the basophilic granulocyte - blood

The Basophilic Granulocyte

By ROBERT E. FREDRICKS AND WILLIAM C. MOLONEY

T HE BASOPHILIC GRANULOCYTE was first described by Paul Ehrlichin 1891.1 At that time he noted the morphologic similarities of the baso-

phil and the tissue mast cell, both of which contain water-soluble, metachroma-

tically staining granules. Ehrlich also recognized the difference in the genesis

of these cells and postulated that the hemic basophil was derived from the

marrow and was morphogenetically analogous to the neutrophilic and eosino-

philic granulocytes. His theory was challenged repeatedly during the next

forty years2’3 but now seems to be established incontrovertibly.2’4’5

During the succeeding years there have been a few observations relating

changes in basophil counts to various clinical states, but the most signfficant

additions to our knowledge of basophils have been concerned with their bio-

chemical characteristics. In 1952, Graham, et al.6’ � demonstrated that baso-

phils contain a high concentration of histamine and most of the total blood

histamine; this has been confirmed by others.81#{176} In 1952, Behrens and Tau-

bert,� and in 1953, Martin and Roka12 produced evidence suggesting that

the basophils were rich in heparin-like material.

Morphology and staining characteristics-The basophil is the smallest of

the granulocytes, normally having a diameter of about 10 to 14 micra.’3 As

Ehrlich pointed out, the cytoplasmic granules are soluble in water and gly-

cerin and stain metachromatically with certain basic dyes ( thionine, toluidine

blue, methylene blue, methylene violet, brilliant cresyl blue, amethyst, akro-

din red, neutral red, pyronin, safranine and azure), giving a somewhat red-

dish tint with the blue dyes and a yellowish hue with the red dyes.2 The

granules are round,2’4 although some may be irregularly shaped in fixed

preparations.13’” They vary considerably in size and are usually smaller than

the eosinophilic granules but larger than the neutrophilic granules4; they have

diameters of 0.3 to 0.8 micron.’3 The basophils contain fewer granules than

the eosinophils.

As seen in a Wright’s stained smear, the mature cells have a marrow band

of light pinkish to lavender cytoplasm surrounding a slightly reddish purple,

polymorphous nucleus having two to four segments, which are usually folded

on themselves and are often indistinct. The filaments joining the segments

are usually short and broad, and the nuclear chromatin appears more homo-

geneous and tends to stain less intensely than that of the eosinophils and neu-

trophils. The characteristic granules are round, dark purple, and distributed

irregularly through the cell, often times overlying and obscuring the nucleus.

From the Hematology Laboratory, I & III Medical Services (Tufts), Boston City Hos-

pital, Boston, Mass.This work was supported in part by Grant No. AT (30-1) 1871, from the Atomic

Energy Commission.

Submitted June 9, 1958; accepted for publication Nov. 1, 1958.

571

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572 FREDRICKS AND MOLONEY

TABLE 1.-Normal Values for Blood Basophils

Basophila cu.mm. Per cent

Avg. Range Basophil. Subject Author and Yea?

0.3-0.6 Normal Children Weidenreich 1908’

0.35 avg. Arneth 1920�

35 0.45 avg. Normal Adults #{176}Alder 1923”

0.4-0.6 Normal Adults Bunting 193214

46.7 11-107 Normal Adult tJames et al. 1953”

Men40.6 8-88 Normal Adult jJames et al. 1953”

Women

21 Normal Infants tJames et a!. 1955”

43 27-69 Ne-whom Negroes fJames et al. 1955”

28.1 5-67 Normal Japanese fMoloney & 1954”

Adults Lange

42.8 9-113 Normnal Adult fAngeli et al. 1954”

Men39.1 15-82 Normal Adult fAngeli et al. 1954”

Women

25 15-50 0.0-0.75 Wintrobe 1956”

#{176}Indirectmethod with 1000 cell differential.

tDirect method or indirect method with 4000 cell differential.

In cases where the basophils are increasing in number or in which there is

a basophilocytosis, the mature basophuls may be sparsely granulated with

small granules,15’16 and younger forms, especially bands, may appear.

