B. G. Maegraith

The Pathogenesis of Mammalian Malaria

Publisher Summary This chapter examines two principal features of mammalian malaria: the pathophysiology of malaria as an inflammation and the possible initiating and maintaining factors involved. Intravascular coagulation has often been blamed for the obstruction of the cerebral circulation in falciparum malaria. In fact, clotting has rarely been demonstrated and there is very little evidence that coagulation thrombosis or embolus play significant roles in producing the vascular lesions (as distinct from being associated with them). When they occur they represent developments following and not preceding the reduction of blood flow. The “plugging” of the small cerebral vessels by parasitized erythrocytes continues to be the common pathological pattern described at autopsy findings in fatal P. falciparum cases. The function of the endothelial membranes of the brain is examined in the laboratory in P. knowlesi and P. berghei infections. The methods for demonstrating the escape of protein across the cerebral vascular endothelium, choroid plexus, ventricular walls, and other parts of the brain are used. The changes in membrane permeability and some of the circulatory disturbances noted are induced by physiologically active peptides, such as kinins. The intravascular coagulation in malaria is also discussed. Many factors are involved in creating the environment that leads to cellular damage in malaria. At some stage in the development of a malaria infection, the pathogenic processes must be initiated by the parasite, either during its development in the erythrocyte or at schizogony. One possible link between the parasite and the host may be the soluble factor, which is capable of inhibiting mitochondria1 respiration and phosphorylation. This and possibly other factors may be involved, acting at various strategic points in the host and influencing its physiological and biochemical balance.

Suppression of Malaria (P. Berghei) by Milk

grossly reduced because of the deficiency in the blood of a factor called the Christmas factor. The Christmas factor can be obtained most readily from serum, and in some features resembles the serum factor VII of Koller et al. (1951). It differs greatly from the antihaemophilic globulin, and the blood from patients with true haemophilia (antihaemophilic globulin deficiency) is as effective as is normal blood in correcting the clotting abnormality in the blood or plasma of patients with Christmas disease. In the treatment of haemorrhage in cases of Christmas disease concentrated preparations of antihaemophilic globulin are ineffective.

The action of adrenaline, L-noradrenaline, acetylcholine and other substances on the blood vessels of the perfused canine liver.

This paper records experiments designed to determine the effects of certain physiologically active substances on the circulation within the perfused canine liver. The results obtained differ in some respects from the rather confficting observations of other workers (Bauer, Dale, Poulsson & Richards, 1932; Chakravarti & Tripod, 1940; McMichael, 1932). It is believed that some of these differences can be accounted for by an improved perfusion technique whereby the period of anoxia to which the organ is subjected during preparation is reduced to a minimum and also by the fact that the perfusions were carried out with blood taken from the same animal.

The action of adrenaline, noradrenaline, acetylcholine and histamine on the perfused liver of the monkey, cat and rabbit.

In an earlier paper (Andrews, Hecker, Maegraith & Ritchie, 1955) we described the actions of adrenaline, noradrenaline, acetylcholine and histamine on the perfused canine liver. In this paper we record briefly a study of the action of the same substances on the livers of the monkey, cat and rabbit. The work has been carried out in order to assess differences in the reactions of the hepatic vessels of these mammals. We were especially interested in the part played by the hepatic veins in the control of liver blood flow.

The induction of amoebic liver abscesses in hamsters by the intraperitoneal inoculation of trophozoites of Entamoeba histolytica.

(1962). The Induction of Amoebic Liver Abscesses in Hamsters by the Intraperitoneal Inoculation of Trophozoites of Entamoeba Histolytica. Annals of Tropical Medicine & Parasitology: Vol. 56, No. 2, pp. 248-254.

Liver involvement in acute mammalian malaria with special reference to Plasmodium knowlesi malaria.

Publisher Summary This chapter concerns mainly with pathogenesis reactions in simian and to some extent in human and rodent malarias. The pathological and physiological disturbances in malaria vary considerably in severity and duration according to the infecting Plasmodium and the host. The processes involved have so far been most carefully studied in P . knowlesi infections in rhesus monkeys (Macaca mulatta). Discussion of the pathogenesis of the liver lesions in malaria must take into account all mechanisms that are responsible for functional and structural disturbances in the organ arising from non-specific reactions, and those that can be attributable more directly to the infection itself. The effects of the latter are frequently also non-specific because a given tissue can react in only a limited number of ways. An example of the first type of reaction in the liver in malaria is the response to the hyperactivity of the sympathetic nervous system initiated by the infection The second type of reaction is exemplified by the histotoxic activity of certain factors, to be discussed later, circulating in the blood of the infected host which cause fatty degeneration of parenchymal cells and inhibit mitochondria1 oxidative phosphorylation.

