bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Glucose-6-Phosphate Dehydrogenase Activity in Red Blood Cells From Hemolytic and Nonhemolytic Variant Subjects
Authors: Yoshida Akira , Lin Mei
Published: October 2019

Because of the strong inhibition of glucose-6-phosphate dehydrogenase by physiologic concentrations of NADPH and ATP, only 0.1%-0.2% of its potential activity (Vmax) is estimated to be expressed in human red cells that contain low concentrations of NADP and glucose 6-phosphate. 6-Phosphogluconate dehydrogenase is also strongly inhibited by NADPH, ATP, and 2,3-diphosphoglycerate under the physiologic conditions, and only about 0.2% of its potential activity is estimated to be expressed in red cells. The very low shunt pathway activity can be explained by these findings. Some human glucose-6-phosphate dehydrogenase variants that are associated with severe enzyme deficiency, such as Gd Union, Gd Markham, and Gd Mediterranean, have no chronic hemolytic problem. On the other hand, several variants with less severe enzyme deficiency, such as Gd Manchester, Gd Alhambra, and Gd Tripler, are associated with chronic hemolytic anemia. Examination of the enzymes from these variant subjects under simulated physiologic conditions revealed that: (1) Enzymes from the hemolytic variant subjects are strongly inhibited by a physiologic concentration of NADPH due to their high Km for NADP or low Ki for NADPH. Thus, these variant enzymes presumably cannot generate NADPH in red cells to maintain an adequate level of reduced glutathione. (2) The nonhemolytic variant enzymes are far less sensitive to the inhibition by NADPH, because of their low Km for NADP and high Ki for NADPH. These variants are also more resistant to the inhibition by ATP. The activities of these variant enzymes in red cells are estimated to be more than 30% of the normal level. In black people, the common variant A—, associated with enzyme deficiency, is less sensitive to the inhibition by NADPH, and it is probably as active as normal in red cells, under physiologic conditions.
Ultrastructure of Presumptive Hematopoietic Stem Cells
Authors: Rubinstein Alicia S. , Trobaugh Frank E. , Conti S. Arthur , Dansbie Max
Published: October 2019

The repopulating potential of bone marrow cells that have been subjected either to cryoprotective or to cryodestructive treatments were assayed by the spleen colony technique. There were four treatments. For each treatment group the ultrastructure of aliquots of the cell suspensions was studied, and an attempt was made to identify the cells responsible for hematopoietic repopulation. The repopulating potential of fresh, glycerolized cells was greater than that of slowly cooled glycerolized cells, and both repopulating potentials were far greater than that of rapidly cooled glycerolized cells. With the exception of one cell type that was constantly well preserved, fresh glycerolized cells and cells frozen at controlled rates showed morphologic disruption. This type of cell was not found in suspensions of bone marrow cells that had been frozen rapidly, and it is proposed that it is the hematopoietic stem cell (presumptive stem cell or PSC). Two observations support the hypothesis that these cells are responsible for effecting hematopoietic repopulation of lethally irradiated mice injected with suspensions of marrow cells frozen to preserve their repopulating potential: (1) They are the only intact cells found in cryopreserved suspensions of marrow cells that effect hematopoietic repopulation. (2) They are not present in suspensions of marrow cells frozen so as to destroy the hematopoietic-repopulating potential.
Characteristics of Folic Acid-binding Protein in Folate-deficient Serum
Authors: Waxman Samuel , Schreiber Carol
Published: October 2019

Folate-deficient serum contains a specific folic acid-binding protein (FABP) that has a rapid association and slow dissociation rate for the binding of 3H-pteroylglutamic acid (3H-PGA). FABP is also present in normal serum but in lesser amounts. The molecular weight of FABP is less than 100,000 and may represent more than one protein. FABP elutes as a beta globulin and is recovered in the transferrin band region in polyacrylamide gel electrophoresis. FABP binds oxidized folyl-, mono-, and polyglutamates in preference to reduced folates. FABP retards the delivery and uptake of 3H-PGA into HeLa cell monolayer cultures. The characteristics of FABP suggest it to be a membrane-derived intracellular folate storage protein and perhaps an important regulator of folate uptake into the cell and a storage site for folyl polyglutamates. The characteristics of serum FABP suggest it to be similar to beta lactoglobulin (the folate-binding protein isolated from cow’s milk).
Von Willebrand's Syndrome Presenting as an Acquired Bleeding Disorder in Association With a Monoclonal Gammopathy
Authors: Mant M. J. , Hirsh J. , Gauldie J. , Bienenstock J. , Pineo G. F. , Luke K. H.
Published: October 2019

The clinical and laboratory findings of a patient with a bleeding disorder, laboratory features of von Willebrand's disease, and a monoclonal gammopathy are described. There was no evidence of von Willebrand's disease in his five children. Laboratory features of von Willebrand's disease in the patient included a long bleeding time, low factor VIII level by one- and two-stage clotting assays and by immunoassay, decreased platelet glass adhesiveness using native and heparinized blood, and correction of platelet adhesiveness by addition of cryoprecipitate in vitro. Attempts to implicate the monoclonal IgG in the pathogenesis of the von Willebrand's syndrome were unsuccessful using the following tests: immunoprecipitation with normal plasma, antibody activity identified by passive cutaneous anaphylaxis, inhibition of biological factor VIII activity, and binding to factor VIII. Despite these negative findings, it is suggested that the clinical pattern of this and previously described cases of "acquired" von Willebrand's disease has an immunologic basis that may be mediated by either humoral or cellular mechanisms.
Atypical Megakaryocytes in Preleukemic Phase of Acute Myeloid Leukemia
Authors: Smith W. Byron , Ablin Arthur , Goodman Joseph R. , Brecher George
Published: October 2019

