Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 128

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

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There are three points in the X-ray work that particularly deserve emphasis.

1. The lesion in all cases is more extensive than the physi- cal signs indicate. We have already learned this from au- topsies and especially from focal tuberculin reactions and have become accustomed to visualize further than a strict interpretation of the physical signs would permit.

2. While in all of our early cases we discover the earliest signs at the apices the X-ray plates show the most marked changes at or near the hilus and bands radiating from here to the apices. This is hardly in accord with anatomical findings and I would ask Dr. Dunham if he can tell us what is the pathological basis of these dense radiating bands.

3. And most important of all I would say that interpre- tation of these stereoscopic plates is as expert a bit of skill as the physical examination. It is certainly no reflection upon Dr. Dunham's work when I confess that I am unable to see in the plates all that Dr. Dunham sees there. From plate readings alone Dr. Dunham will diagnose one case definitely pulmonary tuberculosis, and another as suspicious. From physical examination alone we are unable to do this. We turn back and rely on the clinical symptoms to decide whether the lesion is an active or inactive one.

DR. W. S. THAYER .- I have been considerably impressed during the last year or so with the real value of the radio- grams of the chest in suspected tuberculosis.

The diagnosis of an early or later pulmonary tuberculosis

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. is often made only by the gathering together and the care- fully weighing of a variety of special observations and the results of a radiographic examination are not infrequently of great importance in leading one to the correct conclusion.

The remarkable agreement between the results of physical examination and the radiogram in the cases reported this

evening are extremely satisfactory and encouraging. The go to show how much can be made out by a true, caret: physical examination.

The wonderful stereoscopic pictures which Dr. Dunha: has been able to show us, mark a real step forward in . methods of thoracic investigation.

PAROXYSMAL HEMOGLOBINURIA: BLOOD STUDIES IN THREE CASES.

By W. L. Moss, M. D., Associate in Medicine, Johns Hopkins University.

(From the Research Laboratory, The Phipps Tuberculosis Dispensary, The Johns Hopkins Hospital.)

The studies herein reported have been directed toward the phenomena which the blood of this interesting condition pre- sents, rather than to the clinical features of the disease.

The condition was separated as a clinical entity long ago and the symptom complex sufficiently well known to render diagnosis certain and easy.

From the first recognition of the disease, investigators have busied themselves with the search for an explanation of the re- markable manifestations of the attacks and numerous theories have been advanced to account for them which now have only an historical interest and need not be reviewed, since this already has been done adequately by Eason.'

Our present views on the mechanism of the blood destruc- tion during the attacks in this disease date from the publica- tion of Donath and Landsteiner,' who showed that hemolysis of the blood of hemoglobinuric patients took place in vitro if the temperature was considerably lowered and then raised.

It had already been suggested, especally by Eason, that the hemolysis in these cases was due to a complex hemolysin of amboceptor-complement nature, whose action bore some rela- tion to temperature, but the proof of the amboceptor-comple- ment nature of the hemolysin, as well as the explanation of the part played by cold, seems not to have been furnished be- fore the work of Donath and Landsteiner just cited.

The fundamental facts brought out by them were as follows :

1. To show the relation of temperature to hemolysis.

Blood from hemoglobinuric patients taken in potassium oxalate solution, to prevent clotting, underwent no hemolysis if kept either at low temperature or at body temperature, but hemolysis occurred if the temperature was first lowered and then raised. The same result followed if a mixture of serum and washed corpuscles from a hemoglobinuric patient was used instead of oxalated blood.

2. To show the amboceptor-complement nature of the hemo- lysin.

Heating the oxalated plasma to 45° C. for 15 minutes definitely lowered its hemolytic strength, while heating it to 55° C. for 15 minutes destroyed the same.

Corpuscles chilled in oxalated plasma and then removed by centrifugalization did not undergo hemolysis on the addition

of normal salt solution or of inactivated hemoglobinuric ser. at thermostat temperature, but were promptly dissolved aha the addition of fresh normal serum.

On the above evidence the authors convinced themselves the amboceptor-complement nature of the hemolysin and c. cluded that the serum of paroxysmal hemoglobinuric patiec: contains a hemolytic amboceptor which requires for its unit with the red blood cell a low temperature, while the union complement and consequent solution of the cell takes ples only at higher temperatures.