Ultrastructural localisation of NADH- and NADPH-dehydrogenases in the erythrocytic stages of the rodent malaria parasite, Plasmodium berghei

Abstract i) NADH- and NADPH-dehydrogenase activity was localised mainly on the concentric-membraned organelles, and to a lesser extent on the limiting membrane, food vacuole membrane and nuclear membrane of erythrocytic trophozoites of P. berghei . ii) NADH-dehydrogenase activity was present in larger amounts in the parasites than NADPH-dehydrogenase. iii) The significance of these enzymes in relation to parasite metabolism is discussed in the light of present knowledge.

Studies in Ancylostoma caninum infection in dogs. II. Anatomical changes in the gastrointestinal tract.

(1972). Studies in Ancylostoma caninum infection in dogs. Annals of Tropical Medicine & Parasitology: Vol. 66, No. 1, pp. 107-128.

History of the Liverpool School of Tropical Medicine.

I AM often asked why there should be a tropical school in Liverpool and whether there is a place for such a school in the modem developing world. The simplest way of answering these questions is to sketch the history of the school. In my view history includes the present as well as the past and in this case should deal with the philosophy of the school as well as the people who have served in it. I shall attempt to deal superficially with the history of the Liverpool School in this way. The first question is-Why have a tropical school in Liverpool? The factual answer is, of course, that the school was founded in Liverpool. The first of its kind in the world, it was started at the height of the Colonial Empire, when streams of doctors were going from England to the tropical colonial empire to practise clinical medicine and to deal with indigenous problems of public health. (I separate clinical medicine and health at this stage because this was the unfortunate habit in colonial administration.) At the time the school was created the British Empire needed large numbers of doctors skilled in the specific disciplines of the tropics, but had not provided any central facilities for training them. It was not until 1898 that the British Government realized for the first time that it was sending untrained doctors to work in the colonies. There was no place in Britain which was dedicated to the necessary disciplines and there was no specific reference to them included in the medical curriculum, apart from the elementary parasitology. Moreover, there were no opportunities offered for refresher courses for those returning on leave. Doctors who went to tropical colonies had to learn the hard way by long experience. This reduced their immediate efficiency and generally lowered the standard of their work. Pressed by Manson, who had become Medical Adviser to the Colonial Office, Joseph Chamberlain, then Secretary of State for the Colonial Office, wrote a letter to the General Medical Council and to the main medical schools suggesting that adequate emphasis should be given in the ordinary medical curriculum to tropical medicine and related subjects, in order to help the many doctors who would subsequently go overseas. The G.M.C. replied, as might be expected, that it agreed in principle with the need for such training but no action was forthcoming, as the medical schools clearly considered there was no need to change existing teaching programmes for the sake of a relatively small minority who would eventually learn their tropical medicine in the tropics. Chamberlain then addressed a letter to the Governors of all Colonies, pointing out the great mortality and morbidity arising from endemic tropical diseases such

The Metabolism of the Malaria Parasite and its Host

Publisher Summary This chapter discusses considerations that are necessary in the metabolic investigations of Plasmodia. It discusses some current research trends that seem to advance the knowledge of fundamental biochemical processes occurring in parasites and are involved in the host–parasite relationship. The pentose phosphate pathway (PPP) for which the malaria parasite could have an absolute requirement is probably the principal pathway for the production of pentose sugars necessary for nucleic acid synthesis. There is now evidence that the most of the malaria parasites studied up to the present are dependent on the glucose-6-phosphate dehydrogenase (G-CPD), the initial enzyme of the PPP, the parasites being unlikely to thrive in enzyme-deficient cells and thus unable to produce an overwhelming infection. Further metabolism remains enigmatical, but current trends in research with mammalian species are discussed. Other topics considered are carbon dioxide fixation by malaria parasites, aerobic mechanisms, and the metabolism of chloroquine-resistant malaria parasites. The chapter also considers the metabolism of the host during infection—namely, biological changes in erythrocytes—the effects of acute infection on host–tissue metabolism and host–lipid metabolism. Such studies are enabling some advances to be made in an understanding of the pathological process involved in malaria.