Mono- and binucleated megakaryocytes appeared in the bone marrow of a 6-yr-old white male 9 mo prior to the development of acute myeloid leukemia; in addition, leukopenia and anemia antedated the diagnosis by 3½ and 9 mo, respectively. The report suggests that mono- and binucleated megakaryocytes may be a useful diagnostic finding in early leukemia.
Induction of Aggregation of Human Blood Platelets by Ultraviolet Light: Action Spectrum and Structural Changes
Authors: Doery J. C. G. , Dickson R. C. , Hirsh J.
Published: October 2019

Exposure of washed human platelets to ultraviolet light is followed by platelet aggregation. The effect occurs at wavelengths between 302 and 225 mµ with a maximal response at 248 mµ, and the effect is greatly enhanced by the addition of fibrinogen. Platelets exposed to ultraviolet light show ultrastructural changes which can be induced independently of aggregation if the addition of fibrinogen is omitted.
Lymphocytosis Induced in Mice by Supernatant Fluids of Bordetella pertussis Cultures: A Histopathological Study
Authors: Athanassiades Thomas J. , Morse Stephen I.
Published: October 2019

Intravenous injection into mice of phase I Bordetella pertussis culture supernatants produces a marked lymphocytosis. The evolution of lymphocytosis was correlated with histopathological alterations in the lymphoid organs. The early phase, 17 hr to day 3, was associated with massive depletion of both lymphocytes from the white pulp of the spleen and of cortical thymocytes. There was a corresponding profound decrease of splenic and thymic weights. The later phase was associated with a marked decrease in lymphocytes of lymph nodes while concomitantly the spleen and thymus appeared to be repopulating. Both thymic-dependent and thymic-independent lymphocyte populations were mobilized from spleen and lymph nodes. There was a striking diminution in the number of lymphocytes contained within the walls of postcapillary venules (PCVS) of all lymph nodes between 2 and 7 days. The data suggest that initially the lymphocytosis is due predominantly to release of splenic lymphocytes and to a lesser extent of thymocytes into the circulation. Subsequently, the lymphocytosis is sustained by the depopulation of the lymph nodes. Lymph node depopulation is maintained by the failure of circulating lymphocytes to emigrate from the blood through the PCVS.
Thrombotic Thrombocytopenic Purpura: Report of a Case With Disseminated Intravascular Platelet Aggregation
Authors: Neame P. B. , Lechago J. , Ling E. T. , Koval A.
Published: October 2019

The nature and etiology of the vascular occlusions encountered in thrombotic thrombocytopenic purpura (TTP) have been subject to controversy for a number of years. Disseminated platelet thrombosis has been suggested in the earlier literature, although later views have favored fibrin thrombi resulting from vascular damage or disseminated intravascular coagulation (DIC). The serial coagulation study and the lightand electron-microscopic findings in a case of TTP are described here. The multiple vascular occlusions were due to the presence of densely packed platelet aggregates in which a variable quantity of fibrin was present. Less commonly, loose platelet aggregates were noted. Fibrin under the endothelial lining was occasionally observed in relationship to the vascular occlusion and was thought to be secondary to the release of various substances from aggregating platelets. The serial coagulation study and the histologic examination of tissues showed no evidence of disseminated intravascular coagulation. This case shows that the occlusions observed in TTP can be due to disseminated intravascular platelet aggregation in the absence of DIC. Although TIP might be of variable etiology, it is felt that cases showing disseminated intravascular platelet aggregation should be distinguished from DIC in order to plan therapy on a rational basis.
The Role of Red Cell Energy Metabolism in the Generation of Irreversibly Sickled Cells In Vitro
Authors: Jensen Michael , Shohet Stephen B. , Nathan David G.
Published: October 2019

An acquired membrane defect is believed to be responsible for the maintenance of the sickled shape in oxygenated irreversibly sickled cells (ISC), because the hemoglobin S in these cells is not in the aggregated, "sickled" state. In the present study, it is demonstrated that the acquisition of the membrane defect in vitro depends on cellular metabolism. Only if cellular ATP is almost completely depleted while the cells are sickled, do they become unable to resume the biconcave disk shape upon reoxygenation. If calcium is omitted from the incubation buffer, ISCs are not generated despite metabolic depletion. This suggests an action of ATP mediated through calcium metabolism similar to that which prevents membrane stiffening in normal red cells. No ISCs were produced by repeated sickling and unsickling. Thus, a membrane alteration occurring as a consequence of metabolic depletion seems to be a more important factor in the generation of ISC than sickling-unsickling induced fragmentation.
Effects of Several Androgens and Steroid Metabolites on Erythropoietin Production in the Isolated Perfused Dog Kidney
Authors: Paulo Luiz G. , Fink Gregory D. , Roh Byung L. , Fisher James W.
Published: October 2019

