Created S.P. James and P.G. Shute, Report on the First Results of Laboratory Work on Malaria in England (Geneva: League of Nations Health Organization, 1926).
1926

Created S.P. James et. al., 'Discussion: Observations on malaria made during treatment of general paralysis [Yorke and Macfie],' Transactions of the Royal Society of Tropical Medicine and Hygiene 18 (1-2) (1924), pp. 33-44.
1924

Created S.P. James, 'Epidemiological Results of a Laboratory Study of Malaria in England,' Transactions of the Royal Society of Tropical Medicine and Hygiene 20 (3) (1926), pp. 143-165.
1926
Description:

'The official arrangement in England, by which general paralysis and other mental diseases can be treated with malaria, is an arrangement for inducing the malarial attacks by the bites of infected mosquitoes instead of by direct blood inoculation. I shall only mention one of several essential reasons which led to that decision. This reason will be plain to everyone who examines the stereophotomicrograph No.4, which Dr. CLARKE, Medical Superintendent, Lancashire County Hospital, Whittingham, has kindly lent for demonstration this evening. It shows specimens of the syphilis spirochaete in the aorta of a patient suffering from general paralysis. Obviously it would be indefensible to inoculate the blood of that patient into other patients.

Effects of Malaria on General Paralysis.

Mention of that specimen leads me to speak next of a subject to which some of the other exhibits have reference, namely, the results at present available of the efficacy of the malarial treatment in cases of general paralysis. Here is a statement relating to 821 cases of general paralysis treated by malaria in all institutions for the insane in England and, for comparison, a statement of 400 cases treated in Vienna. It is a curious coincidence that the percentages of 

[table: 'Results of Malaria Treatment of General Paralysls. All Institutions for the Insane, England and Wales. Cases of General Paralysis treated by Malaria.']

"some success" and "no success," namely 48 percent. in the first category, and 52 percent. in the second, are the same in both statements. Of the 821 cases treated in England, 10 percent. were classified as "recovered." That is a low figure, but it must be remembered that the patients in public mental hospitals in England are nearly all in anadvanced stage of the disease, and that practically no selection of cases for treatment was made. Dr. GREENWOOD has suggested to me that a comparison of the average duration of life of treated and untreated general paralytic patients, respectively, would be the most satisfactory statistical method of estimating the value of the treatment. Working, by life table methods, on published statistics of admissions and deaths of untreated general paralysis cases in Holland, he has ascertained that of general paralysis patients admitted to institutions, about 40 percent. may be expected to have died within one year, and about 60 percent. within two years. He suggests that these figures might be used as a standard with which the average duration of life of patients treated by malaria could be compared.

It would be most satisfactory, of course, if the criterion of success or failure could be based on microscopical and bacteriological grounds. Does the malaria treatment kill the spirochaetes in the brain and does it cause the characteristic reactions of the cerebrospinal fluid to disappear? Up to the present the results reported by different observers on these matters are not uniform. In Vienna complete failure to find spirochaetes in the brain tissue of treated patients who have afterwards died from an intercurrent disease has been reported. In England the results are different. In this connection Dr. CLARKE has kindly lent slides Nos. 12 and 14, which are put out this evening. No. 12 is from a general paralytic patient whose history is as follows:-

Inoculated with malaria, 13th September, 1923. Developed the disease 20th September, but his condition was so feeble that quinine was given after one rigor. He improved, and was reinoculated on 23rd October, 1923. Parasites were present 5th November, and he was allowed to have ten rigors before quinine was given. He showed no mental, and only slight physical improvement, and a year later began to have general paralytic seizures. He died in December, 1925. You will see that the sections of his brain tissue contain numerous spirochaetes. Dr. CLARKE tells me that spirochaetes are found most frequently and are most numerous in patients who suffer from seizures, and that they are particularly numerous when death has followed a series of seizures.

Slide 14 is from a patient who had both malaria and tryparsamide treatment. The patient was admitted 27th March, 1924. Given malaria treatment, five rigors, followed by a course of tryparsamide (36grammes), and of mercuric salicylate (12inoculations). Discharged in remission October, 1924. Readmitted April, 1926, and died. Numerous spirochaetes were found in his brain tissues after death. In these two cases, of course, the treatment entirely failed, but there are other cases in which complete disappearance of abnormal cerebrospinal reactions during life and absence of spirochaetes after death occur. Therefore, all that can be said at present is that the malarial treatment succeeds in some cases and fails in others. Perhaps the mass statistics showing that it succeeds in 10 percent. of unselected cases are not very wide of the truth. The results in pre-asylum selected cases treated in general hospitals and private nursing homes in England are certainly much more favourable, but as yet the available figures are not sufficiently numerous to justify summary.

The official arrangement in England by which general paralysis and other mental diseases can be treated by a course of malarial attacks induced by the bites of infected mosquitoes, provides an opportunity of studying in the laboratory certain factors which are important in connection with the epidemiology of malaria. I propose to give in this paper a brief account of our work on that subject and to indicate some conclusions which seem to be justified by the results obtained.

