An Experimental Study op 
the Toxic Properties 
oe Indol. 
BY 
C. A. HEKTEE, M. 1)., 
Visiting Physician to the City (Charity) Hospital; 
Consulting Physician to the Babies’ Hospital. 
N«to York .Ptetrfcal Journal 
KBPBINTED FROM THE 
for July 16 and 23, 1898. Reprinted from the New Yorle Medical Journal 
for July 16 and S3, 1898. 
THE TOXIC PROPERTIES OF INDOL* 
AN EXPERIMENTAL STUDY OF 
0. A. HERTER, M.D., 
VISITING PHYSICIAN TO THE CITY (CHARITY) HOSPITAL ; 
CONSULTING PHYSICIAN TO THE BABIES1 HOSPITAL. 
I wish to bring to your attention this evening cer- 
tain facts relating to the action of indol npon various 
animals, including man. These facts possess a consider- 
able degree of practical interest, because indol is a sub- 
stance produced in some amount in the intestine of most 
adult human beings as the result of bacterial action 
upon proteids. The indol produced in the intestine is 
oxidized within the organism into indoxyl, which, in 
combination with sulphuric acid, as indoxyl-potassium 
sulphate, forms the basis of the well-known indoxyl or 
indican reaction of the urine. It is not uncommon in 
various derangements of digestion to find the indoxyl 
or indiean reaction of the urine much more pronounced 
than in health, and the inference from such increase is 
that an unusual quantity of indol has been formed in 
the intestine and absorbed from it. The question which 
will be discussed and in some measure answered in this 
* Read before the New York Pathological Society, March 9, 1898. 
Copyright, 1898, by D. Appleton and Company. 2 
THE TOXIC PROPERTIES OF INDOL. 
paper is this: What detrimental effects, if any, does the 
excessive formation and absorption of indol entail upon 
the human organism? In order to discuss this ques- 
tion in an intelligent manner it is desirable to review 
systematically the facts that bear upon it. This may be 
conveniently done by considering: 
First: The chemical nature of indol, the conditions 
under which it is produced, and its transformation into 
the indoxyl-potassium sulphate of the urine. 
Secondly; The action of indol upon animal organ- 
isms. 
Thirdly: The clinical conditions in which the in- 
doxyl of the nrine is increased, and their relations to ex- 
cessive indol production. 
1. The Chemical Nature of Indol, the Conditions 
under which it is produced, and its Transformation into 
the Indoxyl-Potassium Sulphate of the Urine.—Al- 
though this section has important bearings on the prob- 
lem to be discussed, I shall refer to it only briefly this 
evening, as it is my intention to make indol production 
the subject of a special and somewhat technical com- 
munication. 
H H H 
C CO CH 
/\ /\ /\ /\ 
HC—CH HC CH HC 0 CH HC—C 
II II II I I » I II II I 
HC CH HC CH HC C CH HC C CH 
\/ V W \/V 
NH C C C NH C 
Pyrrol. H H H H 
Indol is a derivative of the aromatic series and a 
member of the indigo group of compounds. Its empiri- 
cal formula is C 8H7H. Its relation to the aromatic 
Benzene. Naphthalene. Indol. THE TOXIC PROPERTIES OF INDOL. 
3 
series is best seen by considering its probable constitu- 
tional structure, which is represented by a union of 
pyrrol and benzene in such a manner that pyrrol and 
benzene have two carbon atoms in common—as, for in- 
stance, in naphthalene. 
Indol crystallizes in glancing white crystals, has a 
melting point of 52° C., and volatilizes readily with 
steam. It has a characteristic faecal odor, and is partly 
responsible for the odor of normal human faeces. I have 
noticed that the odor is less intense when the indol is 
thoroughly freed from an unknown oily substance * with 
which it is apt to be associated when derived from putre- 
fying fibrin. Indol is a weak base. It is soluble in 
water. A solution containing indol, when treated with 
sulphuric acid and sodium nitrate, undergoes a change 
in color due to the formation of nitroso-indol. The re- 
action is an exceedingly delicate one, for it is recog- 
nizable in a solution of one part of indol in two hundred 
thousand of water. The well-known “ cholera-red ” re- 
action depends on the formation of nitroso-indol. 
Although indol may be produced without the inter- 
vention of bacterial activity—as, for example, by heat- 
ing O-nitro-cinnamic acid with potash and iron fil- 
ings, and by the action of alkalies on proteids—it is 
its production as the result of the action of bacteria 
upon proteids that interests the pathologist. 
It is produced by the action of a considerable variety 
of bacteria, both pathogenic and non-pathogenic. Thus 
it is one of the products of the activity of most varieties 
of the Bacillus coli comm,unis, of the Proteus vulgaris, 
of the typhoid bacillus, of most vibrios, of the comma 
bacillus of cholera, of putrefactive bacteria, etc. The 
* This substance lowers the melting point one or two degrees. 4 
THE TOXIC PROPERTIES OF INDOL. 
formation of indol through bacterial activity is distinct- 
ly influenced by a variety of conditions. It was found by 
Hoppe-Seyler,* for instance, that when an abundance 
of oxygen came into contact with putrefying proteid 
material, which would ordinarily yield indol, and the 
carbon dioxide and ammonium carbonate resulting from 
the putrefactive process were rapidly and entirely re- 
moved, indol, skatol, mercaptan, etc., were not formed 
at all. Salkowski and Blumenthal f found that a slight 
grade of alkalescence was more favorable to the forma- 
tion of indol than a somewhat stronger degree of alkalin- 
ity. Smith has recently shown that the presence of 
sugar retards the indol production of the colon bacillus, 
because micro-organisms act on the sugar rather than 
on proteids until the former is consumed. 
I have found that the addition of the common yeast 
plant to fibrin putrefying under the influence of the 
colon bacillus may cause a marked diminution in the 
usual yield of indol. These examples of influences capa- 
ble of modifying the production of indol must suffice. J 
A knowledge of them helps us to explain the variations 
in indol production that occur in the human intestine. 
Although there is no close relation between the 
pathogenic properties of the colon bacillus and its indol 
* Zeitschrift fur physiologische Chemie, Bd. viii, 1884. 
Zeitschrift fur Min. Medicin, Bd. viii. 
| It was found by Brieger {Zeitschrift fur physiologische Chemie, Bd. 
iii, p. 141) that the entire absence of air greatly slowed but did not wholly 
prevent the production of indol. There appeared to be no difference 
between the effect of the presence of a moderate and an abundant sup- 
ply of air. Salkowski found that indol once formed was not destroyed, 
even in part, by the progress of putrefaction, but some loss by evapora- 
tion took place when air was freely admitted. There is good reason to 
think, however, that indol undergoes decomposition in watery solutions. THE TOXIC PROPERTIES OF IXDOL. 