In an attempt to clarify the role of the kidney in the action of several androgens and steroid metabolites on erythropoietin (ESF) production, ESF titers were measured in perfusates of isolated kidneys from dogs previously exposed to 4-hr hypoxia and perfused with blood containing testosterone (Test), 5α-17β-hydroxyandrostan-3-one (5αDHT), 5β-17β-hydroxyandrostan-3-one (5βDHT), 19-nortestosterone (19-nor), oxymetholone (Oxy), fluoxymesterone (Fluoxy), 3α-hydroxy-5β-pregnane, 11,20-dione (3αOH5βpreg), or 3β-hydroxy-5β-pregnane-20-one (3βOH-5 preg). ESF levels in the perfusates were assayed in exhypoxic polycythemic mice. Test, 5αDHT, oxy, fluoxy, and 3βOH5β-preg were found to produce a significant increase in ESF levels in the kidney perfusates. 5βDHT, 19-nor, and 3αOH5βpreg failed to produce a significant elevation in erythropoietin titers in the perfusates of the isolated perfused kidneys. These data suggest that the 4-5 double bond and the spatial configuration of the hydrogen at the 5 position as well as the lack of a methyl group in the 19 position of the basic androstan nucleus are important in the ability of these steroids to stimulate kidney production of ESF.
Juvenile "Chronic Granulocytic" Leukemia: A Panmyelopathy With Prominent Monocytic Involvement and Circulating Monocyte Colony-forming Cells
Authors: Altman Arnold J. , Palmer Catherine G. , Baehner Robert L.
Published: October 2019

Peripheral blood (PB) from two children with so-called juvenile-type (Ph1 chromosome negative) "chronic granulocytic" leukemia (CGL) was found to contain cells capable of forming large numbers of exclusively monocytic colonies in vitro. These results are markedly different from those reported for classic adult-type (Ph1 chromosome positive) CGL where predominantly granulocytic colonies are produced in vitro from PB. Spontaneously dividing PB and bone marrow (BM) cells from one patient contained a translocation between chromosome 3 and a C-group chromosome; phytohemagglutinin-stimulated PB cells from this patient had normal chromosome morphology, however. Since the translocation was present in 141 of 142 karyotypes from the BM at a time when it contained many dividing erythroid and myeloid cells, the pathologic process is not exclusively confined to the monocyte line, but involves all hematopoietic cells. So-called juvenile CGL is neither a chronic nor a granulocytic leukemia; it is a panmyelopathy with monocyte predominance and should thus be classified as a variant of myelomonocytic leukemia.
Lymphoid Nodules of Bone Marrow: Normal and Abnormal
Authors: Rywlin Arkadi M. , Ortega Rolando S. , Dominguez Carlos J.
Published: October 2019

A study of consecutive bone marrow aspirates from 365 patients without lymphoproliferative disorder, ten patients with chronic lymphocytic leukemia (CLL), and 25 patients with malignant lymphoma disclosed a clear separation of normal from abnormal lymphoid nodules (LN). Normal LN were found in 47% of patients and were classified into lymphoid follicles and lymphoid infiltrates. A new entity, nodular lymphoid hyperplasia (NLH), was diagnosed on ten bone marrows which contained a low-power field displaying four or more lymphoid nodules or showed a lymphoid nodule larger than 0.6 mm. The clinical significance of nodular lymphoid hyperplasia remains unknown; in certain cases it represents a precursor state of a mature lymphocytic lymphoproliferative disorder. Nodular aggregates in CLL are of the infiltrate type and exhibit a tendency to confluence. Eleven of the 25 patients with malignant lymphoma displayed lymphoreticular nodules which were cytologically similar to the original lymphoma and different from normal LN. Two patients, one with reticulum cell sarcoma and one with Hodgkin’s disease, showed NLH of the bone marrow. Bone marrow LN in patients with an established diagnosis of mature lymphocytic lymphoma have to be interpreted with the utmost caution. Confluence of LN, irregular shapes, and the presence of prolymphocytes and lymphoblasts speak for lymphomatous nodules. Additional clinicopathologic studies are necessary to sharpen the distinction between NLH and well-differentiated lymphoproliferative disorders.
A Scanning Electron Microscopic Study of the Spleen
Authors: Weiss Leon
Published: October 2019

The reticulum and vascular sinuses of the normal rat spleen were studied by scanning electron microscopy. Observations were also made of erythrocytes, macrophages, platelets, and other migratory elements. Reticular cells of the periarterial lymphatic sheath, the marginal zone, and cordal spaces were large, bulky, irregular cells with broad processes that formed a spongework. When marked retraction of these cells was induced in the drying phase of tissue preparation, they showed the slender multiple fingerlike processes characteristic of the argyrophilic reticulum. The reticular cells at the periphery of the periarterial lymphatic sheath were flattened and formed cylinders about the central artery. They were, moreover, associated with unusually heavy extracellular fibers. Vascular sinuses were suspended in the reticulum by attachments of cordal reticular cells and of fibrillar reticulum to the adventitial surface. Adventitial cells of the sinus, moreover, branched into the cords. Endothelial cells typically lay side by side without gaps, except as migratory cells passed through the wall. Erythrocytes were commonly observed in passage across the sinus wall. In sinuses and cords, they were often swollen, irregular, and bore blebs and crenulations. Macrophages displayed rich surface folds and processes. Platelets were abundant and were adherent to the surface of reticular cells and the endothelium of sinuses. Such adherence appeared to be the manner in which the platelets were sequestered in the spleen.
Comparison of Normal and CLL Lymphocyte Surface Ig Determinants Using Peroxidase-labeled Antibodies. I. Detection and Quantitation of Light Chain Determinants
Authors: Ternynck Thérsèse , Dighiero Guillermo , Follezou Jean , Binet Jacques-Louis
Published: October 2019

