A Study of Histamine in Myeloproliferative Disease

1. Whole blood histamine content was measured in 80 patients with myeloproliferative disease. Increased levels were found in 60 per cent of patientswith uncontrolled polycythemia vera, in 7 per cent of patients with polycythemia vera being controlled by myelosuppressive therapy, and in 71 percent of a group with "spent" polycythemia, myeloid metaplasia and myelofibrosis.

2. The excretion of histamine in the urine was measured in 60 patients,30 with elevated blood histamine and 30 with normal blood histamine. Theurine findings paralleled the blood findings in 90 per cent of the cases.

3. Measurements of cell-poor and cell-rich fractions of blood showed thatthe histamine is contained in the white cell fraction. Elevated basophil countswere present in 50 per cent of the patients and occurred with the greatestfrequency in the groups with elevated blood and urine histamine. A roughcorrelation between the basophil count and the histamine content of bloodand white cell fractions was observed in normal subjects and most cases withmyeloproliferative disease. Data obtained in some cases of myeloproliferativedisease suggest that the histamine content of the basophil may be abnormaland that other granulocytes may contribute to the total leukocyte histamine.

4. Myelosuppressive agents produced a reduction in histamine (expressedper 10⁹ myeloid cells) and a decrease in urine histamine as control of themyeloproliferative process was achieved. Treatment with phlebotomy aloneproduced no change in histamine levels.

5. The incidence of pruritus, upper gastrointestinal distress and urticarialmanifestations was increased 7-fold, 4-fold and 12-fold, respectively, in patients with elevated histamine levels as compared with those who had normalhistamine levels.

6. Cyproheptadine, a potent antihistaminic, successfully controlled pruritus,relieved pyrosis and suppressed urticarial eruptions in patients with elevatedhistamine levels. Suppression of the reaction to subcutaneously administeredcodeine (a histamine-releaser) afforded objective evidence that cyproheptadine blocked the effects of histamine release in vivo.

7. The metabolism of histamine and the role of elevated histamine levelsin the clinical manifestations and pathophysiology of myeloproliferative diseaseare discussed.

Submitted on September 23, 1965 Accepted on May 24, 1966     

THE EFFECT OF DIET ON THE HEMOGLOBIN, ERYTHROCYTE, AND LEUKOCYTE CONTENT OF THE BLOOD OF THE RHESUS MONKEY (MACACA MULATTA)

1. Rhesus monkeys fed purified rations supplemented with adequate amountsof the B vitamins, ascorbic acid, and whole liver substance maintained the following average blood picture:

See PDF for Table

2. Natural diets or purified rations supplemented with liver extract do not support the above blood picture. The hemoglobin is lower and there is an increase inthe range of the total leukocyte count and in the neutrophil-lymphocyte ratioto 2.0 ([unknown]). These figures are similar to the values in the literature and generallyaccepted as the normal.

3. Previous reports have shown the characteristic blood dyscrasias which develop when monkeys are fed certain B vitamin-deficient diets. These changes aresummarized graphically in this paper.

4. The importance of determining the concentration of hemoglobin and theformed elements of the blood as a diagnostic test in nutritional studies has beenshown.

Note: We wish to acknowledge our indebtedness to Merck and Co., Rahway, N. J., for some of the crystalline vitamins; to Wilson Laboratories, Chicago, Ill., for the various liver preparations; and to LederleLaboratories, Inc., Pearl River, N. Y., for synthetic folic acid.The authors are grateful to Miss Ethel Thewlis for aid in determining cellular elements and to Drs.Harry A. Waisman and James H. Shaw for assisting in early parts of the work.

     

Experimental anemias in the rat; I. Macrocytic anemia in chronic pteroylglutamic acid deficiency and after splenectomy in Bartonella muris infection

1. In agreement with findings by other workers, rats in acute pteroylglutamicacid deficiency showed leukopenia and growth depression followed by death, without any significant change in the red cell picture.

2. In chronic deficiency, however, produced by the addition of small pteroylglutamic acid doses given intermittently, a severe anemia was obtained afterseventy days.