While it is true that they bring forth some further erpe mental evidence in support of this view, it is perhaps sign: cant in the light of the findings of Hoover and Stone,' and' my own results to be reported presently, that Donath Landsteiner do not mention in their first communication ba- ing made any attempts to reactivate hemoglobinurie ser. heated to 56° C. by the addition of fresh normal serum.

In a later publication ' they do report successful reacties tion experiments but it is to be noted that the reactinst. serum (complement) was added to the mixture of inactivaz. patient's serum and corpuscles before the mixture was s. jected to a low temperature and that their reactivation Es periments failed if the hemoglobinuric serum, was inactiva. by subjecting it to a higher temperature than 480 -50℃." 20 minutes.

Hoover and Stone made very complete studies on 55 cases of paroxysmal hemoglobinuria in which they conf .- Donath and Landsteiner's conclusions concerning the relat. : of cold to hemolysis and the amboceptor-complement na ... of the hemolysin, as indeed most investigators subsequent Donath and Landsteiner have done. In opposition to : views of other workers, however, they maintain that, not ce. does the amboceptor, but also the complement, require a ! temperature for its union, the lytic action of the complemer however, only taking place after the temperature is elevated. Their views and the experiments upon which they are la: are best given by a direct quotation from their report.

" 0.5 cc. of inactivated H. S. - washed R. B. C. +5° C. for . minutes + 37° C. for one hour.

Now if the normal serum be added and the mixture is pisa in the thermostat for many hours, no hemolysis follows.

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- voraus a low tem-

rature was not employed in fixing the complementophilic end the amboceptor to the haptophore of the complement. The llowing reactivation experiment proved successful.

0.5 cc. inactivated H. S. + washed R. B. C. + 0.25 cc. of normal rum + 5° C. for 15 minutes.

The mixture was then warmed to 37° C. and hemolysis followed Imediately.

Thus it is apparent that cold is essential for the fixation of th the cytophilic and the complementophilic ends of the ambo- ptor."

While I have repeatedly confirmed the results of the above periments, I differ with Hoover and Stone as to their in- rpretation and will return to this discussion presently.

Meyer and Emmerich ' have made very exhaustive clinical, matological and serological studies of four cases of paroxys- al hemoglobinuria.

Reference need not be made here to their observations on the pod pressure during the paroxysms, the leucocytic changes, e appearance of the derivatives of hemoglobin in the urine ter attacks, nor to the very interesting clinical observations

these authors, since the present paper does not deal with ese phases of the disease.

Meyer and Emmerich report that the blood of their patients d not always show hemolysis when subjected to a low tem- rature followed by high temperature, as described by Donath d Landsteiner. Thus with their first patient they obtained sitive results only 13 times out of 40 tests performed at in- rvals during five months. Similarly the test often failed to ve hemolysis with their other three patients.

The negative results are ascribed in most instances to lack complement since they found that positive results were ob- ined much more frequently if normal serum (complement) s added to the mixture of patient's serum and red blood Is.

They found that the complement deficit usually occurred ortly after an attack of hemoglobinuria and ascribed it to : using up of complement during the attack; although they isider that the complement content of the blood undergoes le variation independently of attacks of hemoglobinuria. It is interesting that the authors found this deficit of com- ment did not protect the patients from attacks of hemoglo- uria, for they observed that at a time when the serum Id be shown to contain no complement the patient might lergo a spontaneous or induced attack ; this paradoxical re- ; they explain on the assumption that complement is ned locally in the surface of the body exposed to the action cold.

With reference to the union of the red blood cell and am- eptor, Meyer and Emmerich state that it makes no differ- e whether the complement is added to the mixture of red d cells and inactivated hemoglobinuric serum before or r cooling the mixture, hemolysis taking place equally well ither case.

special attention is directed to this point since it stands in ›sition to the results of Hoover and Stone and myself.

the blood corpuscle in the cold, but is easily dissociated from the corpuscle at high temperatures." They believe that some of the contradictory reports in the literature are to be ex- plained on this basis. Referring to the work of Hoover and Stone, they say, " While we have seen above, that the binding of the amboceptors to the corpuscles follows in the cold with- out the presence of complement Hoover and Stone report that the mixture must be cooled in the presence of complement. This appearance is readily explained by the easy dissociability of the amboceptor."

Hoover and Stone do not make the point that the union of red blood cell and amboceptor can take place only at low tem- peratures in the presence of complement, but that a low tem- perature is necessary for the union of complement to the cor- puscle-amboceptor combination.

