"Pseudo-Abnormal" Hemoglobins

Three examples of artefactual "pseudo-abnormal" hemoglobins were observed in the course of starch block electrophoresis analysis of over 400 specimens. In fresh samples from the same patients, these components were no longer demonstrable. It is suggested that repeated examination with different bloodspecimens should be done before an unusual component is accepted as atrue hemoglobin variant.

Submitted on February 28, 1961 Accepted on April 7, 1961     

The Unitary Nature of "Complete" and "Incomplete" Pathologic Cold Hemagglutinins

Several human pathologic sera containing high titered cold agglutinins werestudied to determine whether the serologic activity ascribed to an "incompletecold antibody" could be separated from the "complete" cold agglutinin activity.Separation was not achieved by physicochemical methods, including zoneelectrophoresis, density gradient ultracentrifugation, and anion exchangechromatography. Both activities were susceptible to destruction by mercaptans.Neither activity could be differentially absorbed from the sera. Using "Bombay" and I-negative ("i") red cells, a difference in specificity of the two activities for the H or I antigen of human erythrocytes could not be demonstrated.The simplest interpretation of these findings is that there is only one antibodyinvolved, the cold agglutinin, and that the serologic manifestation usually attributed to an additional "incomplete cold antibody", i.e. the production of apositive antiglobulin reaction of the "non--globulin" type, results from aninteraction of complement components with the cold agglutinin-erythrocytecomplex.

Three of these cold agglutinating sera were unreactive with I-negativeerythrocytes, in keeping with the reported anti-I specificity of these antibodies. A fourth serum retained moderate, though greatly reduced, activityagainst these cells, and the interpretation of this finding is discussed.

The anti-H specificity of the incomplete cold antibodies in normal humansera was confirmed by their failure to sensitize "Bombay" erythrocytes. Thiswas in sharp contrast to the excellent reactivity of the pathologic sera withthese cells, demonstrating that pathologic cold agglutinins are unrelated tothe incomplete cold antibodies present in most normal sera.

Submitted on October 23, 1961 Accepted on December 2, 1961     

"Hairy" Cells in Blood in Lymphoreticular Neoplastic Disease and "Flagellated" Cells of Normal Lymph Nodes

During examinations of viable leukocytes from many leukemic and nonleukemic patients, peculiar cells called "hairy" cells were seen in the bloodfrom 2 patients. These cells were characterized by numerous short, thinvilli projecting from the surface of the cells. In one patient, some of thesecells had one or more cytoplasmic masses. The nuclei were oval or crescentic,eccentrically placed, and some had small nucleoli. The cells did not flattenon glass, did not phagocytize latex particles, and were resistant to irradiationwith 2000 r. The cells were considered to be identical to the neoplasticlymphoid reticulum cells of Mitus et al.¹

Both patients with hairy cells had large spleens, moderate anemia, andthrombocytopenia. Radiotherapy of the spleen of one patient resulted in aprompt leukopenia and a delayed decrease in the size of the spleen. Thispatient is alive and asymptomatic 21 months after diagnosis. The secondpatient’s thrombocytopenia was relieved by splenectomy. He is asymptomatic now, 11 months after diagnosis. Hairy cells are still present in smallnumbers in the blood of both patients.

The pathologic hairy cells in the blood were similar to "flagellated" cellsseen in suspensions from several hyperplastic lymph nodes. The flagellatedcells were relatively few in number, large, with numerous long, thin cytoplasmic projections and round, oval or crescentic nuclei, some of which hadsmall nucleoli. The flagellated cells were resistant to irradiation and probablywere identical to the "phagocytic reticular cells" of Sundberg.¹²

Submitted on February 23, 1965 Accepted on July 24, 1965     

"To do no harm"