The work [note: 'My laboratory assistant, Mr. P.G. Shute, has assisted me greatly during the whole of the work summarized in this paper. Without his constant attention to all the details connected with the work it would have been quite impossible to comply with the requests for infected mosquitoes which we received'] may be summarised as follows:--

1. The practical object is the continuous supply of mosquitoes for inducing a pure infection of benign tertian malaria in patients to be treated

2. Between December, 1923, and April, 1926, for the purpose of obtaining supplies of infective insects, twenty-two batches of Anopheles maculipennis were fed on patients whose blood contained gametocytes of Plasmodium vivax, and were incubated in a saturated atmosphere at 22° to 24°C for ten or more days. A successful result was obtained with sixteen batches.

3. About 3,200 female maculipennis (caught as adults in nature) were used in the twenty-two batches, but only about 715 of them lived long enough to be available for infecting new patients.

4. During the period referred to 221 patients were subjected to their bites (some on more than one occasion), for the purpose of inducing malaria. Of these patients 169 developed benign tertian malaria within the usual incubation period of the disease, and 52 failed to do so.

5. The following statement gives details of the above information:--

[table]

I:-- Factors Relating to the Transmission of Malaria from Man to A. Maculipennis.

Our most important observation on this subject is that it is difficult to bring even a few members of a large brood of mosquitoes to a condition in which they will be successful transmitters of malaria. The difficulty is due to a number of causes of which the following may be mentioned:--

1. The Human Source of Infection.- One of the chief causes of failure to infect anopheles is the difficulty of finding a malaria patient who is infective to those insects. It is surprising what a small proportion of patients who suffer from malaria are infective to anopheles, even when their malaria has been allowed to run its course for a considerable period. Quite rarely one comes across a patient who is strikingly infective, but our general experience is that the great majority of patients must be classed as being "poor infectors of anopheles" and a small minority as being "good infectors."

2. The Numbers and Character of the Gametocytes.- In first attacks of benign tertian malaria contracted by the bites of mosquitoes we have never found gametocytes in thin films of blood taken before the seventh day after the first rise of temperature; and our feeding experiments show that about three more days must elapse before the gametocytes become infective to anopheles. This means that a patient in a first attack of malaria does not become infective until at earliest the tenth day of his illness. In relapses, however, gametocytes are present much earlier, usually indeed, on the first day on which the occurrence of the relapse is reported.

There are great differences in the numbers of gametocytes found in the peripheral blood of different cases of malaria and considerable differences in the number present in the blood of the same patient from day to day. The number rises rapidly at the beginning of the second week of the illness, and sometimes falls during the third week. We do not attach so much importance to the number of gametocytes as we do to their quality, for we have had many failures to infect batches of mosquitoes when the number of gametocytes present in the patient's blood was considerably in excess of the often-quoted figure of 1 per 500 leucocytes (12 per c.mm. of blood).

3. The Number of Feeds on Infective Blood.-- This is one of the most important factors in the infection of anopheles. We find that, unless an "exceptionally good infector of anopheles" is available, it is quite necessary to feed a batch of mosquitoes several times upon the malaria case in order that the batch may ultimately become infective (sporozoites in the salivary glands). The infection of maculipennis after one feed upon an infective case is quite uncertain, and we are sure that, in some individual mosquitoes of different batches, young zygotes which have begun to grow well, may cease to develop and may gradually become absorbed without coming to maturity. We have had to discontinue more than one batch which, on the third day, showed a high percentage of infection because by the eighth or ninth day all dissected individuals were negative. We cannot offer any other explanation than that the zygotes failed to continue their development and disappeared. As a result of many trials we have come to believe that mosquitoes which at first seem refractory to infection can be forced, so to speak, to become infective by repeated feeding on a suitable case.

4. Influence of Temperature, Humidity and Season.-- In our experience the best results in infecting A.maculipennis with P. vivax are obtained at temperatures between 22° and 24°C, and in a saturated atmosphere. We have not found any difference between the infectibility of maculipennis at different seasons of the year, or between the infectibility of "hibernating" as compared with recently hatched insects.

5. Influence of Growth of Eggs.--Mosquitoes carrying nearly ripe eggs do not suck nearly so much blood as do mosquitoes with undeveloped ovaries. The reason is that the swollen ovaries fill the abdomen and press against the midgut of the mosquito to such a degree that its cavity is almost obliterated. Therefore mosquitoes with fully developed ovaries are not likely to become heavily infected. Indeed, we find that as regards some female mosquitoes in this condition, the blood does not pass into the midgut at all, but fills and distends the oesophageal diverticula. Examining such a female after it has fed one sees that there is red blood in the abdomen and one concludes that the insect, having fed on the infective patient, will itself become infected. On dissection, however, one finds the midgut quite empty of blood, and the oesophageal diverticula distended like small red bladders. From time to time a little of the blood oozes from the diverticula into the midgut, but not in sufficient quantity to ensure the infection of the insect.