5 
production, both can be increased by the growth of a 
culture in a medium which contains an unusual amount 
of proteid material especially adapted for bacterial as- 
similation.* 
It is, of course, not to be understood that indol is the 
sole aromatic product of proteid putrefaction, although 
under certain conditions it is the chief one. Skatol, 
phenol, parakresol, and benzoic acid are other aromatic 
decomposition products of the proteid molecule. 
The indol which was employed in the experimental 
observations to be described was obtained from the pu- 
trefaction of large quantities of pig’s fibrin. Thus two 
thousand grammes of fibrin after exposure to the air 
for eight days yielded 2.7 grammes of indol. It was 
found that the addition of cultures of the common colon 
bacillus from the faeces of a normal individual resulted 
in a large yield—namely, 4.2 grammes of indol—the 
quantity of fibrin, the duration of the process, and the 
temperature being the same as in the case first men- 
tioned. f It is not necessary to refer here to the meth- 
ods used for the isolation of pure indol, which was pre- 
pared for me in considerable amounts by Dr. A. J. 
Wakeman. 
The indol absorbed from the intestine is not ex- 
creted as such by the urine, bnt undergoes an interesting 
and important change within the organism. 
This change consists, first, in the oxidation of indol, 
and, secondly, in the combination of indoxyl with sul- 
phuric acid to form the indoxyl-sulphate of potassium. 
*A. W. Ward. Journal of Experimental Medicine, September, 189 V, 
p. 569. 
f In a case in which the yeast plant as well as the colon bacillus was 
added to 1800 grammes of fibrin the yield of indol was much smaller 
(1.3 gramme), although the putrefaction continued for about two weeks. 6 
THE TOXIC PROPERTIES OF IXDOL. 
It is as the indoxyl-sulphate of potassium that the 
indoxyl formed within the organism leaves the body 
in the urine. Other putrefactive products than indol— 
for instance, skatol, phenol, and kresol—undergo a simi- 
lar conjugation with sulphuric acid in the organism, 
and are eventually excreted as potassium salts of sul- 
phuric acid. These bodies are sometimes referred to as 
ethereal sulphates, sometimes as combined or conjugated 
sulphates. 
The indoxy 1-potassium sulphate which is found in 
the urine is not to be recognized as such without elabo- 
rate chemical manipulation. The indoxyl radicle may, 
however, be easily oxidized into indigo blue or indiean, 
by means of calcium hypochlorite, as proposed by Jatfe, 
or by means of ferric chloride in hydrochloric acid, as 
proposed by Obermeyer. This appearance of indigo blue 
on oxidation is the reaction employed in the routine ex- 
amination of urine—the so-called indican test, or, as we 
should say, the indoxyl test. By its help we are enabled 
to say whether the urine contains more indoxyl than is 
usual in health, and to detect marked variations from 
day to day, but it scarcely suffices to make us positive 
of the occurrence of slight variations. 
When we come to inquire into the seat in the organ- 
ism of this remarkable synthesis of indol and other 
aromatic compounds with sulphuric acid, it is seen that 
we have no positive knowledge. The observations of 
Baumann,* however, render it probable that the liver 
takes a part in bringing about this conjugation. 
* Baumann. Pflueger’s Archiv, Bd. iii, 1870, S. 448; also, Christian 
und Baumann. Zeitschrift fur physiologische Chemie, Bd. ii, 1878, S. 
350; also, Baumann. Pflueger’s Archiv, Bd. xii, 1876, and Bd. xiii, 
1876. THE TOXIC PROPERTIES OF INDOL. 
7 
That the animal organism is capable of rapidly 
transforming considerable quantities of indol seems 
clear from experiments of which the. following is an ex- 
ample : Into the femoral vein of a strong dog weighing 
about thirty pounds was injected an aqueous .228-per- 
cent. solution of indol at the rate of five cubic centi- 
metres per minute. From time to time small quantities 
of blood were withdrawn from the femoral vein of the 
opposite side. Although as large a quantity of indol as 
half a gramme was introduced into this animal, no 
indol could be detected in the distillate from the blood 
drawn. Very minute quantities of indol are readily de- 
tected in the distillate of blood to which indol is added 
outside the body. 
Although we are wanting in positive information as 
to the parts of the body concerned with the indoxyl syn- 
thesis we have a little light on the equally interesting 
question of the significance of this pairing process to the 
organism. Thus Stolnikow * observed that resorcin and 
pyrogallol are much more toxic than resorcin-sulphuric 
acid and pyrogallol-sulphuric acid respectively. In har- 
mony with this observation is the fact that Baumann 
found phenol to be distinctly more toxic than phenol- 
sulphuric acid. There are as yet no observations, I be- 
lieve, relating to the comparative toxicity of indol and 
indoxyl-potassium sulphate, but it seems safe to infer 
from analogy that in the case of indol, as with phenol, 
the conjugation with sulphuric acid is a process by which 
the poisonous properties of this aromatic product of 
putrefaction are lessened, or, as one might say, the pro- 
cess exerts a detoxicating influence upon the organism. 
There yet remains much to be learned regarding the 
* Zeitschrift fur Physiologic, Bd. viii, S. 280. 8 
THE TOXIC PROPERTIES OF INDOL. 
influences that favor and that inhibit the formation of 
indol within the human intestine. In a recently pub- 
lished paper I advanced experimental evidence in favor 
of the view that the main factor in the production of 
indol in the intestine is the common colon bacillus, and 
it is an indisputable fact that conditions which permit 
the multiplication of this organism are associated with 
the presence of a strong indoxyl reaction in the urine. It 
was found that when large numbers of a pure colon-ba- 
cillus culture from normal human or dog’s faeces were 
injected in watery solution into a loop of the small 
intestine in a dog, the urine invariably gave a very 
strong indoxyl reaction, although it might previously 
have given a negative reaction. On the other hand, 
negative results were obtained with injections of pure 
cultures of the lactic-acid bacillus, which produces little 
or no indol. 
The evidence that the administration of indol is fol- 
lowed by an increase in the indoxyl reaction is beyond 
criticism, as I have satisfied myself in the case of rab- 
bits, dogs, and human beings. It need not be further 
referred to. 
In concluding this abridged presentation of the lead- 
ing facts pertaining to the nature of indol and its rela- 
tion to the indoxyl-potassium sulphate of the urine, it is 
desirable to reiterate and emphasize the fact that we 
possess an unbroken chain of evidence connecting the 
indican of the urine with the putrefaction of proteids 
and the production of indol. This chain consists of the 
following links: 
1. The fact that certain proteids may be in vari- 
ous ways decomposed so as to yield aromatic derivatives, 
including indol. THE TOXIC PROPERTIES OF IXDOL. 
