TOC Helsinki Proceedings (2003 Papyrological Congress)

Relatively Recent dissertations

"Hellenica Oxyrhynchia": Text and translation. State of the question. Historical commentary
by Lerida Lafarga, Roberto, Dr., Universidad de Zaragoza (Spain), 2006, 827 pages; AAT 3257518

The aural "Iliad": Alexandrian performances of an archaic text
by Mitchell, Jack George, Ph.D., Stanford University, 2006, 285 pages
CV at Holy Cross

Materia magica: The archaeology of magic in Roman Egypt, Cyprus, and Spain
by Wilburn, Andrew T., Ph.D., University of Michigan, 2005, 294 pages.

Social networks in Byzantine Egypt
by Ruffini, Giovanni Roberto, Ph.D., Columbia University, 2005, 391 pages.

Traveling the desert edge: The Ptolemaic roadways and regional economy of Egypt's Eastern Desert in the fourth through first centuries BCE
by Gates, Jennifer Erin, Ph.D., University of Michigan, 2005, 393 pages.

Access to law in Late Antiquity: Status, corruption, and the evidence of the "Codex Hermogenianus"
by Connolly, Serena Dawn, Ph.D., Yale University, 2004, 406 pages.

Simonides on the Persian Wars: A study of the elegiac verses of the "new Simonides"
by Kowerski, Lawrence Melvin, III, Ph.D., Rutgers The State University of New Jersey - New Brunswick, 2003.

Church finances from Constantine to Justinian, 312--565 C.E
by Serfass, Adam, Ph.D., Stanford University, 2002, 189 pages.

Fragments from Oxyrhynchus: A case study in early Christian identity
by Luijendijk, Anna Adrienne Marianne (AnneMarie), Th.D., Harvard University, 2005, 324 pages.
forthcoming with Harvard UP

Actresses in the Roman world
by Starks, John H., Jr., Ph.D., The University of North Carolina at Chapel Hill, 2004, 463 pages.

A grammatical analysis of the late Demotic tale Setne II (papyrus BM EA 10822)
by Woods, Andreas, Ph.D., Brown University, 2006, 279 pages.

Literary papyri from the University of Utah Arabic papyrus and paper collection
by Malczycki, William Matthews, Ph.D., The University of Utah, 2006, 255 pages.

The Demotic drama of Horus and Seth (P. Berlin 8278a, b, c; 15662; 15677; 15818; 23536; 23537a, b, c, d, e, f, g)
by Gaudard, Francois P., Ph.D., The University of Chicago, 2005, 481 pages.

Ancient angels: Hellenic angel veneration and Christian reaction (ca. 200--450 C.E.)
by Cline, Rangar H., Ph.D., The Pennsylvania State University, 2005, 215 pages; AAT 3204854

Keeping the imperial peace: Public order, state control and policing in the Roman Empire during the first three centuries AD
byFuhrmann, Christopher J., Ph.D., The University of North Carolina at Chapel Hill, 2005, 321 pages

Studies in the reception of Menander in antiquity
by Nervegna, Sebastiana Giuseppina, Ph.D., University of Toronto (Canada), 2005, 183 pages

Source: ProQuest (not subscribed to at my institution) search by Chuck Jones , for which, heartfelt thanks

SALOMONS and WORP Onomasticon Hibiticum (Khargeh Oasis)

ONOMASTICON HIBITICUM:
AN ONOMASTICON OF PERSONAL NAMES
found in the
KHARGEH OASIS
compiled by
R.P. Salomons Radboud University, Nijmegen) and K.A. Worp (Leiden University)


In the Avertissement (p.vii) to his well known study Les Oasis d’ Égypte (Cairo
1987), and on many pages elsewhere in this volume, the late Guy Wagner alludes to an exhaustive
prosopography of the Great Oasis, compiled by himself but unfortunately for financial reasons
not incorporated in Les Oasis. However, a separate publication of this prosopography, as
announced in the Avertissement, did not appear either. Therefore, the need for such a
prosopography remained unfulfilled.

