bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural killer cells suppress human erythroid stem cell proliferation in vitro
Authors: Mangan KF , Hartnett ME , Matis SA , Winkelstein A , Abo T
Published: October 2019

To determine the role of natural killer (NK) cells in the regulation of human erythropoiesis, we studied the effects of NK-enriched cell populations on the in vitro proliferation of erythroid stem cells at three different levels of maturation (day 14 blood BFU-E, day 5–6 marrow CFU-E, and day 10–12 marrow BFU-E). NK cells were enriched from blood by Percoll density gradient centrifugation and by fluorescence- activated cell sorting (FACS), using the human natural killer cell monoclonal antibody, HNK-1. The isolated enriched fractions were cocultured with autologous nonadherent marrow cells or blood null cells and erythropoietin in a methylcellulose erythroid culture system. Cells from low-density Percoll fractions (NK-enriched cells) were predominantly large granular lymphocytes with cytotoxic activity against K562 targets 6–10-fold greater than cells obtained from high- density Percoll fractions (NK-depleted cells). In coculture with marrow nonadherent cells (NA) at NK:NA ratios of 2:1, NK-enriched cells suppressed day 5–6 CFU-E to 62% (p less than 0.025) of controls, whereas NK-depleted cells slightly augmented CFU-E to 130% of controls (p greater than 0.05). In contrast, no suppression of day 10–12 marrow BFU-E was observed employing NK-enriched cells. The NK CFU-E suppressor effects were abolished by complement-mediated lysis of NK-enriched cells with the natural killer cell antibody, HNK-1. Highly purified HNK- 1+ cells separated by FACS suppressed marrow CFU-E to 34% (p less than 0.025) and marrow BFU-E to 41% (p less than 0.025) of controls. HNK- cells had no significant effect on either BFU-E or CFU-E growth. NK- enriched cells were poor stimulators of day 14 blood BFU-E in comparison to equal numbers of NK-depleted cells or T cells isolated by E-rosetting (p less than 0.01). Interferon boosting of NK-enriched cells abolished their suboptimal burst-promoting effects and augmented their CFU-E suppressor effects. These studies provide evidence for a potential regulatory role of NK cells in erythropoiesis. The NK suppressor effect is maximal at the level of the mature erythroid stem cell CFU-E. These findings may explain some hypoproliferative anemias that develop in certain NK cell-activated states.
Liver endothelium and not hepatocytes or Kupffer cells have transferrin receptors
Authors: Soda R , Tavassoli M
Published: October 2019

Using a visual probe, consisting of latex minibeads covalently linked to transferrin (TF), we found that, in rat liver cell suspensions, transferrin receptors were limited to endothelial cells. Neither hepatocytes nor Kupffer cells contained an appreciable number of TF receptors. Specificity of this reaction was demonstrated by preincubation with non-derivatized TF, which inhibited the binding. This was further confirmed by fractionation of liver cell suspensions on metrizamide gradients. The uptake of either the visual probe or 125I- labeled TF was again limited to the endothelium-rich fraction. Transferrin bound to endothelial membrane was internalized at 37 degrees C, but not at 4 degrees C, via a coated pit system. Again, hepatocytes and Kupffer cells did not internalize the probe. The findings suggest that iron may be first taken up by liver endothelium and then transmitted to parenchymal cells. These results emphasize the generally unappreciated role of endothelium in the transport across the tissue-blood barrier.
Studies on pure red cell aplasia. XI. Results of immunosuppressive treatment of 37 patients
Authors: Clark DA , Dessypris EN , Krantz SB
Published: October 2019

Thirty-seven patients with pure red cell aplasia (PRCA) were seen between 1966 and 1982. Ten patients had accompanying diseases described in association with PRCA, while the remainder had primary PRCA. All but two patients were treated with some form of immune manipulation, including corticosteroids, cytotoxic drugs, antithymocyte globulin, splenectomy, thymectomy, and plasmapheresis. Twenty-three patients (66%) had a remission induced by immunosuppression. In addition, there were 5 spontaneous remissions (14%). Cytotoxic drugs administered in combination with corticosteroids were the most effective form of treatment, producing 18/32 remissions (56%). Twelve of these remissions were in patients resistant to corticosteroids or in patients who had relapsed while taking them. Thirteen of the 23 patients in whom remissions were induced and one-fifth of the patients with spontaneous remissions have relapsed to date. However, with additional treatment, a second remission was induced in 10/13. Fifty-four percent of the patients with induced remissions remained transfusion-free during most of the follow-up period. Median survival in patients with primary PRCA was greater than 10 yr, whereas in patients with secondary PRCA, it was 4 yr. Infection was a major cause of morbidity and mortality. This study demonstrates the value of a variety of immunosuppressive treatments of patients with PRCA.
Leukemic cell differentiation in vivo and in vitro: arrest of proliferation parallels the differentiation induced by the antileukemic drug Harringtonine
Authors: Boyd AW , Sullivan JR
Published: October 2019