3. The anemia was macrocytic and "normochromic." Price-Jones curves showeda preponderance of macrocytes with anisocytosis. This agreed with findings byother workers for other species.

4. The anemia could be cured by single doses of 40 µg. or more of pteroylglutamicacid.

5. There was no significant difference between sexes to pteroylglutamic aciddeficiency. Reduction in the protein content of the diets, containing 1 per centsulfasuxidine, from 18 per cent to 10.5 per cent, produced no significant differencein the time of onset and severity of the blood symptoms.

6. These results were not due to infection with Bartonella muris. This infectionproduced a macrocytic anemia of a different type, and was curable by treatmentwith neoarsphenamine.

Note: ACKNOWLEDGMENTSWe are grateful to Dr. T. H. Jukes of the Lederle Laboratories for generous supplies of aldehyde-freePGA; and to Dr. K. Folkers of Merck Laboratories for the biotin used in these experiments. We wish tothank Dr. W. Jacobson for his advice during the course of this investigation. Valuable technical helpwas provided by Mr. D. R. Ashby, Mr. S. G. Impey, Miss M. J. Kemp and Mr. P. W. Wilson, to whomthe authors are indebted.

     

FURTHER OBSERVATIONS ON THE EFFECT OF BENZENE ON A STRAIN OF MYELOID CHLOROLEUKEMIA IN MICE AND ON CHANGES PRODUCED IN THE LEUKEMIC CELLS BY THE CHEMICAL

Oral administration of 5 mg. of benzene six times weekly to 46 mice that hadbeen injected 24 hours before with the cells of the myeloid chloroleukemia 1394,considerably prolonged the survival of the animals, and in 16 of these mice itseemed to prevent the development of the disease. The spleens of the animals sotreated increased in size at a much slower rate than those of the untreated animals,and the leukemic infiltration of the organs was delayed.

Five mg. of benzene given in a similar manner to mice with advanced chloroleukemia likewise prolonged the survival time of the mice and also slowed therate of increase of the size of the spleens; 25 mg. given five times in a 6 day periodto mice with this leukemia brought about a marked reduction in the size of thespleens. Further treatments slowed the rate of enlargement of the spleens andsurvival was prolonged.

In 8 mice bearing subcutaneous tumors composed of the cells of the chloroleukemia the oral administration of 25 mg. of benzene five times in a 6 day periodfollowed by 5 mg. given six times weekly brought about the disappearance of thelocal tumors as determined by palpation, but in 6 mice the tumors recurred andkilled the animals. Microscopic examination of tumors of mice treated with benzene showed advanced degenerative changes in leukemic cells.

Note: The authors with to thank Miss Pauline Pope, Miss Mary Boon, and Miss Lucille Wolf for theirtechnical assistance.

     

The relationship between carbonic anhydrase activity and zinc content of erythrocytes in normal,in anemic and other pathologic conditions

A good correlation exists between zinc content and carbonic anhydrase activityof the red blood cells under all conditions studied, including anemia and polycythemia. In almost all patients with anemias other than pernicious anemia, bothzinc and carbonic anhydrase levels were lowered in parallel fashion. These changeswere proportional to decreases in hematocrit and hemoglobin levels and erythrocyte counts so that both zinc and carbonic anhydrase values per unit of RBC werein the normal range. In a few instances of anemia associated with leukemia andin one of sickle cell anemia, neither zinc content nor carbonic anhydrase activitywas decreased in proportion to the anemia; in these cases the zinc and carbonicanhydrase levels per unit of blood were both elevated to the same degree.

Patients with pernicious anemia showed no decrease in absolute values for zincand carbonic anhydrase activity in spite of marked lowering of hematocrit andhemoglobin levels and of erythrocyte count. Accordingly, both zinc concentrationand carbonic anhydrase activity per unit of blood were elevated, often to a markeddegree. These increases were parallel, varying inversely with the degree of anemia;when they regressed under treatment, both did so at the same rate.

There are no methods available for estimating carbonic anhydrase concentration;all methods now in use measure only the activity of the enzyme. It is suggestedthat zinc concentration could be used as an indicator of carbonic anhydrase contentof the red blood cells.