There is one paragraph in Hoover and Stone's report which seems to justify the meaning which Meyer and Emmerich ascribe to them, but their further experiments indicate that they did not believe that the presence of complement was necessary for the union between corpuscle and amboceptor to take place, as evidenced by the following quotation from their paper :

" Thus we have shown that if in two stages, 10 drops of a 10 per cent suspension of red cells be added to (1 cc.) the serum and exposed to cold for one hour each time, the amboceptor can be ex- hausted from the inactivated hemoglobinuric serum."

Furthermore, Hoover and Stone in a personal communica- tion to me stated that they did not hold that the presence of complement was necessary in order that union take place be- tween corpuscle and amboceptor.

With reference to the resistance of the red blood cells of hemoglobinuric patients, Meyer and Emmerich carried out experiments to show that the resistance to certain destructive agents, such as saponin, was greater if the corpuscles had an- chored amboceptor than if they were amboceptor-free and therefore they conclude that it is necessary to use amboceptor- free corpuscles in resistance tests. They state that corpuscles from hemoglobinuric patients are less resistant to temperature changes, mechanical influences, dilute acids, and saponin solu- tions, but that they do not differ from normal corpuscles in their resistance to anisotonic salt solutions.

No attempt has been made to give a complete review of the literature on paroxysmal hemoglobinuria, or even to bring out all the facts which have been established concerning it. Refer- ence has been confined largely to those phases of the subject with which my own work has dealt.

CASE REPORTS .*

CASE I .- G. C., female, colored, aged eight years. First Admission to hospital, February 9, 1910. Diagnosis .- Paroxysmal Hemoglobinuria, Congenital Syphilis. Complaint .- Blood in urine.

Family History .- Father and mother natives of British Guiana, South America. Father alive and well. Mother alive, subject to

* For the privilege of studying and reporting Cases I and II, I am indebted to Dr. S. Amberg, who kindly referred them to me

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asthmatic attacks, menstrual periods characterized by profuse sanguinous discharge and each child-birth has been accompanied by troublesome hemorrhage.

The first child, a male, was born in British Guiana 14 years ago, and died at the age of nine years of diphtheria, followed by pneumonia. This child was subject to epistaxis, but withstood ex- posure to cold well.

Second child, female, died a few days after birth of umbilical hemorrhage.

The third child, female, died at the age of one month from umbilical hemorrhage. Bleeding from umbilicus began 12 hours after birth and recurred twice during the month the child lived.

Fourth child (G. C., the present patient), was born eight years ago in Washington, D. C.

Fifth child, male, alive and well.

Sixth child, still-born.

Past History .- Patient suffered from a vaginal hemorrhage shortly after birth. Measles at three years, chicken-pox and diph- theria at four years, typhoid fever at five years, whooping cough at six years. Has had several attacks of tonsillitis, the last being in November, 1908.

Present Illness .- Began five years ago, when it was noticed that exposure to severe cold would be followed in a few hours by a chill and later by fever and the passage of " bloody urine." The elimination of " blood " in the urine has never persisted more than 24 hours after the onset of an attack. Attacks have never occurred during warm weather; they have been most frequent in the spring and fall of the year, especially in cold, damp weather. The patient's mother states that prior to the onset of the present illness, five years ago, exposure to cold frequently caused a profuse eruption of hives over the face and body, but that since the onset of the attacks of hemoglobinuria the patient has never suffered from hives.

The patient suffered an attack on the day before admission to the hospital and another on the morning of admission.

Physical Examination .- A well nourished child, rather small for her age. Pupils widely dilated, react normally. Breathes through mouth, tonsils greatly hypertrophied, rather pals and con- tain deep crypts. Teeth normal. Considerable exophthalmos, von Graefe's sign positive, thyroid not enlarged.

Lungs .- Clear on percussion and auscultation.

Heart .- Not enlarged, sounds clear except for a slight systolic murmur at apex, which is transmitted but a short distance into axilla.

Liver .- Somewhat enlarged and readily palpable 2 cm. below costal margin in mamillary line. Spleen is hard and is just pal- pable at costal margin.

Patellar reflex exaggerated, plantar reflex normal, no ankle clonus. Cervical, axillary, inguinal and epitrochlear lymph glands mark- edly enlarged.