Chronic lymphocytic leukemia (CLL) and normal human blood lymphocytes were investigated with regard to their membrane-associated light (L) chains. Peroxidase-labeled anti-kappa or anti-lambda antibodies were used to visualize by light microscopy the cells bearing L chain determinants. In addition, the activity of the enzyme coupled to the antibody was measured spectrophotometricly in order to determine the number of antigenic determinants on each positive cell. The results demonstrated that 16%-25% of lymphocytes from six normal control subjects were positive for kappa chains, and 4%-10% were positive for lambda chains. The average number of antigenic sites on the surface of each positive cell was calculated to be 90,000. Lymphocytes of each of the 14 CLL patients studied carried either kappa or lambda antigenic determinants on their surface, but not both; 50%-70% of the lymphocytes were stained. The average number of antigenic sites per positive CLL was calculated to be 9000. These results confirm previously reported studies indicating that CLL is a monoclonal proliferative disease. In addition, the quantitative results demonstrate that the CLL lymphocyte surface membrane bears, on the average, only 10% of the L chain determinants present on the normal lymphocyte.
Acetylation and Methylation of Histones in Pernicious Anemia
Authors: Kass Lawrence
Published: October 2019

Acetylation and methylation of erythroid histones was investigated in two patients with pernicious anemia before and after treatment with vitamin B12 in vivo. It was found that vitamin B12 facilitated both acetylation and methylation of histones. Electrophoresis of amino acids obtained from histone hydrolysates prior to treatment with vitamin B12 demonstrated that lysine was present as I-lysine. After treatment with vitamin B12, most of the lysine appeared as methyl-I-lysine. Whether this biochemical lesion is specific for vitamin B12 deficiency or also occurs in folic acid deficiency awaits future studies.
Treatment of Established Human Graft-Versus-Host Disease by Antithymocyte Globulin
Authors: Storb R. , Gluckman E. , Thomas E. D. , Buckner C. D. , Cliff R. A. , Fefer A. , Glucksberg H. , Graham T. C. , Johnson F. L. , Lerner K. G. , Neiman P. E. , Ochs H.
Published: October 2019

Forty successful marrow grafts have been carried out since April 1972 for the treatment of severe refractory aplastic anemia or acute leukemia. All patients were HL-A identical and nonreactive in mixed leukocyte culture tests with the marrow donor. Nineteen of the patients developed moderately severe to severe graft-versus-host disease (GVHD) and were treated with rabbit or goat antihuman antithymocyte globulin (ATG). Under ATG therapy, 12 of the 19 showed complete resolution of GVHD, five showed improvement of most organ systems involved, and two showed no change except for improvement in skin lesions. Six of the 19 became long-term survivors. Five of the six are alive between 276 and 629 days after grafting, and one died on day 346 with chronic respiratory failure. Of the remaining 13 patients, 11 died with interstitial pneumonitis of predominantly viral etiology, and two died with fungal and bacterial infections. In conclusion, the present study demonstrates the relative effectiveness of ATG in reversing human GVHD. Death with interstitial pneumonitis was the single most serious impediment to successful treatment of GVHD by ATG.
Cytochemical and Morphologic Identification of Macrophages and Eosinophils in Tissue Cultures of Normal Human Bone Marrow
Authors: Shoham D. , David E. Ben , Rozenszajn L. A.
Published: October 2019

When normal human bone marrow cells are cultured in soft agar, in the presence of human spleen-conditioned medium, two types of colonies could be recognized by means of the inverted microscope: large colonies consisting of macrophages— monocytes, and small colonies consisting of eosinophils. In the two types of colonies, cells developing from blasts to mature cells could be recognized by their morphologic and cytochemical properties. The identification of macrophage-monocytes and of eosinophils was based on light, phase-contrast, and electron microscopy, the strong positive reaction of α-naphthyl acetate esterase in the macrophage-monocyte, and the positive stain with Luxol Fast Blue, eosin, and peroxidase of the eosinophils.
The Effect of Corticotropin on Mouse Spleen Colony-forming Cells
Authors: Reed Robert E.
Published: October 2019

Several investigators have reported a reduction in the number of colony-forming units (CFU) in the spleens of mice exposed to hypoxia and have postulated that this is secondary to a direct toxic effect of hypoxemia on the CFU. To test the hypothesis that at least part of this effect could be secondary to the stress of the hypoxic exposure, mice were given 12 consecutive daily injections of corticotropin (ACTH), and the number of spleen and marrow CFU were assayed by the spleen colony technique. There was a marked decrease in spleen CFU in these mice when compared with control animals, but marrow CFU were not reduced. These tesults indicate that part of the effect of hypoxemia on CFU may be secondary to the stress of the exposure and suggest that spleen CFU are sensitive to steroid hormones. Further investigation of this and other differences between spleen and marrow CFU could lead to a better understanding of stem cell differentiation.
Hereditary Stomatocytosis With Hemolytic Anemia in the Dog
Authors: Pinkerton Peter H. , Fletch Sheilah M. , Brueckner Peter J. , Miller Denis R.
Published: October 2019

An autosomal recessive mutant (symbol, dan) in the dog causes chondrodysplastic dwarfism and mild anemia as pleiotropic effects. The anemia is characterized by stomatocytosis, macrocytosis, low MCHC, increased osmotic fragility, shortened red cell survival, reticulocytosis, erythroid hyperplasia, and increased iron turnover. Minor changes can be detected in the red cells of heterozygous carriers of the dan gene, but red cell survival is normal and chondrodysplasia is not present. Red cell sodium concentration and water content are increased in anemic dogs and to a lesser degree in carriers. Glutathione deficiency is present. The disorder described here resembles a number of human hemolytic anemias with stomatocytosis, glutathione deficiency, and disordered red cell cation and water content, and further study of the dan mutant, together with investigations of the hereditary human conditions, will elucidate the maintenance of normal red cell cation balance.
Concanavalin A Inhibition of Tissue Factor (Thromboplastin) Activity
Authors: Zacharski L. R. , Rosenstein R. , Phillips P. G.
Published: October 2019