Note: ACKNOWLEDGMENTSDrs. Joseph C. Aub and Ira T. Nathanson were kind enough to refer several patients for study. Dr.Byrl J. Kennedy was most helpful in regard to obtaining samples of blood. The technical work wasperformed by Miss Mary Lou Roney, Betty Hickey and Marion Taylor.

     

Blood exchange in replacement transfusions; studies with erythrocytes tagged with radioactive phosphorus

Red cells labeled with radioactive phosphorus have been used by us to measurethe extent and the rate of the replacement of blood in exchange transfusions. Theexperimental results confirmed the theoretic formulations developed in the preceding paper. On the basis of the above data, it seems reasonable to introduce thesecurves and formulae whenever exchange transfusions are to be performed.

Note: ACKNOWLEDGMENTSWe are indebted to Miss G. Ohno and Miss S. Rezek for technical assistance rendered during thisstudy.

     

SERUM PROTEIN CHANGES IN MYELOGENOUS AND LYMPHOCYTIC LEUKEMIAS AND HODGKIN'S DISEASE

1. Using a methyl alcohol fractionation technic, the albumin, globulin, andtotal protein levels were determined in a series of normal adults and compared withcases of myelogenous and lymphocytic leukemias and Hodgkin’s disease.

2. Statistically significant decreases in albumin and increases in globulin werefound in the cases of Hodgkin’s disease and myelogenous leukemia, but withoutsignificant changes in total protein. Globulin levels above the highest normal valuewere found in 23 per cent of the former and 33 per cent of the latter group.

3. No apparent relationship was noted between the levels of the serum proteinfractions and (1) the hemoglobin level, (2) the erythrocyte count, (3) the peripheral white blood cell picture, and (4) the bone marrow smears.

Note: The authors wish to express their appreciation to Professor Ovid O. Meyer, Department of Medicine,for making available the clinical material in this study and for valuable suggestions. The authors arealso indebted to Professor J. A. E. Eyster, Department of Physiology, for suggestions as to statisticaltreatment of the data.

     

Microscopic and histochemical studies on the Auer bodies in leukemic cells

(1) Seventeen cases of acute leukemia with Auer bodies have been reported.Studies were carried out on 7 cases of acute monocytic leukemia and 3 cases ofsubacute myelogenous leukemia.

(2) Histochemical studies showed the Auer bodies to be oxidase, peroxidase,and periodic acid-Schiff positive; sudanophilic, slightly metachromatic and to givepositive tests for acetal lipids and ribonucleic acid.

(3) The Auer bodies were negative for acid and alkaline phosphatase, lipase,glycogen, desoxyribonucleic acid and were non-birefringent.

(4) A change in the chemical nature of the Auer body from an acid conditionto a more neutral state was noted. This change corresponded with the changesof the normal cytoplasmic granulation of the myelocytes and monocytes duringmaturation.

(5) The effects of cellular movements, trauma, and temperature changes uponthe Auer bodies were studied.

(6) Several leukemic cells, containing Auer bodies, were studied during theprocess of mitosis.

(7) A theory as to the formation and disintegration of the Auer bodies hasbeen presented.

Note: ACKNOWLEDGMENTSThe author wishes to express his thanks to Dr. B. K. Wiseman, Dr. B. C. Houghton, Dr. R. A. Knouff,and Dr. E. R. Hayes for their help and suggestions, and to Dr. J. D. Thomas, Dr.J. F. Gamble, Dr. R. J.Rohn, Dr. H. Schiro, Mrs. Jo Myers, M.Sc., Miss Georgia Gwinner, M.T., Mrs. Susan Ragsdale, M.T.and Mrs. Jeanne Marie Willison, M.T., for their help in securing the experimental material.

     

THE ACTION OF PTEROYL GLUTAMIC ACID AND NATURAL SOURCES OF FOLIC ACID ON BLOOD DYSCRASIAS INDUCED BY SULFONAMIDE DRUGS

Sulfanilamide, sulfathiazole, and sulfadiazine have been fed at 1 per cent levelsin highly purified diets and their effect on growth, mortality, and blood dyscrasiascompared with that of sulfasuxidine.

