246
INDIAN MEDICAL GAZETTE.
/
MALARIAL MELANiEMlA. By Patrick Rehir. m d., f.r.s.e., d.ph. (Cambridge), Lecturer on Medicine and Pathology, Hyderabad Medical School.
To the physician and pathologist in India the of malarial melansemia is one of profound interest for many reasons. It is the commonest abnormal contamination of the blood to be met with in this country ; in cases of malarial infection it is never absent, although in the earlier stage of such poisoning a single or even two observations may fail to detect it; it is believed to be intimately connected with the destruction of the hremoglobin of the red-blood corpuscles caused, by the materies morbi of malarial diseases; and lastly, our knowledge of the subject is still somewhat scanty. We have searched through the greater part of the medical literature of India, and have failed to find a single article, paper or anything beyond meagre references to this condition, the inference being that it has never been made the subject of special investigation, notwithstanding its vast significance, nor have any English writers devoted much attention to it. On the Continent of Europe, however, we find that many authorities have given us elaborate accounts of it, especially Laveran, Mar-
subject
chiafava, Celli, Klebs, Tommasi-Crudeli, Golgi, Cuboni aiub others, although the main part of
our literature regarding it emanates from the As a matter of fact, first three named writers. Laveran found the pigment in the blood of malarial fever patients in Algiers, and it was whilst he was investigating its nature, which he first considered to be parasitic, that he actually made the discovery of the plasmodium malarice. For years after Laveran's discovery of the pigmentary particles in malarial blood, he and
Marchiafava
waged a paper war as to priority of the discovery. The title of this paper is in itself a definition of the mnin feature of the condition under consideration, malarial melancemia, or melanotic pigment in the blood of patients suffering from malarial infection. The term m el ah semi a was, we believe, originally given by Virchow to the presence of pigment in the blood. There is one other condition in which pig ment, free and contained in large white cells, is to be found in the blood, and that is cholera. The nature of the pigment met with, its peculiar distribution and the uniformity of shape of the pigment patches as seen in the field of the microscope were described by the writer in the Supplement to the Indian Medical Gazette, for April 1892. In that paper I ventured to hazard the opinion that I had made an important discovery in the shape of an hsematozoon in the blood of cholera patients, which in its development and morphological characters, had many resemblances to
[July
1894.
khe plasmodium malarise.
The rapidly moving, described and found in a large, fiagelljie certain percentage of cases was another special feature of this organism. This flagellated organism, resembling in certain respects the filaria, sanguinus hominis, must often block uncapillary arterioles, but is rarely met in the blood circulating in the extremities, although it is to be found in the kidneys, in the liver, and capillaries of the lungs. That grave alterations do take place in the blood in cholera is a matter of universal recognition ; but that these changes constitute an important factor both pathologically and possibly etiologically, has not been admitted hitherto. So far back as 1872, Drs. R. T. Lewis and D. D. Cunningham made some very important observations of much the same nature as my own in connection with the blood of cholera cases, and described and pictured an organism which they considered to be a variety of amoeba, that is, a free
protozoon.* The peculiar pathological state which forms the subject of this paper is one which all pathologists in India at least will allow to be of the1 most profound interest, indirectly perhaps more
than any other morbid state in the whole range of pathology. The practitioner of malarial districts is only too familiar with the reasons why it is so overwhelmingly significant. He sees it marked in every case of malaria without exception that comes under his care? to a varying degree certainly, but nevertheless ahvaj's present. Indeed, when we considei' that" malarial diseases are accountable for half the mortality of the world, and that every case of malaria is characterised by the presence of pigment, free in the blood, or otherwise present, apart from the normal colouring matter of the red-blood corpuscles, the significance of the subject in hand comes home to us. We use the word "characterised" in the last sentence advisedly, for the presence of free pigment in the blood in some form or other is the only constant and invariable phenomenon connected with malarial diseases, and especially with malarial fevers. True it is that the plasmodium malarise is also characteristic, but every now and then cases come under observation, in which for some reason this hrematozoon is absent. It cannot be alleged that this occasional absence is due to casual observation, or to the frequent absence of the organism from the peripheral part of the circulation, or to the examination of tlie blood* having been made at unseasonable periods of the day, and so on, because investigators thoroughly familiar with all these possible accidents, and taking all necessary precautions to guard against them, have every now
interesting
* Vide Indian Annuls of Medical Science, Vol. I. and Pathological and Physiological Observations. By R. T? Lewis,
M.B., F.K.S.
