Can we be sure that the human Plasmodium exoerythrocytic developmental stages occur exclusively in the liver?

The development cycle of the malaria parasite, Plasmodium sp., in humans takes place after an infected female Anopheles mosquito injects motile infective forms called sporozoites into the bloodstream. Sporozoites migrate via blood vessels to the liver. This pre-erythrocytic tissue stage is widely accepted to occur in humans exclusively in the liver, contrary to avian malaria where this may occur also in other parenchymatous organs. This concept is based on research conducted by English researchers Henry Shortt and P.C.C. Garnham in the late 1940s. Although Italian researchers as, e.g., Giulio Raffaele, additionally claimed the presence of the parasites in the bone marrow, this is not well acknowledged. So, the question remains whether there exists also a tissue life cycle stage in humans.

Malaria relapses were already known before 1900-a discussion.

For a long time, only two phases of the life cycle of the agents of malaria parasites were known: the cycle inside the mosquito body and the cycle in the red blood cells of humans as intermediate hosts. A possible tissue development cycle inside humans, however, had already been proposed before 1900. In general, Pieter Klaesz Pel is considered the first scientist who has described such a tissue cycle. However, a closer look at Pel's work shows that he still followed an old (conservative) way of thinking, since he still referred to "malaria poison and malaria miasma." Thus, the first idea of a possible tissue cycle must be searched in the work of earlier scientists. Referring to their observations on malaria, Vassilij Danilevsky, Arman Ruffer, Camillo Golgi and Battista Grassi suspected developing parasites in internal organs, before they can be found in the bloodstream.

Clinical implications of a gradual dormancy concept in malaria.

Malaria recurrences after an initially successful therapy and malarial fever occurring a long time after infection are well-known problems in malariology. Currently, two distinct types of malaria recurrences are defined: recrudescence and relapse. A recrudescence is thought to originate from circulating Plasmodium blood stages which do not cause fever before a certain level of a microscopically detectable parasitemia is reached. Contrary, a relapse is thought to originate from quiescent intracellular hepatic parasite stages called hypnozoites. Recrudescences would typically occur in infections due to Plasmodium falciparum. Plasmodium knowlesi, and Plasmodium malariae, whereas relapses would be caused exclusively by Plasmodium vivax and Plasmodium ovale. This schematic view is, however, insufficiently supported by experimental evidence. For instance, hypnozoites of P. ovale have never been experimentally documented. On the other hand, the nonfinding of P. malariae hypnozoites turned into the proof for the nonexistence of P. malariae hypnozoites. Clinical relapse-type recurrences have been observed in both P. ovale and P. malariae infections, and decade-long incubation times have also been reported in P. falciparum infections. We propose a gradual hypothesis in accordance with the continuity concept of biological evolution: both, relapse and recrudescence may be potentially caused by all Plasmodium spp. We hypothesize that the difference between the various Plasmodium spp. is quantitative rather than qualitative: there are Plasmodium spp. which frequently cause relapses such as P. vivax, particularly the P.v. Chesson strain, species which cause relapses less frequently, such as P. ovale and sometimes P. malariae, and species which may exceptionally cause relapses such as P. falciparum. All species may cause recrudescences. As clinical consequences, we propose that 8-aminquinolines may be considered in a relapse-type recrudescence regardless of the causal Plasmodium sp., whereas primaquine relapse prevention might not be routinely indicated in malaria due to P. ovale.

Why do Plasmodium malariae infections sometimes occur in spite of previous antimalarial medication?

Quartan malaria due to Plasmodium malariae is commonly regarded as being preventable by current antimalarials. A case of P. malariae infection occurred in spite of previous treatment of Plasmodium falciparum malaria 4 months earlier with a full therapy course of intravenous quinine hydrochloride and oral doxycycline followed by artemether + lumefantrine. Since the patient was not anymore exposed to agents of malaria in the meantime, a new infection by P. malariae after therapy is unlikely. The present observation is difficult to explain by the current view on the origin of latent P. malariae infections and recurrences which are thought to arise from intra-erythrocytic development stages susceptible to common antimalarials. The most likely explanation of our observation is a delayed pre-erythrocytic development. The latency between infection by P. malariae and the quartan malaria fever attack might have been extended further by an initial subclinical circulation of a low number of intra-erythrocytic asexual parasites in the blood stream preceeding the clinical quartan malaria breakthrough.

