bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythrocyte-endothelial cell adherence in sickle cell disorders
Authors: Smith BD , La Celle PL 
Published: October 2019

Abstract
Detachment of individual sickle erythrocytes from cultured endothelial cell monolayers has been evaluated by a fluid-shearing technique in an effort to quantitate adherence at shear forces that would be anticipated in the in vivo circulation. Nonirreversibly sickled cells (non-ISC) were more adherent at normal oxygen tensions than control cells. More than 1% non-ISC remained attached to the monolayer at forces greater than physiologic shear stresses in capillary and venous circulations, and many of the most avidly attached cells, once separated, immediately reattached to adjacent endothelial cells. These data suggest that hemoglobin S-containing erythrocytes may have a higher frequency of adherence in vivo in regions of low shear stress where prolonged erythrocyte-endothelial cell contact could occur. Some of these cells detached by shear force would subsequently reattach in in vivo conditions. Plasma-enhanced attachment frequency and plasma from blood in a case of sickle crisis caused further increase. These observations further support the concept that sickle erythrocyte- endothelial cell interaction may be a significant factor in initiation of vascular occlusive events in sickle cell disease.
Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor
Authors: Goldberg MA , Antin JH , Guinan EC , Rappeport JM 
Published: October 2019

Abstract
Patients who undergo bone marrow transplantation are generally immunosuppressed with a dose of cyclophosphamide (CYA) which is usually calculated based on the patient's weight. At these high doses of CYA, serious cardiotoxicity may occur, but definitive risk factors for the development of such cardiotoxicity have not been described. Since chemotherapeutic agent toxicity generally correlates with dose per body surface area, we retrospectively calculated the dose of CYA in patients transplanted at our institution to determine whether the incidence of CYA cardiotoxicity correlated with the dose per body surface area. Eighty patients who were to receive CYA 50 mg/kg/d for four days as preparation for marrow grafting underwent a total of 84 transplants for aplastic anemia, Wiskott-Aldrich syndrome, or severe combined immunodeficiency syndrome. Fourteen of 84 (17%) patients had symptoms and signs consistent with CYA cardiotoxicity within ten days of receiving 1 to 4 doses of CYA. Six of the 14 patients died with congestive heart failure. The dose of CYA per body surface area was calculated for all patients and the patients were divided into two groups based on daily CYA dose: Group 1, CYA less than or equal to 1.55 g/m2/d; Group 2, CYA greater than 1.55 g/m2/d. Cardiotoxicity that was thought to be related to CYA occurred in 1/32 (3%) of patients in Group 1 and in 13/52 (25%) patients in Group 2 (P less than 0.025). Congestive heart failure caused or contributed to death in 0/32 patients in Group 1 v 6/52 (12%) of patients in Group 2 (P less than 0.25). There was no difference in the rate of engraftment of evaluable patients in the two groups (P greater than 0.5). We conclude that the CYA cardiotoxicity correlates with CYA dosage as calculated by body surface area, and that patients with aplastic anemia and immunodeficiencies can be effectively prepared for bone marrow grafting at a CYA dose of 1.55 g/m2/d for four days with a lower incidence of cardiotoxicity than patients whose CYA dosage is calculated based on weight. This study reaffirms the principle that drug toxicity correlates with dose per body surface area.
Growth and development following marrow transplantation for leukemia
Authors: Sanders JE , Pritchard S , Mahoney P , Amos D , Buckner CD , Witherspoon RP , Deeg HJ , Doney KC , Sullivan KM , Appelbaum FR 
Published: October 2019

Abstract
One hundred forty-two patients between the ages of 1 and 17 years who survived disease-free more than 1 year after marrow transplantation for hematologic malignancy had growth and development evaluations from one to 14 years posttransplant (median 4 years). Prior to transplant all children received multiagent chemotherapy and 55 also received central nervous system irradiation, but none had growth and development evaluations. Marrow transplant preparation included high-dose chemotherapy and total body irradiation (TBI) given as a single dose of 9.2 to 10.0 Gy (79 patients) or as fractionated doses of 2.0 to 2.25 Gy/d for six to seven days (63 patients). After transplant abnormal thyroid function was present in 39%. Stimulated 11-desoxycortisol levels were subnormal in 24% of patients evaluated. Growth hormone (GH) deficiency was present in 17 of 25 children who received previous cranial irradiation. Partial GH deficiency was present in 4 of 25 who received previous cranial irradiation and in 6 of 18 who had not received cranial irradiation. Height velocity was decreased in all patients. After transplant, height was significantly influenced by chronic graft-v-host disease and single-dose TBI. Sixty-eight percent had delayed development of secondary sexual characteristics. Gonadal failure occurred in nearly all who were postpubertal at transplant. While it is not possible to determine how many of these endocrine abnormalities occurred as a result of treatment administered prior to transplantation, these data do demonstrate that children who become long-term survivors after marrow transplantation for hematologic malignancy have endocrine abnormalities that adversely affect growth and development.
Heterogeneity of large granular lymphocyte proliferations: delineation of two major subtypes
Authors: Chan WC , Link S , Mawle A , Check I , Brynes RK , Winton EF 
Published: October 2019