9 
2. The fact that the common colon bacillus, which 
normally inhabits the human intestine, and some other 
micro-organisms are ordinarily producers of indol when 
acting upon proteid media. 
3. The fact that indol produced in the intestine is 
transformed into indoxyl after absorption, and subse- 
quently into indoxyl-potassium sulphate, within the or- 
ganism, probably in the liver. 
4. The fact that the indoxyl of the urine is con- 
vertible by oxidation into indigo blue or indican. 
2. The Action of Indol upon Animal Organisms.— 
The literature relating to the action of indol upon ani- 
mals is scanty. The first observation relating to the 
subject is probably that of iSTeneki,* who in 1876 ob- 
served that a dog to which one gramme of indol had 
been fed showed no indication of intoxication, but de- 
veloped active diarrhoea and hamaaturia when it received 
two grammes in twenty-four hours. Christiani f two 
years later found that indol, like phenol, was readily 
absorbed by frogs through the medium of the skin, and 
gave rise to increased reflex irritability followed by 
slight transient paralysis when the animals were placed 
in a solution containing ten milligrammes of indol in 
a hundred cubic centimetres of water. 
These symptoms resembled in every respect the 
symptoms observed to follow the absorption of phenol. 
When a frog was placed in twenty cubic centimetres of a 
one-per-cent, solution of indol several paralytic symp- 
toms appeared after thirty-five or forty minutes. Even 
in this condition slight external stimuli gave rise to 
* Berichte der deutsch. chem. GeseUsch. zu Berlin, 1876, S. 299. 
f Ueber das Verhalten von Phenol, Indol und Benzol im Thierkdrper. 
Zeitschriftfur physiologische Chemie, Bd. ii, 1878. 10 
THE TOXIC PROPERTIES OF INDOL. 
tremor. Death occurred invariably at the expiration of 
twenty-four hours. It was further found by Christiani 
that very minute doses of indol gave rise to pronounced 
and persistent symptoms when injected subcutaneously, 
the effects of an injection of 1.2 milligramme being still 
noticeable after forty-eight hours. The abdominal or- 
gans in such cases were found to be congested and the 
liver was colored yellow. 
No further observations were made on the toxic prop- 
erties of indol until 1896, if we may judge by a fairly 
careful search through the literature relating to the 
subject. Then Rovighi * published some experiments in 
relation to the toxic effects of indol, skatol, and phenol. 
He found that indol and skatol produce essentially the 
same derangements in rabbits—namely, torpor, somno- 
lence, widespread paresis, feeble heart action, reduction 
in temperature, and retention of urine and fasces. The 
fatal doses of indol and skatol for rabbits was found to 
be 1.5 to two grammes, when given subcutaneously in 
the course of forty-eight hours. Rovighi found that 
animals became more sensitive to the poison after the 
first dose, as though they no longer possessed the power 
of transforming and excreting it. 
Congestion of the liver was found to succeed acute 
indol poisoning. In chronic poisoning areas of small 
spheroidal cell infiltration were observed surrounding 
the bile ducts. The kidneys were the seat of congestion 
only. 
The experimental observations made by me were con- 
ducted without knowledge of the work of Rovighi, and 
cover a somewhat different field. They relate to acute 
* Azione dei prodotti tossici delle fermentazioni enteriche nella milza 
ed il fegato. Arch, di farmacologia e terapeutica, iv, fas. 3, 1896. THE TOXIC PROPERTIES OF INDOL 
11 
indol poisoning in rabbits and dogs, to chronic indol 
poisoning in rabbits, and to the effects of moderate 
doses, taken by the stomach, on man. 
A. ACUTE INDOL POISONING IN RABBITS AND DOGS. 
Experiment No. 1.—Injection of indol solution in 
the intestine. Large rabbit weighing about three thou- 
sand grammes. 
After laparotomy, 195 cubic centimetres of a 0.1-per- 
cent. solution of indol were injected into the large in- 
testine. During the infusion the pupils became much 
contracted, but afterward returned to normal. There 
was some twitching of the muscles during and after the 
injection. This lasted during several hours. The ani- 
mal developed no new symptoms and was ultimately 
chloroformed. Previous to the injection the urine con- 
tained no indican. After the injection a strong reac- 
tion was present. 
Experiment No. 2.—lnjection of indol solution into 
femoral vein. Eabbit weighing 1,330 grammes. A 0.1- 
per-cent. solution of indol was injected into the femoral 
vein at the rate of five cubic centimetres a minute. 
After thirty cubic centimetres were injected the animal 
was much prostrated, the heart action was very feeble, 
the respiration was weak, and the pupils were very 
strongly contracted. When the injection was stopped, 
the pupils widened a little. The animal remained much 
prostrated and died about two hours later, “ gasping ” 
Nothing abnormal was noticeable at autopsy. 
Experiment No. S.—lnjection of indol solution into 
femoral vein. Eabbit weighing 3,100 grammes. A 0.1- 
per-cent. solution of indol was injected into the femoral 
vein at the rate of five cubic centimetres to the minute. 
Between five and ten cubic centimetres, momentary con- 
traction of pupils; at ten to fifteen cubic centimetres 
pupils were normal. After twenty cubic centimetres, 
pupils were a little smaller than at onset. After forty- 
eight cubic centimetres, rather violent tonic spasm (not 
clearly involuntary). After seventy-two cubic centi- 12 
THE TOXIC PROPERTIES OF INDOL. 
metres, pupils became suddenly contracted. Injection 
was stopped. Pupils remained small about three min- 
utes, then widened. Twitching began in muscles of face. 
Eespiration was shallow and slow, and heart action was 
weak. Injection resumed after about four minutes. 
After ninety-two cubic centimetres there was general 
fibrillary spasm. The reflex excitability of the muscles 
was increased. After stopping the injection (at ninety- 
two centimetres) the animal lay quietly for about two 
hours, the heart and respiration becoming better. Then 
there developed irregular general clonic spasm, depress- 
ing the heart and respiration. Death occurred appar- 
ently from cardiac failure. 
Experiment No. J/..—Injection of indol solution into 
femoral vein. A 0.1-per-cent, solution of indol was 
injected slowly into the femoral vein of a small dog 
weighing about fifteen pounds. After twenty-five cubic 
centimetres the pupils were strongly contracted. After 
fifty cubic centimetres the heart was weak and the res- 
piration slow. Fibrillary contractions occurred, espe- 
cially marked in the legs. After seventy cubic centi- 
metres there were irregular clonic spasms in the legs. 
These soon ceased. The animal was unsteady after the 
injection. At one time he appeared excited and ran 
round and round the room. Eight hours later the ani- 
mal was found dead. 
