Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 98

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189

USA > Ohio > Hancock County > Findlay > Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens > Part 98

Note: The text from this book was generated using artificial intelligence so there may be some errors. The full pages can be found on Archive.org (link on the Part 1 page).

At 8 p. m., on the 24th, quinine sulphate gr. x (0.65 gm.) every four hours was ordered.

On the 25th, the temperature was normal.

Early in the morning of the 26th, there was a slight paroxysm, much less intense than the preceding but lasting a full 24 hours. After this, the temperature remained permanently normal. Quinine was continued for a long period of time and there was no relapse. Repeated examinations of blood showed no parasites whatever and no pigment.

Now, the history of this case, the time of the year at which it occurred, the character of the febrile curve, the palpable spleen, the leucopenia and the apparently specific action of quinine, leave no serious doubt in one's mind that this was a case of malaria, probably æstivo-autumnal.

This is the first case in the history of the hospital in which we have been obliged to resort to the therapeutic test for the proof of the existence of a malarial infection.

Splenic puncture would probably have assisted us materially in the diagnosis. This was not performed because of the danger, minimal though it be. I have, myself, aspirated many spleens with- out the slightest trouble, and, in any case of emergency, I should have no hesitation in so doing again. Some years ago, however, I witnessed a fatal result of splenic puncture. The patient was a foreigner, unable to understand English. He failed to comprehend the procedure and jumped on the introduction of the hypodermic needle. This resulted in a small tear of the splenic capsule with fatal hæmorrhage into the peritoneal cavity. Although I feel con- vinced that with proper precaution, the danger is almost nil-and this has been the experience among more careful Italian observers,

one of whom Prof. Bastianelli, is with us this evening, yet I oz not feel that splenic puncture is justified excepting in cases ;. real necessity.

It is interesting that Ruge * makes the surprising statement the: " the mortality from splenic puncture, which has been observed t; to the present time, amounts to 11/2 per cent."

It is highly probable that the early administration of quinte was in this case responsible firstly, for the development of the regular paroxysms; secondly, for the disappearance of parasites in the peripheral circulation.

CASE IV .- Grave Estivo-Autumnal Tertian Fever. Remorkate Paucity of Parasites in the Peripheral Circulation. Consultit: and Death Following the Subcutaneous Injection of Quinine .-!: addition to these three cases, I would speak of another patie: whose history is remarkable from various standpoints. The chart, as you will see, shows that which on first appearance appears to be a wholly irregular remittent fever. There are, however, or: tain very sharp remissions while many of the smaller oscillation: are dependent upon the administration of baths. A careful study of the chart shows that every other day (on the 14th, 16th, 1St and 20th of October) there was a sharp rise of temperature som= where between 6 and 10 a. m. This is followed by a remisict during the afternoon and night and a second rise on the follow ing day with a fall occurring in the afternoon or evening i: other words, the chart suggests the pseudo-crisis and subsequent elevation first described in æstivo-autumnal tertian fever !! the Italian observers. Such a chart might well suggest an æstir? autumnal tertian.

This patient was a sailor on a bay boat, a Spaniard, aged # who was said to have had malaria 13 years before. One week be fore entry, he began to complain of abdominal pain and diarrhes Four days before entry, there was headache, anorexia and nausea

On Oct. 12, 1909, he was admitted at about 2 p. m. with a tec- perature of 105.8º F .; pulse, 104; respiration, 24. His appearas was typhoidal; the spleen was large, soft and palpable; there were several suggestive rose spots. The blood showed no parasites The count was:

R. B. C. 5,280,000

W. B. C. 5,600

Hæmoglobin 90%

The coagulation time was three minutes, thirty seconds.

Urine: Normal color; sp. gr., 1.015, slight trace of albume: In other respects, not remarkable.

On Oct. 13, 1909, I saw the patient on a morning visit. Tt: temperature had fallen from nearly 106° to 99.4º F. He had : characteristically typhoidal appearance. The temperature was re garded as suggestive of malaria, but fresh and stained specimens of blood were negative. The Widal test was negative; the Diam reaction was positive.

The chart illustrates the course of events. Daily blood examina tions revealed no parasites. There was a leucopenia of 3,80) te 5,200. Five days later, a slight jaundiced tint was noted. T .: blood pressure, which at the outset ranged from 97-114, was e= the 19th, 84 mm. Hg.