Studies with the jackbean lectin, concanavalin A, were undertaken to clarify the relationship between tissue factor and the cell membrane of cultured fibroblasts. Concanavalin A blocks the coagulant activity of tissue factor of cultured human skin fibroblasts and also rabbit brain. The inhibitory effect, which is dose-dependent and reversed by alpha-methyl-D-mannopyranoside, cannot be explained by an effect on other reactants necessary for clot formation. These results support the contention that tissue factor is located on the cell surface. Since concanavalin A does not affect adhesion-related phenomena in cultured cells, these results also suggest that tissue factor produced by trypsinized fibroblasts is a consequence rather than the cause of cell adhesion and that tissue factor is not synonymous with the adhesive site on the cell surface.
Ferritin iron absorption in man
Authors: Layrisse M , Martinez-Torres C , Renzy M , Leets I
Published: October 2019

The iron absorption from ferritin and hemosiderin biosynthetically labeled with radioiron was studied in 108 subjects. The geometric mean absorption of ferritin iron in both normal and iron-deficient subjects was 1.9 percent. Its mean absorption ranged from 0.9 percent in normal subjects to 2.5 percent in subjects with moderate iron deficiency and 5.7 percent in subjects with marked iron deficiency. The administration of this iron compound with vegetals in a meal showed distinctly lower absorption values than the absorption from either maize, wheat, or soybean. Ferritin iron absorption was also different from that of ferric chloride when they were administered together as a drink or mixed with maize or liver. The iron absorption from ferritin was markedly increased when it was administered with either meat or liver, but it did not reach the absorption level of these foods. It is still to be elucidated whether the difference in iron absorption between ferritin and vegetable foods administered together reflect that this iron is incompletely miscible with a nonheme iron pool or that it really forms a third iron pool.
A clinical study of the lupus anticoagulant
Authors: Schleider MA , Nachman RL , Jaffe EA , Coleman M
Published: October 2019

Eighty-three patients with circulating anticoagulants were studied at The New York Hospital. The lupus-type anticoagulant, an inhibitor of the prothrombin activator complex, was demonstrated in 58 patients. The inhibitor was identified using the blood and tissue thromboplastin inhibition tests. Inhibition by the lupus anticoagulant was augmented in 67% of these patients by a cofactor present in normal plasma. The lupus inhibitor was detected primarily because of an unsuspected abnormal coagulation test. One-half of the patients with the lupus-type anticoagulant did not have systemic lupus erythematosus.
Aplastic anemia treated by allogeneic bone marrow transplantation: a report on 49 new cases from Seattle
Authors: Storb R , Thomas ED , Weiden PL , Buckner CD , Clift RA , Fefer A , Fernando LP , Giblett ER , Goodell BW , Johnson FL , Lerner KG , Neiman PE , Sanders JE
Published: October 2019

Forty-nine patients with severe aplastic anemia, 33 due to unknown cause, 11 drug or chemical related, 2 associated with hepatitis, 1 with paroxysmal nocturnal hemoglobinuria, and 2 possibly associated with Fanconi syndrome did not show recovery after 0.5–96 (median 2) mo of conventional therapy. Twenty-two were infected and 21 were refractory to random platelet transfusions at the time of admission. All were given marrow grafts from HLA-identical siblings. Forty-five were conditioned for grafting by cyclophosphamide (CY), 50 mg/kg on each of 4 successive days, and four by 1000 rad total body irradiation. All were given intermittent methotrexate therapy within the first 100 days of grafting to modify graft-versus-host disease (GVHD). Three patients died from infection too early to evaluate (days 1–8). Forty-six had marrow engraftment. Of these, 20 are surviving with good peripheral blood counts between 186 and 999 days, and 18 have returned to normal activities. Chronic GCHD is a problem in five. Twelve patients died of infection following rejection of the marrow graft. Twelve patients died with bacterial or fungal infections or interstitial pneumonia and active GVHD or soon following resolution of GVHD. Two patients died with marrow engraftment and no GVHD, one with an interstitial, and the other with a bacterial pneumonia. Thirty-six patients who had received random donor blood transfusions were randomly assigned to receive either CY or procarbazine-antithymocyte globulin-CY as conditioning regimens to test whether the incidence of graft rejection could be decreased. There was no difference in the incidence of graft rejection between the two regimens. In 13 patients with rejection, second transplants were attempted either with the original marrow donor (9 patients) or another HLA-identical sibling (4 patients). Three of these transplants were not evaluable, seven were unsuccessful and three were successful with only one of the three surviving for more than 468 days. In conclusion, the long-term survival of 41% of the patients in the present study is similar to that achieved in our first 24 patients, and confirms the importance of marrow transplantation for the treatment of severe aplastic anemia. Marrow graft rejection, GVHD, and infections continue to be the major causes of failure.
Characterization of human anti-factor VIII antibodies purified by immune complex formation
Authors: Lavergne JM , Meyer D , Reisner H
Published: October 2019

Anti-factor VIII antibodies from three hemophilia A patients were selectively isolated by immune complex formation and secondary precipitation with polyethylene glycol. These antibodies were characterized as IgG, with only one type of light chains (kappa) and a mixture of IgG3 and IgG4 heavy chains. This finding indicated that stable complexes of factor VIII and homologous anti-factor VIII antibodies could be obtained, and that the immunologic response to the infusion of homologous factor VIII was oligoclonal rather than monoclonal in these patients.
Detection of factor VIII inhibitors with the partial thromboplastin time
Authors: Lossing TS , Kasper CK , Feinstein DI
Published: October 2019