July
1894.]
HEHIR ON MALARIAL MELAN^EMIA.
and then failed to find this parasite in the I have examined thousands of slide preblood. parations of malarial blood, and confess that in a varying percentage of cases (from 8 to 23 in different series of observations) the malarial organism is not to be found. On the other hand, in no case of malarial fever in which it was looked for have I failed to find free pigment resulting from the disintegration of the red-blood corpuscles. It is not always to be found in the first or even in the second slide, but careful examination shows it to be invariably present if a sufficiently careful or persevering examination is made. Laveran was the first to direct attention to the melanaemia of malarial fever. In 1880 he pointed out that in these cases the blood contained pigmented particles which were free in the blood or contained within or adherent to the surface of the red-blood corpuscles. These he considered to be of parasitic nature. It is my experience now, as it was some j'ears ago, that in very malarious places it is seldom one comes across a specimen of healthy blood. Indeed, I remember when in 1890-92 I was anxious to make some control observations, I could not find a single individual whose blood was absolutely healthy, that is, perfectly normal in its histological characters, and I had to wait until I came across a healthy person who had just returned from England. Marchiafava and Celli declare that they were the first to describe the transformation of the haemoglobin of the red-blood corpuscles into a melanin-like material under the action of the Plasmodium malarice, and probably their claim is a just one, although Laveran was the first to point out that pigment, free and contained within cells, was frequently found in the blood of patients suffering from malarial infection. In the more chronic cases and with the absence of fever, pigment may not be found in the blood mass itself for a time, but in such cases it will always be found in the spleen, liver and other organs. If we were asked to name one pathognomonic sign of malarial poisoning we should say it was melanaemia, especially in the earty an(j later stages of paludal infection. We find excessively small spherical or rounded granules or flakes which are either free in the blood plasma or are contained in spherical homogeneous cells of larger size than the white-blood cells in the red-blood corpuscles themselves in the so-called phagocytes, and in the large flagellated spherical bodies which form the highest developmental structure of the malarial organism. Klein tells us that in pyaemia a variety of small bacillus occasionally forms emboli of such size as to completely block up the smaller bloodvessels, and he speaks specially of this occurring in lymphatic glands. Koch also states that a
247
still smaller bacillus in this disease completely occludes the lumen of the arterioles and capillary vessels, and that the micrococci of micesepticsemia does the same. There appears to be a doubt as to whether the term melanin should be applied to this variety of pigment, as some authors at least reserve it for the colouring matter found in dark-coloured new growths such as melanotic sarcoma and melanotic cancer. Others apply the term to pigments generally. All pigments, however, take their origin directly or indirectly from the redblood corpuscles; and in the present imperfect condition of our knowledge of pigments of a black or brown colour, it appears that such refined distinction is not only unnecessary but an affectation that can scarcely meet with approbation. That the disintegration of tissue from high temperature is not the cause of this state is apparent from the fact that often melansemia is met with without there having been any fever Nor is it the result of the affections of at all. the internal organs which take place, because the pigment is not met with in the blood in cases of ordinary parenchymatous inflammations of organs. In other affections its presence in the blood may be said to be accidental, or, at least, not permanent, whereas in malarial infection it is never absent from either the blood plasma or white-blood corpuscles or phagocytes, most frequently being found in the internal organs. As invariable accompaniments of this state we have, during the active period of the disease at least, a marked destruction of the red-blood corpuscles which fact alone serves to indicate the origin of the pigment. Another, although a secondary accompaniment, is hypertrophy of the spleen and also, but to a less extent, of the liver. From all we know of the pathological effect of the parasites of malaria it seems almost, if not quite, justifiable to state that the chief process is the appropriation by them of certain constitutions of the haemoglobin, and probably the albumen and oxygen, with the pigment as I have shown elsewhere that an effete product. as soon as set free the spores appear to attach themselves to the surface of the red-blood corpuscles. It is curious that they never undergo any further change whilst free in the blood, a peculiarity which appears to class them amongst what may be termed amoebic protozoa. They seek out the part of blood richest in oxygen. There is of course oxygen in the plasmatic fluid of the blood in combination with carbonate of sodium, but for some reason or another it is not made use of; whereas once the spore gains access to the red-blood cell it forthwith begins the work of disintegrating the haemoglobin, and continues to do so until practically every particle of available material is devoured.
248
INDIAN MEDICAL GAZETTE.