Abstract
Two major types of lymphocytosis of large granular lymphocytes (LGLs) were observed. The proliferating LGLs in each type had distinct immunophenotypes, functional characteristics, and probably belonged to different cell lineages. The more common form (Type A) consisted of cells derived from the T cell lineage and had the T suppressor/cytotoxic phenotype (T11+, T3+, T8+). The expression of the Leu 7 and HLA-DR antigen was variable. These cells did not have natural killer (NK) function but showed a variable degree of antibody-dependent cell-mediated cytotoxic (ADCC) activity. Neutropenia was invariably present and rheumatoid arthritis and autoantibodies were frequent associations. These lymphocytes had many similarities to the major type of LGLs present in normal adult bone marrow. The other type of LGL lymphocytosis (Type B) consisted of cells lacking the antigens T3 and T8 but expressing M1 and NKH1. These cells possessed strong NK and ADCC activity but their cell lineage was not clear. Neutropenia and autoimmune phenomena were not detected. The cytochemical characteristics of the LGL granules from both types of patients were similar but differences in ultrastructure were observed. LGLs from Type B patients proliferated in the presence of Interleukin 2 (IL-2) and 12- O-tetradecanoyl-phorbol-13 acetate (TPA). Significant changes in their basic T11+, T3-, T8- phenotype were not observed. IL-2 and TPA, however, had profound influence on the NK function of the cells with enhancement in the case of IL-2 and marked suppression when stimulated by TPA.
Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene
Authors: Steinberg MH , Embury SH 
Published: October 2019

Abstract
Recent advances in molecular genetics have permitted detailed study of the human alpha-globin genes and the causes of alpha-thalassemia. In this review, we examine the causes of alpha-thalassemia in the black population and the consequences of the interactions between alpha- thalassemia and structural hemoglobin variants.
The heterogeneity of type IIA von Willebrand's disease: studies with protease inhibitors
Authors: Batlle J , Lopez Fernandez MF , Campos M , Justica B , Berges C , Navarro JL , Diaz Cremades JM , Kasper CK , Dent JA , Ruggeri ZM 
Published: October 2019

Abstract
The absence of large von Willebrand factor (vWF) multimers from plasma is a characteristic of Type IIA von Willebrand's disease (vWD) and is thought to contribute to the clinical expression of this disorder. Recently, three IIA patients have been reported in whom intermediate and large multimers could be restored if blood were collected in 5 mm EDTA, 6 mmol/L N-ethylmaleimide, and 1 mmol/L leupeptin. This suggested that absence of large multimers resulted from in vitro proteolysis. We have now collected blood from ten Type IIA vWD patients in these inhibitors but were not able to detect large multimers in the plasma of any of them. In addition, intermediate-sized multimers were reduced or completely absent in all. The inclusion of inhibitors in the citrate anticoagulant, as compared to citrate alone, was found to increase the relative proportion of intermediate multimers in some patients but had no effect in others, and in none did it restore large multimers to plasma. The results with platelet vWF were more varied. Four patients showed an absence or decrease of large multimers, whereas in seven patients large multimers were present. When compared with citrate anticoagulant alone, the inclusion of inhibitors in the anticoagulant had little or no effect on the platelet multimeric pattern. 1-Deamino-8- D-Arginine Vasopressin (DDAVP) was administered to six patients from five families. Two patients from one family showed complete correction and a third patient showed almost complete correction of her bleeding time. Two patients showed minimal correction and one showed no detectable correction. An increase in multimer size after DDAVP tended to be associated with correction of the bleeding time. However, in no case did the largest multimers appear in plasma even in patients with complete bleeding time correction. The presence or absence of inhibitors in the anticoagulant had little or no effect on the multimeric pattern after DDAVP. These results indicate that Type IIA vWD is a heterogeneous disorder in which absence of largest and intermediate multimers is an in vivo phenomenon.
Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome
Authors: Budde U , Dent JA , Berkowitz SD , Ruggeri ZM , Zimmerman TS 
Published: October 2019