Experiment No. 5.—Injection of indol solution into 
femoral vein. A 0.1-per-cent, solution of indol was in- 
jected at the rate of five cubic centimetres to the min- 
ute into a dog weighing about twenty-five pounds. After 
about five cubic centimetres the pupils were contracted. 
After twenty cubic centimetres the pupils were strong- 
ly contracted and remained so, the respiration was 
slowed, and there was slight clonic spasm in the muscles 
of the leg on the side of the vein infused. This spasm 
increased and the knee-jerks became much exaggerated. 
After a time the spasm became continuous and rather 
violent. After seventy cubic centimetres irregular clonic 
spasm extended to all four extremities. Respiration be- THE TOXIC PROPERTIES OF INDOL. 
13 
came very much slowed and heart action grew feeble. 
At one hundred and sixty-two cubic centimetres the in- 
jection was stopped. The spasm soon ceased wholly 
and the animal ran about freely. The animal wholly 
recovered. 
Experiment No. 6.—lnjection of indol solution into 
femoral vein. A dog was chloroformed and fifty-five 
cubic centimetres of a 0.1-per-cent, solution of indol in- 
troduced into the femoral vein. Only slight contraction 
of the pupils was observed. The animal was bled to 
death. 
Experiment No. 7.—Injection of indol solution into 
femoral vein. A 0.1-per-cent, solution of indol was in- 
jected into the femoral vein of a dog weighing about 
twenty pounds, at the rate of five cubic centimetres a 
minute. After fifteen cubic centimetres the pupils were 
contracted; subsequently they became very strongly con- 
tracted. The reflexes were much exaggerated; the heart 
became slow and weak. After about fifty-five cubic cen- 
timetres clonic spasm occurred in the four extremities. 
The animal was bled to death. 
It is clear from the foregoing experimental records 
that intravenous injections of indol exert marked toxic 
effects upon the nervous system both in rabbits and in 
dogs. Both in rabbits and in dogs the characteristic 
symptoms were cardiac and respiratory depression, gen- 
eral prostration, marked contraction of the pupils, irreg- 
ular clonic spasm, and increased reflex excitability, in- 
cluding increase in the activity of the knee-jerks. When 
a quantity of indol sufficient to cause death was injected, 
the cause of death in several instances seemed to be car- 
diac rather than respiratory failure. In one instance 
only (Experiment No. 6) was myosis not a pronounced 
symptom. In this case the animal had been chloro- 
formed previous to the infusion of the indol solution. 
It is noticeable that in the first experiment (the only 14 
THE TOXIC PROPERTIES OF INDOL. 
oue in which the indol was injected directly into the 
intestine) both myosis and twitching were present. 
Although the effects of intravenous infusion and those 
of intraintestinal infusion are probably similar, there 
seems little doubt that the influence upon the nervous 
system is much more pronounced in the ease of intra- 
venous infusions. Observations upon the temperature 
were not made, nor was it practicable to make studies 
of the arterial pressure. 
The following observations illustrate the effects of 
repeated small doses of indol, given subcutaneously, 
upon rabbits. 
B. CHRONIC INDOL POISONING IN RABBITS. 
Experiment No. I.—lnjection of indol subcutane- 
ously. A rabbit, weighing 1,470 grammes, received ten 
cubic centimetres of a 0.1-per-cent, solution of indol 
subcutaneously daily for six days. Then, after an inter- 
val of five days, the animal received ten cubic centi- 
metres daily during ten days. The only symptoms ob- 
served were marked prostration and gradual loss of 
weight. The animal was well fed and took considerable 
food. Death occurred sixteen days after the beginning 
of the experiment. Weight at death, 1,120 grammes. 
Experiment No. 2.—Injection of indol subcutane- 
ously. A rabbit weighing 1,170 grammes received ten 
cubic centimetres of a 0.1-per-cent, solution of indol 
daily during thirteen days. The animal became pros- 
trated and lost weight. Death occurred at the end of 
thirteen days. At this time the animal weighed 920 
grammes. 
Experiment No. 3.—lnjection of indol subcutane- 
ously. A rabbit weighing 1,480 grammes received ten 
cubic centimetres of a 0.1-per-cent, solution of indol 
daily during twenty-two days. No symptoms were noted 
except that the animal became very quiet and lost 
weight, although he ate fairly well. At the time of THE TOXIC PROPERTIES OF INDOL. 
15 
death, twenty-two days after the beginning of the ex- 
periment, the weight of the animal was 930 grammes. 
These three observations upon rabbits plainly indi- 
cate that even small quantities of indol daily, adminis- 
tered subcutaneously, are capable of initiating profound 
disturbances of nutrition which end in death in the 
course of a few weeks. The total quantities of indol 
required to cause death were in the first case 0.16 
gramme, in the second 0.13 gramme, and in the third 
0.22 gramme. The loss of weight which followed the 
administration of the indol was the most obvious and 
striking feature of its action. It amounted in the first 
case to twenty-three per cent, of the body weight, in the 
second to twenty-one per cent., and in the third to 
thirty-seven per cent. It is impossible to say in how far 
loss of appetite is responsible for this rather rapid 
diminution in weight. Another prominent symptom 
was the prostration and diminished activity observed in 
all three animals. ISTo observations were made upon the 
condition of the pupils nor was the temperature noted. 
The immediate cause of death from chronic indol poi- 
soning is not clear, and deserves to be especially investi- 
gated. 
The histological changes observed in the organs of 
these animals will be elsewhere described. It is sufficient 
to mention here that the chief alterations were found in 
the liver, the capillaries of the lobules being much con- 
gested, and the liver cells being the seat of degeneration 
and pigmentation. 
Before considering the influence of the experimental 
administration of indol on the human subject it may 
be well to state that a small ringtail monkey, weighing 
about fourteen hundred grammes, received five cubic 16 
THE TOXIC PROPERTIES OF IXDOL. 
centimetres of a 0.1-per-cent, solution of indol daily for 
two months without any apparent effect. Later experi- 
ments with larger quantities of indol showed the animal 
to be far less susceptible than rabbits of equal weight. 
C. EXPERIMENTAL INDOL POISONING IN MAN. 
Interesting and suggestive as are the results of indol 
poisoning in dogs, rabbits, etc., they nevertheless fail 
to afford a satisfactory basis for an understanding of the 
influence of this substance upon the human organism. 