6. Influence of Feeding upon Fruit and Foods other than Fresh Blood.-- We believe that when a mosquito feeds on certain fruits the chemical reaction of its stomach becomes unfavourable to oöcyst development, and that mosquitoes may also be refractory to infection when they feed on the blood of certain animals or birds as well as on the blood of the infecting patient. As a result of many trials in this connection, we have decided that for the purpose of obtaining a satisfactory supply of highly infected insects fresh human blood is the only suitable food. We have found that some individual specimens of maculipennis caught in nature may be refractory to infection until they have had several feeds on human blood with omission of all other kinds of food.

7. Influence of the Quantity of Blood Ingested.-- Among every batch of mosquitoes, some feed greedily, some lightly, and some not at all. Some of them also evacuate a considerable proportion of the sucked blood while they are in the act of feeding. These points are of importance in the natural infection of mosquitoes and consideration must be given to them in practical work which has for its object the supply of batches of mosquitoes with a sporozoite rate of 100 percent. In that work this difficulty can be overcome by causing the mosquitoes to feed repeatedly on the infecting patient.

8. Influence of the Length of Life of the Mosquitoes.-- The length of life of mosquitoes is one of the most important factors in relation to their infection. A glance at the tabular statement already given will show what a large supply of mosquitoes must be used in order to obtain batches with infection of the salivary glands ("infective mosquitoes"). Maculipennis is a species which can withstand very low temperatures,-but its mortality rate at temperatures above 22°C is high. According to our figures its rate of mortality under conditions necessary for infection is about 50 percent per week. It seems probable that the short life of mosquitoes during very hot seasons is one of the most important factors in the geographical distribution and seasonal incidence of different species of the malaria parasite.

Comment.-- The difficulties which have had to be overcome in order to obtain supplies of mosquitoes with 100 percent sporozoite infection of the glands have helped us to realise how many special conditions must be fulfilled in nature for the effective transmission of malaria from man to mosquitoes. Our observations on this subject help to explain why it is almost an invariable rule in nature, even in very malarious places, to find only a low percentage of infected mosquitoes. They explain, also, why malaria in nature is essentially a "household disease" for it is obvious that certain kinds of houses or dwellings are the only places in whicha ll the necessary conditions can be fulfilled. This finding is of considerable importance in relation to the endemiology and epidemiology of the disease.

II:- The Persistence of Infectivity of Mosquitos with Sporozoites in the Glands.

When a batch of mosquitoes has become "infective" (sporozoites in the glands), it is our practice to keep the insects in an ice-chest at from 4° to 6°C during the periods between the use of the batch for infecting purposes. This plan reproduces artificially what happens to maculipennis in nature during winter in northern climates. It has enabled us to add something to the literature on the resistance of zygotes and sporozoites to cold, and on the duration of infecting power of mosquitoes. Our observations on these points show that as regards P. vivax the oöcysts in the stomach and the sporozoites in the glands are not killed when a mosquito lives continuously for three weeks at the low teraperature of 4° to 5'5°C nor even when the temperature during six days is below freezing point. Nor are they killed when a mosquito lives intermittently at a low and at a high temperature for a long period. Growth and development of oöcysts are arrested at the low temperatures, but begin again when the temperature becomes sufficiently high. Some of the mosquitoes in our successful batches have lived and continued to be infective for periods ranging between 29 and 92 days after sporozoites were present in their glands. These observations support and supplement the findings of workers who have caught and dissected mosquitoes in nature during the winter in different countries, particularly the findings of SWELLENGREBEL [note: 'SWELLENGREBEL, N.H. 1924. Nederl. Tijdschr. v. Geneesk. p.750.'] in Holland, WENYON [note: 'WENYON, C.M. 1921. Jl. Roy. Army Med. Corps, xxxvii, 187.'] in Macedonia, and SELLA [note: 'SELLA, M. 1920. Internat. Jl. Public Health, i, 341.'] in Rome. Considering the findings of these observers in conjunction with our laboratory results, we do not doubt that P. vivax can be carried through even a severe winter in hibernating mosquitoes, and that the carriage may be in either the oöcyst stage or the sporozoite stage of the parasite or both.

In connection with the persistence of infectivity through the winter (and for a long period at any season), it must be remembered that an infected mosquito nearly always carries zygotes at several different stages of development. These zygotes ripen and rupture at different times, and in consequence the salivary glands are continually being replenished with sporozoites during a considerable period. The following results of dissections exemplify this point:--

[table]

It will be seen from this statement that the mosquitoes of Batch 16, in which the salivary glands were continually being replenished with sporozoites, remained heavily infective during the whole period of their life, but that the mosquitoes of Batch 18, in which the salivary glands were not being replenished, gradually got rid of nearly all their sporozoites.

III:- Observations relating to the Transmission of Malaria from Mosquitos to Man. - Infectivity and Relapse.

I have already mentioned that 52 patients among the 221 who were bitten by the mosquitoes of our infective batches failed to develop malaria within the usual incubation period of the disease. Some of the patients who failed to develop the disease were bitten on more than one occasion by mosquitoes which were proved by subsequent dissection to be highly infective, Fifty of the 52 failures occurred during the winter months between November and March.