Histochemical studies of the basophuls are complicated by the fact that

many of the procedures require the use of liquid media in which the baso-

philic granules are soluble. Consequently, identification of the basophils in

the processed smears is ordinarily very difficult. However, unlike the other

granulocytes, the basophils are peroxidase-negative,2’3 and their cytoplasm

is apparently devoid of alkaline phosphatase activity when the Gomori meth-

ods are used.171#{176}

Counting technics and normal t)alues.-The usual 100 to 500 white blood

cell differential counts are ordinarily inadequate for the evaluation of the

numbers of basophils in the peripheral blood. To be significant the indirect

basophil count should be based on at least a 1000 cell differential count of

leukocytes. Moore and James have developed a relatively simple method for

the direct, �vet, counting of basophils, which, they have shown, has excellent

statistical correlation with indirect basophil counts done by 4,000 cell differ-

ential counts.2#{176}

The basophil counts on cases reported in this paper were done by the

direct method of Moore and James or by the indirect method based on 4,000

cell differential counts. Normal values for the absolute and relative numbers

of basophils in the peripheral blood are shown in table 1.

BASOPHILS IN PAThOLOGIC CONDITIONS

Chronic myelogenous leukeniia.-Ehrlich first noted basophilocytosis in

chronic myelogenous leukemia. Many others have confirmed his observation,




THE BASOPHILIC GRANULOCYTE 573

T�trn� 2.-Basophils in Untreated Cases of Chronic Myelogneous Leukemia

Patient WBC’s/cu.mm. % Baso’s Baso’s/cu.mm.

V.A. 22,800 3.60 821

E.B. 176,000 8.90 15,664M.B. 183,000 3.50 6,422A.C. 230,000 2.95 6,785

L.C. 217,000 0.87 1,887

G.C. 213,500 1.65 3,523

IC. 29,550 3.70 1,093

A.D. 124,000 2.25 2,790

V.F. 310,000 3.00 9,300

K.H. 65,000 3.80 2,470J.Mc. 118,400 0.88 1,036R.M. 501,000 0.60 3,006

R.N. 287,500 1.00 2,875

M.O. 120,000 2.30 2,760

AR. 118,000 7.00 8,260

C.T. 172,000 4.58 7,855P.T. 82,000 4.85 4,977F.T. 570,000 3.70 21,090G.W. 278,000 3.75 10,425

and it is generally accepted that the greatest elevations of basophils occur

in this disease.2”4”6’21’22’2528 In one variety of myelogenous leukemia, so-called

“basophilic leukemia,” basophilocytosis as high as 83.2 per cent has been

recorded.29

The highest levels of blood histamine have also been found in patients

with chronic myelogenous leukemia6’9’10’3040; indeed, it was this feature which

led to the discovery that the basophils contain most of the blood histamine.7’8’10

All the data now available show that the absolute numbers of basophils are

almost always increased in chronic myelogenous leukemia, including the leu-

kopenic type.25 It is of considerable clinical importance that basophilocytosis

is oftentimes one of the earliest manifestations of chronic myelogenous leu-

kemia.22

In our current studies 19 untreated cases of chronic myelogenous leukemia

were investigated, and in these patients basophils ranged from 0.60 per cent

to 8.90 per cent and from 821 to 21,090 per cubic millimeter of blood. (See

table 2.)

Myeloproliferative disorders.-In 1923, Alder reported that basophils were

always markedly increased in polycythemia25; however, it is now well es-

tablished that the basophils are usually moderately increased in polycythemia

vera with associated myeloproliferative features.2’”’22’26 The degree of this

increase is reflected in elevated blood histamine levels in these cases,9”#{176}’32’35’

36,38,39 and is ordinarily less marked than in chronic myelogenous leukemia.

Included in our series were 18 patients with untreated myeloproliferative

disorders (eight cases of polycythemia vera and 10 cases of agnogenic mycloid

metaplasia). Basophils ranged from 0.20 per cent to 6.30 per cent and from

51 to 2,632 per cubic millimeter of blood in 17 of the 18 cases. One patient,





TABLE 3.-Basophils in Untreated Cases of Mycloid Metaplasia

WBC’s/ Per cent BasophilsPatient Diagnosis cu.mm. Basophils cu.mm.