Abstract
In order to evaluate the role of proteolysis in acquired von Willebrand's disease (vWD) associated with the myeloproliferative syndrome, we have determined the relative quantity of von Willebrand factor (vWF) fragments as compared with the intact 225 kDa subunit in four patients. The plasma vWF of each individual lacked large multimers; each had a prolonged bleeding time; and both platelet and leukocyte counts were elevated. Plasma was obtained from blood drawn into 1 mmol/L leupeptin, 6 mmol/L N-ethylmaleimide, and 5 mmol/L EDTA to prevent in vitro proteolysis. vWF was isolated from plasma by immunoadsorbent chromatography, reduced, subjected to SDS-5% polyacrylamide gel electrophoresis, and immunoblotted with a mixture of 55 anti-vWF monoclonal antibodies. In three patients with essential thrombocytosis (ET) the 176 and 140 kDa fragments were increased in proportion to the intact 225 kDa subunit indicating increased proteolysis. Treatment of one ET patient with CCNU (Lomustine) decreased the platelet count and, to a lesser extent, the white blood cell count. This was associated with a correction of the bleeding time, a partial correction of the multimeric abnormality, and a lessening of vWF cleavage. In a patient with polycythemia rubra vera (PRV) the proportion of the 176 kDa fragment was increased to the upper limit of normal but there was no definite evidence of increased proteolysis. These studies provide evidence that proteolysis plays a role in the acquired von Willebrand's disease associated with the myeloproliferative syndrome. However, other mechanisms must also be considered.
Extracellular deposition of eosinophil granule major basic protein in lymph nodes of patients with Hodgkin's disease
Authors: Butterfield JH , Kephart GM , Banks PM , Gleich GJ 
Published: October 2019

Abstract
Lymph nodes from each of the four histologic types of Hodgkin's disease were examined for the presence of eosinophils and for eosinophil degranulation by immunofluorescent localization of eosinophil granule major basic protein (MBP). Eosinophil degranulation shown by MBP deposition outside of eosinophils was found in six of eight nodes from patients with nodular sclerosing disease and in two of eight nodes from patients with lymphocyte depletion-type disease. Three nodes of the mixed cellularity type, one node of the lymphocyte predominance type, and one lymph node of the lymphocyte depletion type showed one or two small foci of extracellular MBP deposition. Lymph nodes from patients without Hodgkin's disease showed no extracellular deposition of MBP. Large numbers of eosinophils were found in seven of eight nodes of the nodular sclerosing variant, but were less frequently seen among the other types of Hodgkin's disease. The presence of extracellular MBP in lymph nodes of patients with Hodgkin's disease indicates that eosinophil degranulation commonly occurs and suggests that the released eosinophil granule proteins may participate in the inflammatory reaction in this disorder more extensively than is presently appreciated.
L-triiodothyronine augments erythropoietic growth factor release from peripheral blood and bone marrow leukocytes
Authors: Dainiak N , Sutter D , Kreczko S 
Published: October 2019

Abstract
To investigate cellular mechanisms involved in thyroid hormone stimulation of erythropoiesis, we studied the response of erythroid burst-forming unit (BFU-E) proliferation to L-triiodothyronine (L-T3) in a serum-free culture system. When added directly to culture, L-T3 stimulates erythroid burst formation by normal human bone marrow cells. In contrast, granulocyte-macrophage colony formation is unaffected. Enhancement of erythroid burst formation by L-T3 required the presence of nylon wool adherent and/or B-4 antigen-positive light-density marrow populations. Addition of other erythropoietic factors including platelet-derived growth factor and insulinlike growth factor II did not abrogate this apparent cellular requirement. Pulse exposure of marrow and peripheral blood mononuclear cells (greater than 95% lymphocytes) to L-T3 accelerates the release of a soluble factor that augments BFU-E proliferation into serum-free liquid culture medium. Time-course studies show that this factor appears in conditioned medium (CM) coincidentally with erythroid burst-promoting activity (BPA). Furthermore, incubation of CM with an antibody known to react with and adsorb BPA from solution removes the inducible mitogen. Biochemical analysis of CM prepared from unexposed and L-T3 pulse-exposed cells indicates that the rate of protein appearance is accelerated by L-T3 in a fashion that immediately precedes growth factor release and that several polypeptides are quantitatively increased. We conclude that unlike erythropoietin, which is mitogenic for progenitor cells directly, L-T3 enhances BFU-E proliferation indirectly by augmenting the release of soluble BPA-like molecules from accessory cells in culture.
Morphological abnormalities in the lymphocytes of patients with the Wiskott-Aldrich syndrome
Authors: Kenney D , Cairns L , Remold-O'Donnell E , Peterson J , Rosen FS , Parkman R 
Published: October 2019

