuri

    2011-06-13

    communities to address the cross-border dimension of malaria control.It was agreed that countries needed to secure adequate domestic and external funding for sustained commitment to malaria elimination; strengthen national malaria control programmes in the context of broader health system strengthening; ensure free access to long-lasting insecticide treated nets and malaria diagnosis and treatment for vulnerable groups; strengthen human resource capacity at central, district and community levels; and establish strong logistics, information and surveillance systems. It is critically important for countries to have a clear vision and strategy for malaria elimination; effective leadership of national malaria control programmes; draw lessons from other African countries that have succeeded to dramatically reduce the burden of malaria; and sustain funding and ongoing interventions.

  16. Malaria control in the African Region: perceptions and viewspoints on proceedings of the Africa Leaders Malaria Alliance (ALMA

    Directory of Open Access Journals (Sweden)

    Sambo Luis

    2011-06-01

    ; and levering of African Union and regional economic communities to address the cross-border dimension of malaria control. It was agreed that countries needed to secure adequate domestic and external funding for sustained commitment to malaria elimination; strengthen national malaria control programmes in the context of broader health system strengthening; ensure free access to long-lasting insecticide treated nets and malaria diagnosis and treatment for vulnerable groups; strengthen human resource capacity at central, district and community levels; and establish strong logistics, information and surveillance systems. Conclusion It is critically important for countries to have a clear vision and strategy for malaria elimination; effective leadership of national malaria control programmes; draw lessons from other African countries that have succeeded to dramatically reduce the burden of malaria; and sustain funding and ongoing interventions.

  17. In vivo experimental model of human gingival mucosa using immunodeficient mice.

    Science.gov (United States)

    Tsukinoki, K; Miyoshi, Y; Aoki, T; Karakida, K; Ohta, Y; Kaneko, A; Ueyama, Y; Watanabe, Y

    2007-08-01

    To establish an in vivo experimental model for examining human periodontal tissue, the present study examined several transplant techniques that maintain the structure and characteristics of human gingival mucosa. Human oral mucosal tissue samples were collected from the gingiva (n = 11), palate (n = 1), and tongue (n = 3). These mucosal grafts were transplanted onto BALB/c nu/scid mice with double-mutant immunodeficiency. Murine skin, twice the size of the graft, was cut open in an ' square superset'-shape. Next, the connective tissue side of the graft was placed onto the murine connective tissue. Immunohistochemical analysis was also performed, using polyclonal rabbit antibody to involucrin, monoclonal antibody to vimentin, monoclonal antibody to CD34, and monoclonal antibody to Ki-67, to determine whether the characteristics of human oral mucosa were maintained. When the connective tissue side of the graft was placed on the murine fascial membrane, the histological structure of the graft was maintained for 60 d. These grafts were examined for human characteristics using human-specific antibodies. Immunohistochemically, the expression patterns of involucrin, vimentin, and Ki-67 indicated that transplanted mucosa revealed normal human characteristics, including differentiation and proliferation up to 80 d. CD34 was not detected in the graft endothelial cells. The present study revealed that the novel technique of transplantation of human gingival mucosa in nu/scid mice may serve as an in vivo experimental model of periodontal disease.

  18. Applications and limitations of Centers for Disease Control and Prevention miniature light traps for measuring biting densities of African malaria vector populations: a pooled-analysis of 13 comparisons with human landing catches.

    Science.gov (United States)

    Briët, Olivier J T; Huho, Bernadette J; Gimnig, John E; Bayoh, Nabie; Seyoum, Aklilu; Sikaala, Chadwick H; Govella, Nicodem; Diallo, Diadier A; Abdullah, Salim; Smith, Thomas A; Killeen, Gerry F

    2015-06-18

    Measurement of densities of host-seeking malaria vectors is important for estimating levels of disease transmission, for appropriately allocating interventions, and for quantifying their impact. The gold standard for estimating mosquito-human contact rates is the human landing catch (HLC), where human volunteers catch mosquitoes that land on their exposed body parts. This approach necessitates exposure to potentially infectious mosquitoes, and is very labour intensive. There are several safer and less labour-intensive methods, with Centers for Disease Control light traps (LT) placed indoors near occupied bed nets being the most widely used. This paper presents analyses of 13 studies with paired mosquito collections of LT and HLC to evaluate these methods for their consistency in sampling indoor-feeding mosquitoes belonging to the two major taxa of malaria vectors across Africa, the Anopheles gambiae sensu lato complex and the Anopheles funestus s.l. group. Both overall and study-specific sampling efficiencies of LT compared with HLC were computed, and regression methods that allow for the substantial variations in mosquito counts made by either method were used to test whether the sampling efficacy varies with mosquito density. Generally, LT were able to collect similar numbers of mosquitoes to the HLC indoors, although the relative sampling efficacy, measured by the ratio of LT:HLC varied considerably between studies. The overall best estimate for An. gambiae s.l. was 1.06 (95% credible interval: 0.68-1.64) and for An. funestus s.l. was 1.37 (0.70-2.68). Local calibration exercises are not reproducible, since only in a few studies did LT sample proportionally to HLC, and there was no geographical pattern or consistent trend with average density in the tendency for LT to either under- or over-sample. LT are a crude tool at best, but are relatively easy to deploy on a large scale. Spatial and temporal variation in mosquito densities and human malaria transmission