Variations of the partial thromboplastin time (PTT) were tested to determine the best screening method for detection of inhibitors of factor VIII. Variables tested included the duration of preincubation of a mixture of patient plasma and factor VIII source (normal plasma), the ratio of the patient plasma to the normal plasma, and the duration of incubation of the normal plasma-patient plasma mixture with kaolin- cephalin suspension prior to recalcification. The following conclusions were reached: (1) The PTT performed on a mixture of equal amounts of patient and normal plasma without preincubation of the mixture was inadequate to detect many factor VIII inhibitors. (2) Factor VIII inhibitors of more than 0.5 Bethesda units could be detected if the PTT was performed on a mixture of four parts patient plasma and one part normal plasma, with preincubation of the mixture for 60 min at 37 degrees C. (3) Factor VIII inhibitors as weak as 0.1 Bethesda units could be detected if the PTT was performed on a mixture of four parts patient plasma and one part normal plasma incubated with kaolin- cephalin suspension for 120 min at 37 degrees C before recalcification. The last method may make detection of mild factor VIII inhibitors possible in routine clinical laboratories not equipped to perform the more technically difficult Bethesda inhibitor assays.
Frequencies of thalassemia in American blacks
Authors: Pierce HI , Kurachi S , Sofroniadou K , Stamatoyannopoulos G
Published: October 2019

The frequency of thalassemia was determined in a group of 541 healthy adult black males. Individuals with decreased mean corpuscular hemoglobin (MCH) values were evaluated further with hemoglobin analysis, iron studies, and globin chain synthesis. Of the males screened, 13.4% had MCH levels below 27.0 pg, while 1.4% had heterozygous beta thalassemia, 2.3% had iron deficiency, and 5.7% had globin synthesis findings compatible with the diagnosis of alpha thalassemia trait (alpha thalassemia-1). This study suggests that thalassemia is one of the most frequent hematologically depictable abnormalities in American blacks.
BLOOD EXCHANGE IN REPLACEMENT TRANSFUSIONS
Authors: WASSERMAN L. R. , SHARNEY L.
Published: October 2019

1. Theoretic effectiveness of different types of exchange transfusions has been determined.

2. Homogeneous and nonhomogeneous solutions used as the exchanging medium differ in final results obtained.

3. The final concentration of original eryrthrocytes (in per cent of total red cells in the circulation) diminishes as the ratio of donor to patient’s initial hematocrit increases for the same volume exchange.

4. Final hematocrit values may be obtained from the calculated data.

5. Optimum considerations for exchange transfusions are discussed.
CHRONIC MARROW FAILURE, MYELOSCLEROSIS AND EXTRAMEDULLARY HEMATOPOIESIS
Authors: WYATT JOHN P. , SOMMERS SHELDON C.
Published: October 2019

Thirty cases, including 20 autopsied, of chronic bone marrow failure, myelosclerosis and osteosclerosis have been presented and compared with similar reports in the literature. The bone marrow histopathologic sequence observed involved repeated necrobiosis of maturing hematopoietic cells, followed by overgrowth of marrow reticulum and frequent ossification. Immature erythrocytes and leukocytes were often found in the circulation, and extrameduallary hematopoiesis was characteristic. One case was complicated by leukemia. Etiologic factors implicated included exogenous toxic chemicals, liver dysfunction, endocrine abnormalities, blood loss or destruction and cardiovascular disease. Suspicion was directed toward the pathogenetic importance of protracted bone marrow exposure to certain substances normally conjugated rapidly in the liver and excreted.
ERYTHROPHAGOCYTOSIS IN HEMOLYTIC DISEASE OF THE NEWBORN
Authors: COOPER MARY B.
Published: October 2019

Blood smears of 27 cases of hemolytic disease of the newborn were studied intensively for erythrophagocytes. In 25 cases, the smears were positive for this phenomenon.

In a control series of 30 normal newborn infants, these cells were not found.

Prolonged search and optimum magnification of the smears were important factors in determining the presence or absence of erythrophagocytes in the cases under study.
Intravenous Iron: Evaluation of the Use of Saccharated Iron Oxide in Iron Deficiency States in Obstetrics and Gynecology
Authors: HOLLY ROY G.
Published: October 2019

Saccharated iron oxide has been given to 23 patients in doses of 480 to 1,430 mg. Toxic symptoms were minimal. Hematologic response was good in 21 patients. Continued bleeding accounted for the poor response in 2 persons. Saccharated iron oxide is a safe preparation for clinical use. It is easy to administer. Further clinical evaluation is warranted. Excessive amounts of intravenous iron should not be given to any individual.
Studies in Rh Sensitization
Authors: WIENER ALEXANDER S. , NAPPI RAFFAELE , GORDON EVE B.
Published: October 2019

The Rh antibody titer was studied during pregnancy and after delivery in 11 cases in which previously sensitized Rh-negative mothers had Rh-negative babies. In addition, 1 case was studied in which a type Rh1 mother, previously sensitized to the rh'' factor, gave birth to a type Rh1 baby. In all cases the babies were normal at birth and the baby’s serum contained univalent Rh antibodies equal in titer to those present in the maternal serum. In no case was there a rise in the antibody titer in the maternal serum either during the pregnancy or after the baby was born. Thus, it has not been possible to confirm claims concerning a "nonspecific anamnestic rise" in Rh antibody titer said to be caused by an Rh-negative baby.