The idea of composing a new onomasticon of the Dakhleh Oasis, or an
Onomasticon Mothiticum as we wish to call it, was born independently during the 5th Dakhleh
Oasis Project conference held in Cairo, June 2006, where Worp gave a paper on Christian names
in fourth century documents from Kellis. An additional incentive for compiling such an
onomasticon was the consideration that Worp himself had already published a substantial number
of documentary papyri, ostraka and wooden tablets from this area ( in particular in P.Kellis, vol.
I, and in O.Kellis). It was, therefore, only a matter of merging his various indices nominum and
adding names of persons from the Dakleh oasis figuring in papyri and ostraka already published
elsewhere. This activity involved collecting the relevant texts from, e.g., the list given by Wagner
in the introduction to his Les Oasis, pp. 3- 6, and a search in the Heidelberger Gesamtverzeichnis
for ‘Ort = Grosse Oase’). Moreover, our colleague R.S. Bagnall kindly made the digital file of his
own index nominum for P.Kellis IV available to Worp.

Source: Papy-L

Nobel Laureate: Charles Louis Alphonse Laveran

 
 
The Nobel Prize in Physiology or Medicine 1907.

"in recognition of his work on the role played by protozoa in causing diseases"

Charles Louis Alphonse Laveran (1845 - 1922) received the Nobel Prize in Physiology or Medicine for discovering that malaria was caused by a protozoan that infects red blood cells. There are many who believe that Laveran should have been recognized before Ronald Ross who received the Nobel Prize in 1902 [Nobel Laureate: Ronald Ross]. The Malaria Site has a very nice description of Laveran and his work [Charles Louis Alphonse Laveran].

The presentation speech was supposed to have been given by Professor C. Sundberg of the Royal Caroline Institute on December 10, 1907 but owing to the death of of King Oscar II two days earlier, the award ceremonies for 1907 were canceled. The text was published.

The Staff of Professors at the Caroline Institute have this year awarded the Nobel Prize for Medicine to Dr. Charles Louis Alphonse Laveran, for his work on the importance of the protozoa as pathogens.

The Staff has thus chosen to single him out not only as the founder of medical protozoology, a branch of medicine that has reached a striking level of development in recent years; but also as the man responsible for experiments and discoveries - followed up until recently - which ensure his continued pre-eminence in this field.

To appreciate properly the importance of Laveran's investigations into the protozoan causes of disease, one must remember the state of this branch of science at the time of Laveran's earliest work, i.e. about 1880. The body of knowledge relating to the causes of infectious diseases was making rapid progress at that time in the field of bacteriology. Pasteur's «Theory of Germs» had provided the key to the riddle of fermentation processes, and its relevance to infectious diseases had been grasped. So several pathogenic bacteria had been discovered by 1880: those of anthrax and relapsing fever; other germs, such as those causing tuberculosis, glanders, pneumonia, typhoid fever, diphtheria, tetanus, Asiatic cholera, traumatic fevers, etc. were discovered one after another during the years 1880-90. All these germs were found to belong to the last category of the plant kingdom, the bacteria.

As a result, it was natural to look for the cause of marsh fevers, like malaria, among micro-organisms of that sort. Indeed, several distinguished bacteriologists believed themselves to be on the trail of such a microbe. We recall the so-called malaria bacillus of Klebs and Tommasi-Crudeli, found in the ooze of the Pontine Marshes.