The soluble drugs produce conditions which are similar to those produced bysulfasuxidine. The growth depression is alleviated in large measure in the case ofsulfanilamide and to a lesser extent for sulfathiazole and sulfadiazine by folic acid.liver extract powder, and dried yeast extract as well as by para-aminobenzoic acid,

The blood dyscrasias due to sulfanilamide, sulfathiazole, and sulfadiazine aresevere leukopenia, granulocytopenia, and mild-to-severe anemia. These are uniformly prevented or the severity greatly curtailed by feeding folic acid, liver extract powder, or dried yeast extract. PABA has a lesser effect in the amounts fed.

Liver extract powder seems to have a beneficial effect on growth and mortalitywhich is not shown by the other supplements. Both free and conjugated folic acid(as yeast extract and in liver extract powder 1:20) are active in combating thedyscrasias.

Evidence from in vitro experiments with Str. haemolyticus (B Lancefield) indicates that neither folic acid, liver extract powder, nor dried yeast extract in ratiosto sulfonamide which are effective in preventing the blood dyscrasias will inhibitor block the bacteriostatic action of the sulfonamide drugs in vitro.

It is suggested that the action of folic acid, liver powder, and yeast extract is notwholly explained by alleviating a folic acid deficiency caused by intestinal bacteriostasis due to the drugs, but by an increased demand of the animals for folicacid in the presence of certain sulfonamides.

Note: We are indebted to Harold Buskirk, Alice Bergdahl, Hallie Ferguson, E. M. Stapert, F. La Plante,and Evon Saggio for valuable assistance in carrying out the experimental work reported here.

     

MONOCYTIC LEUKEMIA AND TUBERCULOSIS

A case of monocytic leukemia associated with active tuberculosis of pleura,pericardium, and lymph nodes is reported.

The criteria for the diagnosis of monocytic leukemia and the factors excludinga leukemoid reaction are presented.

The rarity of monocytic leukemia in contrast with the frequency of tuberculousinfections and the rarity of active tuberculosis in the reported cases of monocyticleukemia indicate that the association of the two diseases is probably coincidental.

Note: Grateful acknowledgment is due to Miss Anne Shiras and Mortimer Cohen, M.D., for the photo-micrographs.

     

A method for obtaining living leukocytes from human peripheral blood by acceleration of erythrocyte sedimentation

A simple method for obtaining living leukocytes from human peripheral blood ispresented. It consists of the addition of fibrinogen to heparinized blood. Essentiallyall the leukocytes remain in plasma suspension and essentially all the erythrocytesare sedimented out at the end of one hour.

Note: ACKNOWLEDGMENTThe authors wish to express their thanks to Miss Alma Manieri, who did all the blood counts forthis study, and to Mr. Antol Herskovitz, who prepared the photomicrographs.

     

THE EXCRETION OF UROBILINOGEN IN THE STOOLS AND URINE DURING MALARIAL INFECTION

In 10 cases of malaria (6 benign tertian, 4 malignant tertian), the excretion ofurobilinogen in the stools and in the urine was studied. In all 10 cases the amountof urobilinogen excreted in the stools was found to be increased. After defervescence and disappearance of parasites from the blood the excretion gradually declined. The increased excretion of urobilinogen in the stools was the constant andsometimes the only evidence of increased blood destruction occurring at times in the complete absence of jaundice and reticulocytosis. Increased excretion of urobilinogenin the urine was not a constant feature.

It is suggested that the development of jaundice and of urobiligenuria is duenot only to the liberation of pigments by the hemolysis, but to a disturbance in theliver function.

This study lends further confirmation to the concept that the only unequivocalevidence of increased blood destruction is shown in an increased output of urobilinogen in the feces.

Note: The author is indebted to Dr. M. Rachmilewitz for his suggestions and criticisms.