The actual
of the red-blood in the spleen, liver, red marrow of bones, or in the blood-vessels, the particles or granules of pigment being carried along with the blood stream quite free, just as the red and white-blood cells are; there is also a continual ingestion of these pigment particles by the leucocytes, but more specially by the phagocytes, finally reaching some of the smaller sized capillaries of the skin, of a mucous membrane, or in some of the internal organs of the body, there to lodge permanently. Emboli of pigment rarely cause obstruction in the circulatory system during the period they are flowing in the vessels because of their comparatively small size individually. When, however, they do block a capillary or small arteriole, other particles join to form an elongated " terminal mass, but such obstructions, except in arteries," give rise to no serious immediate conse-
corpuscles
disintegration
may take
place
quences. These lumps of pigment are often so large as to become arrested in their course through the circulation in the periphery and internal organs, and thus block up arterioles or capillaries. This is especially the case in the terminal arteries of the brain, of the kidneys, of the liver, pancreas, &c. The result of this is that these organs become highly pigmented, and their blood-supply (especially in those organs with terminal arteries, such as the brain and kidneys) being cut off, there is considerable interference with their nutrition and function, which frequently sets up secondary degenerative changes in organisation and often complete metamorphosis. Apart from malarial fever, enlargement and tenderness of the spleen and liver often result from prolonged residence in a malarial climate. This is evident We see it in in almost every part of India. Hyderabad sometimes in cases succumbing to other maladies. In all varieties of malarial poisoning we have this one symptom which is characteristic and pathognomonic. We get it in the mildest form of malarial poisoning with slight fever, malaise, and headache, as well as in malignant remittents and malarial cachexia, and all intermediate conditions between these clinical manifestations of malarial infection. So that the occurrence of melansemia in India is almost always sufficient to diagnose malarial poisoning. When we consider the multiplicity of clinical phenomena owing their origin to malaria, this diagnostic feature ot malarial melansemia is a matter of the
greatest possible significance.
Some writers consider that there can be little doubt but that the pigment which is found in the blood and internal organs, mucous membranes, and sometimes in the skin, which is so characteristic a phenomenon of malarial fevers, results from the destruction of the haemoglobin of the
[July
1894.
red-blood cells by the plasmodium malariae of Laveran. Sometimes the surface of the pigment has a refractive appearance as if it were crystalline, at others it is dull. It would appear that the condition of the pigment varies considerably with its position and age, as in other forms of pigmentary deposits. As met with in mucous membranes it is likely to be granular, and if in the brain, amorphous or partly crystalline. Slategrey discolouration of the intestinal mucous membrane points either to prolonged catarrh or portal congestion. But a similar condition may arise from malarial pigmentation. The material is certainly not haematin nor haematoidin, nor is it the amorphous pigmentary matter found on the living, the walls of an exIt is not, travasation cyst from haemorrhage. of course, soluble in the blood, nor in weak alkaline or acid solutions, although these break it up into smaller particles or granules. From its general characteristics and history it cannot be the excessively black pigment of the blood either granular or crystalline which we call melanin, because we know this body to be haematoidin, which has undergone certain chemical and physical changes, chief amongst which is the acquisition of more carbon, and decrease in
solubility. The general opinion seems ment deposited in the spleen
to be that the pigis reabsorbed into the blood, and redeposited either in areas where pigment is usually present as the skin or mucous membrane ; or in certain internal organs. But the pigment differs in character from that met with in the blood in the later stages of melanotic cancer, or melanotic sarcoma, and although having originally precisely the same origin, it differs considerably in the mechanism of its production. Apart from the pains of the febrile stage in undeveloped malaria, there is often for days a tenderness occurring throughout the body with more or less malaise, and a general want of the feeling of bien etre. The malarial origin of these cases is often shown therapeutically by the complete and permanent disappearance of all trouble after 15-grain doses of quinine have been taken two or three times. Often this state is combined with slight pyrexial phenomena, the temperature Thus we have not going beyond 100? or 101?F. an absolute specific in sulphate of quinine. The latest researches on the pigment of malaria are those of Dr. Cuboni communicated to the Academy of Medicine of Paris. Dr. Cuboni, as the result of special experiments, believes he can identify the pigmevtum malaricum with haematin. As brown haematin is a product of the gastric and pancreatic digestion of lisemoglobin, in malaria, according to Dr. Cuboni, it is the product of the intracellular digestion of the haemoglobin by the 'plasmodium malarice.
(To
be
continued.)
