bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE ACTION OF PTEROYL GLUTAMIC ACID AND NATURAL SOURCES OF FOLIC ACID ON BLOOD DYSCRASIAS INDUCED BY SULFONAMIDE DRUGS
Authors: PETERING H. G. , DELOR R. A. , MURRAY H. C. 
Published: October 2019

Abstract
Sulfanilamide, sulfathiazole, and sulfadiazine have been fed at 1 per cent levels in highly purified diets and their effect on growth, mortality, and blood dyscrasias compared with that of sulfasuxidine.
The soluble drugs produce conditions which are similar to those produced by sulfasuxidine. The growth depression is alleviated in large measure in the case of sulfanilamide and to a lesser extent for sulfathiazole and sulfadiazine by folic acid. liver extract powder, and dried yeast extract as well as by para-aminobenzoic acid,
The blood dyscrasias due to sulfanilamide, sulfathiazole, and sulfadiazine are severe leukopenia, granulocytopenia, and mild-to-severe anemia. These are uniformly prevented or the severity greatly curtailed by feeding folic acid, liver extract powder, or dried yeast extract. PABA has a lesser effect in the amounts fed.
Liver extract powder seems to have a beneficial effect on growth and mortality which is not shown by the other supplements. Both free and conjugated folic acid (as yeast extract and in liver extract powder 1:20) are active in combating the dyscrasias.
Evidence from in vitro experiments with Str. haemolyticus (B Lancefield) indicates that neither folic acid, liver extract powder, nor dried yeast extract in ratios to sulfonamide which are effective in preventing the blood dyscrasias will inhibit or block the bacteriostatic action of the sulfonamide drugs in vitro.
It is suggested that the action of folic acid, liver powder, and yeast extract is not wholly explained by alleviating a folic acid deficiency caused by intestinal bacteriostasis due to the drugs, but by an increased demand of the animals for folic acid in the presence of certain sulfonamides.
PERNICIOUS ANEMIA, NUTRITIONAL MACROCYTIC ANEMIA, AND TROPICAL SPRUE
Authors: WILLS LUCY 
Published: October 2019

Abstract
The following tentative conclusions as to the relationship of pernicious anemia, nutritional macrocytic anemia and tropical sprue to one another and their pathogenesis are drawn from a study of the literature and from unpublished work:
1. That these three clinical conditions are three distinct entities possessing a common characteristic in the presence of a panhemopoietic dystrophy characterized by a megaloblastic erythropoiesis and corresponding changes in the myeloid cells and platelets.
2. That this panhemopoietic dystrophy possibly results from the breakdown of an intracellular enzyme system but that the deficiencies causing the breakdown differ; in pernicious anemia the liver principle is apparently at fault, in endemic nutritional macrocytic anemia another unidentified factor is missing, in sprue either or both may be at fault.
3. Folic acid is active therapeutically in all three diseases, but in all it generally fails to restore completely normal blood levels.
4. Pernicious anemia is probably due to a genetic defect which produces an atrophy of the gastric mucosa. As a consequence of this interference with gastric function there is a failure in the formation or absorption of the liver factor and possibly of another neurotrophic factor, which failure results in the development of a macrocytic megaloblastic anemia and the characteristic changes in the nervous system. Indefinite replacement therapy is necessary as the changes in the gastric mucosa are irreversible. The cause of the increased hemolysis is unknown.
5. Endemic nutritional macrocytic anemia is an unconditioned food deficiency, the deficiency being in a factor other than the liver principle, possibly a co-enzyme present in or associated with good biologic protein and the vitamin B2 complex. There are no characteristic pathologic changes except those of the hemopoietic organs which are not specific to the disease. A hemolytic type of the disease occurs in areas of high malarial incidence. After successful treatment the disease does not relapse if the diet is satisfactory. Pregnant women are particularly liable to develop the disease.
6. Tropical sprue is due to a functional disorder of the intestine, possibly primarily a failure in phosphorylation of fatty acids, glycerol and glucose. Diarrhea with characteristic stools and a macrocytic anemia are characteristic findings. The macrocytic anemia may be due to a failure in absorption of one or more essential hemopoietic factors or to a lack of Castle’s intrinsic factor. The cause of the functional breakdown is unknown. Treatment is with a high protein diet and liver extracts. Relapses are common.
My thanks are due to my colleagues for carrying on my work while I wrote this paper.
NORMAL BLOOD COUNTS IN DIFFERENT SEASONS
Authors: ENGELBRETH-HOLM J. , VIDEBAEK AA. 
Published: October 2019