     

The Rh chromosome frequencies in England

The results are reported of testing 1073 English bloods with the Rh antibodiesanti-C, anti-C^w, anti-c, anti-D, anti-E and anti-e. The results of another series of927 bloods, already published, are here reproduced. The total of 2000 bloods hasbeen used by Fisher to estimate, by his method of maximum likelihood, the Rhchromosome frequencies in England. The estimates are: CDe 40.75 per cent, cde38.86 per cent, cDE 14.11 per cent, cDe 2.57 percent, C^wDe 1.29 per cent, cdE 1.19per cent, Cde 0.98 per cent, and CDE 0.24 per cent.

A brief account is given of the three pairs of alternative antigens shown byFisher to be the basis of the Rh blood groups. Fisher’s interpretation must now beconsidered as established beyond doubt. A possible genetic basis of these relatedantigens is discussed.

Note: ACKNOWLEDGMENTSWe are deeply indebted to Professor Fisher for many reasons, but we should particularly like toacknowledge his kindness in allowing us to publish the results of his calculations of the chromosomefrequencies.For the antisera used in the investigations we are indebted to the following: Doctors E. F. Aubert,Sheila Callender, D. S. Dick, R. J. Drummond, Mr. I. Dunsford, Doctors A. J. McCall, Brenda Morrison,J. Murray, E. Wordley and R. A. Zeitlin.We also thank Dr. H. F. Brewer of the London Red Cross Blood Donor Service, and Dr. J. F. Loutit ofthe National Transfusion Service, for providing us with large numbers of blood samples.We also wish to acknowledge the assistance of Dr. Marjory N. McFarlane in the earlier part of thisinvestigation.

     

The effect of artificial surfaces on blood coagulability,with special reference to polyethylene

1. The reaction to small pieces of polyethylene and lucite in the subcutaneoustissues of 30 rats was studied at intervals up to three months after insertion. Polyethylene was shown to compare favorably in respect to minimum tissue reaction,with the well-tolerated lucite.

2. A series of clotting times was performed in polyethylene, paraffin, collodionand glass tubes. The clotting time in polyethylene tubes was about twice as longas in glass, and nearly as long as in paraffin and collodion-lined tubes. These dataare similar to Hirschboeck’s findings for lucite tubes.

3. Clot retraction was found to be moderate and essentially similar in polyethylene, paraffin, and glass tubes. It was slight or absent in collodion tubes.

4. Capillary tubes of polyethylene were shown to repel water initially and thengradually to attract water over a period of days to a maximum height about one-half of that in glass tubes. Thus polyethylene follows Lampert’s rule, which statesthat the effect of a surface in delaying the coagulation of blood is proportional tothe capacity of that surface for repelling water.

Note: ACKNOWLEDGMENTSThe authors wish to express appreciation to Drs. H. G. Saroff, J. Sendroy, Jr., J. L. Tullis, E. P.Cronkite, and Miss M. E. Tarver, for helpful advice and cooperation in these studies.

     

Experimental anemias in the rat; II. The effect of various sulfonamides in producing a pteroylglutamic acid deficiency and the pteroylglutamic acid activity of test substances

1. Different sulfonamides were tested to ascertain their effect in producing thecharacteristic symptoms of acute PGA deficiency in rats fed on synthetic diets.Sulfasuxidine (1 per cent) and the less soluble phthalylsulfathiazole (1 per cent)were equally effective. Sulfathiazole in 1 per cent concentration produced a hemolytic anemia not reversible by PGA or whole liver powder. In a 0.5 per cent concentration it was also effective, but in view of its toxicity, the less soluble sulfonamides were to be preferred. A mixture of 0.5 per cent sulfathiazole and 0.5 percent sulfadiazine was extremely toxic and produced a hemolytic anemia. Sulfaguanidine was toxic at 1 per cent concentration.

2. When intermittent small doses of PGA were given to PGA-deficient rats toprolong their life from 45 up to 155 days, 1 per cent sulfasuxidine or phthalylsulfathiazole, or 0.5 per cent sulfathiazole were equally efficient in producing regularlya macrocytic normochromic anemia.

3. The response of PGA-deficient rats to single doses of PGA has been studiedand an assay procedure has been suggested which uses the weight increase andduration of cure as the measure of the response. The W.B.C. and reticulocyte response can also be used as a qualitative indication of PGA activity.