Under the system of treatment by 10 grains of quinine three times a day for five days, the relapse rate in mosquito-infected cases is about 25 percent., but in most cases there is only one relapse which is either recovered from "spontaneously," or is cured as readily as the original attack. We do not find that relapses are more frequent in patients infected by a large dose of sporozoites or by infection on several occasions than they are in patients infected by a small dose on only one occasion. Neither have we observed that the incubation period of the attack of malaria or its severity is influenced significantly by the amount of the infective dose. Both these results are surprising in view of accepted opinion on the cause of relapses in war malaria. Our patients are in the following four groups:---

a) Those infected by the bite of one mosquito on a single occasion.

(b) Those infected by the bites of several mosquitoes (3 to 10) on a single occasion.

(c) Those infected by the bites of many mosquitoes (up to 120) on a single occasion.

(d) Those infected by the bites of several or many mosquitoes on different dates during the incubation period of the disease.

What we find is that different individuals react very differently to malarial infection. A patient who has been infected by the bites of, say, 60, 80 and 30 mosquitoes respectively, on three occasions, may have only a relatively mild attack, which is not followed by a relapse, while another patient who has been infected by only two or three bites of mosquitoes of the same batch may have a severe attack, and may also have one or more relapses. Our observations seem to demonstrate that the qualities possessed by the blood and tissues of the individual concerned are much more important than the degree and frequency of infection. There seems to be no doubt that some individuals are very "susceptible" to malarial infection, and that some are relatively quite "refractory" to infection. Intermediate between these two extreme classes there are the great majority of people who may be described as being normally susceptible.

To illustrate this point I show you three statements: There is first the  statement of a patient (Mrs. G.) of normal susceptibility. She was infected on two occasions and suffered normal attacks which were not followed by any relapses. The second is the statement of a patient (Mrs. W.) of high susceptibility. She was infected on only one occasion with the same mosquitoes that were used for the infection of Mrs. G. She suffered a severe attack which is now being followed by a prolonged series of relapses. It will be obvious at once that in this patient we have an example of a case which corresponds precisely with the class of relapsing patients who were such a cause of anxiety during the war. The third is the statement of a patient (Mrs. H.) who is not at all susceptible to infection Two attempts to infect this patient failed, and at the third trial she had only a mild attack from which she recovered spontaneously without any quinine treatment.

It seems to me that consideration of these three types of people enables us to understand some of the malarial cases which occurred during the war. It is clear, for example, that quinine had nothing to do with those frequently relapsing cases. The probable explanation seems to be, that the many thousand soldiers who contracted malaria during the war included a certain number whose natural degree of susceptibility to malaria was about the same as that of our patient, Mrs. W. (Type B). It was a problem of a peculiar class of individuals who reacted to malarial infection in an unusual way.

These considerations lead then to the conclusion that the susceptibility to relapse is a susceptibility to malaria. They may equally be used to explain its original failure to develop in a person bitten by infective mosquitoes. I have, for instance, mentioned our observation that 52 among the 221 patients who were bitten by the mosquitoes of our infective batches failed to develop malaria.

For a considerable time we tried to explain the failures on technical rather than on bioIogical grounds. We are now convinced that the failures cannot be explained as being due to failure of the mosquitoes to inject a sufficient dose of sporozoites. As I have already explained, we now regard them as being due to some unusual chemical or other condition, as yet unknown, in the blood or tissues of certain persons. The persons in whom infection failed are persons to be classified in the refractory group, of which the statement of the case of Mrs. H. is an example. What the failures show is that the peculiar condition of being refractory is not necessarily permanent. Of course, it is equally important to note that the peculiar condition of susceptibility may also be temporary. The facts that all our failures occurred during the winter months, that some patients in whom infection failed during the winter were able to be infected in the following spring and summer, and that even during the winter some patients who were kept in bed in a warm room during the incubation period developed the disease, while others who were allowed to be up and about in the cold failed to do so, show that in some patients the condition of being susceptible or refractory is influenced by very slight stimuli. Warmth and cold are stimuli which are sufficient to change the condition in some patients, and, obviously, quinine is another and more powerful stimulus. We find in the case of our chronically relapsing patient (Mrs. W.) that 5 grains of quinine are sufficient to effect the necessary change.

If I have made that point clear it will be plain to everyone that we have reached a point where we are greatly in need of the services of the physiologist and the biochemist. We want someone to tell us in the first place whether there are any simple chemical differences between the bloods of the three classes of patients, which would account for the very different degrees of hospitality to the malaria parasite which I have indicated. Then we want a test which will enable us to classify people according to their respective susceptibility to malaria. Such a test would be of immense value throughout the world. Incidentally the biochemical research suggested might indicate how quinine acts in malaria and how the disease might be treated in a more scientific manner than at present.

Conclusions.