  19. Iron, anemia and hepcidin in malaria.

    Science.gov (United States)

    Spottiswoode, Natasha; Duffy, Patrick E; Drakesmith, Hal

    2014-01-01

    Malaria and iron have a complex but important relationship. Plasmodium proliferation requires iron, both during the clinically silent liver stage of growth and in the disease-associated phase of erythrocyte infection. Precisely how the protozoan acquires its iron from its mammalian host remains unclear, but iron chelators can inhibit pathogen growth in vitro and in animal models. In humans, iron deficiency appears to protect against severe malaria, while iron supplementation increases risks of infection and disease. Malaria itself causes profound disturbances in physiological iron distribution and utilization, through mechanisms that include hemolysis, release of heme, dyserythropoiesis, anemia, deposition of iron in macrophages, and inhibition of dietary iron absorption. These effects have significant consequences. Malarial anemia is a major global health problem, especially in children, that remains incompletely understood and is not straightforward to treat. Furthermore, the changes in iron metabolism during a malaria infection may modulate susceptibility to co-infections. The release of heme and accumulation of iron in granulocytes may explain increased vulnerability to non-typhoidal Salmonella during malaria. The redistribution of iron away from hepatocytes and into macrophages may confer host resistance to superinfection, whereby blood-stage parasitemia prevents the development of a second liver-stage Plasmodium infection in the same organism. Key to understanding the pathophysiology of iron metabolism in malaria is the activity of the iron regulatory hormone hepcidin. Hepcidin is upregulated during blood-stage parasitemia and likely mediates much of the iron redistribution that accompanies disease. Understanding the regulation and role of hepcidin may offer new opportunities to combat malaria and formulate better approaches to treat anemia in the developing world.

  20. Iron, anemia and hepcidin in malaria

    Directory of Open Access Journals (Sweden)

    Natasha eSpottiswoode

    2014-05-01

    Full Text Available Malaria and iron have a complex but important relationship. Plasmodium proliferation requires iron, both during the clinically silent liver stage of growth and in the disease-associated phase of erythrocyte infection. Precisely how the protozoan acquires its iron from its mammalian host remains unclear, but iron chelators can inhibit pathogen growth in vitro and in animal models. In humans, iron deficiency appears to protect against severe malaria, while iron supplementation increases risks of infection and disease. Malaria itself causes profound disturbances in physiological iron distribution and utilization, through mechanisms that include hemolysis, release of heme, dyserythropoiesis, anemia, deposition of iron in macrophages, and inhibition of dietary iron absorption. These effects have significant consequences. Malarial anemia is a major global health problem, especially in children, that remains incompletely understood and is not straightforward to treat. Furthermore, the changes in iron metabolism during a malaria infection may modulate susceptibility to coinfections. The release of heme and accumulation of iron in granulocytes may explain increased vulnerability to non-typhoidal Salmonella during malaria. The redistribution of iron away from hepatocytes and into macrophages may confer host resistance to superinfection, whereby blood-stage parasitemia prevents the development of a second liver-stage Plasmodium infection in the same organism. Key to understanding the pathophysiology of iron metabolism in malaria is the activity of the iron regulatory hormone hepcidin. Hepcidin is upregulated during blood-stage parasitemia and likely mediates much of the iron redistribution that accompanies disease. Understanding the regulation and role of hepcidin may offer new opportunities to combat malaria and formulate better approaches to treat anemia in the developing world.

  1. Ethics of animal research in human disease remediation, its institutional teaching; and alternatives to animal experimentation.