SIR, We read with interest the article by Walker and Moots [1].We share their apparent frustration with the recent withdrawalof rofecoxib, valdecoxib and co-proxamol. However, we feel inorder to reach a balanced view in this argument, we need toexplore the logics and reasoning behind the decision to withdrawthese drugs. The first question we should ask ourselves surely is, wouldany pharmaceutical company of world renown, simply withdrawa universally acclaimed product and relinquish a market worthbillions without clear and compelling reasons for doing so?We agree that the industry feared an unacceptably high levelof future litigations, which forced immediate drug withdrawal.This fear was based on an     

Hypothesis: "Immunologic" Oncogenesis

The evidence that immunologic mechanisms may predispose to malignancyis reviewed, and an attempt is made to relate neoplasia possibly induced byimmunologic or other reactions involving the recognition of self and not-selfto known oncogenic mechanisms. It is suggested that "immunologic" oncogenesis as well as malignant transformation induced by known oncogenic agentsmay be mediated at least in part by chromosomal aberrations. These couldact directly to promote neoplasia, or the cell death and proliferation consequentto them could promote other mutational events. Alternatively, the chromosomal changes themselves may not be sufficient for oncogenesis, but they maypotentiate malignant transformation by other agents such as viruses.

Submitted on January 10, 1967 Accepted on May 31, 1967     

"Aspirinated" platelets are hemostatic in thrombocytopenic rats with "nonaspirinated" vessel walls--evidence from an exchange transfusion model

The contrasting effects of aspirin on bleeding time (BT) might be related to the drug's inhibitory activity on platelets and vascular prostaglandin I2 (PGI2). To test this, we developed an exchange transfusion model in the rat and studied the BT in animals whose platelets but not vessels had been exposed to aspirin. Rats with severe experimental thrombocytopenia were exchange-transfused with blood from normocythemic rats pretreated with aspirin 6 hr before. The platelet count was raised from 2% to about 70% of basal level and the BT returned to control values even though the platelets neither responded to arachidonic acid nor produced detectable amounts of malondialdehyde and vascular PGI2 was not inhibited. These results indicate that "aspirinated" platelets may be hemostatically active and that the BT is not necessarily affected by unbalanced prostaglandin production in platelets and the vessell wall.     

Abnormal peroxidase-positive granules in "specific granule" deficiency

"Specific granule" deficiency (SGD) has been previously associated with lactoferrin deficiency. The antimicrobial peptides termed defensins, comprising 30% of normal primary granule proteins, have also been shown to be markedly deficient in SGD. The present study was undertaken to correlate these findings with ultrastructural morphometric analysis and peroxidase cytochemistry. Peroxidase-positive, rim-stained, large, defensin-rich dense granules, previously described as a subpopulation of azurophil or primary granules in normal neutrophils, were markedly decreased in a patient with SGD. Morphometric studies of peroxidase- positive granules indicated an average peroxidase-positive granule area (all profiles) in the patient of 0.019 +/- 0.017 micron 2 (mean +/- SD, n = 941) compared to control values from normal neutrophils of two volunteers of 0.049 +/- 0.033 micron 2 (n = 896) and 0.050 +/- 0.039 micron 2 (n = 873) (P less than 0.001 between patient and control samples). Granule histograms showed a single peak of small peroxidase- positive granules, whereas control samples contained more prominent subpopulations of larger peroxidase-positive granules. The total number of peroxidase-positive granules per 100 micron 2 of cytoplasm in the patient was 255 +/- 124 (mean +/- SD, n = 15 cell profiles), which was similar to control values of 266 +/- 63 and 212 +/- 109. Thus, the defensin deficiency in SGD is associated with a decrease in size rather than number of peroxidase-positive granules; suggesting that defensins contribute to normal peroxidase-positive granule size and that SGD is a more global granule deficiency than originally thought.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prognostic discrimination in "good-risk" chronic granulocytic leukemia