I next saw the patient on Oct. 20, 1909, just a week after mi first visit. At that time, the temperature was about 105º F. Thex was a great change in the general picture. The facies was very dull and typhoidal. There was a very distinct anæmia and a sligt: greenish-yellow jaundice. The respirations were from 28 to The liver was readily palpable. The appearance was wholly char- acteristic of malaria. A fresh specimen of blood was taken in- mediately and a considerable number of æstivo-autumnal para- sites were found. These were for the most part bodies containing

* Einführung in das Studium der Malariakrankheiten, 2 auf. S. Jena, 1906, Fischer, 221.

Digitized by Google

"una Der (ere segmenting bodies). The patient was viously an ill man. It was suggested that he be given vigorous eatment, i. e., quinine bi-muriate gr. xv (1 gm.) in 10 cc. normal It solution intravenously, to be repeated, if necessary, in four urs, and afterwards, quinine sulphate gr. v (0.325 gm.) every ir hours by mouth.

The solution was not made by the apothecary until several urs after the visit and then, by a misunderstanding, of double 'ength, so that at 12 o'clock on the 20th, the patient was ven quinine bi-muriate gr. xv (1 gm.) in 5 cc. of normal salt ution. Immediately after its introduction, there was a momen- y convulsion accompanied by a slight twitching of the eyelids d lower lip, followed at once by general spasmodic contractions the trunk and extremities. The eyes were rolled up and the ad was somewhat retracted and turned to the right. Recovery s almost instantaneous and the patient soon seemed better than was before. Thereafter, he was given quinine sulphate gr. x .6 gm.) by the mouth, every four hours.

Det. 21. At 1 a. m. the patient was given a second intravenous jection of quinine bi-muriate gr. xv (1 gm.) without unpleasant sults. In the morning, the temperature had fallen to 100° F., : pulse was from 90 to 100, and the patient seemed better. At ). m., however, the temperature was rising again and a third :ravenous injection of quinine bi-muriate gr. xv (1. gm.) was ministered. Immediately upon its introduction the patient be- a to show convulsive twitching of the eyelids and lips; this was lowed by a general convulsion. There was marked cyonosis; pulse disappeared; the patient failed to respond to stimulants artificial respiration.

Re-examination of the stained specimen of blood made on the :h, showed, after long search, two characteristic æstivo-autumnal igs, which had been overlooked on a previous examination.

The necropsy made by Dr. Thomas twenty-eight hours after ath, showed a severe but not intense malarial infection. The Lin showed nothing remarkable-little pigment in the ves- s. The spleen was large and soft, and microscopically showed ch pigment-for the most part in leucocytes. Smears showed nerous segmenting parasites. The liver weighed 2700 grammes I was of a slate color; the cut surface was opaque. There was rked parenchymatous degeneration and the capillaries con- led much pigment. The bone marrow showed numerous para- s in smears.

oth kidneys showed marked cystic degeneration,-the right tsuring 16 x 10 x 7 cm. The entire surface was studded with 's, the diameter of which ranged from a millimetre or less to :m. The contents varied in color-clear-brownish-opales- :, and in some instances apparently contained changed blood. pelves were greatly dilated. On section, the tissue which re- ned showed few changes in gross, but microscopically, there a definite increase in fibrous tissue and some congestion of the i recta; in the portion of the kidney showing cystic change, e was considerable cloudy swelling with marked increase in us tissue. The cysts were lined with cuboidal epithelium. Lis case is exceedingly interesting as an example of grave in- on with few parasites in the peripheral circulation through- week of study and observation.

e occasional absence of parasites in the peripheral circula- especially in grave cerebral cases, has been emphasized by " observers, notably by Bastianelli. I have never seen, how- a case of such severity with so long an absence of parasites .* e correct diagnosis was suggested here by the character of wer, the general appearance of the patient and the leucopenia,

though I did not examine these daily specimens, seeing the it but twice, yet I am sure of the care with which the case allowed by a most capable ward physician.

wu, Greu is the absence of parasites, i should have ordered quinine when I saw him on the 20th.

The most interesting point in connection with the case is the question as to the cause of death. From the result of the necropsy and from my observation of the patient, I should feel sure that it was not due directly to his malarial infection; on the other hand, I should feel reasonably sure from the history of the case that it was directly due to the intravenous injection of the quinine.

The literature upon quinine poisoning is very large and there are many instances of apparent death from large doses. The amount administered to this patient was, however, by no means remarkable, although considerably larger than that which is cus- tomary in this hospital. Several points are, however, worthy of note.

The first of these is the concentration of the dose. The speaker has always been in the habit of giving quinine intravenously according to the method of Bacelli in a solution consisting of

gm.

Quin. dihychior. Aquæ

10.