    Science.gov (United States)

    Cheluvappa, Rajkumar; Scowen, Paul; Eri, Rajaraman

    2017-08-01

    Animals have been used in research and teaching for a long time. However, clear ethical guidelines and pertinent legislation were instated only in the past few decades, even in developed countries with Judeo-Christian ethical roots. We compactly cover the basics of animal research ethics, ethical reviewing and compliance guidelines for animal experimentation across the developed world, "our" fundamentals of institutional animal research ethics teaching, and emerging alternatives to animal research. This treatise was meticulously constructed for scientists interested/involved in animal research. Herein, we discuss key animal ethics principles - Replacement/Reduction/Refinement. Despite similar undergirding principles across developed countries, ethical reviewing and compliance guidelines for animal experimentation vary. The chronology and evolution of mandatory institutional ethical reviewing of animal experimentation (in its pioneering nations) are summarised. This is followed by a concise rendition of the fundamentals of teaching animal research ethics in institutions. With the advent of newer methodologies in human cell-culturing, novel/emerging methods aim to minimise, if not avoid the usage of animals in experimentation. Relevant to this, we discuss key extant/emerging alternatives to animal use in research; including organs on chips, human-derived three-dimensional tissue models, human blood derivates, microdosing, and computer modelling of various hues. © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

  2. The development of human factors technologies -The development of human factors experimental evaluation techniques-

    Energy Technology Data Exchange (ETDEWEB)

    Shim, Bong Sik; Oh, In Suk; Cha, Kyung Hoh; Lee, Hyun Chul [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1995-07-01

    In this year, we studied the followings: (1) Development of operator mental workload evaluation techniques, (2) Development of a prototype for preliminary human factors experiment, (3) Suitability test of information display on a large scale display panel, (4) Development of guidelines for VDU-based control room design, (5) Development of integrated test facility (ITF). (6) Establishment of an eye tracking system, and we got the following results: (1) Mental workload evaluation techniques for MMI evaluation, (2) PROTOPEX (PROTOtype for preliminary human factors experiment) for preliminary human factors experiments, (3) Usage methods of APTEA (Analysis-Prototyping-Training-Experiment-Analysis) experiment design, (4) Design guidelines for human factors verification, (5) Detail design requirements and development plan of ITF, (6) Eye movement measurement system. 38 figs, 20 tabs, 54 refs. (Author).

  3. Experimental pain in human temporal muscle induced by hypertonic saline, potassium and acidity

    DEFF Research Database (Denmark)

    Jensen, K; Norup, M

    1992-01-01

    The study was aimed at developing a reference model for experimental pain and tenderness in the human temporal muscle by the local injection of hypertonic saline, potassium chloride and acidic phosphate buffer, using isotonic saline as control. The design was randomized and double-blind. Twenty...

  4. Reflections on the Ethics of Experimentation with Human Subjects with Respect to Arrowsmith (1931

    Directory of Open Access Journals (Sweden)

    Agustín del Cañizo Fernández-Roldán

    2008-10-01

    Full Text Available The moral tension between individual rights versus common good in experimentation with human subjects has been constant throughout history. Taking as a basis the film Arrowsmith in which this problem is well reflected, an ethical analysis is made, bearing in mind the time when the film was made, some historical antecedents and, finally, establishing a comparison with the current situation.

  5. Reflections on the Ethics of Experimentation with Human Subjects with Respect to Arrowsmith (1931)

    OpenAIRE

    Agustín del Cañizo Fernández-Roldán

    2008-01-01

    The moral tension between individual rights versus common good in experimentation with human subjects has been constant throughout history. Taking as a basis the film Arrowsmith in which this problem is well reflected, an ethical analysis is made, bearing in mind the time when the film was made, some historical antecedents and, finally, establishing a comparison with the current situation.

  6. Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions.

    Science.gov (United States)

    Wrzos, Claudia; Winkler, Anne; Metz, Imke; Kayser, Dieter M; Thal, Dietmar R; Wegner, Christiane; Brück, Wolfgang; Nessler, Stefan; Bennett, Jeffrey L; Stadelmann, Christine

    2014-04-01

    Neuromyelitis optica (NMO) is a chronic, mostly relapsing inflammatory demyelinating disease of the CNS characterized by serum anti-aquaporin 4 (AQP4) antibodies in the majority of patients. Anti-AQP4 antibodies derived from NMO patients target and deplete astrocytes in experimental models when co-injected with complement. However, the time course and mechanisms of oligodendrocyte loss and demyelination and the fate of oligodendrocyte precursor cells (OPC) have not been examined in detail. Also, no studies regarding astrocyte repopulation of experimental NMO lesions have been reported. We utilized two rat models using either systemic transfer or focal intracerebral injection of recombinant human anti-AQP4 antibodies to generate NMO-like lesions. Time-course experiments were performed to examine oligodendroglial and astroglial damage and repair. In addition, oligodendrocyte pathology was studied in early human NMO lesions. Apart from early complement-mediated astrocyte destruction, we observed a prominent, very early loss of oligodendrocytes and oligodendrocyte precursor cells (OPCs) as well as a delayed loss of myelin. Astrocyte repopulation of focal NMO lesions was already substantial after 1 week. Olig2-positive OPCs reappeared before NogoA-positive, mature oligodendrocytes. Thus, using two experimental models that closely mimic the human disease, our study demonstrates that oligodendrocyte and OPC loss is an extremely early feature in the formation of human and experimental NMO lesions and leads to subsequent, delayed demyelination, highlighting an important difference in the pathogenesis of MS and NMO.