Abstract
Report is given of examinations carried out on 40 healthy males and 29 healthy females in the months of January, March, June and October, with determination of the hemoglobin, the number of erythrocytes and reticulocytes, the sedimentation rate, the white cell and differential counts. The hemoglobin value appears to be lowest in October, the number of reticulocytes highest in June, the sedimentation rate lowest in June. The remaining figures present no exact seasonal variations. Some individuals have a high leukocyte level, others a low one. Normal values are illustrated.
THE USE OF FOLIC ACID ANTAGONISTS IN THE TREATMENT OF ACUTE AND SUBACUTE LEUKEMIA
Authors: DAMESHEK WILLIAM 
Published: October 2019

Abstract
In summary, the folic acid antagonists have, in varying degrees, the capacity to induce remissions in about one third of the cases of acute and subacute leukemia, in adults as well as in children, and in both leukemic and leukopenic forms.
Clinical, hematologic and (to lesser extent) marrow remissions, are obtained most commonly in the lymphoblastic types, least often in the monocytic types.
It is possible that folic acid is required by the primitive white cell as a growth factor. The folic acid antagonists, which resemble folic acid so strikingly in chemical structure, may result in cell death by modifying various enzyme systems within the primitive cells.
Both clinical and hematologic observations indicate that the proliferative process is by no means cured with aminopterin treatment. Acute leukemia may be likened to "wildfire" which, although damped by aminopterin, continues to "smolder." This smoldering may suddenly light up again into an active leukemic picture, unless continued maintenance therapy is given. Despite maintenance therapy, there finally comes a point in the leukemic process at which both the leukemia and increasing toxicity to drug make further progress impossible, and the patient dies.
Other growth factors or enzymes are probably of at least as great an importance as PGA in the metabolism of the primitive white cells and when these are discovered and their antagonists synthesized, the therapeutic results in acute leukemia may be of more consistent and durable nature. It should be realized further that chemotherapeutic methods against leukemia and the leukocytic proliferations in general (and, in fact, against all proliferative disease) are at least in their very infancy. The results thus far obtained in acute leukemia, although to large extent disappointing, indicate that well-defined remissions can be secured in about a third of the cases. For a disease such as acute leukemia, in which remissions previously were highly unusual and of sporadic nature, this indicates a well-defined therapeutic advance and a need for continued investigation along the same general lines.
Differences in results obtained by various groups of workers are difficult to explain. Several points may nevertheless be considered: some of the workers have given inadequate dosage of drug or have failed to use maintenance therapy; some have given folic acid in conjunction with anti-folic acid therapy; in some cases, a crude folic acid antagonist was used; and it is possible that some cases were not observed as minutely as seems necessary. An important factor, which can be determined only by the study of a large group of cases, is the natural variability of acute leukemia from case to case. We have the impression that our best results are obtained in the relatively subacute cases. The fulminating cases, with rapid onset of bleeding and a quick downhill course, are only slightly affected.
A new form of hereditary persistence of fetal hemoglobin in blacks and its association with sickle cell trait
Authors: Stamatoyannopoulos G , Wood WG , Papayannopoulou T , Nute PE 
Published: October 2019

Abstract
A new form of hereditary persistence of fetal hemoglobin (HPFH) producing 3%-8% Hb F in heterozygotes and an elevation of F-cell counts as measured by both the Kleihauer test and an antibody fluorescent procedure was found during the study of a black family. Individuals with this anomaly also had sickle cell trait. A sickle cell homozygote who had apparently inherited the HPFH determinant had 20.3% Hb F. Both types of gamma-chains were present in equal proportions in the Hb F of these individuals. A population study revealed other AS individuals with increased Hb F synthesis, three of whom were sibs. The presence of this previously unrecognized form of HPFH might explain the mild clinical manifestations and the hemoglobin phenotypes of sickle cell homozygotes with unusual elevations of Hb F.
Thymidylate synthetase activity in bone marrow cells in pernicious anemia
Authors: Sakamoto S , Niina M , Takaku F 
Published: October 2019

