The use of placebos in randomised controlled trials is a subject of considerable ethical debate. In this paper we present a set of considerations to evaluate the ethics of placebo controlled trials that includes: social value of the study; need for a randomised controlled trial and placebo; standards of care; risks of harm due to administration of placebo and the harm benefit balance; clinical equipoise; and double standards. We illustrate the application of these considerations using a case study of a (...) large ongoing multicentre, placebo-controlled, double-blinded, randomised trial to determine primaquine anti-relapse efficacy in vivax malaria. There is an urgent need for primaquine anti-relapse studies in order to rationalise the management of a potentially fatal disease. An ethical justification for the use of the placebo arm is provided on the grounds that the actual current applied standard of care in most endemic places does not include primaquine. It has also been argued that there is clinical equipoise among the primaquine study arms and that the risk of harms of being in the placebo arm is the risk of having relapse, which is no more than not being included in the trial, and that there are no double standards. Based on our set of considerations, we conclude that a placebo arm is not only justified but imperative in this study. We propose that similar considerations should be prospectively applied to other placebo controlled trials and observational control arms where no treatment is offered. (shrink)

The term “hypnozoite” is derived from the Greek words hypnos and zoon. Hypnozoites are dormant forms in the life cycles of certain parasitic protozoa that belong to the Phylum Apicomplexa and are best known for their probable association with latency and relapse in human malarial infections caused by Plasmodium ovale and P. vivax. Consequently, the hypnozoite is of great biological and medical significance. This, in turn, makes the origin of the name “hypnozoite” a subject of interest. Some “missing” (...) history that is now placed on record shows that Miles B. Markus coined the term “hypnozoite”. While a PhD student at Imperial College London, he carried out research that led to the identification of an apparently dormant form of Cystoisospora. In 1976, he speculated: “If sporozoites of Isospora can behave in this fashion, then those of related Sporozoa, like malaria parasites, may have the ability to survive in the tissues in a similar way.” He adopted the term “hypnozoite” for malaria in 1978 when he wrote in a little-known journal that this name would “… describe any dormant sporozoites or dormant, sporozoite-like stages in the life cycles of Plasmodium or other Haemosporina.” At that time, the existence of a hypnozoite form in the life cycle of Plasmodium was still a hypothetical notion. In 1980, however, Wojciech A. Krotoski published details concerning his actual discovery of malarial hypnozoites, an event of considerable importance. (shrink)

Fast and effective detection of the causative agent of malaria in humans, protozoan Plasmodium parasites, is of crucial importance for increasing the effectiveness of treatment and to control a devastating disease that affects millions of people living in endemic areas. The microscopic examination of Giemsa‐stained blood films still remains the gold‐standard in Plasmodium detection today. However, there is a high demand for alternative diagnostic methods that are simple, fast, highly sensitive, ideally do not rely on blood‐drawing and can (...) potentially be conducted by the patients themselves. Here, the history of Plasmodium detection is discussed, and advantages and disadvantages of diagnostic methods that are currently being applied are assessed. (shrink)

The examination of the complex cell biology of the human malaria parasite Plasmodium falciparum usually relies on the time‐consuming generation of transgenic parasites. Here, metabolic labeling and click chemistry are employed as a fast transfection‐independent method for the microscopic examination of protein S‐palmitoylation, an important post‐translational modification during the asexual intraerythrocytic replication of P. falciparum. Applying various microscopy approaches such as confocal, single‐molecule switching, and electron microscopy, differences in the extent of labeling within the different asexual developmental stages of (...) P. falciparum and the host erythrocytes over time are observed. (shrink)

The two vegetative cell types of the acellular slime mould Physarum polycephalum ‐ amoebae and plasmodia ‐ differ greatly in cellular organisation and behaviour as a result of differences in gene expression. The development of uninucleate amoebae into multinucleate, syncytial plasmodia is under the control of the mating‐type locus matA, which is a complex, multi‐functional locus. A key period during plasmodium development is the extended cell cycle, which occurs in the developing uninucleate cell. During this long cell cycle, many (...) of the changes in cellular organisation that accompany development into the multinucleate stage are initiated including, for example, alterations in microtubule organisation. Genes have been identified that show cell‐type specific expression in either amoebae or plasmodia and many of these genes alter their pattern of expression during the extended cell cycle. With the introduction of a DNA transformation system for P. polycephalum, it is now possible to investigate the functions of genes in the vegetative cell types and their roles in the cellular reorganisations accompanying development. (shrink)