A variety of chemical agents have been shown to induce differentiation in in vitro cultured neoplastic cell lines. We noted that blast cells in the peripheral blood of acute nonlymphoid leukemia patients treated with the drug Harringtonine appeared to undergo morphological changes that suggested differentiation. In view of the relatively minimal myelotoxicity of Harringtonine, we hypothesized that harringtonine was acting by differentiation-induction, which concomitantly arrested cell division. We tested this hypothesis using two different experimental approaches. First, the promyelocytic leukemic cell line, HL-60, was cultured with Harringtonine and shown to differentiate into a cell, which, by functional cell surface marker and morphological criteria, closely resembled normal monocytes. Furthermore, these changes were accompanied, and indeed slightly preceded by, loss of proliferative capacity. Second, to prove that the leukemic blasts were the cells undergoing the changes observed in vivo, freshly isolated leukemia cell populations were cultured with Harringtonine, and morphological changes paralleling those seen in the patients were observed. Thus, the antileukemic effect of Harringtonine appeared to be due to diversion of the proliferating blast cells into a differentiation pathway, which, as in normal myeloid cells, resulted in the arrest of proliferation.
Pre-B cell leukemia responds poorly to treatment: a pediatric oncology group study
Authors: Crist W , Boyett J , Roper M , Pullen J , Metzgar R , van Eys J , Ragab A , Starling K , Vietti T , Cooper M
Published: October 2019

Seventy-eight of 362 children with acute lymphocytic leukemia (ALL) had leukemic cells similar in phenotype to normal pre-B cells. When the clinical and laboratory features of patients with pre-B and “null” cell phenotypes of ALL were compared, no significant differences were noted, except that the pre-B cell ALL phenotype had a higher percentage of black children. In contrast, patients with T cell ALL had a higher median age at diagnosis, frequent thymic involvement, and higher WBC counts. Patients with pre-B and “null” cell ALL were treated identically and patients with T cell ALL differently. Although no difference in remission induction rates was noted between patient groups with pre-B and “null” cell ALL, the remissions were of shorter duration for patients with pre-B cell ALL (p = 0.004). Similarly, overt leukemic involvement of both the central nervous system (CNS) and bone marrow was noted sooner in the patient group with pre-B cell ALL. Univariate and multivariate Cox life table regression analyses demonstrate the independent prognostic significance of the pre-B phenotype and illustrate that the prognostic influence of potential relapse risk factors, such as WBC, sex, and age, are specific for leukemia phenotype. These findings may have importance for the design and tailoring of therapy for children with acute leukemia.
Polymorphonuclear leukocyte elastase activity is increased by bacterial lipopolysaccharide: a response inhibited by glucocorticoids
Authors: Hart DH
Published: October 2019

Human neutrophil elastase is thought to play an important role in connective tissue destruction in diseases such as emphysema and arthritis. In this article, it is demonstrated that the elastase activity of mature human peripheral blood neutrophils can be rapidly increased in vitro by treatment of the cells with lipopolysaccharide from E. coli and that this increase is inhibited by corticosteroid pretreatment of the cells and by inhibitors of protein synthesis. Alterations in intracellular enzyme content of the mature polymorph in response to bacterial products or other stimuli may be important for amplification of the inflammatory response.
Platelet secretion defect in patients with the attention deficit disorder and easy bruising
Authors: Koike K , Rao AK , Holmsen H , Mueller PS
Published: October 2019

Platelet function was evaluated in 12 patients with the attention deficit disorder and lifelong history of easy bruising. Aggregation and 14C-serotonin secretion studies in platelet-rich plasma in response to adenosine diphosphate (ADP), epinephrine, and arachidonic acid did not reveal striking abnormalities. Secretion of adenosine triphosphate (ATP), ADP, beta-hexosaminidase, and beta-glucuronidase by gel-filtered platelets in response to the divalent cation ionophore A23187 and low concentrations of thrombin (less than or equal to 0.1 U/ml) was impaired in patients as compared to normals. The aggregation response to A23187 (4 microM) was absent in 8 of the 12 patients. The total stores of the secretable constituents, the retention of incorporated 14C-serotonin, and the arachidonate metabolism of the platelets were normal. Our findings suggest a new platelet disorder with impaired secretion mechanism, without storage pool deficiency or impaired arachidonate metabolism. The secretion defect in platelets represents a tissue disorder in a functional psychiatric disease. We refocus attention on the role of platelets as a model for neurons in functional disorders, with emphasis on secretion mechanisms rather than amine uptake, storage, and metabolism.
Development of factor VIII:C antibodies in dogs with hemophilia A (factor VIII:C deficiency)
Authors: Giles AR , Tinlin S , Hoogendoorn H , Greenwood P , Greenwood R
Published: October 2019

Classic hemophilia A (factor VIII:C deficiency) was diagnosed in a miniature Schnauzer dog and a breeding program established. Inbreeding and crossbreeding produced 16 hemophilic animals. All were initially treated with canine cryoprecipitate, as required, for sporadic hemorrhagic events. Five animals developed potent antibodies to canine factor VIII:C. All were the offspring of obligate carriers, resulting from the mating of a hemophilic purebred miniature Schnauzer male to a normal female Brittany spaniel. The mean age at first treatment and factor VIII exposure at the time of inhibitor development was 10.3 wk and 286.3 U, respectively. The remaining hemophilic animals have not developed antibodies, despite receiving a mean factor VIII dosage of 1.5 X 10(3) U. This group includes animals derived from a mating between the same purebred miniature Schnauzer hemophilic male and a purebred miniature Schnauzer carrier female. In each case, the antibodies recognize both canine and human but not porcine VIII:C. They are non-precipitating IgG immunoglobulins. Following inhibitor development, infusion of canine cryoprecipitate was hemostatically ineffective and factor VIII:C recovery at 30 min was negligible. Infusion of a concentrate of porcine factor VIII resulted in a correction of the hemostatic defect and optimal factor VIII:C recovery. All animals receiving porcine factor VIII:C subsequently developed antibodies to this protein. The chance occurrence of this complication should facilitate further studies directed at elucidating the pathogenesis and management of hemophilia complicated by the development of antibodies to factor VIII:C.
Beta-2-microglobulin in myeloma: optimal use for staging, prognosis, and treatment--a prospective study of 160 patients
Authors: Bataille R , Grenier J , Sany J
Published: October 2019