J.E. Polycythemia Vera 71.500 1.40 994

F.G. Polycythemia Vera 21,500 0.60 129

P.M. Polyeythemia Vera 107,500 1.12 1,204

N.Mc. Polycythemia Vera 25,300 0.20 51

A.M. Polycythemia Vera 17,350 0.78 136

M.M. Polycythemia Vera 12,700 0.45 57

JR. Polycythemia Vera 12,000 2.38 286

R.W. Polycythemia Vera 17,800 1.74 310

BA. Agnogenic Myeloid Metaplasia 83,000 0.38 315

E.A. Agnogenic Myeloid Metaplasia 46,800 1.48 693

T.B. Agnogenic Myeloid Metaplasia 96,000 1.30 1,248

E.D. Agnogenic Myeloid Metaplasia 25,450 1.62 412

G.D. Agnogenic Myeloid Metaplasia 41,500 6.30 2,632

H.G. Agnogenic Niyeloid Metaplasia 60,000 1.20 720

J.H. Agnogenic Myeloid Metaplasia 52,000 3.05 1,586

S.H. Agnogenic Myeloid Metaplasia 150,000 0.0 0

with acute bronchopneumonia

& pyelonephritis

D.P. Agnogenic Myeloid Metaplasia 88,000 0.20 176

M.P. Agnogenic Myeloid Metaplasia 44,500 2.33 1,057

S.H., who had myeloid metaplasia complicated by bronchopneumonia and

pyelonephritis, was found to have no basophils in a 4,000 cell differential

count. ( See table 3.)

Cirrhosis.-Several textbooks of hematology list cirrhosis as a condition in

which basophilocytosis may occur. In our experience no patient with cirrhosis

has shown increased basophils. Moreover, there is only one report in the

medical literature describing an increase of basophils in cirrhosis, and in

that series of eighteen cirrhotics, studied with 500 cell differential counts,

only occasional elevations of the relative number of basophils were de-

scribed.4’ Blood histamine studies of patients with liver disease have not

provided sufficient information to resolve this question.36’38 Since the avail-

able evidence has been meager, it was impossible to draw a definite con-

clusion; however, it seems unlikely that basophilocytosis accompanies liver

disease.

Anemias.-Prior to the modern era of medical therapy, when most anemias

persisted without effective treatment, it was noted that chronic hemolytic,

iron deficiency and “toxic” anemias were associated with moderate increases

of basophils, in contrast to pernicious anemia, in which basophil counts were

stated to be normal.25’30’34’35 Alder recorded an average of 1.09 per cent

basophils in “constitutional hemolytic icterus,” 1.9 per cent in chronic iron

deficiency anemias and 1.38 per cent in prolonged anemias secondary to blood

loss, neoplasia and infections; and he observed that the basophilocytosis sub-

sided when these anemias responded to treatment.25

Only one example of basophilocytosis associated with anemia has come

to our attention; in this case, the patient had acquired hemolytic hypoplastic




Patient

SB.

WBC’s/ Per cent Basophilscu.mm. Basophils cu.mrn.

34,100 0.01 3.13

Diagnoeis

Portal Cirrhosis with Hepatic

Necrosis

B.B. Pneumonia and Thrombophiebitis 20,500 0 0GB. Lymphoblastic Lymphoma 27,475 0.01 1.67C.C. Pneumonia 18,900 0.05 9

J.C. Pulmonary Tuberculosis 53,500 0.00 0CD. Pneumonia and Pyelonephritis 34,200 0.00 0

H.D. Portal Cirrhosis, decompensated 20,800 0.22 46

S.F. Pyelonephritis with Bacteremia 42,000 0.00 0

L.H. Necrotizing Renal Papillitis,

Bacterial Endocarditis andCirrhosis

19,350 0.00 0

R.K. Hodgkin’s Granuloma 25,900 0 0

E.L Carcinoma of Renal Pelvis

and Ureter, Pyelonephritis,

and Post-op. Retroperitoneal

Hematonla

170,000 0.00 0

L.M. Bronchiogenic Carcinoma and

Pneumonia

26,300 0.00 0

G.M. Carcinoma of Stomach with

Hepatic Metastases

88,000 0 0

F.N. Bronchiogenic Carcinoma 21,750 0.09 18.7

M.O. Carcinomatosis; questionable

primary site

21,350 0 0

C.S. Portal Cirrhosis with Acute

Gastrointestinal Bleeding

44,600 0.022 0.10

M.T. Pneumonia 53,050 0.00 0


TABLE 4.-Basophils in Cases with Neutrophilic Lenkocytosis or Leukernoid Reaction

anemia of unknown etiology. She was observed to have increased basophils

about four months after the onset of her symptoms of anemia, and since then

the basophils have varied, without apparent relationship to transfusions or

other therapy, ranging up to 3.5 per cent and 150 per cubic millimeter of

blood. In this and similar cases in which the etiology remains obscure, final

judgment about the relationship of the anemia and basophilocytosis should

be reserved.