Sod. chloridi 0.065,

one-half of this being given in one median basilic vein and one- half in the other. In this instance, a dose of double the concen- tration was given at once. The patient had received 6 grammes of quinine in 24 hours, 7 in 28 hours, 3 grammes having been administered intravenously. The direct sequence of the symptoms in connection with the first and third injections of quinine was such as to leave little doubt as to the relation of the dose to the manifestations. While the dose was certainly strikingly concen- trated, yet one must probably assume also that the individual was hyper-susceptible to the drug.

The specimen of quinine was from the same sample which had been used in other cases, and, so far as could be made out, showed no impurity.

A point of interest in connection with the case which may have an important bearing upon the fatal outcome, is the fact that the patient had cystic disease of his kidneys. Prof. Abel was much impressed by this fact, feeling that it suggested strongly that an unusual retention of the drug might have contributed toward ren- dering the patient more susceptible to the last dose. It must be said that the excretory powers of the kidneys seemed to be good and that anatomically, there was still considerable cortical sub- stance. However this may be, the observation seems to be worth recording. I have for years been in the habit of advising the in- travenous injection of quinine in urgent cases. Such an expe- rience as this would certainly suggest caution in administering a solution of a concentration greater than 10 per cent. More than this, it points, it seems to me, to the advisability of conservatism in the administration of quinine intravenously in other than urgent cases of pernicious malaria.

In conclusion, let me emphasize one point, an old lesson, after all, which these two latter cases illustrate, i. e., that while care- ful and repeated examinations of blood in a vast majority of cases answer the question as to the presence or absence of mala- rial infection, really grave malaria may exist for considerable periods of time without demonstrable parasites or pigment in the peripheral circulation. In case of doubt, do not delay too long before applying the therapeutic test.

THE JOHNS HOPKINS HOSPITAL REPORTS.

Vol. XIII, Studies in Urological Surgery-605 pages, with 6 plates, 201 figures and 1 colored chart.

Vol. XIX, Studies in Hypertrophy and Cancer of the Prostate- 632 pages, with 97 figures. Price per volume in paper, net $5, in cloth, $5.50.

Orders and remittances should be made to

THE JOHNS HOPKINS PRESS, BALTIMORE, MD.

Digitized by Google

106

JOHNS HOPKINS HOSPITAL BULLETIN.

[No. is

THE PREPARATION OF ANTITOXIN .*

By E. J. BANZHAF, PH. D.,

(Research Laboratory, New York City Board of Health.)

I accepted the invitation of your secretary, Dr. Moss, to speak to this well-known medical society, of the Johns Hop- kins Hospital, upon the subject of antitoxin, with a mixed feeling of pleasure and trepidation. With pleasure at the honor bestowed upon me, through your secretary, and with trepidation that I might not fulfill your expectations. Inas- much as the protective and curative value of the antitoxins is well established, the chemistry of these antibodies is possibly not so attractive as researches on the more baffling diseases. However, any knowledge we can gain from the chemistry of the antibodies will help to solve other difficulties in general biology, physiology and pathology.

It is now about fifteen years since diphtheria antitoxin was introduced for the treatment of diphtheria. Hopes were en- tertained that the antitoxin would be isolated and purified. Up to the present time these hopes have been only partly ful- filled.

As early as 1893, Brieger and Ehrlich attempted to isolate the antitoxin from the milk of immune animals. Smirnow, in 1895, was probably the first to work with antitoxic horse serum. He showed that the active substance was precipi- tated with the globulins on saturating the serum with mag- nesium sulphate.

Brieger and Boer, in 1896, precipitated the globulins by adding neutral salts of the heavy metals and found the anti- toxin in that protein. Aronson, in 1897, stated that the globulin precipitated by dialysis contained antitoxin.

Dieudonné showed that the globulins precipitated by carbon dioxide did not contain antitoxin.

The protein precipitate, obtained by both these workers, corresponded to the globulins of the serum as originally de- fined. This globulin is now known as euglobulin. Brodi, in 1897, separated the globulins into four fractions, by the pro- gressive addition of ammonium sulphate to one half satura- tion. All four fractions contained, however, relatively equal amounts of antitoxin. Belfanti and Carbona, Freund and Sternburg, Marcus, Seng, Hiss, Atkinson and others confirmed the results of Brodi and Dieudonné.

Atkinson, in 1900, working in the Research Laboratory, saturated with sodium chloride a solution of globulins con- taining the antitoxin. By employing heat, he differentiated the globulins into several fractions containing antitoxin. The antitoxin corresponded to the quantities of globulin in the precipitates.

Pick, in 1901, attempted to differentiate the active portion of the serum by fractional precipitation with ammonium sulphate.