Two illustrative cases are described in detail. In one of the cases described, there was no appreciable change in Rh antibody titer during the pregnancy despite the use of so-called Rh hapten; nor had there been an appreciable change in titer for as long as two and one-half years previously. The Rh antibody titer of the baby’s blood dropped about 98 per cent by the end of the sixth month, while during the same period of time the maternal antibody titer fell only approximately 35 per cent. Based on the course of the Rh antibody titer of the baby’s serum, the half-life of the antibody globulin molecule is estimated to be about thirty days.
Photosensitive or Congenital Porphyria with Hemolytic Anemia
Authors: ALDRICH ROBERT A. , HAWKINSON VIOLET , GRINSTEIN MOISES , WATSON CECIL JAMES
Published: October 2019

1. The clinical features, laboratory findings and special studies of a case of photosensitive (congenital) porphyria in a 4 year old girl have been presented. This case was of particular interest in view of severe hemolytic anemia with hepatosplenomegaly.

2. Copro- and uroporphyrin I were isolated from the urine and feces. The ratio of these porphyrins in the urine varied from 1:10, to 1:30 respectively, while in the feces the ratio was reversed at about 70:1. Coproporphyrin III was isolated in much smaller amount than the type I isomer, from both urine and feces. Isomer analyses of the coproporphyrins in the excreta indicated that approximately 98 per cent was type I.

3. Prior to splenectomy copro- and uroporphyrin I were isolated in crystalline form for the first time from circulating human erythrocytes. Coproporphyrin III was also isolated in lesser amount. Uroporphyrin I was crystallized from the plasma, which also contained coproporphyrin I. Microfluorospectrometry of the bone marrow revealed large amounts of porphyrin in the developing red cells. The porphyrin fluorescence spectra indicated that at least three porphyrins were present.

4. Splenectomy was followed by disappearance of uro- and coproporphyrins from the erythrocytes, and a marked decrease in plasma, urine and feces without any essential change in the type of porphyrins excreted. The metabolic defect porphyria, was still present, but now latent in character. Reduction in porphyrin excretion was apparently related to elimination of hypersplenic hemolysis and compensatory increase of erythropoiesis. Anemia and dermal photosensitivity to sunlight disappeared simultaneously with the reduction in porphyrin excretion.

5. Efforts to reproduce the skin lesions by artificial light were unsuccessful.
Photosensitive or Congenital Porphyria with Hemolytic Anemia
Authors: GRINSTEIN MOISES , ALDRICH ROBERT A. , HAWKINSON VIOLET , LOWRY PAUL , WATSON CECIL JAMES
Published: October 2019

1. Porphyrin and hemoglobin metabolism have been studied in a case of photosensitive or congenital porphyria with the aid of glycine containing N15. The case was that of a 4 year old girl who also exhibited splenomegaly and hemolytic anemia. The reticulocytes and fecal urobilinogen were markedly increased and the bone marrow was hyperplastic-normoblastic. The urine contained large amounts of uroporphyrin I and lesser amounts of coproporphyrin I, while the reverse was true in the feces. Splenectomy resulted in disappearance of anemia, together with marked reduction of porphyrin excretion.

2. In two separate periods of study a rapid incorporation of glycine N15 was observed in the hemoglobin protoporphyrin, in both coproporphyrin isomers of the urine and in the type I isomer in the feces; also in the uroporphyrin I of the urine, and in the protoporphyrin and stercobilin of the feces.

3. The N15 data obtained for the urinary and fecal coproporphyrin and the urinary uroporphyrin, clearly reveal a synthesis similar in character to that of the hemoglobin protoporphyrin. The striking decline in formation of copro- and uroporphyrin after splenectomy is believed to be correlated directly with the reduced erythropoiesis incident to removal of the excessive hemolysis.

4. In both experiments the peak concentration of N15 was earlier and greater in the copro- than in the uroporphyrin. This, together with the closely similar slopes of decrease of the N15 curves for the two substances, does not appear to support a transition of uro- to coproporphyrin in the present case. The data are more consistent with the view that coproporphyrin I is a precursor of uroporphyrin I, or that both porphyrins are synthesized independently from common precursors.

5. The amount of coproporphyrin III in the excreta was too small to permit N15 analysis except in one period early in the first experiment; here the value was approximately the same as that of the copro- I for the same period, indicating a closely related synthesis.
A Method of Measuring the Severity of a Series of Cases of Hemolytic Disease of the Newborn
Authors: MOLLISON P. L. , CUTBUSH MARIE
Published: October 2019

1. The hemoglobin concentration in the cord blood of infants affected with hemolytic disease is very closely related to their chance of survival. If the hemoglobin concentration is plotted against the chance of survival, a sigmoid curve is obtained. Probit analysis can be applied and the results of treatment can then be summarized in terms of the severity of the cases treated. For example, in the present series the cord hemoglobin concentration corresponding to a 50 per cent chance of survival was 8.09 Gm./100 ml.

2. Application of probit analysis makes it possible to compare results obtained in different centers, for due allowance is made for any difference in severity in the cases included in the different series.

3. In the present series, despite uniform treatment (exchange transfusion), over-all mortality fell from 37 percent in 1947 and 1948 to 3 per cent in 1950. It is shown that this can be entirely explained by a decrease in the number of severely affected infants.

4. Predictions of survival based on the cord hemoglobin concentration and cord bilirubin concentration combined are not significantly better than predictions based on cord hemoglobin concentration alone.