The purpose of our laboratory work on the infection of mosquitoes would not be fulfilled unless, in addition to complying with official requirements relating to the treatment of mental diseases with a pure strain of P. vivax in mosquitoes, it enabled us at the same time to add something to existing knowledge of the epidemiology of malaria. It is obvious that the application of our observations to that end necessitates the assumption that what happens under artificial laboratory conditions will also happen in nature. Allowing that this assumption is justifiable I may summarize some of our conclusions briefly as follows:--

1. Our observations seem to show clearly that of the vast numbers of anopheles mosquitoes which exist in malarious places, only a very few become transmitters of malaria. This being so, it may well be asked how it comes about that in many places all the inhabitants are infected with the disease. The answer is certainly given by the observation that a mosquito which has succeeded in becoming infective, retains its infecting power for a long period, and can infect many people. Different batches of our mosquitoes lived and continued to be infective for periods ranging from one month to three months after the date in which sporozoites were present in their salivary glands. Some of the mosquitoes in these batches, after biting between 30 and 40 patients, still had numerous sporozoites in their glands. This was because the glands were replenished from time to time with sporozoites from oöcysts which ripened and ruptured at different times. In nature, a mosquito which has made its home in a house containing several malarious children who are untreated, has frequent opportunities of becoming freshly infected; the result is that its stomach carries oöcysts in many stages of growth, and its salivary glands are restocked with sporozoites from time to time throughout the remainder of its life.

2. The observations relative to the resistance of oöcysts and sporozoites to cold, coupled with the observations on persistence of infectivity just mentioned, lead to the conclusion that benign tertian malaria can be carried through even severe winter in hibernating mosquitoes. This persistence of infectivity through the winter explains some of the occurrences in Northern Europe of primary attacks of malaria during that season and in early spring.

3. Why is it that in nature only a very few anopheles become effective transmitters of the disease? Our observations on the difficulties of bringing even a few members of a large brood of mosquitoes to a condition of infectivity seem to us to help considerably in the solution of this problem, and that the observations have an important practical application in relation to anti-mosquito measures against malaria. Let me begin by saying that we were greatly surprised to find that, in the highly favourable laboratory conditions in which we work, failures to obtain supplies of infective insects (i.e., with sporozoites in the glands) were so frequent. Our mosquitoes lead a sheltered life. They are protected against sun, wind and rain, and against unfavourable changes of temperature and against natural enemies. The food upon which they thrive best and live longest is available to them without effort or risk, and care is taken to prevent the ingestion of a diet which is unsuitable or is contaminated with bacteria or moulds; when a mosquito refuses to feed it is separated from the rest of the batch and nursed at a lower temperature until it will do so. It seems quite plain that if special conditions of this kind are necessary for the infection of mosquitoes in the laboratory they will be equally necessary in nature. Therefore we need not hesitate to affirm that in nature the only mosquitoes which become transmitters of malaria are those rare individuals which happen to pass their life under equally sheltered and peculiar conditions. Moreover, our observations show that even among the relatively few anopheles which in nature come to rest in a place which is favourable to their infection, not many will ultimately become infective unless certain additional conditions are fulfilled as, for example, that the mosquito must have an opportunity of feeding every day, that it must feed several times on the infective patient, and that it must have no other kind of food than human blood. When one appreciates the importance of these conditions, one realises how small is the chance in nature that any particular brood of anopheles will ever be concerned in transmitting malaria. One realises that the role of being a malaria-transmitter is reserved for only a very few individual mosquitoes which happen to pass their life in an environment, and in a manner very different from that of the remainder of the brood. And when we accept this conclusion, we must accept also the inference to which it leads, namely, that the secret of a successful control of malaria lies not in the general knowledge that the disease is spread by mosquitoes of a certain genus or species, but in the particular and exact knowledge of the life history of the few individual mosquitoes whose habits are such that they are likely to get into the special environment and conditions, and to live their life in the special manner, in which alone a mosquito can become a malaria-transmitter. No one who fully appreciates the importance of this conclusion, and accepts it as true, can fail to look upon anti-mosquito measures for dealing with malaria from a new point of view. He will at once realise what a great waste of effort is involved in measures directed against the breeding places of mosquitoes as a whole, and even in similar measures directed against one species. Instead of considering those measures, he will think constantly of examples such as I have recorded on page 150 of this paper. He will appreciate at once how dangerous even a single mosquito may be, when it is continuously infective in the manner exemplified for Batch 16 on that page. He will see the futility of employing his staff on anti-larval measures in the fields and marshes while permitting a mosquito of that kind to continue for weeks to work its wicked will in the houses of the people. Instead of continuing his enquiry into the habits of particular genera or species of mosquitoes as a whole, he will begin at once to study the habits of the particular individual mosquitoes which get into the dangerous infective condition indicated. He will find that the habits and life history of these individuals are quite different from those of the general specific group to which they belong entomologically. As I have already said, these individuals pass their life in a manner quite different from that of the remainder of their brood. An essential difference is that instead of making flights in the open-air, they pass almost the whole of their life in the particular house in which they first settled. At their first feed in this house they become overloaded with blood and almost too heavy and sluggish to make a satisfactory flight. They find a sheltered dark corner or hole within a few feet of the beds of the occupants of the house, and night after night make the short passage between their hiding place and the sleeper in the bed in order to gorge themselves with blood. Their eggs ripen only very slowly, and even when they are ripe the insect is very loth to make the flight necessary for laying them. Often she drops them carelessly after a very short flight, and returns to the hole which she has made her home. Life in the household, with the nightly feed of blood, has become a habit to which everything else is subordinated.