Proscher attempted to isolate and establish the non-protein

* Read before the Johns Hopkins Medical Society, December 19, 1910.

nature of antitoxin by digesting the serum with trypsin. E. stated that in this way he obtained a solution containing art- toxin which was free from protein.

Mellanby and I, working independently in 1908, could not confirm Procher's work. The ratio of digestion of the pre- tein was approximately the rate at which the antitoxin we destroyed.

That the antitoxins belong to that class of substances know as proteins, practically all investigators now agree.

It might be well, at this point, to call your attention to the fact that, in the early days, the antitoxic serum contained le: than 100 units per cubic centimeter. This low grade of serar. was principally due to the inability to produce a strong dip .- theria toxin. Park and Williams, in 1896, isolated a diph- theria culture from a child with a mild case of diphtheria This culture proved to be a strong toxin producer and is now used and known throughout the world as " Culture No. 8." With the toxin from this culture a more potent antitoxin was gradually obtained. Thus smaller injections of serum wer required to give the same number of units. This was desirable, for it was early recognized, by Pirquet and Schick, that it- jections of antitoxic sera were sometimes followed, after & incubation period of eight to thirteen days, by urticaria' eruptions, joint pains, fever, swelling of the lymph nodes edema and albuminuria. These disturbances have no dira: bearing on the antitoxic properties of the serum, for the; showed that normal horse serum produces the same effect This reaction Pirquet and Schick have termed "Serum Sich. ness."

Although almost all the investigators mentioned, and others. established the fact that the antitoxins were associated with the globulins, there was practically no record of actual si- ministration of these globulins. Park, in 1900, first studie' the possibility of eliminating serum rashes and other die- turbances, by testing a considerable number of cases with an antitoxic globulin prepared by Atkinson. The results wEs: practically identical with an equal number of cases treated with the whole serum from the same horse.

In 1905, Gibson, working in the Research Laboratory, per- fected a practical method of recovering the pseudoglobulin containing the antitoxin. He placed the precipitated glot- ulins obtained by half saturating with ammonium sulphate, iz saturated sodium chloride solution. In this way the globulin. insoluble in saturated sodium chloride solution, i. e., englo- ulin, present in Atkinson's preparation, was eliminated. The pseudoglobulin, which is insoluble in the saturated sodium chloride, was precipitated with acetic acid. This precipitate was then dialyzed. The finished concentrated product w2: about two and a half times the original potency.

With this product, Dr. Park again took up the study of rashes. The results of this work were favorable. Less early

Digitized by Google

"nvwavu, were noted. This

'eparation was so satisfactory, that the New York Board of ealth laboratory in 1906 sent out only this product. Other poratories then followed suit.

At Dr. Park's suggestion, Gibson and I fractioned the anti- tic serum with progressive amounts of ammonium sulphate to one-half saturation. Our experiments resulted some- at differently from those reported by Brodi, Atkinson and :k. We found that the pseudoglobulin of the higher frac- is contained uniformly much more antitoxin, per gram tein, than that precipitated by lower concentrations of nonium sulphate.

Both from a theoretical and practical view, the results were / satisfactory. This fractioning of the antitoxic sera was pted in preference to Gibson's original method.

fter the partially purified antitoxin product was well es- ished, the question occasionally arose regarding its pro- ve and curative value in comparison with that of the whole m from which it was derived. According to certain ich investigators and others, the antitoxic serum most e therapeutically is not always the one which contains greatest number of antitoxic units. They maintain that erum contains, besides antitoxin, other important pro- re and curative substances, which are not measured by the nt method of standardization. For instance, they state a given quantity of a 200-unit serum is occasionally more :, both preventively and curatively, than the same quan- f a 500-unit serum. Roux, Marfan, Martin, Momont, ilhier, and lately Kraus and Schwoner, support the h views, while on the other hand, some of the German, sh and American investigators support Ehrlich's method idardization.

conclusions of the work of Steinhardt and myself, in we used several strains of a 24-hour agar culture of live eria bacilli, with antitoxic serum of widely varying :hs, were that, with diphtheria in the guinea-pig, the eutic value of the serum depended upon the number of ic units present. No other substance, besides the anti- played an important role. The conclusions of our work concentrated globulin containing the antitoxin, and the erum from which it was derived, were the same as just Since our work, in 1908, Kraus and Schwoner have ed four papers on this subject. The conclusions of all are diametrically opposed to our findings. Berghaus, · in Ehrlich's laboratory, corroborated our findings, ed that he found great discrepancies in Kraus' stand- on of the antitoxic value of the serum.

;ht state that we obtained three different samples of serum that Kraus and Schwoner used in their work. ere labelled to contain 200, 350 and 600 units, re- y.