5. Infants with positive direct Coombs tests whose cord hemoglobin concentrations exceed 15.5 Gm./100 ml. have some risk (approximately 1 in 12) of developing kernicterus, if untreated.
A clinical trial of anti-idiotype therapy for B cell malignancy
Authors: Meeker TC , Lowder J , Maloney DG , Miller RA , Thielemans K , Warnke R , Levy R
Published: October 2019

Eleven patients with B lymphocytic malignancy were treated with mouse monoclonal anti-idiotype antibodies. All but one of the patients in this study had received extensive prior treatment with conventional lymphoma therapy. All antibodies were prepared against, and uniquely reactive with, the patient's own tumor. Ten patients were treated with a single antibody, but one patient received three antibodies concurrently. The treatment protocol initially used an escalating dose schedule that was intended to evaluate toxicity, pharmacokinetics and, eventually, to achieve appreciable levels of free mouse antibody in the circulation. The last two patients received substantial initial doses. Tumor sampling was performed before and during therapy to evaluate tissue penetration by antibody. None of the patients had serum paraproteins by routine clinical testing, but six had idiotype protein detectable by a sensitive immunoassay at levels greater than 1 microgram/mL, two of which were greater than 200 micrograms/mL. Plasmapheresis was capable of reducing these levels temporarily. However, the presence of serum idiotype increased the requirement for mouse antibody to achieve tumor penetration. Another obstacle to treatment was immune response to mouse Ig, which occurred in five of the 11 patients. Once an immune response had begun, further infusions of antibody were not capable of reaching the tumor or inducing tumor regression and were associated with toxicity. Our initial patient remains in an unmaintained complete remission 42 months after receiving antibody. Five of ten additional patients have had objective remissions that were also clinically significant. However, these remissions were not complete and were of relatively short duration. This therapy shows promise as an alternative modality for the treatment of B cell malignancy. Further study will be needed to determine the mechanisms of the antitumor effect and to improve the clinical results.
Inhibitors of cholera toxin-induced adenosine diphosphate ribosylation of membrane-associated proteins block stem cell differentiation
Authors: Dexter TM , Whetton AD , Heyworth CM
Published: October 2019

Two potent inhibitors of mono-adenosine diphosphate (ADP) ribosylation have recently been described and characterized, named p- methoxylbenzylaminodecamethylene guanidine sulfate (MBAMG) and benzylaminododecylguanine hydrochloride (BADGH). We have used these agents to investigate the role of ADP ribosylation in hematopoiesis using long-term marrow cultures. The addition of MBAMG (10(-6) mol/L) or BADGH (5 X 10(-4) mol/L) led to both an inhibition of mature cell production and the development of colony-stimulating factor (CSF-1)- responsive GM-CFC, but had no effect upon spleen colony-forming units (CFU-S) or on progenitor cells which respond to the multilineage stimulating factor present in WEHI-3B cell-conditioned medium. These data indicate that these inhibitors of mono-ADP ribosylation can block the commitment and/or differentiation of stem cells and infers that ADP ribosylation may be of some importance in the hematopoietic process.
Influence of Dimethylaminoazobenzene on Leukocyte Production in the Rat
Authors: DINNING JAMES S. , PAYNE LOU DEWEES , DAY PAUL L.
Published: October 2019

1. Supplementation with p-dimethylaminoazobenzene plus vitamin B12 prevented leukopemia in rats fed a methionine-deficient basal diet. p-Dimethylaminoazobenzene was ineffective in this regard in the absence of supplementary vitamins B12.

2. Possible relationships of this observation to the theory of p-dimethylaminoazobenzene carcinogenesis are discussed.
Genetic Aspects of Sickle Cell Anemia and Microdrepanocytic Disease
Authors: SILVESTRONI E. , BIANCO I.
Published: October 2019

1. A brief review is presented of the genetic theories of sickle cell anemia and the sickle cell trait.

2. The genetic data on 2 families of asymptomatic individuals with the sickle cell trait and of 3 families of patients with sickle cell anemia are reported. These data confirm the heterozygous-homozygous theory of Neel.

3. The possibility is considered that many of the cases of sickle cell anemia described in the white race are actually examples of "microdrepanocytic disease."

4. Microdrepanocytic disease is a new syndrome, first described by the authors from Italy. It has some of the characteristics of both sickle cell anemia and Mediterranean anemia. On the basis of studies in 11 families, the presence of the sickle cell trait in one parent and of microcythemia (Mediterranean anemia trait) in the other, results in microdrepanocytic disease in some of the offspring. Hematologic studies in these patients indicate the simultaneous presence of both sickle cell and microcythemic genes.

5. Genetic studies of these families suggests that the genes for microcythemia and for sicklemia are located on different chromosomes and are inherited independently of each other. On the other hand, their simultaneous presence leads to a disease of a moderate degree of severity having many of the features of sickle cell anemia.
Hemorrhagic Disease in an Infant Due to Deficiency of a Previously Undescribed Clotting Factor
Authors: SCHULMAN IRVING , SMITH CARL H.
Published: October 2019

1. A case of hemorrhagic disease in an infant due to deficiency of a previously undescribed plasma coagulation factor has been presented.

2. The patient demonstrated all presently accepted criteria for a diagnosis of hemophilia, but the deficient factor was demonstrably different in the two conditions.

3. The deficient factor was found in both normal and hemophilic plasmas.

4. The plasma factor deficient in the patient appeared essential for the formation of active thromboplastin.

5. Localization of the deficient factor was carried out by means of plasma fractionation.

6. The possible relationship of the patient to other cases of nonfamilial hemophilia was suggested.