The prognostic significance of disease features recorded at the time of diagnosis was examined among 813 patients with Philadelphia chromosome- positive, nonblastic chronic granulocytic leukemia (CGL) collected from six European and American series. The survival pattern for this population was typical of "good-risk" patients, and median survival was 47 mo. There were multiple interrelationships among different disease features, which led to highly significant correlations with survival for some that had no primary prognostic significance, such as hematocrit. Multivariable regression analysis indicated that spleen size and the percentage of circulating blasts were the most important prognostic indicators. These features, and age, behaved as continuous variables with progressively unfavorable import at higher values. The platelet count did not influence survival significantly at values below 700 X 10(9)/liter but was increasingly unfavorable above this level. Basophils plus eosinophils over 15%, more than 5% marrow blasts, and karyotypic abnormalities in addition to the Ph1 were also significant unfavorable signs. The Cox model, generated with four variables representing percent blasts, spleen size, platelet count, and age, provided a useful representation of risk status in this population, with good fit between predicted and observed survival over more than a twofold survival range. A hazard function derived from half of the patient population successfully segregated the remainder into three groups with significantly different survival patterns. We conclude that it should be possible to identify a lower risk group of patients with a 2-yr survival of 90%, subsequent risk averaging somewhat less than 20%/yr and median survival of 5 yr, an intermediate group, and a high- risk group with a 2-yr survival of 65%, followed by a death rate of about 35%/yr and median survival of 2.5 yr.     

"A"-Antigen Variation in Pigeon Erythrocytes: II. Selection against the "A"-Inagglutinable Cells in Circulating Blood

Experiments were carried out for testing selection effects against the "A"-inagglutinable red cells. Three birds picked at random and not exposed tox-irradiation showed decreases in the number of inagglutinable cells in aCr⁵¹-labeled cell population at 7 days. Two of these decreases were quitelarge, being >5-fold, and the three averaged an ICF change of -3.57-fold. Thesubstantial reduction in survival of the "A"-inagglutinable cells was attestedby the lowered inagglutinable cell frequency at 7 days postinfusion.

Seven birds uniform in titer and in their negative response to previousirradiation (360 r) averaged a 3.75-fold decrease in ICF at 8 days postinfusion.Four birds of a similar group but which had been very responsive to previousirradiation were treated in identical fashion. At 8 days postinfusion the averagechange in ICF was +0.80. This change is not significant, being within theexperimental error of ±1.5-fold.

The marked difference in results between the "low-response" group (-3.75±0.56) and the "high-response" group (+0.80 ±0.88) was interpreted to bedue to negative selection operating strongly in the former group.

Submitted on July 21, 1966 Accepted on February 27, 1967     

Antibodies to HTLV-III and the Lymphadenopathy Syndrome in Multitransfused β-Thalassemia Patients

Antibodies to HTLV-III have been investigated in 118 multitransfused beta-thalassemia patients. Thirteen patients (11.01%) were found to be positive; 3 of these 13 showed clinical and immunological signs of the lymphadenopathy syndrome. A retrospective study carried out on 65 sera has shown that at least 6 patients were negative 3 years before the present investigation. This is the first extensive study on HTLV-III infection in multitransfused beta-thalassemics. It suggests that these patients are at risk for the acquired immune deficiency syndrome and related diseases.     

Follow-Up of Anti-IgA Antibodies in Primary Immunodeficient Patients Treated with γ-Globulin

The levels of anti-IgA antibodies and the appearance of adverse reactions following gamma-globulin administration in 41 patients affected by primary antibody defects treated with intramuscular (IMGG) or intravenous gamma-globulin (IVGG), and 3 patients with the Wiskott-Aldrich syndrome (WAS) have been studied during a 31-month period. Anti-IgA antibodies were restricted to patients with circulating B lymphocytes and measurable amounts of IgA. The incidence of anti-IgA antibodies in the immunodeficient patients studied was 22.7%, and 2 of the 3 WAS patients also had high levels of anti-IgA antibodies. The presence of moderate levels of anti-IgA antibodies (up to 1/1,600) was not associated with adverse reactions. Our results indicate a significant relationship (p less than 0.02) between persistence of anti-IgA antibodies and IMGG administration.     