When Laveran, in 1879, began his research at the military hospital of Bône in Algeria, he only set himself the task of explaining the role of the particles of black pigment found in the blood of people suffering from malaria. After 1850, when these particles, called melanins, were discovered, methods had been discussed of determining whether they were only to be found in patients suffering from malaria, or were present in other diseases as well. Laveran first set about solving this problem, which was particularly important to the diagnosis of malaria. During his investigations, Laveran not only found the particles he had been looking for: he also found some entirely unknown bodies with certain characteristics which led him to suppose that parasites were involved. His initial investigations were carried out on fresh blood without using chemical reactions or any staining process. He was none the less successful, using this primitive method of examination, in distinguishing and describing most of the more important forms adopted by these new bodies, which varied so much in their appearance. In 1882, he moved the scene of his investigations for a while to the dangerous marshy regions of Italy. There he again found the same bodies in the blood of people suffering from marsh fever, and his hope of having found the malarial parasite became a certainty. Laveran published his first great work on these parasites, Traité des fièvres palustres, in 1884. In this, he draws on 480 examined cases of malaria.

This work is the foundation on which subsequent investigations of marsh fever are based. Laveran showed that the parasites, during their development in the red blood corpuscles, destroy them; and the red pigment in the corpuscles is changed into the melanin particles mentioned above. He described all the main forms of this polymorphic parasite, even those which have subsequently been found to be different developmental phases of the parasite. Continuing his work, Laveran concerned himself in the first place with the important problem of the existence of these parasites outside the patient's body. To this end he examined the water, soil, and air of the marshlands, hoping to find the parasite. His perseverance was unrewarded. We should not, however, fail to recognize the merit of this work, despite its negative outcome, since it has fundamentally aided subsequent research. As far as Laveran was concerned, these apparently fruitless investigations led him to the conclusions which he expresses in the book of 1884, and has also maintained on a number of occasions, such as the Congress of Hygiene at Budapest (1894): that the marsh-fever parasite must undergo one phase of its development in mosquitoes, and be inoculated into humans by their bites. Laveran based his conclusion not only on the negative experiments already mentioned, but also on an analogy with the mode of transmission of the Filaria worm, which, according to Manson, is mosquito-borne. When Laveran was recalled from Algeria to Paris, and so forced to interrupt his work on malaria, he had already clearly formulated the problems that had first to be solved in this field.

The new parasite discovered by Laveran was not a bacterium. Although it was impossible to classify accurately, certain resemblances to other micro-organisms put it in the same group as the protozoa. We know how difficult it is to demonstrate the presence of malarial parasites in blood which has not been treated beforehand with the stains now in general use, but still unknown at the time of Laveran's discoveries, which make these small parasites more readily visible; so one can appreciate at their true value the insight and keen eye of Laveran, who never allowed himself to be misled by the simultaneous successes of bacteriology, or discouraged by the opposition met with from several quarters, notably from workers studying marsh fever.

However, little by little Laveran's theories made headway, and it can be said that the year 1889 marks the date when his discovery finally achieved recognition.

When Laveran had to leave the marshlands, he saw himself deprived of materials indispensable if he were to continue working on the still unanswered questions, i.e. those dealing with the parasite's developmental cycle, and its existence away from the patient. He then tried to solve them by an indirect approach, by studying animal parasites, especially those of birds: these parasites had only recently been discovered and showed resemblances to the malarial parasites. The numerous observations Laveran made in the course of this research cannot be indicated here: they belong by rights to the specialist sphere of interest. Now, as always happens after a notable discovery, workers multiplied in the new field. Some of the many workers who were able to continue Laveran's work on the spot, in marshy areas, were destined to reach the goal before Laveran by the indirect approach which he had indicated. Thus, in 1897 the American Mac Callum elucidated the sexual reproduction of these parasites; and, in 1898, the impressive work of Ronald Ross, the Nobel Prize winner for 1902, brought the mosquito theory from the realm of hypothesis into that of established fact. One can imagine the interest with which Laveran must have received the preparations sent to him by Ross from India in May 1898, and the joy with which he confirmed that Ross was in fact dealing with malaria parasites in the mosquitoes he was investigating.