  7. Plant Foods versus Compounds in Carcinogenesis: Observational versus Experimental Human Studies

    NARCIS (Netherlands)

    Kampman, E.; Arts, I.C.W.; Hollman, P.C.H.

    2003-01-01

    The protective role of plant foods and its constituents in cancer prevention is under renewed debate since the results of recent observational studies on colorectal cancer as well as large-scale human experimental studies on colorectal adenoma recurrence are disappointing. However, most short-term

  8. Using experimental human influenza infections to validate a viral dynamic model and the implications for prediction.

    Science.gov (United States)

    Chen, S C; You, S H; Liu, C Y; Chio, C P; Liao, C M

    2012-09-01

    The aim of this work was to use experimental infection data of human influenza to assess a simple viral dynamics model in epithelial cells and better understand the underlying complex factors governing the infection process. The developed study model expands on previous reports of a target cell-limited model with delayed virus production. Data from 10 published experimental infection studies of human influenza was used to validate the model. Our results elucidate, mechanistically, the associations between epithelial cells, human immune responses, and viral titres and were supported by the experimental infection data. We report that the maximum total number of free virions following infection is 10(3)-fold higher than the initial introduced titre. Our results indicated that the infection rates of unprotected epithelial cells probably play an important role in affecting viral dynamics. By simulating an advanced model of viral dynamics and applying it to experimental infection data of human influenza, we obtained important estimates of the infection rate. This work provides epidemiologically meaningful results, meriting further efforts to understand the causes and consequences of influenza A infection.

  9. Experimental models of testicular development and function using human tissue and cells

    DEFF Research Database (Denmark)

    Tharmalingam, Melissa D; Jorgensen, Anne; Mitchell, Rod T

    2018-01-01

    . In this review, we outline experimental approaches used to sustain cells and tissue from human testis at different developmental time-points and discuss relevant end-points. These include survival, proliferation and differentiation of cell lineages within the testis as well as autocrine, paracrine and endocrine...

  10. Experimental evidence of human recreational disturbance effects on bird-territory establishment.

    Science.gov (United States)

    Bötsch, Yves; Tablado, Zulima; Jenni, Lukas

    2017-07-12

    The worldwide increase in human outdoor activities raises concerns for wildlife. Human disturbances, even at low levels, are likely to impact species during sensitive periods of the annual cycle. However, experimental studies during the putative sensitive period of territory establishment of birds which not only investigate low disturbance levels, but which also exclude the effect of habitat modification (e.g. walking trails) are lacking. Here, we experimentally disturbed birds in forest plots by walking through twice a day during territory establishment. Later we compared the breeding bird community of experimentally disturbed plots with that of undisturbed control plots. We discovered that the number of territories (-15.0%) and species richness (-15.2%) in disturbed plots were substantially reduced compared with control plots. Species most affected included those sensitive to human presence (assessed by flight-initiation distances), open-cup nesters and above-ground foragers. Long-distance migrants, however, were unaffected due to their arrival after experimental disturbance took place. These findings highlight how territory establishment is a sensitive period for birds, when even low levels of human recreation may be perceived as threatening, and alter settlement decisions. This can have important implications for the conservation of species, which might go unnoticed when focusing only on already established birds. © 2017 The Author(s).

  11. Prevention of murine experimental autoimmune orchitis by recombinant human interleukin-6

    DEFF Research Database (Denmark)

    Li, Lu; Itoh, Masahiro; Ablake, Maila

    2002-01-01

    We studied the effect of exogenously administered recombinant human interleukin (IL)-6 on the development of experimental autoimmune orchitis (EAO) in C3H/Hej mice. IL-6 significantly reduced histological signs of EAO and appearance of delayed type hypersensitivity against the immunizing testicul...

  12. Can experimental data in humans verify the finite element-based bone remodeling algorithm?

    DEFF Research Database (Denmark)

    Wong, Christian; Gehrchen, P Martin; Kiaer, Thomas

    2008-01-01

    A finite element analysis-based bone remodeling study in human was conducted in the lumbar spine operated on with pedicle screws. Bone remodeling results were compared to prospective experimental bone mineral