What is the evidence for the existence of Plasmodium ovale hypnozoites?

Relapsing human malaria is regarded to be caused by Plasmodium vivax and Plasmodium ovale. P. vivax relapses originate from dormant liver stages: "hypnozoites". Also, P. ovale, a species considered as closely related to P. vivax, is in analogy assumed to display hypnozoites. A close biologic relationship is, however, not supported by molecular genetic studies. Therefore, original literature published since the description of P. ovale in 1922 was systematically screened for the demonstration of hypnozoites or circumstantial evidence for their existence, i.e. the occurrence of true relapses. In P. ovale infection, hypnozoites have never been demonstrated by biological experiments, and the few reports published on relapses have conflicting results.

Species sanitation of malaria in the Netherlands East Indies (1913-1942)--an example of applied medical history?

To the World Health Organization malaria remains "one of the world's most important public health concerns". During the post-eradication era of the 1980s there was no clear answer to the following question: what kind of intervention could be effective against malaria in the 'roll-back malaria' programme? In this situation there were also calls for an 'applied history of medicine', since the anti-malaria programmes during the pre-eradication era might help overcome the crisis of finding an appropriate way to fight malaria. At this point the concept of species sanitation was considered. Developed in the 1920s in the former Netherlands East Indies the thrust of this concept is that anopheles, as obligatory vectors of malaria, have species-specific breeding sites; when these sites are sanitised, malaria is deprived of its ecological preconditions. This double question - the history of species sanitation and the possibility of an applied history of medicine - is the starting point of this paper. The results of the historical analysis are that in terms of the biological, technical, economical, social and political conditions, species sanitation remains limited to a few locally specified exceptions. The attempt to find answers in history demonstrates that an evaluation of historical anti-malaria measures can be helpful in determining the fundamental elements of a given situation necessary for an effective malaria control programme.

[Current status and future prospects of the history medicine in Germany--dedicated to Ulrich Hadding]. / Stand und Perspektiven der Medizingeschichte in Deutschland--für Ulrich Hadding.

Science aims at generalised knowledge about human beings. Medical action, by contrast, is directed towards individuals and their subjectivity. Thus, in the doctor-patient encounter the scientific object-orientation of medical science turns into the subject-orientation of medical practice. This means that modern medicine can essentially be explained through the social sciences and the arts and humanities. Among these approaches, historiography explores the aspect of action in time. The historiography of medicine therefore aims genuinely at the specific aspect of medical action under its conditions in time. In its current transition from the natural sciences to the life sciences, medicine meets its boundaries not only in science and practice, but also in the individual person and in the social world. It is of utmost importance, for medicine as well as for society, to analyse the historicity of medical knowledge and action by historiographical methods. The results of historiographical research are to be explained--as a history of medicine--to the public and--as a history in medicine--to medicine itself. And in a sort of a pragmatic history in medicine they are to be turned to practical use for current problems of medical action.

[Science cultures in the global perspective. Thoughts on content design and operation of the Leopoldina Study Center]. / Wissenskulturen in globaler Perspektive. Gedanken zur inhaltlichen Konzeption und zur Arbeitsweise des Leopoldina-Studienzentrums.

The Leopoldina Center for the Study of the History of Science and Science Academies is a place to openly discuss the cooperation between science and society across all of the disciplines represented at the Leopoldina and beyond. This dialogue shall, by all means, also include researchers who are not members of the Leopoldina and people from outside of the academia who are interested in the topic. Like the Leopoldina, its Study Center builds bridges: between various academic disciplines, across generations and in local, national, and international communities. All interested members of the Leopoldina--not just members from the humanities, the social sciences or the behavioral sciences, but also scientists from the areas of the natural sciences, technology, the life sciences and physicians--are kindly invited to incorporate their research interests, with regard to the history and theory of their respective academic disciplines, in the research portfolio of the Leopoldina Study Center. In so doing, the Leopoldina Center for the Study of the History of Science and Science Academies should and will become a source of energy for permanent reflection and innovation when contemplating the issues of science and society.