INDIAN MEDICAL GAZETTE.
/
MALARIAL MELANiEMlA. By Patrick Rehir. m d., f.r.s.e., d.ph. (Cambridge), Lecturer on Medicine and Pathology, Hyderabad Medical School.
To the physician and pathologist in India the of malarial melansemia is one of profound interest for many reasons. It is the commonest abnormal contamination of the blood to be met with in this country ; in cases of malarial infection it is never absent, although in the earlier stage of such poisoning a single or even two observations may fail to detect it; it is believed to be intimately connected with the destruction of the hremoglobin of the red-blood corpuscles caused, by the materies morbi of malarial diseases; and lastly, our knowledge of the subject is still somewhat scanty. We have searched through the greater part of the medical literature of India, and have failed to find a single article, paper or anything beyond meagre references to this condition, the inference being that it has never been made the subject of special investigation, notwithstanding its vast significance, nor have any English writers devoted much attention to it. On the Continent of Europe, however, we find that many authorities have given us elaborate accounts of it, especially Laveran, Mar-
subject
chiafava, Celli, Klebs, Tommasi-Crudeli, Golgi, Cuboni aiub others, although the main part of
our literature regarding it emanates from the As a matter of fact, first three named writers. Laveran found the pigment in the blood of malarial fever patients in Algiers, and it was whilst he was investigating its nature, which he first considered to be parasitic, that he actually made the discovery of the plasmodium malarice. For years after Laveran's discovery of the pigmentary particles in malarial blood, he and
Marchiafava
waged a paper war as to priority of the discovery. The title of this paper is in itself a definition of the mnin feature of the condition under consideration, malarial melancemia, or melanotic pigment in the blood of patients suffering from malarial infection. The term m el ah semi a was, we believe, originally given by Virchow to the presence of pigment in the blood. There is one other condition in which pig ment, free and contained in large white cells, is to be found in the blood, and that is cholera. The nature of the pigment met with, its peculiar distribution and the uniformity of shape of the pigment patches as seen in the field of the microscope were described by the writer in the Supplement to the Indian Medical Gazette, for April 1892. In that paper I ventured to hazard the opinion that I had made an important discovery in the shape of an hsematozoon in the blood of cholera patients, which in its development and morphological characters, had many resemblances to
[July
1894.
khe plasmodium malarise.
The rapidly moving, described and found in a large, fiagelljie certain percentage of cases was another special feature of this organism. This flagellated organism, resembling in certain respects the filaria, sanguinus hominis, must often block uncapillary arterioles, but is rarely met in the blood circulating in the extremities, although it is to be found in the kidneys, in the liver, and capillaries of the lungs. That grave alterations do take place in the blood in cholera is a matter of universal recognition ; but that these changes constitute an important factor both pathologically and possibly etiologically, has not been admitted hitherto. So far back as 1872, Drs. R. T. Lewis and D. D. Cunningham made some very important observations of much the same nature as my own in connection with the blood of cholera cases, and described and pictured an organism which they considered to be a variety of amoeba, that is, a free
protozoon.* The peculiar pathological state which forms the subject of this paper is one which all pathologists in India at least will allow to be of the1 most profound interest, indirectly perhaps more
than any other morbid state in the whole range of pathology. The practitioner of malarial districts is only too familiar with the reasons why it is so overwhelmingly significant. He sees it marked in every case of malaria without exception that comes under his care? to a varying degree certainly, but nevertheless ahvaj's present. Indeed, when we considei' that" malarial diseases are accountable for half the mortality of the world, and that every case of malaria is characterised by the presence of pigment, free in the blood, or otherwise present, apart from the normal colouring matter of the red-blood corpuscles, the significance of the subject in hand comes home to us. We use the word "characterised" in the last sentence advisedly, for the presence of free pigment in the blood in some form or other is the only constant and invariable phenomenon connected with malarial diseases, and especially with malarial fevers. True it is that the plasmodium malarise is also characteristic, but every now and then cases come under observation, in which for some reason this hrematozoon is absent. It cannot be alleged that this occasional absence is due to casual observation, or to the frequent absence of the organism from the peripheral part of the circulation, or to the examination of tlie blood* having been made at unseasonable periods of the day, and so on, because investigators thoroughly familiar with all these possible accidents, and taking all necessary precautions to guard against them, have every now
interesting
* Vide Indian Annuls of Medical Science, Vol. I. and Pathological and Physiological Observations. By R. T? Lewis,
M.B., F.K.S.