The plasmodium of _Physarum polycephalum_ is a unicellular and multinuclear giant amoeba with computational abilities. The plasmodium has been widely used as a model organism in the field of bio-computing; however, its ability to perform computation related to its biological nature itself in the essential sense has not yet been fully realized. Therefore, in this study, we focused on the phenomenon in which a plasmodium trapped in a closed space surrounded by repellent substances escapes from the field (...) by changing its own behavior rules. We demonstrated that this phenomenon is bio-computationally important in that it may enable the implementation of biological characteristics in computing. (shrink)

Plasmodium falciparum is the most deadly human malarial parasite, responsible for an estimated 207 million cases of disease and 627,000 deaths in 2012. Recent studies reveal that the parasite actively regulates a large fraction of its genes throughout its replicative cycle inside human red blood cells and that epigenetics plays an important role in this precise gene regulation. Here, we discuss recent advances in our understanding of three aspects of epigenetic regulation in P. falciparum: changes in histone modifications, nucleosome (...) occupancy and the three‐dimensional genome structure. We compare these three aspects of the P. falciparum epigenome to those of other eukaryotes, and show that large‐scale compartmentalization is particularly important in determining histone decomposition and gene regulation in P. falciparum. We conclude by presenting a gene regulation model for P. falciparum that combines the described epigenetic factors, and by discussing the implications of this model for the future of malaria research. (shrink)

Definitive diagnosis of malaria requires the demonstration through laboratory tests of the presence within the patient of malaria parasites or their components. Since malaria parasites can be present even in the absence of malaria manifestations, and since symptoms of malaria can be manifested even in the absence of malaria parasites, malaria diagnosis raises important issues for the adequate understanding of disease, etiology and diagnosis. One approach to the resolution of these issues adopts a realist view, according to which the needed (...) clarifications will be derived from a careful representation of the entities on the side of the patient which form the ultimate truthmakers for clinical statements. We here address a challenge to this realist approach relating to the diagnosis of malaria, and show how this challenge can be resolved by appeal to Basic Formal Ontology (BFO) and to the Ontology for General Medical Science (OGMS) constructed in its terms. (shrink)

Chloroquine-resistant plasmodium falciparum malaria is a serious public health threat that is spreading rapidly across Sub-Saharan Africa. It affects over three quarters (80%) of malarial endemic countries. Of the estimated 300-500 million cases of malaria reported annually, the vast majority of malarial-related morbidities occur among young children in Africa, especially those concentrated in the remote rural areas with inadequate access to appropriate health care services. In Liberia, in vivo studies conducted between 1993 and 2000 observed varying degrees of (...) class='Hi'>plasmodium falciparum malaria infections that were resistant to chloroquine, including sulfadiazine-pyrimethamine. As the country emerges from a prolonged civil war, the health care delivery system may not be adequately prepared to implement an effective nation-wide malarial control strategy. As a result, the management of uncomplicated malaria in Liberia poses a significant public health challenge for the government-financed health care delivery system. Therefore, based on extensive literature review, we report the failure of chloroquine as an effective first-line drug for the treatment of uncomplicated plasmodium falciparum malaria in Liberia and recommend that national health efforts be directed at identifying alternative drug(s) to replace it. (shrink)

Reorganization of cell organelle‐deprived host red blood cells by the apicomplexan malaria parasite Plasmodium falciparum enables their cytoadherence to endothelial cells that line the microvasculature. This increases the time red blood cells infected with mature developmental stages remain within selected organs such as the brain to avoid the spleen passage, which can lead to severe complications and cumulate in patient death. The Maurer's clefts are a novel secretory organelle of parasite origin established by the parasite in the cytoplasm of (...) the host red blood cell in order to facilitate the establishment of cytoadherence by conducting the trafficking of immunovariant adhesins to the host cell surface. Another important function of the organelle is the sorting of other proteins the parasite traffics into its host cell. Although the organelle is of high importance for the pathology of malaria, additional putative functions, structure, and genesis remain shrouded in mystery more than a century after its discovery. In this review, we highlight our current knowledge about the Maurer's clefts and other novel secretory organelles established within the host cell cytoplasm by human‐pathogenic malaria parasites and other parasites that reside within human red blood cells. (shrink)