Laveran's discoveries concerning malaria had the additional effect of focussing direct and vigorous attention on the hypothesis that other infectious diseases could be brought about similarly by protozoa. In the tropics especially, but in other areas as well, diseases have been recognized for a long time among men and animals, which are similar to malaria in many respects, such as impoverishment of the blood, loss of strength, and associated fever, but which, unlike malaria, are not affected by the classical treatment, quinine, and are clearly shown by the absence of marsh-fever parasites not to belong to the same group as the marsh sicknesses. Since 1890 a whole series of parasites causing these diseases has been described. Once, thanks to Laveran, attention was drawn to the protozoa as agents of disease, discoveries of such protozoa took place in rapid succession. Among diseases due to protozoa, the trypanosomiases take precedence. The list of these diseases alone is long, and we will mention only the scourges known as Nagana, Surra, Caderas sickness, and the Galziekte of Equatorial Africa, etc. which ravage large parts of Africa, Asia and South America, attacking various members of the Bovidae, horses, camels, donkeys, etc. as well as the big game, antelopes, deer, etc. sometimes wiping out great herds. All these infections are caused by corkscrew-shaped micro-parasites, called trypanosomes, and are transmitted to animals by various types of biting flies. However important these diseases may be to Man from the point of view of commerce and nutrition, yet, among all the trypanosomiases, the endemic disease generally known as «sleeping-sickness» takes precedence from the medical point of view. The sleeping-sickness trypanosome was discovered in 1901 by Forde in a European ship's captain who had navigated the river Gambia for several years. Forde does not seem to have examined the parasite in detail. Later, the same case was studied by Dutton, and following on his reports on the parasite and the disease, an expedition was sent from Liverpool and London to carry the investigation further. This expedition also solved the first problems relating to the disease. There is certainly much one could say about these diseases; unfortunately we may not dwell on them here. Let us rather take a quick look at the part played by Laveran in the elucidation of these problems.

It can be said, it seems to us, that Laveran took up these problems again at the exact point where circumstances had forced him to interrupt his own research on malaria. He had discovered the parasites for the latter group of diseases, but others, notably Golgi and Ross, followed up the biological investigation of the parasites. As far as the trypanosomiases are concerned, the opposite holds good: the parasites were discovered by other investigators, who were able to study the investigations on the spot in a number of different places, but Laveran, more than anyone else, extended our understanding of the finer points of the morphology, biology, and pathological activity of the parasites. He made this work possible by having many artificially-infected experimental animals brought to his Paris laboratory, as well as larger animals which had contracted the disease naturally. Not content with this great quantity of material, he extended the scope of his investigations even further by studying the trypanosomes of rats, birds, fishes and reptiles; and these investigations often threw light on the true pathogenic trypanosomes at the same time. The trypanosomes thus studied and described by Laveran number about thirty; he discovered a greater number of new species than any other worker we know of. In addition, he discovered a new genus of trypanosomes, the trypanoplasmias.

Laveran published his discoveries, sometimes in collaboration with other workers, in many articles and annotations, and later, in 1904, he gathered them together in one great work, so far unique of its kind: Les trypanosomes et trypanosomiasis.

Still more recently, in 1906, there appeared the accounts of his research on the parasites causing the malignant Mbori, Souma, and Baléri diseases, which are widespread among the Bovidae, camels and horses of the Upper Niger.

It is obviously impossible to compress into a few words the rich content of all his writings, his investigations, and his numerous discoveries. In them we find technical inventions for the study of parasites, morphology, theories of infection, accounts of parasite reproduction, experiments in immunization, etc. These works are proof that the creator of protozoan pathology continues to be its leading authority. For these reasons and many others that could be added, the Staff of Professors of the Caroline Institute have pleasure in awarding this year's Nobel Prize to this pioneer of science, this tireless benefactor of humanity.

Nobel Laureate: Ronald Ross

 
 
The Nobel Prize in Physiology or Medicine 1902.