July
1894.]
HEHIR ON MALARIAL MELAN^EMIA.
and then failed to find this parasite in the I have examined thousands of slide preblood. parations of malarial blood, and confess that in a varying percentage of cases (from 8 to 23 in different series of observations) the malarial organism is not to be found. On the other hand, in no case of malarial fever in which it was looked for have I failed to find free pigment resulting from the disintegration of the red-blood corpuscles. It is not always to be found in the first or even in the second slide, but careful examination shows it to be invariably present if a sufficiently careful or persevering examination is made. Laveran was the first to direct attention to the melanaemia of malarial fever. In 1880 he pointed out that in these cases the blood contained pigmented particles which were free in the blood or contained within or adherent to the surface of the red-blood corpuscles. These he considered to be of parasitic nature. It is my experience now, as it was some j'ears ago, that in very malarious places it is seldom one comes across a specimen of healthy blood. Indeed, I remember when in 1890-92 I was anxious to make some control observations, I could not find a single individual whose blood was absolutely healthy, that is, perfectly normal in its histological characters, and I had to wait until I came across a healthy person who had just returned from England. Marchiafava and Celli declare that they were the first to describe the transformation of the haemoglobin of the red-blood corpuscles into a melanin-like material under the action of the Plasmodium malarice, and probably their claim is a just one, although Laveran was the first to point out that pigment, free and contained within cells, was frequently found in the blood of patients suffering from malarial infection. In the more chronic cases and with the absence of fever, pigment may not be found in the blood mass itself for a time, but in such cases it will always be found in the spleen, liver and other organs. If we were asked to name one pathognomonic sign of malarial poisoning we should say it was melanaemia, especially in the earty an(j later stages of paludal infection. We find excessively small spherical or rounded granules or flakes which are either free in the blood plasma or are contained in spherical homogeneous cells of larger size than the white-blood cells in the red-blood corpuscles themselves in the so-called phagocytes, and in the large flagellated spherical bodies which form the highest developmental structure of the malarial organism. Klein tells us that in pyaemia a variety of small bacillus occasionally forms emboli of such size as to completely block up the smaller bloodvessels, and he speaks specially of this occurring in lymphatic glands. Koch also states that a
247
still smaller bacillus in this disease completely occludes the lumen of the arterioles and capillary vessels, and that the micrococci of micesepticsemia does the same. There appears to be a doubt as to whether the term melanin should be applied to this variety of pigment, as some authors at least reserve it for the colouring matter found in dark-coloured new growths such as melanotic sarcoma and melanotic cancer. Others apply the term to pigments generally. All pigments, however, take their origin directly or indirectly from the redblood corpuscles; and in the present imperfect condition of our knowledge of pigments of a black or brown colour, it appears that such refined distinction is not only unnecessary but an affectation that can scarcely meet with approbation. That the disintegration of tissue from high temperature is not the cause of this state is apparent from the fact that often melansemia is met with without there having been any fever Nor is it the result of the affections of at all. the internal organs which take place, because the pigment is not met with in the blood in cases of ordinary parenchymatous inflammations of organs. In other affections its presence in the blood may be said to be accidental, or, at least, not permanent, whereas in malarial infection it is never absent from either the blood plasma or white-blood corpuscles or phagocytes, most frequently being found in the internal organs. As invariable accompaniments of this state we have, during the active period of the disease at least, a marked destruction of the red-blood corpuscles which fact alone serves to indicate the origin of the pigment. Another, although a secondary accompaniment, is hypertrophy of the spleen and also, but to a less extent, of the liver. From all we know of the pathological effect of the parasites of malaria it seems almost, if not quite, justifiable to state that the chief process is the appropriation by them of certain constitutions of the haemoglobin, and probably the albumen and oxygen, with the pigment as I have shown elsewhere that an effete product. as soon as set free the spores appear to attach themselves to the surface of the red-blood corpuscles. It is curious that they never undergo any further change whilst free in the blood, a peculiarity which appears to class them amongst what may be termed amoebic protozoa. They seek out the part of blood richest in oxygen. There is of course oxygen in the plasmatic fluid of the blood in combination with carbonate of sodium, but for some reason or another it is not made use of; whereas once the spore gains access to the red-blood cell it forthwith begins the work of disintegrating the haemoglobin, and continues to do so until practically every particle of available material is devoured.
248
INDIAN MEDICAL GAZETTE.