Previous reports have shown that serum beta-2-microglobulin (S beta2M) is a reliable marker of presenting tumor mass, response to chemotherapy, and prognosis of patients with multiple myeloma (MM). In order to more thoroughly evaluate the optimal use of S beta2M in plasma cell dyscrasias (PCD), S beta2M levels were serially measured in 160 patients with MM, in comparison with 37 normal controls (NC) and 28 patients with monoclonal gammopathy of undetermined significance (MGUS). In MGUS, S beta2M did not differ significantly from that of NC, but was significantly lower than that of MM (p less than 0.001), including low cell mass MM (p less than 0.02). In MM, S beta 2M was highly correlated with the total body burden of myeloma cells as derived from the staging of Durie and Salmon, both at diagnosis and in remission (residual tumor mass) (p less than 0.001). During the plateau phase, S beta 2M remained very stable and was always within the normal range for patients with greater than or equal to 75% tumor regression. The most striking finding was that S beta 2M gave an extremely reliable fit for survival prediction at (1) diagnosis, (2) remission, and (3) early relapse, with higher S beta 2M levels in each instance being in favor of poorer prognosis. We conclude that S beta 2M is an extremely useful marker in initial stratification and follow-up of patients with MM.
Functional properties of neoplastic T cells in adult T cell lymphoma/leukemia patients from the Caribbean
Authors: Miedema F , Terpstra FG , Smit JW , Daenen S , Gerrits W , Hegde U , Matutes E , Catovsky D , Greaves MF , Melief CJ
Published: October 2019

The neoplastic T cells from five patients with adult T cell lymphoma/leukemia (ATLL), born in the Caribbean, were studied with respect to immunoregulatory activity on pokeweed mitogen (PWM) driven immunoglobulin (Ig) synthesis as well as surface-marker phenotypes with monoclonal antibodies. The neoplastic T cells in all patients had an OKT1+4+8–11+M1-I1–3A1- phenotype, but differed in the reactivity with OKT3. None of the patients' cells exerted helper activity on PWM- induced Ig synthesis. The neoplastic cells of three patients had suppressor activity on PWM-induced Ig synthesis. All patients were positive for human T cell leukemia/lymphoma virus (HTLV) or had antibodies against HTLV antigens. It has previously been shown that the neoplastic cells in Japanese ATLL patients and in patients from the Caribbean are indistinguishable by morphology and marker phenotype. We now show them to be also similar with respect to their functional properties.
Fibrinogen proteolysis and platelet alpha-granule release in preeclampsia/eclampsia
Authors: Borok Z , Weitz J , Owen J , Auerbach M , Nossel HL
Published: October 2019

Serial measurements of the plasma concentration of fibrinopeptide A, thrombin-increasable fibrinopeptide B (reflecting B beta 1–42), desarginyl fibrinopeptide B, beta thromboglobulin, and platelet factor 4 were made before, during, and after delivery in patients with preeclampsia/eclampsia. The data were correlated with routine coagulation studies, hematologic and renal status, as well as with the clinical manifestations. In 11 patients with mild preeclampsia, there were small increases in the fibrinopeptides at the time of delivery, but no other hematologic changes. In 5 patients with severe preeclampsia/eclampsia, there were marked increases in plasma levels of fibrinopeptides and platelet alpha granule proteins, which correlated in time with the clinical manifestations. When the changes in these patients were compared with those occurring in patients undergoing intraamniotic hypertonic saline infusion, it was noted that: (1) patients with severe preeclampsia/eclampsia usually presented when plasmin action on fibrinogen exceeded that of thrombin; (2) in patients with preeclampsia/eclampsia the increase in fibrinopeptides lasted from 3 to 7 days, rather than for several hours as occurred after the infusion of hypertonic saline, indicating a more persistent stimulus to intravascular coagulation in preeclampsia/eclampsia; (3) severe thrombocytopenia and increased platelet protein levels were seen in these patients and were disproportionate to the degree of increase in the fibrinopeptide A level, suggesting that a mechanism other than thrombin must have contributed to the platelet changes; and (4) in two patients with severe preeclampsia/eclampsia, high desarginyl fibrinopeptide B levels preceded renal insufficiency, possibly reflecting fibrin II formation in renal vessels.
Antigenic analysis of hematopoiesis: II. Expression of human neutrophil antigens on normal and leukemic marrow cells
Authors: Strauss LC , Skubitz KM , August JT , Civin CI
Published: October 2019

The binding of five antineutrophil monoclonal antibodies AHN-1, -2, -3, -7, and -8, to normal and leukemic bone marrow cells was studied. AHN-7 bound to many granulocytic precursors, particularly myelocytes, and both lymphoid and blast cells in normal marrow, and to most but not all granulocyte-macrophage progenitors (CFC-GM). AHN-8 bound only to late (band and segmented) neutrophilic cells and not to CFC-GM. AHN-1, -2, - 3 bound to morphologically identifiable neutrophil precursors, but not to (day-14) CFC-GM. Approximately half of nonlymphoid leukemia specimens were positive with AHN-1 or AHN-7; by contrast, lymphoid leukemia specimens were rarely positive. AHN-8 was rarely found on leukemic cells. These antineutrophil antibodies appear to detect distinct granulopoietic subsets and may be useful in the analysis of hematologic differentiation and in the subclassification of leukemias.
The effect of splenectomy on platelet formation and megakaryocyte DNA content in rats
Authors: Tanum G , Sonstevold A , Jakobsen E
Published: October 2019