Neutrophilic leukocytosis and leukemoid reactions.-Our series of 17 cases

of neutrophilic leukocytosis or leukemoid reactions due to infection, neo-

plasia, tissue necrosis or acute anemia was characterized by abnormally low

absolute and relative basophil counts. Indeed, the basophils almost always

disappeared completely from the peripheral blood in these cases.2’5’10’34’3638

( See table 4 and figure 1.)

Miscellaneous conditions.-In the acute leukemias, monocytic leukemias and

chronic lymphatic leukemias, basophil counts are usually relatively low, and

are never elevated.2’21’25’304#{176}

Basophilocytosis has been said to occur in Hodgkin’s disease, small pox,

chicken pox, and following injections of foreign proteins.2’14’27 In general,

these conclusions seem to be based on an occasional slight elevation of the




576 FREDRICKS AND MOLOMEY

CHRONICUVELOGENOUS

LEUKEMIA20,00010,000 #{149}..

.#{149}

5000 #{149} MYELOID

#{149} METAPLASIAS

:!a

1000 #{149}#{149}

-#{149}-- #{149}#{149}

500

#{149}:#{149}

#{149} LEUKOCYTOSESI &

100 ‘- LEUKEMOID

#{149} REACTIONS50-

Normol Ronge

10- �j,5-

#{149}

#{149}

0

Fic. 1.-Chart showing range of absolmmte basophil counts in normal persons and in

patients with chronic myelogenous leukemia, myeloid metaplasia, and neutrophilic leu-

kocytosis or leukemoid reaction.

relative number of basophils determined from a 200 to 300 white cell differ-

ential count.42’43 Several investigators have failed to confirm the reports of

basophilocytosis in response to the injection of foreign proteins in humans.2’25

The reported normal blood histamine levels in patients with Hodgkin’s dis-

ease imply that the basophil counts were normal in these cases.32’34’35

Medical texts refer to an association of basophilocytosis with “allergic”

eosinophilia. The one reported instance of this association concerned a case

of hookworm disease, for which details about the clinical findings and the

counting technic employed were not given.3

it is of interest that basophilopenia has been observed in normal persons44’45

and in several patients with thrombocytopenic purpura following steroid ad-

ministration. The data concerning this phenomenon are very limited both

quantitatively and qualitatively; further studies will be needed to establish

the relationship of steroids to basophilopenia.




A: Before �

B After ,‘�

j

wed

I00�W. P.


#{176}Myleran is the trade name for 1:4 dimethanesulphonyl-oxybutane.

570,000

� 100,000

� 50,000

� IO,OOO�

I000�

500�

Patient: F.T.

FIG. 2.-Decrease in total leukocytes and basophils following treatment with P” in two

cases of chronic myelogenous leukemia.

THE EFFECTS OF TREATMENT ON BASOPHILS IN PATIENTS WITH CmloNIc

MYELOGENOUS LEUKEMIA AND PATIENTS WITH MYELOID METAPLASIA

Observations on 12 patients with chronic myelogenous leukemia and two

with myeloid metaplasia during a total of 27 courses of Myleran#{176} treatment

revealed no special resistance of basophils to this alkylating agent. Figures 2

and 3 illustrate the effects of p32 and x-ray treatments on the total leukocyte

and basophil counts in patients with chronic myelogenous leukemia and mye-

bid metaplasia. In each instance there was a decrease in the absolute baso-

phil counts which roughly paralleled the decline in total leukocytes in re-

sponse to the therapy. This observation was confirmed by basophil counts

and other information noted as incidental data in similar cases reported in

the medical literature (table 5) 27,30,3336,46

Apparently radiation and Myleran act on the myeloblast in order to pro-




A Before TreatmentB #{149}After Treatment100,000

50,000

10,000

5000

1000

500100

�J 50

10

51st Course 2nd Course 3rd Course

Patient ML

1st Course 2nd Course

Patient E.D. -‘


Fic. 3.-Concomitant fall in total leukocytes and basophils following x-ray therapy to

the spleen in two cases of myeloid metaplasia.