The actual
of the red-blood in the spleen, liver, red marrow of bones, or in the blood-vessels, the particles or granules of pigment being carried along with the blood stream quite free, just as the red and white-blood cells are; there is also a continual ingestion of these pigment particles by the leucocytes, but more specially by the phagocytes, finally reaching some of the smaller sized capillaries of the skin, of a mucous membrane, or in some of the internal organs of the body, there to lodge permanently. Emboli of pigment rarely cause obstruction in the circulatory system during the period they are flowing in the vessels because of their comparatively small size individually. When, however, they do block a capillary or small arteriole, other particles join to form an elongated " terminal mass, but such obstructions, except in arteries," give rise to no serious immediate conse-
corpuscles
disintegration
may take
place
quences. These lumps of pigment are often so large as to become arrested in their course through the circulation in the periphery and internal organs, and thus block up arterioles or capillaries. This is especially the case in the terminal arteries of the brain, of the kidneys, of the liver, pancreas, &c. The result of this is that these organs become highly pigmented, and their blood-supply (especially in those organs with terminal arteries, such as the brain and kidneys) being cut off, there is considerable interference with their nutrition and function, which frequently sets up secondary degenerative changes in organisation and often complete metamorphosis. Apart from malarial fever, enlargement and tenderness of the spleen and liver often result from prolonged residence in a malarial climate. This is evident We see it in in almost every part of India. Hyderabad sometimes in cases succumbing to other maladies. In all varieties of malarial poisoning we have this one symptom which is characteristic and pathognomonic. We get it in the mildest form of malarial poisoning with slight fever, malaise, and headache, as well as in malignant remittents and malarial cachexia, and all intermediate conditions between these clinical manifestations of malarial infection. So that the occurrence of melansemia in India is almost always sufficient to diagnose malarial poisoning. When we consider the multiplicity of clinical phenomena owing their origin to malaria, this diagnostic feature ot malarial melansemia is a matter of the
greatest possible significance.
Some writers consider that there can be little doubt but that the pigment which is found in the blood and internal organs, mucous membranes, and sometimes in the skin, which is so characteristic a phenomenon of malarial fevers, results from the destruction of the haemoglobin of the
[July
1894.
red-blood cells by the plasmodium malariae of Laveran. Sometimes the surface of the pigment has a refractive appearance as if it were crystalline, at others it is dull. It would appear that the condition of the pigment varies considerably with its position and age, as in other forms of pigmentary deposits. As met with in mucous membranes it is likely to be granular, and if in the brain, amorphous or partly crystalline. Slategrey discolouration of the intestinal mucous membrane points either to prolonged catarrh or portal congestion. But a similar condition may arise from malarial pigmentation. The material is certainly not haematin nor haematoidin, nor is it the amorphous pigmentary matter found on the living, the walls of an exIt is not, travasation cyst from haemorrhage. of course, soluble in the blood, nor in weak alkaline or acid solutions, although these break it up into smaller particles or granules. From its general characteristics and history it cannot be the excessively black pigment of the blood either granular or crystalline which we call melanin, because we know this body to be haematoidin, which has undergone certain chemical and physical changes, chief amongst which is the acquisition of more carbon, and decrease in
solubility. The general opinion seems ment deposited in the spleen
to be that the pigis reabsorbed into the blood, and redeposited either in areas where pigment is usually present as the skin or mucous membrane ; or in certain internal organs. But the pigment differs in character from that met with in the blood in the later stages of melanotic cancer, or melanotic sarcoma, and although having originally precisely the same origin, it differs considerably in the mechanism of its production. Apart from the pains of the febrile stage in undeveloped malaria, there is often for days a tenderness occurring throughout the body with more or less malaise, and a general want of the feeling of bien etre. The malarial origin of these cases is often shown therapeutically by the complete and permanent disappearance of all trouble after 15-grain doses of quinine have been taken two or three times. Often this state is combined with slight pyrexial phenomena, the temperature Thus we have not going beyond 100? or 101?F. an absolute specific in sulphate of quinine. The latest researches on the pigment of malaria are those of Dr. Cuboni communicated to the Academy of Medicine of Paris. Dr. Cuboni, as the result of special experiments, believes he can identify the pigmevtum malaricum with haematin. As brown haematin is a product of the gastric and pancreatic digestion of lisemoglobin, in malaria, according to Dr. Cuboni, it is the product of the intracellular digestion of the haemoglobin by the 'plasmodium malarice.
(To
be
continued.)