Abstract
Lymphocytes from 18 patients with the Wiskott-Aldrich Syndrome (WAS) were examined by scanning electron microscopy (SEM). Most peripheral blood lymphocytes from normal individuals are covered with slender microvillus projections, but a large proportion of lymphocytes from WAS patients were found to be relatively devoid of microvilli. A lymphocyte morphology scoring system was developed to quantify the density of microvilli: Grade 4 classified those lymphocytes with greater than 75% of the surface covered with microvilli with progressive decrements to grade 1, which were those without microvilli. The mean lymphocyte morphology score of eight normal individuals was 3.62 +/- .22. The mean lymphocyte score of WAS patients was substantially lower (2.89 +/- .27, P less than .001). In addition, WAS lymphocytes often were qualitatively abnormal, with short, blunted microvilli. These morphological criteria were used to diagnose WAS from the cord blood lymphocytes of one “at-risk” patient. Thus, WAS is the first primary immunodeficiency in which morphological abnormalities have been identified that can aid in diagnosis.
Classifying acute leukemia by immunophenotyping: a combined FAB- immunologic classification of AML
Authors: Neame PB , Soamboonsrup P , Browman GP , Meyer RM , Benger A , Wilson WE , Walker IR , Saeed N , McBride JA 
Published: October 2019

Abstract
A panel of commercially available monoclonal antibodies and five heteroantisera were used to distinguish and subtype 138 cases of acute leukemia (AL). The immunophenotype was compared with the French- American-British (FAB) classification obtained on the cases. The immunophenotype discriminated acute myelogenous leukemia (AML) from acute lymphoblastic leukemia (ALL) and recognized cases not distinguished by cytochemistry (22% of cases), mixed lineage phenotypes (13% of cases), and cases with separate populations of lymphoblasts and myeloblasts (one case). Using the immunologic panel and derived criteria to subtype AML, correspondence of the immunophenotype to the FAB subtypes M1, M2, M4, and M5 was possible in greater than 80% of cases. A combined classification of the immunophenotype and FAB morphology/cytochemistry was devised for AML subtyping. It is recommended that immunophenotyping should be done at least in all cases with negative orinconclusive cytochemistry. At present, we suggest that until a “gold standard” for identifying leukemic subtypes is developed, the best method for typing acute leukemia is by using a combination of morphology, cytochemistry and immunophenotyping.
In vitro tumor cell cytolysis mediated by peptide defensins of human and rabbit granulocytes
Authors: Lichtenstein A , Ganz T , Selsted ME , Lehrer RI 
Published: October 2019

Abstract
We examined the activity of defensins, cysteine-rich cationic peptides that are abundant in the cytoplasmic granules of human and rabbit granulocytes, against various tumor targets. The three human defensins, HNP-1, HNP-2, and HNP-3, lysed human and murine targets in chromium release and dye exclusion assays. Defensin-mediated tumor cell lysis was concentration-dependent, inhibited by serum, and dependent on temperature-sensitive events. Lysis was first detected by three hours of incubation and it reached a plateau between eight and 14 hours. In vitro exposure of murine teratocarcinoma cells to HNP 1–3 abrogated their oncogenicity in vivo. Nonmalignant target cells were also susceptible to defensin-mediated lysis. Four rabbit granulocyte defensins exerted marked (NP-1, NP-2) or moderate (NP-3a, NP-3b) cytotoxic activity, whereas defensin NP-5 was not cytotoxic. When tumor cells were incubated with human defensins in combination with hydrogen peroxide, synergistic cytotoxicity was detected. As defensins are released from granulocytes by various stimuli, their release could contribute to extracellular cytotoxicity which is independent of reactive oxygen intermediates.
Subunit assembly of hemoglobin: an important determinant of hematologic phenotype
Authors: Bunn HF 
Published: October 2019