"for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it"

Ronald Ross (1857 - 1932) received the Nobel Prize in Physiology or Medicine for discovering that the malaria parasite was transmitted by mosquitoes. You can read a detailed description of Ross' work on The Malaria Site [Sir Ronald Ross]. He was a remarkable man.

This Nobel Prize—only the second one to be awarded—was controversial. Read the presentation speech by Professor the Count K.A.H. Mörner of the Royal Caroline Institute below and note the mention of several other workers, including Patrick Manson, Ross' mentor, and Alphonse Laveran, who discovered the malaria parasite. There are many who believe that Manson and Laveran should have received part of the prize. Laveran was recognized five years later when he received his own Nobel Prize [Nobel Laureate: Laveran].

Your Majesty, Your Royal Highnesses, Ladies and Gentlemen.

Among the stipulations Alfred Nobel set forth in his will, on which the Nobel Foundation is based, that concerning the international character of the prizes occupies an important place. This proves not only his love of mankind and his wish that we should regard one another as brethren, but it is also a witness of his extensive and prescient views more especially concerning medical science and its advancement.

All the branches of medical science and their promotors in different countries have the same ultimate aim, that of gaining the most thorough knowledge possible both about the human body and the processes in it, as also about noxious influences and the means of their prevention. All medical workers unite in pursuing that aim and in doing so feel members of one great fellowship. Nevertheless, the different fields of medical science lie at such a distance one from another, that the individual worker on many occasions must look afar in the attempt to get a thorough view of the progress of the work.

With respect to diseases they are often of different kinds and import in divers regions of the world. For instance, malaria is nowadays of little importance here in Sweden, whereas it is a veritable scourge in other regions. For elucidating this question by an instance from a European country, it may be mentioned that in Italy of late the annual average of deaths by malaria has been about 15,000, and the yearly number of cases is calculated as about two millions. Still more overwhelming are the numbers from India. Of the British Army, amounting to about 178,000 men, close upon 76,000 men were admitted into hospital for malarial fever in the year 1897. In this single year the mortality from «fever» among the civil population in India amounted to a total of more than five millions. It is moreover a well-known fact, that malaria dominates so severely in vast territories that it causes the very greatest difficulties for the cultivation of countries which, but for the malaria, are specially favoured by Nature.

The question of the real nature of malaria, its origin, its manner of entering the organism, and the consequent question of the possibility of preventing this disease, are all of the greatest importance and have from remote ages occupied investigators, for a long time without success.

A very important discovery concerning malaria was made - now long ago, more than two decades - when Laveran, a French army surgeon, ascertained, that malaria is a parasitic disease, caused by a very low form of animal life, that he found in the blood of malarious patients. By this discovery the name of Laveran has for ever become renowned in the history of malaria.

Research about malaria in the last two decades has chiefly been based on Laveran's discovery. Science has thereby been enriched with many an important fact. We have gained knowledge of the different forms of the malarial parasite in blood. We have found, that it differs in the special forms of the disease. We have learned the relations between the parasite and the red blood corpuscles, in which it is chiefly to be found. We have furthermore been able to survey the manner in which it multiplies in the blood; the Italian investigator Golgi has in this respect revealed the remarkable fact that the periodicity of the malarial attacks depends on the appearance of new generations of the parasite in the blood. We have moreover found allied parasites in the blood of several mammals and birds.

The important question, previously mentioned, as to the possibility of the malarial parasite living outside the body, and its way of obtaining entrance into the blood remained unanswered. For some reasons, among others owing to various facts that were known concerning other parasites of an animal nature, it was supposed that the malarial parasite in some way leaves the blood so as to exist in some form in nature, probably as a parasite of some other being. As nothing indicated that the parasite was to be found in the secretions or excretions, the supposition lay near at hand, that suctorial insects would assist in carrying the parasite to a place, where it had to pass the aforementioned part of its life-cycle. Attention was therefore directed to the mosquito, which was thus supposed to spread the malarious infection. The importance of the mosquito in this respect has now been proved. In this case, as in several others, tradition anticipated science; it is even said, that negroes in the East-Africa use the same name for the mosquito and for malaria.