Urine on admission was of a dark red, smoky color. Sp. Gr. 1015, faintly acid, contained no sugar, much albumin, and gave a positive guiac test for blood. Microscopically a few white blood cells were seen, but no red cells or casts. Subsequent examina- tions of the urine during the patient's stay in the hospital re- vealed no abnormality. The temperature on admission was 99.8º F., but fell to normal within a few hours and remained normal.

from the Pediatric Dispensary of the Johns Hopkins Hospital, and to Dr. L. F. Barker, who subsequently admitted the cases to his service in the Johns Hopkins Hospital and permitted these studies to be carried out.

For the privilege of studying Case III, I am indebted to Drs. Hoover and Stone, this being one of the two cases reported by them.

Blood Examination .- Fresh specimen showed no poikilocytos or anisocytosis, no parasites seen.

R. B. C. 4,000,000

W. B. C. 22,000

Hb. 70%

Wassermann reaction positive.

Patient discharged February 23, 1910. Second admission to hospital, November 10, 1910.

Patient passed through the summer months without attack but with the onset of cold weather in the autumn the attacks > gan to recur.

Wassermann reaction still positive. Differential blood count on admission:

Polymorphonuclear neutrophiles. 50%

Polymorphonuclear eosinophiles 10%

Basophiles 12%

Large mononuclears 9%

Small mononuclears 30%

Transitionals 12%

The above count was made during the interval between attact: a considerable time having elapsed since the last attack.

November 15, 1910 .- Intravenous injection of 0.3 gram Ehrliche " 606." The patient remained in hospital until December 8, 18." During most of this time she was kept in bed and not exposed : a sufficient degree of cold to induce an attack of hemoglobinuri Nevertheless, on December 3, without premonitory symptoms, voided a dark brown urine, which gave a positive guiac test br blood. Wassermann reaction positive.

CASE II .- F. L., male, colored, aged seven years. Admitted to hospital November 6, 1910. Diagnosis .- Paroxysmal Hemoglobinuria, Congenital Syphilis Complaint .- Blood in urine.

Family History .- Father alive and well, mother alive and WE- One brother died at two months of age, cause unknown. Mock has had four miscarriages. No positive history of syphilis : either parent.

Past History .- At the age of one month the patient had & (7 junctivitis lasting a week. At two and a half months of $5 pleurisy, otorrhoa at 18 months of age, pneumonia at one par Since then has had measles and whooping cough.

Patient was shocked by lightning 18 months ago; since then !! has had at times some pain in right leg and occasional swelling right knee and ankle joints.

Present Illness .- Began in April, 1908, three days before the c. set of an attack of measles. After exposure to severe cold ; tient had a chill, folowed by fever and the passage of "block urine." Since that time the patient has had very numeros attacks, as many as three or four in a week. The attacks out. only in cold weather, never in the summer.

Physical Examination .- Normal looking child. Pupils and react normally. Teeth appear normal, tonsils enlarged injected. Lungs and heart normal. Liver and spleen not : larged. Patellar reflex normal.

Blood Examination .- Fresh specimen showed no poikitocrues or anisocytosis, no parasites seen.

5,488,000

R. B. C.

10,280

W. B. C.

74%

Hb. Sp. Gr. B.

Urine Examination .- Specimen is clear yellow.

Reaction acid, no sugar, no albumen, no sediment. Micross; cally no abnormal constituents seen. Guiac test for blood 12 tive.

Wassermann reaction positive.

CASE III .- J. S., male, white, aged 32, Austrian. Complaint .- Passage of bloody urine following exposure to :

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wwwve and well, one brother dead as result of accident, one half- rother and two half-sisters alive and well.

Past History .- General health has been good. As a child had carlet fever, measles and chicken-pox. Has had grippe repeatedly nd " catches cold " easily. While in the army ten years ago had n attack of arthritis, which kept patient in bed for two weeks, onvalescence occupied several weeks. Pain and swelling started rst in knee joint, then the hip, shoulder, wrist and temporo- axillary joints were successively involved. Venereal infection enied.

Present Illness .- Began December 7, 1902. Following exposure severe cold patient had a chill lasting one-half to one hour, icceeding which there was high fever for two or three hours. he first urine voided following the chill was " bloody." The at- .ck was over in five or six hours. Within a week he had a second id ever since has been subject to attacks whenever he gets very uch chilled. They are most frequent during spring and fall, pecially during cold damp weather. He never suffers from them iring the summer.