The DNA content of rat bone marrow megakaryocytes (MK) was studied by Feulgen photometry following splenectomy and sham operation, respectively. The DNA measurements were preceded by acetylcholinesterase staining for identification of the 2N-8N MK. The number of 2N-8N MK decreased to minimum values, while the number of 16N- 64N MK increased to maximum values about 4 days following both splenectomy and sham operation. However, the changes were somewhat more pronounced following splenectomy than sham operation. The total MK number did not change significantly. Platelet production, measured by 35S incorporation into platelets, increased during the first 2 days and remained high for 6–7 days, increasing the platelet counts. All values were about normal 30 days after surgery, except for a minor thrombocytosis following splenectomy. The early, highly significant thrombocytosis, following both splenectomy and general surgery, is caused by increased production of platelets due to the surgical trauma. This is caused by a direct action on bone marrow MK by transforming 2N- 8N MK into higher ploidy classes. Lack of splenic platelet pooling may influence the grade and duration of the early thrombocytosis after splenectomy. The late, long-lasting, minor thrombocytosis, which occurs after splenectomy but not after sham operation, can be explained by the removal of the splenic platelet pool.
alpha-Actinin and vinculin in normal and thrombasthenic platelets
Authors: Langer BG , Gonnella PA , Nachmias VT
Published: October 2019

Recently, the contractile protein alpha-actinin was identified in normal human platelets by its antigenic cross-reaction with a monospecific antibody to purified muscle alpha-actinin. In this study, we extend that preliminary identification of platelet alpha-actinin. Amino acid analysis, one-dimensional peptide maps, and silver stain analysis on polyacrylamide gels demonstrate that human platelet alpha- actinin shows a greater degree of similarity to smooth muscle alpha- actinin than to striated muscle alpha-actinin. There is no evidence to suggest that alpha-actinin is a glycoprotein. In addition, we find that thrombasthenic platelets, which are deficient in glycoproteins IIb and IIIa (GPIIb and GPIIIa) contain normal amounts of alpha-actinin, confirming the recent finding that alpha-actinin and GPIIIa are different proteins in human platelets. We demonstrate that both normal and thrombasthenic platelets also contain vinculin, a 130,000-dalton polypeptide found in many cell types at sites of end-on attachment of microfilaments to the plasma membrane. Thus, the thrombasthenic defect in GPIIb and GPIIIa does not diminish the content of either alpha- actinin or vinculin.
Burkitt's lymphoma in AIDS: cytogenetic study
Authors: Whang-Peng J , Lee EC , Sieverts H , Magrath IT
Published: October 2019

Cytogenetic studies were done in two cases of Burkitt's lymphoma in homosexual individuals with possible acquired immune deficiency syndrome (AIDS). The chromosomal abnormalities found are consistent with those previously described in the nonendemic form of Burkitt's lymphoma, with one of the two patients having the variant translocation, t(8;22). The production of the kappa light chain immunoglobulin by the tumor cells from the patient having t(8;22) and the occurrence of the different sites of translocation of the duplication of 1 q in the second patient are unusual findings. Whether there is an increase in the incidence of the variant translocation t(8;22) is yet to be determined.
L-asparaginase: acute effects on protein synthesis in rabbits with normal and increased fibrinogen production
Authors: Alving BM , Barr CF , Tang DB
Published: October 2019

The acute effects of a single intravenous dose of L-asparaginase on protein synthesis were studied in normal rabbits and in animals that had received turpentine to stimulate fibrinogen production. Male New Zealand rabbits received L-asparaginase (500 U/kg) 16 hr before the injection of the radiolabeled amino acid [75Se]selenomethionine (75SeM). Incorporation of 75SeM into fibrinogen and serum proteins in the L-asparaginase-treated rabbits was the same as for saline-treated controls, with fibrinogen representing approximately 5% of the labeled plasma proteins. In turpentine-treated rabbits, the maximal incorporation of 75SeM into serum proteins remained unchanged, whereas 75SeM-fibrinogen increased sixfold and accounted for 25% of the labeled proteins. Animals that received L-asparaginase at the same time as turpentine or 14 hr later showed significant decreases in synthesis of both serum proteins and fibrinogen. 75SeM-fibrinogen that was purified from L-asparaginase-treated rabbits underwent normal catabolism when injected into normal recipient rabbits. These data indicate that L- asparaginase can acutely cause partial inhibition of both serum protein and fibrinogen synthesis when administered to rabbits shortly before or during a period of increased fibrinogen production. Fibrinogen that is synthesized in the presence of L-asparaginase does not have an abnormal rate of catabolism.
Thrombin pretreatment of human platelets impairs thromboxane A2 synthesis from endogenous precursors in the presence of normal cyclooxygenase activity
Authors: Reimers HJ , Scharf RE , Baker RK
Published: October 2019