duce an essentially uniform depression of all granubocytes. Other studies,

such as leukophoresis in dogs,47’48 support this concept, which is in direct

opposition to the frequently repeated idea that basophils are radioresistant.2’16’27,29,49-51

The theory of basophil radioresistance was promulgated in 1906, when

Joachim reported a terminal case of “basophilic leukemia,” in which an in-

creasing relative basophibocytosis was noted following x-ray therapy.2#{176} Similar

cases of “basophilic leukemia” associated with increasing basophibocytosis

following x-ray treatments have also been described.2’16’27’28’49-53 One of our

patients, who had chronic myebogenous leukemia of two years’ duration, de-

veloped a spinal cord chloroma late in the course of her disease; she received

1900 r x-ray to the lumbar area then gradually developed leukopenia (2,000

to 1,000 white blood cells per cubic millimeter) and marked basophilocytosis

(38 per cent to 40 per cent) just prior to death. This case and those of “baso-

philic leukemia” which have been reported probably represent a distinct type





TABLE 5.-Effect on Basophils of Myleran Treatment of Chronic Myelogenous

Leukemia and Myeloid Metaplasia

Pretreatment Post-TreatmentWBC’s/ % Bas&s/ Myleran WBC’s/ % Baso’s/

Patient Course cu.mm. Baso’s cu.mm. mg. cu.mm. Baso’s cu.mm.

Chronic Myelogenous Leukemia

V.A. 1st. 107,500 6.75 7,256 176 � 6,550 5.38 352

2nd. 44,400 3.05 1,354 1 12 5,000 3.03 152

E.B. 1st. 176,000 8.90 15,660 192 9,500 2.75 261

2nd. 23,600 2.85 673 156 5,200 3.60 187

MB. 1st. 183,500 3.50 6,422 196 28,000 3.75 1.050

2nd. 89,000 1.45 1,291 308 10.550 6.10 644

3rd. 65,000 1.50 975 148 14,480 2.38 345

4th. 92,500 0.70 648 222 5,050 1.80 91

5th. 20,600 1.2 247 126 4,000 1.28 51

G.C. 1st. 213,500 1.65 3,523 196 11,300 2.50 283

I.C. 1st. 29,550 3.67 1,084 142 11,400 6.03 684

2nd. 88,500 4.60 4,071 166 14,200 5.10 724

3rd. 64,000 4.70 3,008 224 11,000 3.16#{176} 348

4th. 38,700 3.65 1,412 182 5,500 5.53 304

\‘.F. 1st. 310,000 3.00 9,300 720 4,050 1.75 71

MO. 1st. 177,000 6.03 10,670 308 11,200 4.00� 448

\V.P. 1st. 146,000 2.25 3,285 188 25,500 1.02 260A.R. 1st. 118,000 7.00 8,260 444 8,050 6.45 519

CT. 1st. 172,000 4.58 7,855 546 20,400 4.63 945

F.T. 1st. 70,000 1.67 2,112 108 13,900 4.15 577

2nd. 58,000 1.75 1,015 144 11,400 0.64#{176} 73

3rd. 41,500 2.00 830 352 4,500 0.27#{176} 12

4th. 88,000 2.75 2,420 430 5,200 0.75#{176} 39

G.W. 1st. 278,000 3.75 10,425 354 6,850 2.28 156

2nd. 76,500 1.10 342 246 22,40t) 1.70 381

Myeloid Metaplasia

E.D. 1st. 43,000 1.48 636 106 20,600 1.00 206

D.P. 1st. 88,000 0.20 176 84 38,500 0.15 58#{176}Based on 2000 cell differential.

of terminal chronic myebogenous leukemia, as Doan and Reinhardt28 and

others16’53 have suggested, and an etiobogic relationship to radiation therapy

seems unlikely.

DISCUSSION

The functions of the basophil remain unknown. Basophibocytosis in bin-

mans following injection of heparin54 and biochemical characteristics of baso-

phils11’12 suggest that these cells might be heparin carriers. On this basis it

has been postulated that the basophib, like the mast cell, is a “heparinocyte”

which releases its anticoagulant material in areas of inflammation in order to

prevent clotting and stasis of blood and lymph.1 1,55-57 However, further ex-

perimental and biochemical proof is necessary before this thesis can be

firmly established. No functional significance has become associated with

the high concentration of histamine in the basophils.