Yet it is with its effect upon the human organism that 
we are chiefly concerned. There are two ways in which 
the effect of indol upon the human animal may be in- 
vestigated. One of these is the careful observation of 
clinical conditions that are characterized by the pres- 
ence of a markedly excessive excretion of an indoxyl 
compound. This method has been much employed by 
clinicians in the study of nutritive derangements. It 
is open to the very obvious objection that it is hardly 
possible to study with satisfaction the influence of a 
single factor in the production of disease where other 
factors of perhaps equal significance are not only opera- 
tive, but operative in a more or less variable way. The 
history of oxaluria and of the symptomatology which 
has been affixed to it is an instructive illustration of 
the pitfalls that lie in the course of the observer who 
relies wholly on the clinical method of studying the 
pathological factors in nutritive disorders. 
The second method that is open to the investigator 
possesses the great advantage of enabling him to vary 
one factor at a time in the experiments which he insti- 
tutes. This method consists in administering to human 
subjects the substance the influence of which it is de- 
sired to determine. If, then, such' conditions as food 
and drink, exercise, mental work, the use of tobacco, 
etc., be kept reasonably constant, it is safe to assume that 
unusual symptoms varying concomitantly with the ad- 
ministration of the substance under investigation are 
dependent on this substance. THE TOXIC PROPERTIES OF INDOL. 
This is the course that was pursued in the case of our 
study of the properties of indol. Three healthy men 
were induced to take indol in increasing doses, the vari- 
ous hygienic conditions referred to above being kept 
nearly constant from day to day for a period previous to 
the administration of the indol as well as during this 
period. The indol was given in gelatin capsules contain- 
ing a tenth of a gramme each. In order to minimize 
digestive derangement from the irritant action of the 
indol it was administered immediately after meals. 
The first observation relates to a man thirty-two 
years of age, weighing a hundred and fifty pounds, and 
in exceptionally robust health. Table A gives the main 
data pertaining to the experiment. 
The second observation relates to a vigorous medical 
student, twenty-five years of age, weighing about a hun- 
dred and sixty pounds. 
The doses given in this case were very large. 
Date. 
Quantity of indol taken. 
Symptoms. 
January 30th.... 
1 gramme in divided 
doses. 
Xo symptoms whatever. 
January 31st 
1.2 gramme in divided 
doses. 
Intestinal flatulence during 
morning. Xo other symp- 
toms until evening. Then 
incapacity for mental work; 
can not memorize. Xo 
symptoms during the day. 
February 1st 
2 grammes in divided 
doses. 
Slept only a short time during 
the night. Eestless and very 
active mentally. Such sleep 
as was obtained was inter- 
rupted by vivid dreams. 
February 2d 
0.6 gramme in divided 
doses. 
Headache on rising. Soon 
passed away. Xo other 
symptoms. 
February 3d 
1 gramme in divided 
doses. 
Sleep much disturbed by 
dreams. 
February 4th 
1 gramme in divided 
doses. 
Insomnia. 
Observation No. 2. 18 
THE TOXIC PROPERTIES OF INDOL, 
There can be little doubt that the insomnia in this 
subject was due to the action of the indol taken, as he 
is an exceptionally deep sleeper, and his habits of life 
were unchanged during the period of the experiment. 
The amounts of indol taken were so large as to deprive 
the effects observed of much of their interest, it being 
questionable whether such large quantities are ever 
formed in the human intestine, except perhaps where 
the gut is occluded. 
Table B shows the changes in the indoxyl reaction 
and in the ethereal sulphates which were occasioned by 
the administration of indol. 
The third observation was made upon a medical stu- 
dent twenty-six years of age, in good health, but not 
especially robust, and weighing at the time a hundred 
and thirty pounds. He was told to keep a record of the 
pulse, temperature, and respiration, morning and after- 
noon, and to note any definite symptoms that might 
arise. The observation upon this person is made up of 
three different trials, as will be seen by Table C, 
which takes note of the leading features of the experi- 
ment. 
The chief effect recorded in the first observation is 
the occurrence of slight frontal headache and a sensa- 
tion of “ light-headedness ”or giddiness. An interest- 
ing feature was the occurrence of colic followed by diar- 
rhoea. This being a very exceptional occurrence in the 
subject of the observation, it can hardly he questioned 
that it was dependent upon the rather large doses of 
indol taken during the day. The occurrence of diar- 
rhoea corresponds with the fact that diarrhoea has been 
observed, as already mentioned, after the administration 
of indol to dogs. It is noteworthy that although the sub- THE TOXIC PROPERTIES OF INDOL. 
19 
ject received 0.5 gramme of indol (a large dose) on the 
following day, he felt entirely well with the exception 
of a little unsteadiness in the legs and stiffness in walk- 
ing upstairs. It occurs to one that the effects of indol 
may have been minimized through the apparently thor- 
ough emptying of the colon which occurred. 
The main features of the third observation resem- 
ble those of the first. The symptoms were, however, a 
little more pronounced, although the quantity of indol 
was smaller. During the first trial frontal headache or 
a “ sensation of fullness in the forehead ” was present 
the greater part of the time. A sensation of dizziness 
was also noted at one time. Toward the end of the 
observation the knee-jerks seemed increased as com- 
pared with previous days. As soon as the indol was 
stopped the symptoms wore away, and there was no re- 
currence of similar disturbances until after the begin- 
ning of the second trial, five days after the completion 
of the first. Then, after the administration of rather 
large quantities of indol, the original symptoms, espe- 
cially frontal headache, returned. The headache and 
prostration were in fact so marked that it was consid- 
ered best to discontinue the experiment. As in the first 
trial, the discontinuance of the indol was quickly fol- 
lowed by an entire subsidence of symptoms. The aim of 
the third trial was to give quantities of indol which, 
while occasioning definite symptoms, should not cause 
such pronounced derangements as to make the con- 
tinuance of the experiment over a longer period of time 
impossible. The period covered by this trial was eight 
days. Although marked headache was present only 
once during the period, a sensation of discomfort in the 
frontal region was an almost continuous feature of the THE TOXIC PROPERTIES OF INDOL. 
experiment. The characteristic feature, however, of the 
trial was a decided sense of fatigue. The subject of the 
experiments summed up his experience by saying that 
the first and second trials gave him headache, while the 
third trial gave rise to lassitude and inability to work. 
In all three cases the influence of the administration 
of indol upon the indoxyl reaction and upon the com- 
bined or ethereal sulphates was pronounced, as may be 
seen by the tables. 
A feature of the third observation which is of some 
interest is that previous to the use of indol the urine 
failed to give any indoxyl reaction, but gave it strongly 
after the indol was begun, only to lose it when the indol 
was discontinued. 
In the second case, in which very large quantities of 
indol were given, the intensity of the indoxyl reaction 
was very unusual, and the increase in the ethereal sul- 
phates was greater than I have ever observed in natural 
pathological conditions. 