Exposure of horse platelets to thrombin has been reported to cause nearly complete inactivation of cyclooxygenase within 30 sec. This contrasts with the observation that human platelets, depleted of their granule constituents by stimulation with thrombin, still aggregate in response to arachidonic acid, a reaction presumably mediated by thromboxane A2 (TxA2) formation. Because of this conflicting evidence, TxA2 formation was measured by radioimmunoassay in washed human platelets depleted of their alpha- and dense-storage granule constituents by prior stimulation with thrombin. These platelets aggregated in response to adenosine diphosphate (ADP), collagen, arachidonic acid, and thrombin, and formed TxA2. However, collagen- and thrombin-induced TxA2 formation by these platelets was reduced in comparison to control platelets that had not been depleted of their storage granule constituents by prior thrombin stimulation. In contrast, arachidonic acid-induced TxA2 formation was not significantly different in thrombin-depleted and control platelets. These results demonstrate that thrombin can induce degranulation of platelets without concomitant inactivation of cyclooxygenase.
Blastic transformation of essential thrombocythemia: dual expression of myelomonoblastic/megakaryoblastic phenotypes
Authors: Frei-Lahr D , Barton JC , Hoffman R , Burkett LL , Prchal JT
Published: October 2019

Three patients developed blastic transformation of essential thrombocythemia (tET). Morphological studies in all patients showed that the majority of blasts had either myeloblastic or myelomonoblastic differentiation. Immunologic assays of hematopoietic cells were performed in two patients. In patient 1, 86% of peripheral blood mononuclear cells (predominantly blasts) reacted with a monoclonal antibody specific for granulocytes and monocytes (MMA), and 15% of mononuclear cells reacted with Tab, a monoclonal antibody specific for megakaryocyte-platelet glycoproteins (PGP) IIb and IIIa. In patient 2, 41.5% of peripheral blood mononuclear cells (predominantly blasts) were MMA-positive, 22.5% were Tab-positive, and 40% reacted with rabbit anti- human PGP. These results suggest either that two subpopulations of blast cells exist in tET, or that blast cells simultaneously express surface markers of myeloblastic/monoblastic and megakaryoblastic differentiation. In these three and in nine previously reported cases of tET, neither age, sex, nor previous therapy were obvious etiologic factors. tET occurred 24.2 +/- 14.4 mo after diagnosis of essential thrombocythemia, and a majority of patients had hepatomegaly and/or splenomegaly, anemia, leukocytosis, and thrombocytopenia. Leukemic cell morphology was myeloblastic and/or monoblastic in 12/12 patients, 5/12 had marrow fibrosis. Despite various treatments, death occurred in 3.6 +/- 2.7 mo; one patient had a brief complete remission.
The megakaryocyte DNA content and platelet formation after the sublethal whole body irradiation of rats
Authors: Tanum G
Published: October 2019

The DNA content of rat bone marrow megakaryocytes (MK) was studied by Feulgen photometry, following whole body irradiation with 2 Gy. The DNA measurements were preceded by acetylcholinesterase staining to avoid missing the smaller 2N-8N MK. The number of 2N-8N MK declined immediately following irradiation, whereas the number of 16N-64N MK remained normal for 4 days before decreasing. The number of 2N-8N and 16N-64N MK reached minimum around days 7 and 10, respectively, and thereafter increased to supranormal values at days 14 and 20, respectively. Platelet production, measured by 35S incorporation into platelets, increased during the first 4 days, then decreased to minimum about day 10. A rise to supranormal values was present at day 20. All values were about normal 30 days after exposure. The observed pattern may be explained as follows: Most of the 16N-64N MK survive the applied dose and maintain their ability to produce platelets. Some of the 2N-4N and 8N MK survive irradiation and transform into platelet-producing MK. No influx of cells from the MK stem cell compartment into the MK compartment can be observed before day 7 after irradiation. One explanation for this time lag may be that thrombocytopenia, which does not occur before then, is an essential stimulus for MK stem cell activation.
Large cell lymphoma complicating acute lymphoblastic leukemia
Authors: Ellerbroek R , Foucar K , Kowal-Vern A , Kemp JD , Kisker T , Tannous R , Strauss R
Published: October 2019

Non-Hodgkin's lymphoma (NHL) is a very rare complication of acute lymphoblastic leukemia (ALL). We present the pathologic, clinical, immunologic, and ultrastructural features of the third reported example of NHL following successfully treated ALL. This white girl developed ALL with predominantly L1 cells at 3.5 yr of age. The lymphoblasts were terminal deoxynucleotidyl transferase (TdT) positive and were non-B, non-T cells. She achieved a complete remission with standard induction therapy and has remained in continuous complete remission. Four and one- third years after the onset of ALL, she developed multifocal, pleomorphic large cell lymphoma of the small bowel, which resulted in episodes of intussusception and obstruction. These pleomorphic and frequently multinucleated lymphoma cells lacked TdT, common ALL antigen, and all tested markers of B cell, T cell, and histiocyte differentiation. Following three small bowel resections, systemic multiagent chemotherapy, and abdominal irradiation, she is currently free of disease.
Liver dysfunction rather than intravascular coagulation as the main cause of low protein C and antithrombin III in acute leukemia
Authors: Rodeghiero F , Mannucci PM , Vigano S , Barbui T , Gugliotta L , Cortellaro M , Dini E
Published: October 2019

Protein C, a newly identified inhibitor of blood coagulation, was measured immunologically in 58 patients with untreated acute leukemias and compared with that of normal subjects. On the average, slightly lower values were found. However, the 17 patients with overt laboratory pictures of decompensated disseminated intravascular coagulation (DIC), including 11 cases with acute promyelocytic leukemia, had protein C concentrations no lower than those of the remaining 41 patients without DIC. Antithrombin III activity and antigen were normal and, like protein C, not lowered in DIC. The concentrations of both proteins were closely correlated with changes in the indexes for liver synthetic function. A subgroup of 13 patients with hyperleukocytic leukemias had lower protein C and antithrombin III, in line with the more compromised synthetic function of their livers. Our findings indicate that liver impairment rather than DIC is the main cause of the changes in the two naturally occurring inhibitors of blood coagulation.
A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial
Authors: Vogler WR , Winton EF , Gordon DS , Raney MR , Go B , Meyer L
Published: October 2019