Basophilopenia is commonly found with steroid treatment of nonleukemic

patients and in conditions such as infection, neoplasia, tissue necrosis and

acute anemia. This relationship to “stressful” conditions suggests that the fall

of the basophils, like that of the eosinophils, might be mediated via the

pituitary-adrenocortical axis.

SUMMARY

1. The history, morphology and technics of counting of basophils have been

briefly reviewed.

2. A marked relative and absolute increase of basophils was always found

in chronic myelogenous leukemia. Moderate relative and absolute increases of

basophils usually occurred in myeloid metaplasias ( including polycythemia

vera with leukocytosis ) . In some cases of iron-deficiency, hemobytic and toxic

anemias of long standing there may be moderate increases of blood basophils.

3. Marked relative and absolute decreases of basophils occurred in almost

all cases of neutrophilic leukocytosis or leukemoid reaction, associated with

infection, neopbasia, tissue necrosis or acute anemia. Patients with chronic

lymphatic leukemia, monocytic leukemia or acute leukemia almost always

have relative and absolute decreases of circulating basophils.

4. In our experience there is no evidence that basophils possess any pe-

culiar radioresistant qualities. In general, the basophils fall proportionately

with the decline of beukocyte counts during Myleran, P32 and x-ray therapy

of chronic myelogenous leukemia and myeboid metaplasia. The suppressing

action of these therapeutic agents seems to be on the proliferating blast cell.

5. The function of the basophils is not known, but it has been postulated

that they might act as “heparinocytes,” inhibiting clotting and stasis of blood

and lymph in areas of inflammation.

6. There is suggestive evidence that the basophilopenia in cases of infec-

tion, neoplasia, tissue necrosis and acute anemia is analogous to the eosino-

philopenia of the “stress reaction” mediated via the adrenal glands; however,

it must be admitted that this has not been unequivocally established, and

other mechanisms may play a role in controlling the levels of circulating baso-

phils.

SUMMARIO IN INTERLINGUA

1. Es presentate un breve revista del historia, morphologia, e technica del

numeration de basophilos.

2. Un marcate augmento relative e absolute del basophilos esseva semper

trovate in chronic leucemia myelogene. Moderate augmentos relative e ab-

solute del basophibos occurreva usualmente in metaplasias myeboide, incluse

polycythemia ver con leucocytosis. In certe casos de carentia de ferro e de

hemolytic e toxic anemias de bonge duration, il pote exister moderate grados

de augmento del basophibos del sanguine.

3. Marcate reductiones relative e absolute del basophibos occurreva in

quasi omne casos de leucocytosis neutrophilic o de reaction leucemoide as-

sociate con infection, neoplasia, histonecrosis, o anemia acute. Patientes con





chronic leucemia lymphatic, leucemia monocytic, o leucemia acute manifesta

reductiones relative e absolute del basophilos circulante in quasi omne casos.

4. In nostre experientia, nihil prova que basophilos possede special quali-

tates radio-resistente. In general, le basophilos se reduce proportionalmente

con le reduction del numeration leucocytic in le curso del uso de Myleran,

�32 e radios X in le tractamento de chronic leucemia myelogene e de meta-

plasia myeloide. Le action depressori exercite per le mentionate agentes thera-

peutic pare afficer le proliferante blastocytos.

5. Le function del basophilo non es cognoscite, sed on ha postulate que

illos es possibilemente “heparinocytos” que inhibi le coagulation e le stase

de sanguine de de lympha in areas de inflammation.

6. Il existe indicios que pare indicar que le basophilopenia in casos de in-

fection, neoplasia, histonecrosis, e anemia acute es analoge al eosinophilia

del “reaction de stress” que es mediate via le corpores suprarenal. Tamen, il

debe esser admittite que isto ha non ancora essite establite de maniera in-

equivoc, e il es ben possibile que altere mechanismos participa in le regula-

tion nivellos de basophilos circulante.

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1959 14: 571-583

ROBERT E. FREDRICKS and WILLIAM C. MOLONEY The Basophilic Granulocyte

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