The mosquito theory of malaria was introduced to science by King no less than 18 years ago. The theory, however, remained a conjecture without other evidence than some suggestions given by epidemiological observations. The attempts made in Italy in the early nineties with the view of examining the theory experimentally, and, eventually, proving it to be true, gave results that seemed anything but encouraging; being far more likely to prevent the investigators from following this line.

A person we deem of great merit concerning the solution of the problem is the English investigator, Patrick Manson. It was a change in the appearance of the parasite, which was sometimes observed to occur, as the blood is shed, that Manson especially regarded as the first stage of its life outside the body. This phenomenon has afterwards been shown by the American pathologist Mac Callum to imply an act of reproduction of the parasite. Manson was moreover guided by his experience regarding another parasite of the blood, a little worm, filaria, the transference of which from one part of its life-cycle to another he had found effected by the mosquito, and more particularly by special species of the mosquito. By his views set forth on malaria, and by exciting expectation that the solution of the malaria problem was to be found in the direction he indicated, Manson gave an impulse to the further testing of the mosquito-theory and at last to its being established. Manson, who lived in England, had no opportunity of taking up the experimental work of the problem. The solution came from India.

It was an English army surgeon in India, Ronald Ross, who, impressed by Manson's induction, undertook the experimental testing of the matter. Critically arranging his experiments, he caused mosquitoes that were hatched from larvae in the laboratory, to bite malarious patients, and endeavoured to follow the parasite in the body of the mosquitoes. The results of the first two years' labour, although assiduous and scrupulous, gave little promise of success. But in August 1897 all at once he made vast progress towards his aim. While experimenting with another, less common species of mosquito, in the wall of its stomach he found bodies that very probably were an evolutionary stage of the human malarial parasite.

Ross, being prevented by circumstances from pursuing his plan in studying the malarial parasite of man, continued his work with an allied malarial parasite of birds. The result was that not only could he confirm his discovery concerning human malaria, as he found corresponding facts for avian malaria, but he also in a short time succeeded in revealing the further development of the avian malarial parasite in the body of the mosquito.

This development is briefly as follows. In the stomach of the mosquito a process of fecundation at first takes place; the form of the parasite, thereby produced, penetrates the stomach wall, embedded in which it grows to button-like structures projecting into the body-cavity. In these structures a large number of elongated organisms, «sporozoites», are formed. On the consequent bursting of the said structures the «sporozoites» escape into the general body-cavity of the mosquito, and accumulate in the salivary or poison glands, which are in connection with the proboscis with which the bites of the insect are inflicted. A bite of the mosquito, at that time, inoculates the parasite, and if the individual is susceptible to the parasite, this develops in the manner known and described long ago.

Ross's discoveries into malaria were immediately followed by a series of important works.

Thus the Italian investigator, Grassi, in association with his colleagues, Bignami and Bastianelli, proved that the human malarial parasite not only in its early stage, already detected by Ross, but also in its further development undergoes the same evolution that Ross described for the growth of the avian malarial parasite in the body of the mosquito. Grassi also has precisely indicated the species of mosquito that are of import for the malaria of man. Many valuable works, besides these, have been issued by Ross, by the Italian investigators, by Robert Koch and by many others, works, by which not only our knowledge of the malarial parasite has been enlarged, but this knowledge has been made useful in combating and preventing malarial disease.

The eminent scientific value of Ross's work, its importance as a basis for the success of the recent investigations into malaria, its rich contents as regards the art of medical practice and especially hygiene, will be obvious from the above.

It is owing to these merits, that the Professorial Staff of the Royal Caroline Institute has decided to allot the Medical Nobel Prize of this year to Ronald Ross.