The Southeastern Cancer Study Group conducted a post-remission induction randomized trial in adult acute myelogenous leukemia to assess the efficacy of alternate drug therapy during consolidation and of immunotherapy during maintenance. Of 508 evaluable patients entered into the study, 335 (66%) achieved a complete remission treated with a 7-day infusion of cytosine arabinoside at a dose of 100 mg/sq m/day and 3 days of daunorubicin at a dose of 45 mg/sq m/day. Those in remission were randomized to receive 3 courses of 1 of 3 consolidation regimens: (A) a continuous infusion of 5-azacytidine, 150 mg/sq m/day for 5 days; (B) 5-azacytidine plus beta-deoxythioguanosine, 300 mg/sq m/day for 5 days; or (C) cytosine arabinoside, 100 mg/sq m/day intravenously, and thioguanine, 100 mg/sq m orally every 12 hr, plus daunorubicin, 10 mg/sq m every 24 hr daily for 5 days. There was no difference in relapse rate among the 3 arms. Those completing consolidation and remaining in remission were randomized to 1 of 3 maintenance regimens: (D) chemotherapy, 5-day infusion of cytosine arabinoside and 2 days of daunorubicin (same doses as induction) given every 13 wk for 1 yr; (E) BCG given twice weekly for 1 mo and then monthly for 1 yr; or (F) the combination of regimens D and E. The median duration of remission was significantly better on regimen D (17.4 versus 9.4 and 9.5 mo), and median survival was 29 mo compared to 21 mo for the other regimens. Those given different drugs during consolidation than used for induction (regimens A and B) and subsequent chemotherapy for maintenance (regimen D) had the longest remission durations and survival. Immunotherapy was not as good as intensive chemotherapy for maintenance.
A role for sulfhydryl groups in granulocyte aggregation
Authors: Kraut EH , Sagone AL Jr
Published: October 2019

Polymorphonuclear leukocytes (PMN) stimulated by high concentrations of the complement component C5A form cellular aggregates, and both the rate and degree of aggregation are influenced by changes in the PMN plasma membrane and cytoskeleton. Since sulfhydryls are important constituents of the plasma membrane and cytoskeleton, we investigated the effect of agents that oxidize and bind sulfhydryls on C5A-induced aggregation. PMN incubated with diamide, a nonspecific sulfhydryl- oxidizing agent, had a marked increase in their aggregation response to C5A. Tertiary butyl hydroperoxide (BHP), which reacts specifically with the soluble sulfhydryl glutathione (GSH), had no effect on aggregation. The enhancement of PMN aggregation by diamide, but not BHP, suggested that oxidation of non-GSH sulfhydryls contributes to the aggregation response. To test the requirement for sulfhydryls in PMN aggregation, PMN were treated with the sulfhydryl-binding agent N-ethylmaleimide (NEM). NEM markedly impaired aggregation without affecting resting or methylene blue-stimulated [14C]-L-glucose oxidation of the granulocytes. P-chloromercuriphenyl sulfonic acid (PCMPSA), an external sulfhydryl-binding agent, had no effect on aggregation. These studies suggest that cellular sulfhydryls are required for optimal PMN aggregation and that oxidation of these sulfhydryls may be one of the biochemical changes that contributes to aggregation.
Glutathione-dependent protection against oxidative damage of the human red cell membrane
Authors: Fujii S , Dale GL , Beutler E
Published: October 2019

Glutathione (GSH) dependent protection against oxidative damage of human red cell membrane was examined. An artificial system was used in which chloroform/methanol-extracted red cell lipids, in the form of liposomes, were subjected to attack by a peroxidation system consisting of ascorbate-Fe3+. Human erythrocytes contained a nondialyzable factor, completely inactivated by heating in a boiling water bath for 3 min, which showed GSH-dependent inhibition against lipid peroxidation and was devoid of GSH peroxidase activity. On the other hand, GSH-S transferase, highly purified by affinity chromatography, had no inhibitory activity. These findings strongly indicate that the GSH- dependent protection against lipid peroxidation of human red cell membrane is mediated by one or more proteins other than GSH peroxidase and GSH-S transferase.
Hyperleukocytosis and leukostasis: common features of childhood chronic myelogenous leukemia
Authors: Rowe JM , Lichtman MA
Published: October 2019

Ten patients under 20 yr of age with the usual (adult) type of chronic myelogenous leukemia (CML) were seen at the University of Rochester Medical Center from 1970 to 1982. The mean white cell count in these 10 patients at presentation was 360,000/microliter, as compared to a mean of 137,000/microliter in 80 CML patients over 20 yr of age seen during the same time interval (p less than 0.02). Analyses of all 90 cases revealed a significant decrease in the average leukocyte count at presentation with increasing age. The childhood cases also had a significantly higher proportion of blood blasts, promyelocytes, and myelocytes than did the adult subjects (p less than 0.01). Signs of leukostasis were present in 12% of adult cases as compared to 60% of the 10 childhood cases, and in these 6 subjects, the mean white cell count was 510,000/microliter. In these 6 patients, leukapheresis and/or chemical therapy was initiated rapidly, and this was followed by complete resolution of the clinical signs of leukostasis. A review of the literature from 1960 to 1982 identified 61 childhood cases that were reported with the usual type of CML. In this group, the frequency of hyperleukocytosis and the distribution of white cell counts corresponded very closely to the 10 cases studied at the University of Rochester. Thus, the usual type of CML presenting in childhood differs from that of adults in that hyperleukocytosis, blood granulocyte immaturity, and leukostatic central nervous system, retinal, and respiratory signs are significantly more common and extreme and merit rapid cytoreductive treatment.
Micropipette aspiration of human blood platelets: a defect in Bernard- Soulier's syndrome
Authors: White JG , Burris SM , Hasegawa D , Johnson M
Published: October 2019