The Clinical Conditions in which the Indoxyl of the 
Urine is increased and their Relation to Excessive Indol 
Production.—We come now to the most difficult and im- 
portant part of our subject, the interpretation of the 
clinical significance of excessive indol production in the 
intestine and of its excessive absorption as indicated by 
the presence of a strong indoxyl reaction in the urine. 
One of the' obvious difficulties with which one is 
met on the onset in any attempt to determine the sig- 
nificance of excessive indol absorption lies in our inabil- 
ity to set up a satisfactory standard for deciding what is 
to be looked upon as a normal indoxyl reaction. We know 
there are many individuals in good health whose urine 
yields a certain amount of indigo blue, and we must rec- THE TOXIC PROPERTIES OF INDOL. 
21 
ognize that the presence of an indoxyl compound in the 
urine is a normal characteristic, although in many nor- 
mal individuals the reaction is commonly entirely want- 
ing. There are, on the other hand, a good many per- 
sons who complain of various trivial disturbances, such 
as headache, depression of spirits, fugitive muscle pains 
or muscular rheumatism, and various neurasthenic 
symptoms, whose urines almost regularly yield an in- 
doxyl reaction that is much stronger than is usual in 
health. It often happens that these symptoms grow 
less or disappear under influences that coincidently re- 
duce or stop the excretion of indoxyl. Observing this 
concomitant variation, one is led to speculate as to the 
relation which the phenomena bear to one another; or, to 
put it more definitely, to ask whether it is correct to 
refer any or all of a certain group of symptoms to the 
excessive absorption of indol. In some respects the con- 
ditions of the problem resemble the oxaluria question. 
In both cases a normal but not necessary constituent 
of the urine is apparently excreted in excess, especially 
in persons presenting certain nervous disturbances, and 
in both cases the symptoms are apt to retrogress when 
the excessive excretion stops. In both cases we have to 
recognize the fact that this relationship, which suggests 
cause and effect, may be one of mere coincidence. In 
regard to both questions we have to confess that actual 
proofs of the suspected relation of cause and effect are 
wanting, and that the symptoms which one is inclined 
to attribute to a particular agency may be dependent on 
one or more unknown influences. In the case of indol, 
the experimental observations just recorded aid us in 
forming a conception of what symptoms may be attrib- 
utable to excessive indol absorption. The first and third 22 
THE TOXIC PROPERTIES OF INDOL. 
observations make it in the highest degree probable that 
frontal headache, as well as cephalic sensations not 
strictly to be called headache, may be produced through 
the agency of indol. It is, of course, conceivable that the 
occurrence of these symptoms was a coincidence, but, as 
the correspondence between the head symptoms and the 
administration of the indol was exceedingly close, the 
likelihood of mere coincidence, in the case of persons 
seldom troubled with headache, seems very small—too 
small to consider seriously. An interesting feature of 
the headache in the third subject was the improvement 
which on several occasions followed out-of-door exer- 
cise. 
We may, therefore, regard headache, especially fron- 
tal headache, as one of the conditions referable to indol, 
but when we come to consider how frequently indol is 
the chief or sole cause of such headache it is necessary 
to proceed with the greatest caution. Such experience 
as I have had in the study of headache leads me to think 
that most frontal headaches depend upon other causes, 
and it is only in the cases (which I believe to be few) 
where the appearance and departure of headache corre- 
spond with distinct and wide fluctuations in the indoxyl 
of the urine that such a causation is to be suspected. 
Even here it is likely that the suspicion is justifiable 
only when the reaction is strongly marked. It seems to 
me likely that sensations of discomfort in the head, 
hardly amounting to headache, may more often be the 
result of excessive indol absorption than actual head- 
ache, and that the cephalic sensations of constipation 
may be, in part at least, thus explained. The very pro- 
nounced sense of fatigue developed in the third subject 
suggests that the long-continued excessive absorption THE TOXIC PROPERTIES OF INDOL. 
23 
of indol from the intestine may sometimes be responsible 
for lassitude and a sense of fatigue disproportionate to 
the amount of mental and muscular energy expended. 
The very large proportion of strong indoxyl reactions 
observed among neurasthenic persons lends some clini- 
cal support to this view.* It seems to me that the evi- 
dence,, though not conclusive, strongly favors the view 
that the long-continued overproduction and absorption 
of indol is a factor at least in rendering some persons 
more readily fatigued than normal individuals. 
An interesting question which suggests itself is 
whether indol is capable of increasing the excitability of 
the lower reflex arc in man. In this connection the posi- 
tive increase in the tendon reflexes noted in rabbits and 
dogs is suggestive. The observation that the knee-jerks 
* With a view to examining the clinical evidence of a relationship 
between neurasthenic states and the excessive absorption of indol, I 
have tabulated all the cases of which I have records, of patients whose 
chief complaint is the readiness with which physical or mental fatigue 
or both may develop. In the cases selected, a chronic disposition to 
easily induced fatigue has been the leading clinical characteristic, and 
all cases have been excluded in which debility was due to discoverable 
organic conditions, or in which dyspeptic derangements have been a 
prominent feature. A list was then made of all cases, of whatever 
character clinically, in which a strong indican reaction was a feature of 
the condition. Cases showing only moderately strong reactions were 
excluded. It was found of 32 cases, in which the clinical characters 
were those of neurasthenia, that 21 showed a strong indican reaction, 
and 11 gave either no reaction or only a slight reaction. Fourteen cases, 
other than neurasthenic in character, gave a strong indican reaction; 
one case of myxcedema, two of muscular rheumatism, one of acute 
intestinal obstruction, one of pseudo-hypertrophic paralysis, three of 
epilepsy, one of urticaria, one of leucaemia, one of tetany, one of arthritis 
deformans, and one of chronic nephritis. The impossibility of setting 
up an absolute clinical standard of neurasthenia diminishes the value of 
these results, but they seem of sufficient interest to mention. THE TOXIC PROPERTIES OF INDOL. 
were increased in two of our human subjects is hardly 
more than suggestive, because the supposed increase may 
have been wholly a coincidence. More carefully con- 
trolled observations in relation to this point are much to 
be desired. The question whether excessive indol pro- 
duction and absorption in epileptics is capable of influ- 
encing the occurrence of seizures is one of much interest. 
It appears to me that it would be possible to determine 
positively whether epileptic persons suspected of being 
influenced in regard to their seizures by intestinal tox- 
aemias are or are not influenced by the administration 
of indol. 