Professor Ronald Ross. In announcing that the Professorial Staff of the Royal Caroline Institute has decided to award to you the Medical Nobel Prize of this year on account of your work on malaria, in the name of the said Institute I congratulate you on your investigations. By your discoveries you have revealed the mysteries of malaria. You have enriched science with facts of great biological interest and of the very greatest medical importance. You have founded the work of preventing malaria, this veritable scourge of many countries.

Plasmodium falciparum Causes Malaria

 
Malaria is caused by a small protozoan parasite called Plasmodium falciparum (left). The Plasmodium is a single-celled organism with a complex life cycle. It is classified in the nebulous Protist kingdom within the phylum Apicomplexa [NCBI Taxonomy].

The life cycle is described in many places but one of the best comes from the Applied Biosystems website.

Human malaria is caused by infection with intracellular protozoan parasites of the genus Plasmodium that are transmitted by Anopheles mosquitoes. Four species of Plasmodium infect humans: P. falciparum, P. vivax, P. ovale, and P. malariae, with P. falciparum accounting for the majority of infections and being the most lethal. The causative agent of malaria was discovered in 1880 by Charles Alphonse Louis Laveran (Ref.1).

Plasmodium falciparum is exclusively transmitted by female Anopheles mosquitoes, mainly from members of the Anopheles gambiae complex. The parasites have a complicated life cycle that requires a vertebrate host for the asexual cycle and a female Anopheles mosquito for completion of the sexual cycle. Infection of humans by P. falciparum is initiated by injection of sporozoites into the bloodstream by an Anopheles mosquito (Ref.2). During a mosquito blood meal,infectious Sporozoites in the mosquito's saliva enter the host bloodstream and invade its hepatocytes. While some evidence indicates that Sporozoites are first trapped by Kupffer cells and then transported to hepatocytes,other findings suggest that Sporozoites home to hepatocytes directly. Sporozoite reaches liver via bloodstream in 30 minutes....

In the hepatocytes asexual multiplication (exoerythrocytic schizogony) occurs, leading to the production of several thousand merozoites. In 1 to 2 weeks, a single sporozoite can give rise to 30,000 merozoites. During this pre-erythrocytic stage,no illness is induced by malaria. In P. vivax infections, which are characterized by relapses,a dormant stage, called the hypnozoite, remains in the liver. From this stage relapsing infections may occur at a later stage. P. falciparum infection relapses do not occur. It is, therefore, assumed that the sporozoites of this species develop uniformly producing pre-erythocytic schizonts at the same time and these schizonts, once formed,discharge all the merozoites simultaneously; do not remain dormant as in P. vivax (Ref.3).


These Merozoites are released into the bloodstream and invade erythrocytes. The asexual erythrocytic cycle begins when a single merozoite invades a host red blood cell and is enclosed within a parasitophorous vacuole,separate from the host cell cytoplasm. Three morphologically distinct phases are then observed. The ring stage,lasting approximately 24 h in P. falciparum, accounts for about half of the intraerythrocytic cycle, but it is metabolically nondescript. It is followed by the trophozoite stage; a very active period during which most of the red blood cells cytoplasm is consumed. Finally,parasites undergo 4-5 rounds of binary divisions during the schizont stage, producing 8-36 new merozoites that burst from the host cell to invade new erythrocytes,beginning another round of infection. This phase of the infection (erythrocytic schizogony) is responsible for malaria pathogenesis. Much of the morbidity and mortality associated with malaria is caused by the rupture of iRBCs (Infected Red Blood Cells) during the asexual reproductive stages of the parasite. Intense fever, occurring in 24-72 hour intervals, is accompanied by nausea, headaches,and muscular pain among other symptoms. The characteristic fever spike has been correlated with incremental rises in serum levels of TNF-Alpha associated with the release of parasite proteins during erythrocytic rupture. Furthermore,a variety of potentially fatal symptoms,including liver failure, renal failure,and cerebral disease are associated with untreated P. falciparum. These symptoms are consequences of the unique ability of the parasite to bind to endothelial surfaces; this adherence inhibits circulation and causes localized oxygen-deprivation and sometimes hemorrhaging. It has been proposed that ICAM1 (Intercellular Adhesion Molecule-1), E-selectin,VCAM1 (Vascular Cell Adhesion Molecule-1), and CSA (Chondroitin Sulfate-A), and CD36 are some of the surface molecules responsible for parasite-endothelial adherence (Ref.4).