Previous reports have suggested that platelets from patients with Bernard-Soulier's syndrome (BSS) are not giant cells. Rather, they are normal-sized in suspension, but spread out on glass slides more readily than control cells, yielding the impression of being giant. The present study has used cell sizing techniques, electron microscopy, and micropipette aspiration to evaluate platelets from three patients with BSS. Cell sizing techniques revealed that BSS platelets were considerably larger than normal. The increased size was confirmed in electron microscopic studies of BSS platelets fixed in suspension. However, the BSS platelets did not contain increased amounts of internalized surface membrane considered to be the source of membrane necessary for excessive spreading. A possible explanation for increased spreading of BSS platelets was found in studies of their resistance to deformation in micropipettes. BSS platelets were much less resistant to deformation than normal cells or other abnormal platelets when aspirated under the same negative pressure. Their unusual deformability may explain the tendency of BSS platelets to spread more readily than normal cells on glass slides.
The rare alpha-thalassemia-1 of blacks is a zeta alpha-thalassemia-1 associated with deletion of all alpha- and zeta-globin genes
Authors: Felice AE , Cleek MP , McKie K , McKie V , Huisman TH
Published: October 2019

Restriction endonuclease mapping with alpha and zeta-globin gene probes showed differences between the alpha-thalassemia-1 (alpha-thal-1) condition in two patients with HbH disease. One patient had the rare black type of alpha-thal-1 together with alpha-thal-2 and HbS heterozygosities. The second patient was a Laotian child with HbE, Hb Constant Spring (alpha-thal-2), and alpha-thal-1 heterozygosities. The diagnoses were based on clinical, hematologic, and biochemical data. Whereas DNA fragments hybridizing to a zeta-probe were obtained from the Laotian type of alpha-thal-1, neither alpha nor zeta-gene fragments could be identified deriving from the black type of alpha-thal-1. Therefore, the black type of alpha-thal-1 is associated with a deletion of the entire zeta 2-psi zeta-psi alpha-alpha 2-alpha 1 gene complex and can be considered a zeta alpha-thal-1. It is likely that homozygosity for such a condition will lead to embryonic wastage, explaining the absence of hydrops fetalis in blacks.
Platelet size and age determine platelet function independently
Authors: Thompson CB , Jakubowski JA , Quinn PG , Deykin D , Valeri CR
Published: October 2019

This study was undertaken to examine the interaction of platelet size and age in determining in vitro platelet function. Baboon megakaryocytes were labeled in vivo by the injection of 75Se- methionine. Blood was collected when the label was predominantly associated with younger platelets (day 2) and with older platelets (day 9). Size-dependent platelet subpopulations were prepared on both days by counterflow centrifugation. The reactivity of each platelet subpopulation was determined on both days by measuring thrombin-induced aggregation. Platelets were fixed after partial aggregation had occurred by the addition of EDTA/formalin. After removal of the aggregated platelets by differential centrifugation, the supernatant medium was assayed for remaining platelets and 75Se radioactivity. Comparing day 2 and day 9, no significant difference was seen in the rate of aggregation of a given subpopulation. However, aggregation was more rapid in the larger platelet fractions than in the smaller ones on both days. A greater percentage of the 75Se radioactivity appeared in the platelet aggregates on day 2 than on day 9. This effect was independent of platelet size, as it occurred to a similar extent in the unfractionated platelets and in each of the size-dependent platelet subpopulations. The data indicate that young platelets are more active than older platelets. This study demonstrates that size and age are both determinants of platelet function, but by independent mechanisms.
Monoclonal antibodies detecting antigenic determinants with restricted expression on erythroid cells: from the erythroid committed progenitor level to the mature erythroblast
Authors: Yokochi T , Brice M , Rabinovitch PS , Papayannopoulou T , Stamatoyannopoulos G
Published: October 2019

Two new cell surface antigens specific for the erythroid lineage were defined with cytotoxic IgM monoclonal antibodies (McAb) (EP-1; EP-2) that were produced using BFU-E-derived colonies as immunogens. These two antigens are expressed on in vivo and in vitro derived adult and fetal erythroblasts, but not on erythrocytes. They are not detectable on resting lymphocytes, concanavalin-A (Con-A) activated lymphoblasts, granulocytes, and monocytes or granulocytic cells or macrophages present in peripheral blood or harvested from CFU-GM cultures. Cell line and tissue distributions distinguish McAb EP-1 and EP-2 from all previously described monoclonal antibodies. McAb EP-1 (for erythropoietic antigen-1) inhibits the formation of BFU-E and CFU-E, but not CFU-GM, colonies in complement-dependent cytotoxicity assays. By cell sorting analysis, about 90% of erythroid progenitors (CFU-E, BFU-E) were recovered in the antigen-positive fraction. Seven percent of the cells in this fraction were progenitors (versus 0.1% in the negative fraction). The expression of EP-1 antigen is greatly enhanced in K562 cells, using inducers of hemoglobin synthesis. McAb EP-2 fails to inhibit BFU-E and CFU-E colony formation in complement-dependent cytotoxicity assays. EP-2 antigen is predominantly expressed on in vitro derived immature erythroblasts, and it is weakly expressed on mature erythroblasts. The findings with McAb EP-1 provide evidence that erythroid progenitors (BFU-E and CFU-E) express determinants that fail to be expressed on other progenitor cells and hence appear to be unique to the erythroid lineage. McAb EP-1 and EP-2 are potentially useful for studies of erythroid differentiation and progenitor cell isolation.
Characterization of 25 monoclonal antibodies to factor VIII-von Willebrand factor: relationship between ristocetin-induced platelet aggregation and platelet adherence to subendothelium
Authors: Stel HV , Sakariassen KS , Scholte BJ , Veerman EC , van der Kwast TH , de Groot PG , Sixma JJ , van Mourik JA
Published: October 2019