4. Of the substances tested by this procedure, vitamin B₁₂, purified perniciousanemia preparations, ascorbic acid and xanthopterin showed no PGA activity. Acommercial yeast preparation and Teropterin were found to possess biologic activity comparable with that found by other workers in assays on chicks.

Note: ACKNOWLEDGMENTSWe wish to thank Dr. E. Lester-Smith, of the Glaxo Laboratories, for the generous supply of vitaminB₁₂, Dr. T. H. Jukes, of the Lederle Laboratories, for the gift of PGA and Teropterin, and Dr. W. Jacobson for the samples of purified P. A. liver preparations and xanthopterin.

     

The effect of quantitative and qualitative protein deficiency on blood regeneration; white blood cells

1. The effect of diets, varying in quantity or quality of protein, on white bloodcell regeneration was studied in leukopenic rats, the leukopenia having been induced by a protein-free diet.

2. Diets containing different amounts of casein (3, 6, 9 and 18 per cent, respectively), were fed ad libitum. At the 3 per cent level, a further decrease occurred ofwhite blood cells, whereas the other three diets initiated a regeneration of leukocytes, its degree being more or less in proportion to the casein content.

3. In experiments with diets containing 18 and 30 per cent of casein, the amountof protein eaten and not its level in diet was the decisive factor in the regenerationof leukocytes. The white blood cell regenerating effect of a diet containing anoptimal level of protein, may be neutralized when given in restricted amounts.

4. Diets containing nutritionally inferior proteins, fed at 9 per cent level, alsoimpaired normal regeneration of leukocytes. The white blood cell regenerationafforded by the proteins investigated was found to increase in the following order:maize, gelatin, wheat, casein, processed soya, peanut, meat, egg.

5. In white blood cell regeneration promoted by dietary protein, granulocyteswere found to react to a greater degree than lymphocytes and monocytes.

     

Blood destruction in the polycythemia induced by hypoxia

The hemoglobin catabolism during the development and during the disappearance of polycythemia induced by hypoxia was studied by measuring the totalcirculating hemoglobin and the daily bile pigment excretion in bile-fistula dogsbefore, during, and after prolonged periods of exposure to 20,000 feet simulatedaltitude.

1. The inscreased erythropoiesis during the first weeks of altitude exposure wasaccompanied by a signiflcant increase in bile pigment output. The possible sourcesof this pigment excretion are discussed.

2. The life spans of the red cells during altitude exposure was found to be about115 days. No differences were observed in the longevity of the cells in animals atground level and at altitude.

3. The normalization of the polycythemic blood levels took place within sixto eight weeks after returns to ground level, and was achieved by the combinedeffect of a depressed erythropoiesis and of an increased blood destruction. Theincrease in red cell destruction observed under these conditions demonstratesthe existence of an "active" mechanism of blood destrunction by which the organism is able to destroy normal blood cells before their life span is exhausted. Thisincreased red cell destruction, however, accounted for only 21 to 39 per cent ofthe hemoglobin which disappeared from circulation after return to ground level.The major part of the normalization of altitude polycythemia was brought aboutby a temporary depression of erythropoiesis which was estimated to amount to30 or 40 per cent of the normal cell production in the six weeks after the discontinuation of the altitude exposure.

Submitted on September 15, 1951 Accepted on October 25, 1951     

EXPERIMENTAL LEUKOCYTOSIS. THE INEFFICACY OF P-CHLOROXYLENOL AND METHYL ACETAMIDE AS BONE MARROW STIMULANTS

1. Single and multiple injections of CXM (methyl acetamide and p-chloroxylenol) have a similar action in increasing the total number of polymorphonuclearleukocytes in the peripheral blood of a group of 32 rats. No "shift to the left"takes place.

2. There is no stimulation of the myeloid elements of the bone marrow to suggest that this leukocytosis is due to hyperplasia.

3. The evidence suggests that the mechanism for the leukocytosis produced bythe CXM consists of releasing blood cells from depots in the body. This action isselective for the granulocytes as the red cells and platelets are not affected.