"A"-Antigen Variation in Pigeon Erythrocytes: I. Effect of X-Irradiation on the "A"-Inagglutinable Cell Frequency

Experiments were carried out on the nature of "A"-inagglutinable cells. Theeffect of x-rays on the inagglutinable cell frequency was determined in pigeonsby comparing the frequency before and after irradiation. Initial results in thetreated birds were highly variable. Considerable reduction in the variabilityof response was obtained by control of dose, agglutinogen titer, breed, age andsex. Data was also obtained showing that there were individual differences inresponse to irradiation.

Significant increases in the frequency of the inagglutinable cells over that ofthe controls were obtained for both males and females at 2 and 4 months following irradiation with 360 r.

The relation of cell age to inagglutinability was tested by comparing theinagglutinable cell frequency of isolated young cells with that of the total cellpopulation. The comparable frequencies which were observed indicate thatcell age is not related to "A"-inagglutinability.

Submitted on July 21, 1966 Accepted on February 27, 1967     

THE BONY CHANGES IN "CHONDROMALACIA PATELLAE"

In eleven patellae excised from patients with the clinical condition"chondromalacia patellae" the following constant pathologicalchanges are seen: (1) hyperplasia of the chondrocytes, withvascularization and advancing ossification into the deep zoneof the articular eartilage; (2) new bone formation and thinningof the subchondral osseous plate; (3) focally or diffusely severeosteoporosis of the trabecular bone. In some cases we have observedsuperficial fibrillation of the cartilage and discreet nodularaggregates of woven bone on osteoporotic trabeculae. Radioisotopebone scans confirmed disordered calcium metabolism in this condition.The over-all findings do not support the concept that the clinicalcondition known as chondromalacia patellae is due to osteoarthrosisor primary cartilaginous degeneration. ^*Paper read at the Annual Meeting of the British Associationof Physical Medicine and Rheumatology, London, March 1971, andawarded the Association prize.     

Heterophile Antibodies in the Serum of Children with Nephrotic Syndrome1

Serum of children with the nephrotic syndrome contained high titers of a (19s) IgM antibody against sheep, horse, guinea pig, rat, and rabbit red blood cells but not against cow red blood cells. There was high correlation between high titers of antisheep antibodies and active nephrotic syndrome in the children with minimal change nephrotic syndrome. The antibody differed from the Paul-Bunnell antibody found in patients with infectious mononucleosis and from the anti-Forssman, Hangautziu-Deicher antibody found in patients with horse serum sickness. Rabbit red blood cells completely absorbed the antibody, but horse or guinea pig red blood cells removed only the anti-Forssman activity.     

"Early-peak" carbon monoxide production in certain erythropoietic disorders

The "early-labeled" peak (ELP) of 14CO excretion following injection of glycine-2-14C was used to study erythropoiesis in a patient with sideroblastic anemia and in four subjects with myeloproliferative disorders. The ELP was greatly enlarged in all patients, as compared with a normal volunteer. The contour of the peaks from the hematologically abnormal subjects suggested the presence of increased erythroid heme degradation. In the patient with sideroblastic anemia, all hours of the early peak were significantly reduced after transfusion. This was interpreted to mean that even the earliest or "nonerythroid" phase of the peak is influenced by erythropoietic activity, at least under conditions of erythropoietic stress.     

The Effect of "Minute" and "Titrated" Amounts of Folic Acid on the Megaloblastic Anemia of Tropical Sprue

A therapeutic trial with "minute" and "titrated" doses of folic acid wasperformed in 30 patients with the megaloblastic anemia of tropical sprue.Eleven patients responded hematologically to 25 µg. daily doses of thevitamin; nine patients responded to "titrated" doses ranging from 75 to 250µg. daily. Eleven patients failed to respond to either "minute" or "titrated"doses of the vitamin. The implications and possible reasons for the successor failure of microdoses of folic acid in sprue were discussed.

Submitted on June 12, 1961 Accepted on September 14, 1961