The principle then emerges that in Nature the only Anopheles maculipennis which play an important part in the transmission of malaria are certain individual mosquitoes which lead an abnormal life.

It seems clear from our observations on the factors necessary for the infection of ananopheles mosquito that the individuals of this genus which lead a normal life, partly in houses, partly in the open air, getting their meals sometimes from man, sometimes from animals, sometimes from fruit, and subject to the risks of exposure and of egg-laying under natural conditions, can seldom or never become successful transmitters of malaria. Some of the reasons are given in my paper, but from lack of space many details have been omitted. The closer one studies these details the more one becomes convinced that in nature the role of being a malaria transmitter is reserved for only a very few individual mosquitoes which pass their life in an environment and in a manner which is quite abnormal. If this is true, a new field of enquiry has been opened up concerning the conditions and circumstances of the abnormal life which is necessary for infection, and of the factors which induce certain individual mosquitoes to lead that life. We know something of the life itself, but almost nothing of the events which precede it. It seems probable that enquiry into these factors and events in different localities, seasons and circumstances, would lead to useful results.

I have said enough to indicate the point of view to which our laboratory work on the infection of anopheles seems to lead. It seems to confirm, experimentally, the view already arrived at by many epidemiologists, that in nature the human house or dwelling is invariably the "laboratory" where malaria infection has its origin and is cultivated. It is essentially a disease of certain kinds of houses or other dwellings which fulfil the "laboratory conditions" which we have described.

Our laboratory work will not have been in vain if it directs attention once more to the knowledge that human dwellings are the laboratories where malaria in nature is bred and cultivated, and to the reasonable inference that the disease should be dealt with primarily in the interior of those dwellings.'

Created S.P. James, 'History of a Group of Anopheles Mosquitoes Infected with Plasmodium vivax (Grassi & Feletti),' Abhandlungen aus dem Gebiet der Auslandskunde 26 (1927), pp. 220-222.
1927

Created S.P. James, 'Laboratory Meeting: Further Specimens and Charts Illustrating Naturally Infected Malaria in Cases of General Paralysis in England,' Transactions of the Royal Society of Tropical Medicine and Hygiene 18 (1-2) (1924), pp. 2-4.
1924
Description:

'[Chart: 'Case W.']

Colonel S.P. JAMES.-- Further Specimens and Charts illustrating Naturally Infected Malarla in Cases of General Paralysis in England.

My exhibition to-night relates to the treatment of general paralysis with malaria, and is in continuation of the demonstration on the same subject which I gave at the Society's last labora$ory meeting. The material shown comprises:-- 

1. Copies of an official memorandum recording the chief results of the enquiry into the technique of the treatment as it has been carried out hitherto in England, and of the rules which it is desired should be followed in future.

2. Selected temperature charts from a series of sixteen cases, in which the malaria has been induced not by direct inoculation of blood but by the bites of infected mosquitoes.

3. Microscopic specimens of the parasite in the blood of the patients and in the stomach and salivary glands of the mosquito.

It is recorded in the memorandum that, in some instances, the malaria induced by direct inoculation of blood has been of an unusually severe type, accompanied by pronounced complications and with a tendency to fatality. We believe that this severity is a consequence in part of an increased activity and virulence resulting from the cultivation of the parasite by direct passage through many human hosts. Having in view what happens as regards acquired characters in some other protozoa, I thought it possible that passage of the strain through its insect host would cause it to lose this added virulence. I may say at once that this conjecture has not been confirmed. The temperature charts show that the malaria in the mosquito-infected cases is of quite a severe type, and that in the majority of instances we have been obliged to resort to quinine after the patient has passed through seven or eight [2-3]

[chart: [patient 'A']]

paroxysms. The copurse of the temperature of the patient A----, who was infected by inoculating 2c.c. of blood from the mosquito-infected patient M----, is particularly instructive. It is quite clear from the chart that if the strain of parasites by passage through the mosquito has undergone any change of virulence, the change is an increase rather than a diminution. From the point of view of the treatment of general paralysis, it is, of course, a great advantage to have available a strain of parasites which cause high temperatures, but it means that great care must be taken in the nursing and treatment of the cases. If the fever influence is that of a "spirochaeticide," it would seem, from the experiments of WEICHBRODT and JAHMEL, that a temperature of 105° or 106° must be reached to be effective. On this ground our present strain is probably the most effective yet obtained.

The charts show the course of the temperature during the incubation period and early days of the febrile attacks, and demonstrate that, though the patients were bitten on only one occasion, their fever in most cases was of quotidian type.