Abstract
Hemoglobin's physiologic properties depend on the orderly assembly of its subunits in erythropoietic cells. The biosynthesis of alpha- and beta-globin polypeptide chains is normally balanced. Heme rapidly binds to the globin subunit, either during translation or shortly thereafter. The formation of the alpha beta-dimer is facilitated by electrostatic attraction of a positively charged alpha-subunit to a negatively charged beta-subunit. The alpha beta-dimer dissociates extremely slowly. The difference between the rate of dissociation of alpha beta- and alpha gamma-dimers with increasing pH explains the well-known alkaline resistance of Hb F. Two dimers combine to form the functioning alpha 2 beta 2-tetramer. This model of hemoglobin assembly explains the different levels of positively charged and negatively charged mutant hemoglobins that are encountered in heterozygotes and the effect of alpha-thalassemia and heme deficiency states in modifying the level of the variant hemoglobin as well as Hb A2. Electrostatic interactions also affect the binding of hemoglobin to the cytoplasmic surface of the red cell membrane and may underlie the formation of target cells. Enhanced binding of positively charged variants such as S and C trigger a normally dormant pathway for potassium and water loss. Thus, the positive charge on beta c is responsible for the two major contributors to the pathogenesis of Hb SC disease: increased proportion of Hb S and increased intracellular hemoglobin concentration. It is likely that electrostatic interactions play an important role in the assembly of a number of other multisubunit macromolecules, including membrane receptors, cytoskeletal proteins, and DNA binding proteins.
Characterization of the inhibition of tissue factor in serum
Authors: Broze GJ Jr , Miletich JP 
Published: October 2019

Abstract
Tissue factor (TF) is a lipoprotein cofactor that markedly enhances the proteolytic activation of factors IX and X by factor VIIa. The functional activity of TF is inhibited by serum in a time- and temperature-dependent fashion. The inhibitory effect is also dependent on the presence of calcium ions and can be reversed by calcium chelation (EDTA) and dilution, thus excluding direct proteolytic destruction of TF as the mechanism for inhibition. Using crude TF, serum immunodepleted of factor VII, and serum depleted of the vitamin K- dependent coagulation factors by BaSO4 absorption, it is shown that TF factor inhibition requires the presence of VII(a), X(a), and an additional moiety contained in barium-absorbed serum. When each of the other required components were at saturating concentrations, half- maximal inhibition of TF occurred in reaction mixtures containing 2% (vol/vol) of TF at a factor VII(a) concentration of 4 ng/mL (80 pmol/L), a factor X concentration of 50 ng/mL (850 pmol/L), and a concentration of barium-absorbed serum of 2.5% (vol/vol). Catalytically active factor Xa appeared to be required for the generation of optimal TF inhibition. The results are consistent with the conclusions of Hjort that barium-absorbed serum contains a moiety that inhibits the VIIa- Ca2+-TF complex. The role of factor X(a) in the generation of the inhibitory phenomenon remains to be elucidated. The inhibitor present in serum (plasma) may in part be produced by the liver in vivo since cultured human hepatoma cells (HepG2) secrete this inhibitory activity in vitro.
Selective expression of fos proto-oncogene in human acute myelomonocytic and monocytic leukemias: a molecular marker of terminal differentiation
Authors: Mavilio F , Testa U , Sposi NM , Petrini M , Pelosi E , Bordignon C , Amadori S , Mandelli F , Peschle C 
Published: October 2019

Abstract
Expression of human fos proto-oncogene (c-fos) was analyzed in primary cells from 50 untreated acute lymphocytic (ALL) and myeloblastic (AML) leukemias. c-fos RNA, analyzed by blot hybridization, was detected virtually only in myelomonocytic (M4) and monocytic (M5) AML. Both M4 and M5 samples show a strong positive correlation between the amount of c-fos transcripts and the percentage of leukemic cells expressing surface antigens specific for mature monocytes and macrophages. Normal mature monocytes exhibit a detectable level of c-fos RNA, which is virtually unaltered on activation to macrophage differentiation, but is always below that observed in M4 through M5 monocyticlike cells. These data provide evidence that c-fos expression is linked to terminal monocyte and macrophage differentiation in normal and leukemic hemopoiesis.