The second observation upon the human subject—- 
namely, that in which a large quantity of indol (two 
grammes) was taken in less than forty-eight hours with- 
out giving rise to any symptoms except flatulence and 
incapacity for mental work—is most suggestive when 
considered in connection with the effects produced in the 
other cases. There can be no doubt that the indol taken 
by the subject of this experiment was absorbed from 
the intestine to a considerable extent, for the reaction 
given by the urine was exceptionally strong. The fact 
that such slight symptoms were produced indicates a 
much smaller susceptibility to the action of indol than 
was observed in the other cases, and emphasizes the fact 
that this susceptibility is a highly individual thing. Two 
elements can be distinguished as entering into this sus- 
ceptibility. One is the character of the nervous system, 
the other is the ability of the organism to transform 
indol into less toxic substances—this transformation 
perhaps occurring chiefly in the liver. It would be most 
instructive to select subjects for experiment with refer- 
ence to these two elements. On the one hand, persons THE TOXIC PROPERTIES OF INDOL. 
25 
with irritable nervous systems should be compared with 
persons who react slowly and moderately to external 
stimuli; on the other hand, normal subjects should be 
contrasted with patients suffering from extensive dam- 
age to the parenchyma of the liver, as in cirrhosis, and 
in fatty or amyloid liver. 
It need hardly be said that the facts collected in this 
paper constitute no more than the introduction to a 
satisfactory knowledge of the toxic properties of indol. 
They have been presented this evening partly for the 
sake of the facts themselves, and partly to emphasize the 
importance of studying the products of bacterial activ- 
ity which are suspected of a toxic agency in the human 
organism upon the human organism itself when that is 
practicable. 
In summing up, we might answer as follows the 
question propounded in the beginning of this paper, 
What detrimental effects, if any, does the excessive for- 
mation and absorption of indol entail upon the human 
organism? The effects of indol upon the human subject, 
taken in conjunction with a study of the clinical con- 
ditions in which the indoxyl reaction is markedly in- 
creased, justify us in believing that prolonged and ex- 
cessive indol absorption is capable of causing headache, 
especially frontal headache, abnormal cephalic sensa- 
tions, and indisposition for mental and physical exer- 
tion. The latter condition, if prolonged, may perhaps 
form the basis of a neurasthenic state. Although this is 
as far as we can safely go with our present knowledge, 
it is not at all unlikely that further investigation will 
enable us to detect other effects of excessive indol absorp- 
tion. That the individual susceptibility varies much 
seems clear from the results of experiment, and it is like- 26 
THE TOXIC PROPERTIES OF INDOL. 
ly that this difference in susceptibility relates both to the 
intensity and to the character of the influence which is 
exerted. There is no doubt that some robust persons 
may habitually excrete a large amount of indoxyl-potas- 
sium sulphate without showing definite evidence of de- 
rangement of health, but these cases are certainly excep- 
tional. While, therefore, we can not regard indol as an 
indifferent substance in the human organism, we can not 
regard it as ordinarily exerting highly toxic effects, even 
when it is absorbed in unusually large amounts. This 
conclusion accords with what one might on a 'priori 
grounds expect in the case of a normal decomposition 
product of proteid food. Table A.—Observation No. 1. 
Date. 
Quantity of indol taken. 
Symptoms. 
Indoxyl reac- 
tion. 
Preformed sulphates. 
Ethereal sulphates. 
Ratio. 
December 28th... 
0,1 gramme at middle 
of day. 
Toward evening “ dull feeling ” in 
front of head ; feels slightly giddy. 
Sensation at times as of slight 
headache, but can hardly call the 
feeling a pain. 
Faint. 
1.24 gramme. 
0.150 gramme. 
8.13 
December 29th,.. 
0.3 gramme indol dur- 
ing day in doses of 
0.1 gramme. 
Slight frontal headache most of day; 
some sensation of “ lightness ” in 
head at times. No other symp- 
toms. 
Increased. 
1.80 gramme. 
0.318 gramme. 
5.66 
December 30th... 
0.5 gramme indol dur- 
ing day. 
At 2 a. m. was awakened by very se- 
vere colic. Then had large watery 
movement, followed by relief of 
colic. During the day felt entirely 
well. No perceptible effect from 
indol, except that toward evening 
there was some unsteadiness in the 
legs and stiffness in the muscles on 
walking upstairs. 
December 31st.... 
No indol 
Felt perfectly well during morning. 
Knee-jerks seem increased as 
compared with December 2*7th. 
Pupils normal; no contraction. 
Sensation of “lightness” in head; no 
January 1st 
0.4 gramme indol in the 
morning. 
headache. Otherwise, entirely well. 
Table B. 
Date. 
Indoxyl reaction. 
Preformed sulphates. 
Combined sulphates. 
Ratio. 
January 29th 
Previous to administration of indol. 
Well marked. 
2.44 grammes. 
0.21 gramme. 
11.64 
January 30th 
“ 
“ “ 
Well marked. 
2.39 grammes. 
0.238 gramme. 
10.02 
January 31st 
During administration of indol. 
Very strong—black. 
1.345 gramme. 
0.608 gramme. 
1.76 
February 1st 
U 
u a 
Very strong—black. 
0.915 gramme. 
0.686 gramme. 
1.33 
February 2d 
U 
u a 
Very strong—black. 
0.603 gramme. 
0.732 gramme. 
0.823 
February 3d 
u 
a u 
Very strong—black. 
1.159 gramme. 
0.484 gramme. 
2.39 
February 4th 
a 
u a 
Very strong—black. 
1.235 gramme. 
0.726 gramme. 
1.70 
February 5th 
u 
u u 
Very strong—black. 
0.769 gramme. 
0.692 gramme. 
1.11 
February 6th 
Indol stopped. 
Slight. 
1.973 gramme. 
0.263 gramme. 
7.50 
Date. 
Quantity of indol taken. 
Symptoms. 
Indoxyl reac- 
tion. 
Preformed sulphates. 
Combined sulphates. 
Ratio. 
December 2d 
0.025 gramme after 
lunch. 
No symptoms. 
Negative. 
1.832 gramme. 
0.289 gramme. 
6.34 
December 3d 
0.050 gramme after 
lunch. 
Little effect. A little unsteady in 
legs. Bad taste in mouth on ris- 
ing. A little nervous toward even- 
ing. “ Slight fullness ” in fore- 
head during afternoon. No symp- 
toms after dinner. 
Strong. 
1.664 gramme. 
0.296 gramme. 
6.62 
December 4th. ... 
0.2 gramme during day. 
Dreams more distinct than usual. 
No unsteadiness on feet. No per- 
ceptible derangement Dull sensa- 
tion in head, perhaps from dissect- 
ing longer than usual. Knee-jerks 
seem increased. 
Strong. 
1.287 gramme. 
0.467 gramme. 
2.76 
December 5th.... 
0.2 gramme during day. 
Dull sensation in head lasting all 
day. Slight dizziness during even- 
ing. Knee-jerks increased as com- 
pared with previous days. 
Very strong. 
1.988 gramme. 