· standardizations, I found the first to contain 185 Deterioration in transit might account for this differ- he sample said to contain 350 units actually con- 35 units. The 600-unit sample contained only 360

units. In regard to the accuracy of their standardization on the two latter samples, no comment is necessary.

We will now discuss briefly the work by Gibson and myself, on the quantitative changes in the proteins in serum of horses in the course of immunization.

Seng, Joachim, Atkinson and Ledingham observed that when an animal is immunized against bacterial toxins, there result certain characteristic quantitative changes in the pro- teins of the blood plasma. The content of the globulins is strikingly increased even up to double the normal amount; at the same time, there is a diminution in the albumin.

Atkinson showed that this globulin increase is in some de- gree proportional to the antitoxic potency of the serum.

Ledingham, in a paper published while our work was under way, gave results of the determination of the total protein, the globulins and the albumin in the course of immunization against diphtheria toxin. The serum was obtained at short intervals from two horses.

In one horse, which failed to yield a high grade of anti- toxin, the globulins of the serum were not essentially increased over the normal. The other horse gave ultimately a 650-unit serum ; the globulins here had progressively increased along with the antitoxic potency. From Ledingham's results from the two horses, a relation between the development of the anti- toxic properties and the increase in the globulins is indicated. Ledingham and Joachim state that the increase of the glob- ulins is in the euglobulin fraction.

It may be desirable to discuss the fractioning of the glob- ulins. The globulins are commonly stated to consist of at least two different proteins, the euglobulin, and a more soluble protein, the pseudoglobulin. The euglobulin is insoluble in pure water, and accordingly precipitated on dilution or dial- ysis; it is also thrown down by slight acidification. The pseudoglobulin belongs by definition to the group of true al- bumins; i. e., it is soluble in pure water. In practice, in- vestigators have commonly used the fractional precipitation by salting out with ammonium sulphate. A half volume of saturated ammonium sulphate solution is added to the serum ; i. c., one-third saturation. The precipitate is the euglobulin. The separation is not sharp at all. The filtrate contains the albumin and pseudoglobulin; the latter can be thrown down by the further addition of saturated ammonium sulphate solution to half saturation. In current writings the identity of this " fractioned " euglobulin has been confused with the slight precipitate obtained on dialysis, dilution, or slight acidifica- tion, in spite of the early work of Freund and Joachim. By employing the ammonium sulphate fractioning, Ledingham, like Joachim, found the increase in the globulins affected the euglobulin more than the pseudoglobulin fraction, i. e., the great increase in the globulins took place in the non-antitoxic protein. Ledingham's interpretation of his results, as regards this point, seems inconclusive, for he does not grasp the sig- nificance of the limitations in the salt fractioning of the pro- teins. His observations, associating the increase in the glob- ulins with the questionable euglobulin fraction, were made by direct precipitation of the serum with half its volume of satu-

Digitized by

Google

108

JOHNS HOPKINS HOSPITAL BULLETIN.

rated ammonium sulphate solution ; i. e., one-third saturation. When re-precipitated for purification, the protein was usually re-dissolved to the original volume and the same amount of ammonium sulphate solution added as before. Inasmuch as the globulins may have been doubled as the result of immuni- zation, would not a great part of this increase be found natu- rally in the euglobulin fraction, since solubility of the protein must be considered? The precipitate obtained at one-third saturation is not free from antitoxin. It may contain the greater part of it when the undiluted serum is precipitated by the addition of a half volume of saturated ammonium sul- phate solution. To illustrate this, Gibson and I precipitated ten cubic centimeters of plasma by the direct addition of five cubic centimeters of saturated ammonium sulphate solution; again, ten cubic centimeters of the plasma were diluted to 33} cubic centimeters with water and precipitated by the addi- tion of 16§ cubic centimeters of the saturated ammonium sul- phate solution, and finally, a third ten cubic centimeters of the plasma were diluted to 66§ cubic centimeters with water and precipitated with 33} cubic centimeters of the saturated ammonium sulphate solution. We then had ultimate dilutions of 15, 50 and 100 cubic centimeters each, at one-third satura- tion. The precipitates were allowed to stand for a few hours, with occasional shaking, to permit mechanically precipitated protein to return into solution. The precipitates, at the three dilutions, were then determined. We found the fraction to in- clude 5.39, 1.78 and 0.98 grams of protein per 100 cubic centi- meters at the three respective dilutions.

Need help finding more records? Try our genealogical records directory which has more than 1 million sources to help you more easily locate the available records.

Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 98

Author: Jacob Anthony Kimmell Publication date: 1910 Publisher: Number of Pages: 1189

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189