The Plasmodium falciparum genome‐sequencing project has provided malariologists with vast amounts of new information pertinent to a multitude of cellular processes that previously were only guessed about. In exploring this morass of predicted genes and proteins, there is now a danger of simply re‐inventing the cell. Fortunately, new global transcriptional analyses reassure malariologists that they are not dealing with just “any old cell.” The informative papers on the plasmodial transcriptome by Le Roch et al. (2003)1 and Bozdech et al. (...) (2003)2 discussed below forge a bridge between the genomics and proteomics of P. falciparum. They are likely to act as a fulcrum upon which much future research will turn: for example, the study of regulation and feed‐back loops. BioEssays 26:339–342, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Malaria is a Plasmodium parasitic disease transmitted by infected female Anopheles mosquitoes. Climatic factors, such as temperature, humidity, rainfall, and wind, have significant effects on the incidence of most vector-borne diseases, including malaria. The mosquito behavior, life cycle, and overall fitness are affected by these climatic factors. This paper presents the results obtained from investigating the optimal control strategies for malaria in the presence of temperature variation using a temperature-dependent malaria model. The study further identified the temperature ranges in (...) four different geographical regions of sub-Saharan Africa, suitable for mosquitoes. The optimal control strategies in the temperature suitable ranges suggest, on average, a high usage of both larvicides and adulticides followed by a moderate usage of personal protection such as bednet. The average optimal bednet usage mimics the solution profile of the mosquitoes as the mosquitoes respond to changes in temperature. Following the results from the optimal control, this study also investigates using a temperature-dependent model with insecticide-sensitive and insecticide-resistant mosquitoes the impact of insecticide-resistant mosquitoes on disease burden when temperature varies. The results obtained indicate that optimal bednet usage on average is higher when insecticide-resistant mosquitoes are present. Besides, the average bednet usage increases as temperature increases to the optimal temperature suitable for mosquitoes, and it decreases after that, a pattern similar to earlier results involving insecticide-sensitive mosquitoes. Thus, personal protection, particularly the use of bednets, should be encouraged not only at low temperatures but particularly at high temperatures when individuals avoid the use of bednets. Furthermore, control and reduction of malaria may be possible even when mosquitoes develop resistance to insecticides. (shrink)

The hypothesis of extended cognition (HEC) claims that the cognitive processes that materially realise thinking are sometimes partially constituted by entities that are located external to an agent’s body in its local envi- ronment. We show how proponents of HEC need not claim that an agent must have a central nervous system, or physically instantiate processes organised in such a way as to play a causal role equivalent to that of the brain if that agent is to be capable of (...) cognition. Focusing on the case of spatial memory, we make our argument by taking a close look at the striking example of Physarum Polycephalum plasmodium (i.e., slime mould) which uses self- produced non-living extracellular slime trails to navigate its environment. We will argue that the use of exter- nalized spatial memory by basal organisms like Physarum is an example of extended cognition. Moreover, it is a possible evolutionary precursor to the use of internal spatial memory and recall in animals thus demonstrating how extended cognition may have emerged early in evolutionary history. (shrink)

How international research might contribute to justice in global health has not been substantively addressed by bioethics. This article describes how the provision of ancillary care can link international clinical research to the reduction of global health disparities. It identifies the ancillary care obligations supported by a theory of global justice, showing that Jennifer Ruger’s health capability paradigm requires the delivery of ancillary care to trial participants for a limited subset of conditions that cause severe morbidity and mortality. Empirical research (...) on the Shoklo Malaria Research Unit’s (SMRU) vivax malaria treatment trial was then undertaken to demonstrate whether and how these obligations might be upheld in a resource-poor setting. Our findings show that fulfilment of the ancillary care obligations is feasible where there is commitment from chief investigators and funders and is strongly facilitated by SMRU’s dual role as a research unit and medical non-governmental organization. (shrink)