We have studied the role of factor VIII-von Willebrand factor (FVIII- vWF) in both platelet adherence to subendothelium and ristocetin- induced platelet aggregation using monoclonal antibodies to human FVIII- vWF. Twenty-five monoclonal antibodies were obtained, two of which were directed to the factor VIII moiety of FVIII-vWF; one of these two completely inhibited the procoagulant activity (FVIII:C). The remaining 23 monoclonal antibodies were directed to the von Willebrand factor moiety of FVIII-vWF. The ability of the latter monoclonal antibodies to inhibit platelet adherence to arterial subendothelium was investigated with a perfusion model. According to the number of platelets adhering to the subendothelium, three groups of monoclonal antibodies could be discerned: (A) antibodies not affecting platelet adherence; (B) antibodies that inhibited platelet adherence to the level as observed when von Willebrand's disease plasma was tested; and (C) antibodies that completely inhibited both platelet adherence to subendothelium and ristocetin-induced platelet aggregation. The two antibodies present in group C competed for the same or closely related epitope(s) present on FVIII-vWF. These results demonstrate that a domain is present on the FVIII-vWF molecule that is associated both with ristocetin-induced aggregation and with the ability of FVIII-vWF to support platelet adherence to the subendothelium. Based on these observations, it is concluded that ristocetin-induced binding of FVIII-vWF to platelets reflects, at least in part, a physiologic mechanism regulating the function of FVIII-vWF in primary hemostasis.
T lymphocyte colony assay in hemophiliacs
Authors: Ragni MV , Winkelstein A , Evans TL , Lewis JH , Bontempo FA , Spero JA , Rabin BS
Published: October 2019

Unexplained lymphadenopathy, with or without accompanying symptoms, known as the “lymphadenopathy syndrome,” has been recognized in groups at risk for acquired immune deficiency syndrome (AIDS), namely, homosexuals and hemophiliacs. To date, however, no test has been defined that discriminates between asymptomatic individuals and those with adenopathy in these high-risk groups. The T colony assay, which measures T lymphocyte growth in soft agar and which allows selective T cell proliferation with minimal cell-cell contact, was evaluated in asymptomatic hemophiliacs. Significantly lower mean colony counts were found in eight hemophiliacs with adenopathy (HA), 763 +/- 348 (+/- SEM), than in 16 healthy hemophiliacs (HH) 3,044 +/- 661 (P less than .005), or than in 24 heterosexual control subjects, 3,964 +/- 395 (P less than .005). The in vitro addition of exogenous interleukin-2 (IL- 2) restored normal colony growth in the HA population. These results indicate that the T colony assay can detect abnormal cell-mediated immunity among hemophiliacs and specifically discriminates between asymptomatic hemophiliacs (HH) and those with adenopathy (HA). In addition, IL-2 may be of potential benefit in improving T cell defects in AIDS or the “lymphadenopathy syndrome”; however, this remains to be proven.
Unusual karyotypic changes and B cell involvement in a case of lymph node blast crisis of chronic myelogenous leukemia
Authors: Hogge DE , Misawa S , Testa JR , Leavitt RD , Pollak A , Schiffer CA
Published: October 2019

A patient with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) entered a blast crisis localized to lymph nodes. On light microscopy, by morphology and histochemical staining, the blasts were undifferentiated. In spite of terminal deoxynucleotidyl transferase positivity, some of the lymph node cells expressed a myeloid differentiation antigen, OKM1, and were peroxidase positive by transmission electron microscopy (TEM). However, the majority of cells were peroxidase negative on TEM and expressed OKT-10, a marker found on both primitive myeloid and lymphoid cells. Cultures of lymph node cells stimulated with Epstein-Barr virus or lipopolysaccharide (LPS) revealed the Ph1, indicating B cell involvement in the CML. T cells from cultures stimulated with L4-phytohemagglutinin and T cell growth factor were negative for the Ph1. In unstimulated lymph node cells, the uncomplicated Ph1 could not be demonstrated; instead, a unique complex karyotype involving a masked Ph1 was identified in these and the LPS cultures. This karyotype was not found in bone marrow (BM) metaphase cells. Instead, BM cells showed either the simple Ph1 or the Ph1 with a rearrangement involving chromosomes 13 and 20. The patient had transient responses to three chemotherapy regimens, two of which were designed to treat acute lymphocytic leukemia, but he died 8 months after disease acceleration without BM blast crisis. These findings are compatible with an extramedullary blast crisis originating in a primitive cell with both myeloid and lymphoid characteristics.