Abstract
The tritium release assay for the demonstration of thymidylate synthetase activity has been applied to the measurement of enzyme activity in the bone marrow of four patients with pernicious anemia and nine normal subjects. On the average, an approximately ninefold increase in enzyme activity was observed in patients with pernicious anemia. In the absence of 5, 10-methylene-tetrahydrofolate, enzyme activity was reduced in both normal and in pernicious anemia cells. Addition of 5, 10-methylene-tetrahydrofolate to the assay medium resulted in a far greater activation of thymidylate synthetase activity in megaloblastic bone marrow cells than in the cells of control subjects.
Lack of CD45 antigen on blast cells in childhood acute lymphoblastic leukemia is associated with chromosomal hyperdiploidy and other favorable prognostic features [see comments]
Authors: Behm FG , Raimondi SC , Schell MJ , Look AT , Rivera GK , Pui CH 
Published: October 2019

Abstract
The leukocyte common antigen (CD45) was detected on the surface of leukemic cells in 217 (87%) of 249 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). All 55 cases of T-lineage ALL, compared with 159 of 191 B-lineage cases, expressed the CD45 antigen (P = .0005). The frequency of CD45 expression did not differ between cases of early pre-B (CD19+, cytoplasmic mu-) and pre-B (CD19+, cytoplasmic mu+) ALL. Cases of ALL lacking CD45 had significantly lower leukocyte counts (P = .002) and serum lactic dehydrogenase (LDH) levels (P = .007) and were more likely to have leukemic cell hyperdiploidy greater than 50 (P less than .0001) or a DNA index greater than 1.15 (P less than .0001), as compared with cases positive for the antigen. Of the 130 patients whose follow-up duration was sufficient for analysis of event-free survival, the 53 with the highest levels of CD45 expression (greater than or equal to 90%) were the most likely to have an adverse event on intensive multiagent chemotherapy. Patients without detectable CD45 had a negligible risk of failure. This study suggests a relationship between the expression of the CD45 antigen on leukemic lymphoblasts and other biologic factors that influence prognosis in ALL.
Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice
Authors: Voncken JW , Morris C , Pattengale P , Dennert G , Kikly C , Groffen J , Heisterkamp N 
Published: October 2019

Abstract
The Philadelphia (Ph) translocation is responsible for the generation of the chimeric BCR/ABL oncogene. The Ph chromosome constitutes the earliest detectable chromosome abnormality in chronic myelogenous leukemia and is also found in acute lymphoblastic leukemia. Mice transgenic for a P190 BCR/ABL-producing DNA construct develop lymphoblastic leukemia/lymphoma and provide an opportunity to study early stages of the disease as well as progression. In this study, we have karyotyped the bone marrow of 10 19-day-old BCR/ABL P190 transgenic mice from a line that reproducibly develops leukemia/lymphoma. Leukemic cells from 17 terminally ill transgenic founders and progeny were also karyotyped as well as bone marrow transplant recipients of leukemic donor marrow. Karyotypically visible aberrations were absent from the early stages of BCR/ABL P190-generated leukemia and normal metaphases could be found even in the terminal stages of the disease. A high frequency of aneuploidy was found in advanced leukemia, with a marked preference for the gain of mouse chromosomes 12, 14, or 17. These results point to a primary role for BCR/ABL in leukemogenesis and suggest a destabilizing effect of the BCR/ABL gene on the regulation of cell division.
Demonstration of a human epsilon-globin gene silencer with studies in transgenic mice
Authors: Raich N , Papayannopoulou T , Stamatoyannopoulos G , Enver T 
Published: October 2019

Abstract
The human epsilon-globin gene displays normal developmental regulation in transgenic mice; it is expressed only in embryonic and in definitive erythroid cells. We show here that deletion of a negative element located between -182 and -467 bp upstream of the epsilon-globin gene cap site results in continuation of epsilon gene expression in the definitive erythroblasts of the fetal liver and in the red blood cells of adult transgenic mice. These data provide direct in vivo evidence that cis acting silencing elements are involved in the developmental control of the epsilon-globin gene.
Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA)
Authors: Estey EH , Kurzrock R , Kantarjian HM , O'Brien SM , McCredie KB , Beran M , Koller C , Keating MJ , Hirsch-Ginsberg C , Huh YO 
Published: October 2019