Bioethicists have long debated the content of sponsors and researchers' obligations of justice in international clinical research. However, there has been little empirical investigation as to whether and how obligations of responsiveness, ancillary care, post-trial benefits and research capacity strengthening are upheld in low- and middle-income country settings. In this paper, the authors argue that research ethics guidelines need to be more informed by international research practice. Practical guidance on how to fulfil these obligations is needed if research groups and (...) other actors are to successfully translate them into practice because doing so is often a complicated, context-specific process. Case study research methods offer one avenue for collecting data to develop this guidance. The authors describe how such methods have been used in relation to the Shoklo Malaria Research Unit's vivax malaria treatment (VHX) trial (NCT01074905). Relying on the VHX trial example, the paper shows how information can be gathered from not only international clinical researchers but also trial participants, community advisory board members and research funder representatives in order to: (1) measure evidence of responsiveness, provision of ancillary care, access to post-trial benefits and research capacity strengthening in international clinical research; and (2) identify the contextual factors and roles and responsibilities that were instrumental in the fulfilment of these ethical obligations. Such empirical work is necessary to inform the articulation of obligations of justice in international research and to develop guidance on how to fulfil them in order to facilitate better adherence to guidelines' requirements. (shrink)

Thanks to the extensive use of recombinant DNA technology and immunological methods, much insight into cellular functions of the human malaria parasite Plasmodium falciparum has been gained since it was learnt ten years ago how to grow this organism in culture. The amino acid sequence of over a dozen surface proteins of the parasite and of several proteins the parasite excretes into its most important host cell, the erythrocyte, have been determined. Interestingly many of these proteins show blocks of (...) repeated amino acids. Several proteins have been shown to be involved in specific aspects of the complex hostparasite interaction, such as penetration of host cells or increased stickiness of infected red blood cells in the blood vessels. Some of the proteins described here may be protective antigens and may become important in vaccine development. (shrink)

Graphical AbstractVarious diagnostic methods are available to detect the six human pathogenic Plasmodium species that replicate within host erythrocytes and cause different types of malaria. Every currently available diagnostic method has distinct advantages and disadvantages. There is still a high demand for simple, fast, and highly sensitive alternative diagnostic methods that ideally do not rely on blood drawing and might be applied by the patient at home. In article number 1900138, Brian Gitta and Nicole Kilian discuss the history of (...) Plasmodium detection and assess advantages and disadvantages of diagnostic methods that are currently being applied. (shrink)

The development of technologies for the biopreservation of infectious organisms requires careful analysis of benefits and risks. This article reviews the regulatory landscape and oversight responsibilities in the United States in respect to pathogen biopreservation. Focused on two globally significant pathogens, Cryptosporidium and Plasmodium, the article explores advantages and potential risks of biopreservation concerning biosafety, biosecurity and biocontainment.

The immunology of falciparum malaria, the lethal type of human malaria, has been transformed by two developments. First, a culture system for the asexual blood stages of Plasmodium falciparum.1 Secondly, the cloning and expression of genes coding for a large number of the protein antigens of this malaria parasite over the past two years. Data on proteins, protein antigens and epitopes of P. falciparum supplied by gene cloning techniques have been supplemented by monoclonal antibody approaches, peptide synthesis, and high‐resolution (...) immunochemistry. (shrink)

The paper considers main features of two groups of logics for biological devices, called Physarum Chips, based on the plasmodium. Let us recall that the plasmodium is a single cell with many diploid nuclei. It propagates networks by growing pseudopodia to connect scattered nutrients. As a result, we deal with a kind of computing. The first group of logics for Physarum Chips formalizes the plasmodium behaviour under conditions of nutrient-poor substrate. This group can be defined as standard (...) storage modification machines. The second group of logics for Physarum Chips covers the plasmodium computing under conditions of nutrient-rich substrate. In this case the plasmodium behaves in a massively parallel manner and propagates in all possible directions. The logics of the second group are unconventional and deal with non-well-founded data such as infinite streams. (shrink)