Instead of producing new schizonts, some merozoites, after invasion of the erythrocyte, arrest their cell cycle and develop into male (micro) or female (macro) gametocytes, the forms that are required for transmission to the mosquito (asexual parasites do not survive ingestion by the insect). Inside the mid-gut of the mosquito, fertilization occurs, producing zygotes, which develop into ookinetes. The ookinetes form oocysts, which then grow and divide and rupture to give rise to sporozoites, which migrate to the salivary glands. Then the infectious cycle of malaria can repeat itself (Ref.5). While all four species of Plasmodium have a haemolytic component ie. when a new brood of parasites break out of the red blood cell this is usually of little consequence. The exception is falciparum malaria where the parasites multiply very rapidly and may occupy 30% or more of the red blood cells causing a very significant level of haemolysis. One reason for this is that P. falciparum invades red cells of all ages whereas P. vivax and P. ovale prefer younger red cells, while P. malariae seeks mature red cells. Malaria places an increasing burden on global public health resources. In the face of growing resistance of the malaria parasite to available antimalarial drugs, there is a need for new drugs and the identification of new chemotherapeutic targets (Ref.6).

---

Image Credits:

Plasmodium falciparum, the parasite that causes malaria in humans, needs a living host in …. [Photograph]. Retrieved July 25, 2007, from Encyclopædia Britannica Online: http://www.britannica.com/ebc/art-55545

Life Cycle diagram is from Don Forsdyke.

The red blood cell image is from The Scripps Research Institute.

Quinine and Malaria

 
Monday's Molecule #36 was quinine, an alkaloid isolated from the bark of Chichona, or quinine tree [Cinchona pubescens]. The tree originally grew only on the eastern slopes of the Andes in South America where the bark was widely used by the natives to prevent malaria and other diseases. Following the discovery of its amazing properties by Europeans, it was transported to other tropical parts of the world.

Quinine works by attacking the parasite that causes malaria. This protozoan parasite, Plasmodium falciparum, feeds on red blood cells. It can easily digest hemoglobin but can't handle the heme groups that are released when the protein is degraded. These heme groups are toxic to the parasite so they are stored in an inactive form inside a membrane-bound organelle called a digestive vacuole. Quinine interferes with this storage causing the hemes to remain free where they poison the cell. The exact mechanism is unknown but it is known that quinine has to enter the vacuole in order to be effective. The most likely mechanism is quinine binding to the heme molecule to prevent its conversion to the inactive form celled haemozoin.

Resistance to quinine and related compounds is usually due to mutations in transporter proteins that are found in the membranes of the digestive vacuole. The mutations prevent the accumulation of quinine in the vacuole.

Quinine is present in tonic water that was widely consumed in the last century to ward off malaria. The quinine imparts a bitter taste to tonic water so, as the story goes, British tourists used to dilute it with gin to hide the taste. The gin & tonic mixture became quire popular.

As a matter of fact, quinine is still present in modern bottles of tonic water. This can be easily demonstrated by shining ultraviolet light on a bottle of tonic water since quinine is fluorescent (left). To see how much quinine you get in a gin & tonic see [The Half-Decent Phamaceutical Chemistry Blog].

Quinine was synthesized after World War II but it isn't economical to make the drug and the only effective source is the bark of Chichona. However, a more effective drug called chloroquine (below) became widely available after World War II and it has mostly replaced quinine as the preferred drug against malaria.