Note.-- The case of W----, which has developed since the laboratory meeting was held, is of particular interest in this connection, and I have, therefore, asked to be permitted to publish the temperature chart of the case in these TRANSACTIONS. The patient, a boy aged 13, was a case of infantile general paralysis under the care of Dr. FIRTH, at King's College Hospital. On 15th March, in the forenoon, two mosquitoes (maculipennis) were applied to the patient's thigh and closely watched. Only one of them was seen to bite, and when they were removed from the leg it was found that neither of them had sucked blood. But as the mark of one bite was plainly visible, and later became a definite wheal, I did not consider it necessary, that the patient [3-4] should be bitten again. The attack of malaria which the chart illustrates began on the tenth day following the single bite, which (as no blood had been extracted by the mosquito) could not have lasted more than a few seconds. We know from numerous examinations of the strain in other patients, both before and after its passage through the mosquito, that it is a pure benign tertian strain, but I find it difficult to explain why it causes so frequently a quotidian type of fever. In the case illustrated the fever was quotidian from the first, but, unfortunately, I had no opportunity of making the frequent blood examinations which would be necessary for endeavouring to correlate the growth and sporulation of the parasites with the particular times at which the rigors occurred. It would be very surprising if it could be shown that a strain of Plasmodium vivax, which has been passed through many human hosts and through a mosquito, goes through its asexual cycle in the blood of man in a period of approximately twenty-four hours instead of forty-eight.'

Created S.P. James, 'Laboratory Meeting: The Parasites of Inoculated Malaria in England (in general paralytic patients),' Transactions of the Royal Society of Tropical Medicine and Hygiene 17 (6-7) (1923), p. 340.
1923
Description:

'Colonel JAMES said: The specimens shown were collected during an enquiry into some of the clinical trials which are being made in mental hospitals in England of the method initiated a few years ago in Austria of treating general paralysis of the insane by inducing attacks of inoculated malaria. The enquiry is being undertaken by the Ministry of Health in collaboration with the Board of Control, primarily to ensure that all needful steps are taken to guard against the accidental spread of malaria, either in the hospitals concerned or to neighbouring populations. The first point to be ascertained in this enquiry is whether and to what degree a strain of parasite, which has been passed by direct inoculation from patient to patient through many human hosts, still remains infective to the anopheles mosquitoes of this country. There were many difficulties in carrying out this investigation during the winter, but in the result we have specimens of four insects showing sporozoites in the salivary glands and proboscis, and many specimens showing zygotes in the stomach wall. Under the particular conditions of our experiments from seventeen to twenty days elapsed between the date offeeding upon patients and the date when the finding of sporozoites in the salivary glands proved that the mosquitoes were infective to human beings.

The specimens of parasites in the blood of inoculated patients show some of the morphological characters of a strain which has been passed through about twenty human hosts. The strain was originally obtained from a case of benign tertian malaria contracted in the tropics. The slides show that in the inoculated case concerned the parasites were very numerous, and that the peripheral blood contained many large endothelioid macrophages and degenerated red-blood corpuscles: Typical male and female gametocytes are also shown, and a type of gametocyte which seems to resemble somewhat the forms described by THOMPSON and WOODCOCK on page 1,541 of the malaria article in BYAM and ARCHIBALD'S Practice of Medicine in the Tropics.'

Created S.P. James, 'The Shute Method of Making Preparations of Ex-flagellating Gametocytes and Oökinetes of Malarial Parasites,' Transactions of the Royal Society of Tropical Medicine and Hygiene 28 (1) (1934), pp. 104-105.
1934

Created S.P. James, ‘Note on conference relative to permanent arrangements for the malarial treatment of general paralysis in asylums’ (19th April 1928).
19 Apr 1928
Description:

‘As arranged by Sir George Buchanan, I met Mr. Brock and Dr. Bond at the Office of the Board of Control this morning, the 19th April. The questions discussed were:

(1) Dr. Meagher’s Report. Mr. Brock said that the Board of Control will publish this with an historical introduction by Dr. Bond. Dr. Bond is anxious that there should be no earlier publication of the results of the inquiry elsewhere. Therefore it was agreed to refrain from giving a summary of them at the forthcoming meeting of the Office International d’Hygiene Publique.

(2) Proposal for Dr. Meagher to visit Vienna. Dr. Bond had noticed Wagner-Juaregg’s statement (reproduced in Dr. Meagher’s report) to the effect that in the Vienna clinic “deaths from malaria have ceased to occur”. As this is contrary to average English experience, he wishes to ascertain what special measures may be adopted in Vienna to combat the acknowledged risk. Mr. Brock supported the view that Dr. Meagher should visit Vienna to ascertain the practice in this respect (as well as to enquire into some other matters which emerge from Dr. Meagher’s report) and both he and Dr. Bond are desirous that I should accompany Dr. Meagher on this visit, which is not expected to last many days. As the special point referred to relates to malaria, I agreed that I would be willing to go if our Ministry has no objection and is prepared to allow the travelling expenses.