0.426 gramme. 
4.69 
December 6th, -.. 
Indol stopped. 
Head feels well. 
Slight. 
2.012 grammes. 
0.188. gramme. 
10.69 
Table C.—Observation No. 3 (First Trial). 
Observation No. 3 (Second Trial 
December 10th... 
0.2 gramme indol dur- 
ing day. 
Feeling well. A little “ fullness ” in 
forehead and slight nausea. 
Negative. 
1.695 gramme. 
0.24V 
gramme. 
6.81 
December 11th... 
0.1 gramme at break- 
fast, 0.2 gramme at 
lunch, 0.2 gramme at 
dinner. 
Headache continued through the 
night. Relief after rising, but 
“ heavy feeling ” continues. Dur- 
ing afternoon felt very tired. Dull 
frontal headache returned. Head- 
ache continued during evening. 
Slight cramplike pains in legs dur- 
ing walking. 
Very strong. 
1.845 gramme. 
0.4404 gramme. 
4.19 
December 12th. .. 
Indol stopped. 
Headache continues. Bad taste in 
mouth. By 5 p. m. feeling as well 
as ever. 
Very strong. 
1.524 gramme. 
0.555 
gramme. 
2.V5 
December 18th... 
No indol. 
No symptoms. 
Negative. 
1.686 gramme. 
0.330 
gramme. 
5.11 
Observation No. 3 (Third Trial). 
December 14th. .. 
0.1 gramme at 7.45 p. m. 
feeling well during day. 
Negative. 
1.652 gramme. 
0.352 gramme. 
4.69 
December 15th. .. 
0.3 gramme during day; 
0.1 gramme at each 
meal. 
As usual during morning. After 
dinner, during afternoon, felt 
tired. Slight pain and stiffness in 
shoulders, lasting oidy a short 
time. During evening, dull feeling 
in head, hardly headache. 
Medium. 
1.337 gramme. 
0.405 gramme. 
3.30 
December 16th. .. 
0.2 gramme during day. 
Bad taste in mouth. Sleep much 
disturbed by dreams, feels “ tired 
all over.” This lasted through aft- 
ernoon. A little stiffness in shoul- 
ders after sitting. Slight pain in 
front of thighs. 
Yery strong. 
2.223 grammes. 
0.396 gramme. 
5.62 
December 17th... 
0.2 gramme during day. 
Bad taste in mouth. Disturbed 
sleep. A little weakness in legs. 
Dull feeling in head. After break- 
fast felt tired all over. Could not 
study. Dull feeling in head con- 
tinued ; no ache. During after- 
noon felt tired; weak in knees. 
Slight pains in head lasting a few 
seconds. At night, severe frontal 
headache, coming on gradually 
since dinner. Can eat, but is not 
hungry. 
Strong. 
1.601 gramme. 
0,339 gramme. 
4.72 
December 18th... 
0.2 gramme during day. 
Sleep disturbed. Bad taste in mouth. 
Headache lasted through night. 
Improvement on rising, but head 
still dull. Tired all day. Dull 
sensation in head. 
Strong. 
1.596 gramme. 
0.390 gramme. 
4.09 
December 19 th... 
0.2 gramme during day. 
Sleep less disturbed than previously. 
(Walked a little longer than usual 
on previous evening.) “ Dull, tired 
feeling” continues. 
1.913 gramme. 
0.460 gramme. 
4.16 
December 20th. .. 
0.2 gramme during day. 
Slept well. Head feels tired and 
dull. Unpleasant frontal sensation 
all day. 
1.676 gramme. 
0.381 gramme. 
4.40 A PRACTICAL TREATISE OH THE 
SURGICAL DISEASES OF THE 
GEHITOURIHART ORGAHS, 
IHOLUDIHG SYPHILIS. 
Designed as a Manual fob Students and Pbaotitxonebs. 
WITH ENGRAVINGS. 
E. L. KEYES, A. M., M. D., 
Professor of Genito-Urinary Surgery, Syphilology, and Dermatology in Bellevue 
Hospital Medical College. 
BEING A REVISION OF A TREATISE, BEARING THE SAME 
TITLE, BY VAN BUREN AND KEYES. 
Second edition, thoroughly revised and somewhat enlarged. 
“ The progress made in surgery during the last ten years, the changes of prac- 
tice by the best surgeons with regard to several operative procedures, notably 
litholapaxy, suprapubic cystotomy, and operations upon the kidney itself, and 
other matters as well, rendered necessary a thorough revision of the work published 
some years ago as the joint production of Drs. Van Buren and Keyes. Much of 
the work has been rewritten entirely. There is a large amount of entirely new 
matter presented in this volume, to make room for which the reports of cases given 
in the former work are all omitted in this. The work in its present form stands 
fairly abreast of the latest advances in genito-urinary surgery. Dr. Keyes says 
of the book that it is an honest exhibit of his views upon all the subjects considered, 
and, in view of his wide experience and unquestioned skill, we commend his book 
to the notice and study of all who work in this field.”—St. Louis Courier of 
Medicine. 
Bvo. 688 pages. Cloth, $5.00; sheep, $6.00. 
“ This handsome volume is not merely a new edition of the well-known work of 
Van Buren and Keyes, but a complete revision of that text-book. The original 
plan of the older work has been retained, and its scope remains the same ; but it 
has been entirely recast, and in a large measure rewritten. This course has been 
made necessary by the vast progress which has marked the history of surgery dur- 
ing the last ten years, especially in the field of therapeutics and operative pro- 
cedures. To bring the book up abreast of the times upon the new device of litho- 
lapaxy, suprapubic cystotomy, and modem surgery of the kidney, the treatment 
now followed in diseases of the tunica vaginalis, and the many minor changes 
which find expression in the use of new agents, Dr. Keyes was compelled to omit 
manj; things, to add considerable new matter, and largely to modify much of the 
remainder. Some chapters are entirely new, and in order to make room for de- 
sired additions all the cases have been dropped. As it now stands, it is a treatise 
■which may safely be consulted, and which fairly and freely speaks of the most 
modem methods. Dr. Keyes is enthusiastic in his commendations of litholapaxy, 
and cordially indorses the high operation for stone, while he decides that the 
time-honored and brilliant methods of reaching the bladder through the perinaeum 
are only applicable in the cases of male children with stones of moderate size. 
Dr. Keyes says the book ‘ is an honest exhibit of my views upon all the subjects 
consideredI;'and as his experience has been large, and his skill and prudence are 
undisputed, we have no hesitation in saying there is no one in this country whose 
judgment is more worthy of confidence or whose directions may be more safely 
followed.”—American Journal of the Medical Sciences. 
D. APPLETON AND COMPANY, NEWYORK.