4. There is progressive degeneration of the parenchymal cells of the liver aftersingle and multiple injections of these substances.

5. If less toxic combinations of methyl acetamide and para-chloro-xylenol couldbe obtained, they might be of value in the treatment of certain patients withleukopenia or agranulocytosis more particularly when the bone marrow is hyperplastic but the granulocytes are not released.

Note: The author expresses his appreciation to Dr. Oscar Riddle for the generous provision of animal andlaboratory facilities.

     

The Mitotic Activity of Circulating Atypical Mononuclear Cells in Infectious Mononucleosis

An investigation has been made into the mitotic and premitotic activity ofthe circulating atypical mononuclear cells which occur in infectious mononucleosis. Dividing and binucleate cells were found in 2.4 per cent of blood filmsand in 63.9 per cent of white cell concentrates. The number of cells in mitosiswas small and they were most commonly encountered during the first threeweeks of the disease; cells in prophase and metaphase predominated. The incidence of dividing cells in white cell concentrates was increased by a preliminary period of incubation with colchicine. The uptake of ³H-thymidine wasshown to be increased during the first four weeks of the disease, with peaklabeling in the second and third weeks; in one autoradiograph, 5.4 per centlabeling was observed. The label was confined to the nuclei of certain atypicalmononuclear cells, most of which showed rather marked cytoplasmic basophilia. Karyotype analyses were consistently normal. The occurrence of similarlarge mononuclear cells, capable of taking up ³H-thymidine, in other pathological conditions and in normal subjects is stressed. Their origin, function andpotentialities are ill-understood at the present time.

Two further autoradiographic studies^21,22 dealing with the mitotic activityof atypical mononuclear cells in infectious mononucleosis have recently appeared, both of which record increased DNA synthesis. Epstein and Brecher²¹observed peak labeling during the first two weeks of the disease; most of thelabeled cells showed enhanced cytoplasmic basophilia. No variation in labeling at different phases of the disease was found by Schmid et al.,²² who,unlike previous workers, characterize the labeled cells in some detail asplasmacytoid, monocytoid and lymphocytoid elements.

Submitted on December 2, 1964 Accepted on February 14, 1965     

Granulomatous lesions in the bone marrow in infectious mononucleosis; a comparison of the changes in the bone marrow in infectious mononucleosis with those in brucellosis,tuberculosis, sarcoidosis and lymphatic leukemia

1. The findings in the blood and in aspirated bone marrow in 23 cases of infectious mononucleosis have been described.

2. Unequivocal evidence of involvement of the bone marrow has been found in70 per cent of the cases.

3. Evidence of granulomatous inflammation of the marrow was found in 48 percent of the cases.

4. Epithelioid cells were found in the films of bone marrow in 48 per cent of thecases. These cells appear morphologically identical with those seen in imprints oflymph nodes from infectious mononucleosis and sarcoidosis and with the epithelioid cells seen in films of the marrow in brucellosis, sarcoidosis and tuberculosis.

5. The granulomatous lesions of infectious mononucleosis seem most similar tothose of brucellosis, but they also resemble the small granulomatous lesions ofsarcoidosis and tuberculosis.

6. Lymphocytosis of the marrow as well as of the blood was demonstrated in allcases. Evidence of formation of lymphocytes in the marrow was presented, and thealtered lymphocytes of infectious mononucleosis were found in films of the marrow.The degree of lymphocytosis of the marrow in infectious mononucleosis was shownto be less than that in lymphatic leukemia. Lymphocytosis of the marrow was notfound in brucellosis, sarcoidosis or tuberculosis. The lymphocytic reaction demonstrable in the marrow in infectious mononucleosis is believed to be of value in differential diagnosis.

Note: ACKNOWLEDGMENTSWe wish to acknowledge the generous cooperation of Dr. Ruth E. Boynton and the Staff of theStudent’s Health Service of the University of Minnesota throughout the course of this year long studyof infectious mononucleosis. We are indebted to Dr. T. Edward Bell and Dr. James Cardy for performingthe sternal aspirations. The photomicrographs were made by Mr. Henry Morris.