(3) Permanent arrangements for the treatment. Dr. Bond feels sure that the L.C.C. will agree to almost any plan proposed by the Board provided that it will not involve the L.C.C. in expense. The Board is not inclined to favour the idea of collecting all patients in a central hospital for treatment, as such a plan would deprive keen superintendents of the opportunity of carrying out the treatment themselves. We agreed that, whatever arrangements are made, a necessary preliminary is to place the arrangements at Horton on a permanent basis and that the requirements for this purpose are as stated in my note, namely:

(1) to increase the number of patients treated at Horton,

(2) to increase the laboratory arrangements and subordinate staff,

(3) to provide a whole-time medical officer.

Discussion was chiefly on the question as to what Department should be responsible for providing the medical officer & subordinate staff, and as to how to obtain their salary etc. I understood Dr. Bond to favour an endeavour to get the L.C.C. to second Dr. Nicol permanently, but that plan would not overcome the difficulty of paying a substitute for him. At present the substitute is paid out of the Ministry’s Scientific Fund.

The question was left more or less in the air, but Mr. Brock said that he would take an early opportunity to discuss the problem personally with Mr. Leggett.

S.P. James.

19th April 1928.’

Created S.P. James, ‘Some General Results of a Study of Induced Malaria in England,’ Transactions of the Royal Society of Tropical Medicine and Hygiene 24 (5) (1931), pp. 477-525.
1931

Created S.P. James, ‘The treatment of “General Paralysis of the Insane” by causing the patients to suffer from a mild form of malaria’ [minute], 25th May, 1923.
25 May 1923
Description:

‘During my recent visit to Austria I had an opportunity of seeing the above treatment carried out by Professor von Weeber at the State Mental Disease Asylum in Graz.

Dr. Weeber emphasised the necessity of using a mild strain of benign tertian malaria which in the first event had been contracted in the country concerned, not from an imported case, but from a local case in an area where the disease is mildly endemic. He considered that the use of an imported strain would probably do more harm than good as being likely to produce alarming or dangerous symptoms in the particular patients treated, especially as the attack of malaria induced must be allowed to run its course through several parozysms [sic] (10 or 12 days) before being checked by quinine. This desideratum has apparently been accepted as necessary by physicians in other countries for I understand that some patients from Denmark (were local malaria is believed not to occur) have been sent to Austria for inoculation with the mild strain which is maintained from patient to patient there.

The strain is also a special one in that it has never been subjected to the action of quinine: it was inoculated from the child who first contracted the infection before the child had received any treatment; and the passage from patient to patient has since been performed during the period before the commencement of quinine treatment.

The patients who maintain the strain of the parasite are sufferers from G.P.I. with adequate proof of former syphilis for which they have been vigorously treated during some months or years prior to receiving the treatment by malaria attack.

Every precaution is taken to avoid inoculation of patients who cannot be proved to have suffered from syphilis.

The blood for inoculation (2 c.c.) is drawn from a vein while parasites are present but not necessarily during a febrile attack. One c.c. is injected under the skin in the scapular region and then Dr. Weeber makes a number of scarifications of the surface of the skin with the point of the needle and makes a surface inoculation of the rest of the blood into these scarifications. (The idea is to reproduce the kind of inoculation made by a mosquito!)

The temperature charts and clinical accounts which I saw show that the attacks of malarial fever produced are typical in character. Treatment with quinine is begun after some days (6 to 10 presently) and at the same time the patient is usually treated with neosalvarsan.

Dr. Weeber showed us five persons who had formerly been inmates of the Asylum suffering from G.P.I. but were now back in their own homes apparently cured. He also showed a number of statistics which appeared to indicate that the new treatment had effected a considerable reduction in the number of cases and deaths from the disease during recent years. On the other hand he expressed a guarded view as to final prognosis and emphasised that the treatment is still in the experimental stage. He noted that the procedure had been successful in one or two cases of epilepsy.

I should add, perhaps, that if it were desired to essay the treatment experimentally in England it could only be done in an Institution where the Ministry or other responsible Government Department could control the arrangements for the diagnosis of syphilis and for otherwise safeguarding the interests of the patients who act both as the subjects of treatment and as carriers of the particular strain of malaria parasites. Given a well worked-out scheme we could doubtless obtain a strain of parasites fulfilling the desired requirements from one or other of the centres of endemic malaria in England.

(Signed) S.P. James, 25th May 1923.’

Created S.P. James, W.D. Nicol and P.D. Shute, 'Experiments on the Treatment of Malaria in England,' in Report of the 7th Congress of the Far Eastern Association of Tropical Medicine, British India, December 5th, 10th, 24th, 1927 (Calcutta: 1929), pp. 788-803.
1929

Created S.P. James, W.D. Nicol and P.G. Shute, ‘Clinical and Parasitological Observations on Induced Malaria,’ Proceedings of the Royal Society of Medicine 29 (1936), pp. 879-894.
1936

Created S.P. James, W.D. Nicol, and P.G. Shute, 'A Study of Induced Malignant Tertian Malaria,’ Proceedings of the Royal Society of Medicine 25 (8) (1932), pp. 1153-1186.
From 1935 to 1932