Wassermann reaction positive.

The hematological studies carried out on the foregoing ises were directed along the following lines:

1. The demonstration of the peculiar hemolysin character-

tic of paroxysmal hemoglobinuria.

2. The determination of the group (according to the iso-ag- utination reaction). to which the patients belong and pres- ice or absence of normal iso-hemolysins.

3. Determination of the relation of temperature to the tion of (a) amboceptor and corpuscle, (b) complement and nboceptor-corpuscle.

4. Separation of the auto- and iso-hemolysin contained in e same serum, in order to determine if the auto-hemolysin capable of dissolving those individuals' corpuscles for nich the serum in question contains an iso-hemolysin.

5. Resistance of the red blood cells.

6. Wassermann reaction.

7. Effect of the administration of Ehrlich's " 606," (a) on

e Wassermann reaction, and (b) on the clinical course of ¿ disease.

For all of these studies blood was obtained from an arm n by means of an aspirating syringe. The syringe was rays washed out with sterile sodium citrate solution before ng in order to remove the small amount of water which re- ins in the syringe after boiling and which might cause ;ht laking of the blood.

Having drawn the blood into the syringe, 2 or 3 cc. are in- duced into a centrifuge tube containging 12 cc. of a 1.5% ium citrate in 0.85% sodium chloride solution for cor- cles. The remainder of the blood is placed in a sterile cen- uge tube and allowed to coagulate at 37º C. in order to tin serum. After the clot has formed the separation of the m is facilitated by a few minutes' centrifugalization. The r serum, which must be perfectly free from hemoglobin, low pipetted off and transferred to another tube. The her preparation of the corpuscles consists in washing them e times in 0.85% sodium chloride solution to free them

corpuscles in 0.85% sodium chloride solution.

1. The demonstration of the peculiar hemolysin character- istic of paroxysmal hemoglobinuria.

The test employed for this demonstration was carried out as follows * and always gave the same result :

Pt. serum 0.25 cc. + Pt. corp. 0.25 cc. (5 % susp.) 0° C. ¿ hr. 37° C. 2hrs. = + hemolysis.

Control : Pt. serum 0.25 cc. + Pt. corps. 0.25 cc. (5% susp.) 37° C. 2 hrs. = 0 hemolysis.

At no time did the blood of any of the three cases reported fail to give hemolysis when subjected to the cold-warm test as indicated above, notwithstanding the fact that repeated tests were made, especially in Case I, which has been under obser- vation for over a year. This is in rather striking contrast with the infrequency of positive results reported by Meyer and Emmerich (only 13 times positive in 40 tests) but may possi- bly be explained by the fact that I made no especial effort to examine serum from my cases at short intervals after attacks.

2. The determination of the group (according to the iso- agglutination reaction) to which the patients belong, and presence or absence of normal iso-hemolysins.

It has been shown 6, 7 that all individuals, regardless of health or disease, can be divided into four groups, according to the ability of their serum to agglutinate the corpuscles of other individuals and of their corpuscles to be agglutinated by the serum of other individuals.

This classification may be stated as follows :

Group I. Serum agglutinates no corpuscles. Corpuscles ag- glutinated by the serum of Groups II, III and IV.

Group II. Serum agglutinates corpuscles of Groups I and III. Corpuscles agglutinated by the serum of Groups III and IV.

Group III. Serum agglutinates corpuscles of Groups I and II Corpuscles agglutinated by serum of Groups II and IV. Group IV. Serum agglutinates corpuscles of Groups I, II and III. Corpuscles agglutinated by no serum.

The group to which an individual belongs is established shortly after birth and thereafter undergoes no change." A strict classification of individuals according to the iso-hemoly- tic properties of the blood has not been accomplished since this reaction, unlike the iso-agglutination reaction, is not en- tirely constant; certain general laws, however, have been formulated as a result of observations on the iso-hemolytic reaction. Thus the serum of Group I, which contains no iso- agglutinin, never contains an iso-hemolysin, while the cor- puscles of Group I may or may not in a given case be hemo- lysed by the serum of a member of Group II, III or IV.

The serum of a given member of Group II may or may not contain an iso-hemolysin, but if it does it can act only against corpuscles of members of Groups I and III, but not neces- sarily against the corpuscles of all members of these two

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Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 128

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

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