Abstract
We administered one course of 2-chlorodeoxyadenosine (2CdA) at 4 mg/m2 daily for 7 days by continuous intravenous infusion to 46 patients with hairy cell leukemia. Complete remissions occurred in 36 patients (78%; 95% confidence limits, 63% to 89%), partial remissions in five (11%), and a minor response in one. One patient died of candida sepsis 3 weeks after beginning treatment and three patients were clearly resistant to therapy. These three either had morphologically atypical hairy cells, less than 20% of which expressed Ig light chain on the cell surface, or had failed prior treatment with deoxycoformycin and interferon-alpha. At a median of 37 weeks since discontinuation of therapy, recurrent thrombocytopenia has developed in one patient, whose marrow remains normal, while a bone marrow relapse has occurred in another patient, whose blood counts remain normal. Treatment produced a greater than 50% decrease in neutrophil count in 26 patients, which lasted 3 to 4 weeks and was associated with an increased incidence of febrile episodes. These episodes occurred in 21 patients but were associated with documented infection in only four patients. Decreases in the number of CD4+ lymphocytes appeared to occur regularly after treatment and have persisted for a median of 18 weeks without obvious clinical significance. Although years of follow-up will be needed, our results confirm Piro et al's observation (N Engl J Med 322: 1117, 1990) that 2CdA appears to be highly effective in the treatment of hairy cell leukemia.
Functional expression of the macrophage colony-stimulating factor receptor in human THP-1 monocytic leukemia cells
Authors: Datta R , Imamura K , Goldman SJ , Dianoux AC , Kufe DW , Sherman ML 
Published: October 2019

Abstract
Macrophage colony-stimulating factor (M-CSF) is required for the proliferation, differentiation, and activation of monocytes. High- affinity receptors for M-CSF are encoded by the c-fms proto-oncogene. In the present study, we show that c-fms transcripts are detectable in human THP-1 myeloid leukemia cells. Furthermore, radiolabeled 125I-M- CSF is rapidly internalized into THP-1 cells and then degraded intracellularly. The results also show that treatment of THP-1 cells with M-CSF is associated with the activation of protein kinase C (PKC) and the induction of tumor necrosis factor (TNF) gene expression. TNF transcript levels were low to undetectable in uninduced THP-1 cells, reached maximal levels by 1 hour of exposure to M-CSF, and returned to those of control cells by 24 hours. Transcriptional run-on analysis showed that a low level of TNF transcription is detectable in untreated THP-1 cells, and M-CSF treatment increased the rate of TNF transcription. Pretreatment of THP-1 cells with pertussis toxin inhibited the increase in PKC activity but not the induction of TNF transcripts by M-CSF. Moreover, exposure of THP-1 cells to inhibitors of protein kinase activity blocked the increase in TNF messenger RNA. These findings suggest that at least two M-CSF-mediated signaling pathways exist in THP-1 cells and that the induction of TNF may be regulated by a protein kinase-dependent mechanism distinct from PKC.
Platelet adhesion to laminin: role of Ca2+ and Mg2+ ions, shear rate, and platelet membrane glycoproteins
Authors: Hindriks G , Ijsseldijk MJ , Sonnenberg A , Sixma JJ , de Groot PG 
Published: October 2019

Abstract
The adhesion of platelets to purified laminin under flow conditions was investigated. Adhesion to laminin was strongly dependent on the presence of divalent cations. In the absence of cations platelet adhesion (8% coverage in 5 minutes) was maximal at a shear rate of 100/s and no adhesion could be detected at shear rates above 800/s. In the presence of 0.8 mmol/L Mg2+ and 2 mmol/L Ca2+ platelet adhesion reached its maximum (30% coverage) around 800/s. At 1,800/s platelets still adhered to purified laminin (coverage of 6%). Antibodies against the E8 domain of laminin and antibodies against the alpha 6 and beta 1 chains of platelet membrane glycoprotein very late activation antigen-6 (VLA-6), completely inhibited adhesion. No inhibition was found with antibodies against glycoprotein IIb:IIIa, against the alpha 2 chain of VLA-2, and against the alpha 5 chain of VLA-5. Fibronectin and von Willebrand factor were not involved in laminin-dependent adhesion. Anti- VLA-6 partly inhibited platelet adhesion to the extracellular matrix of endothelial cells at shear rates below 800/s. Preincubation of the matrices with antilaminin E8 antibodies did not influence the adhesion. These results show that purified laminin supports platelet adhesion and that the presence of VLA-6 is important for platelet adhesion under flow conditions. The protein in the matrix with which VLA-6 interacts is currently unknown.
Specific Domains of Fibronectin Mediate Adhesion and Migration of Early Murine Erythroid Progenitors
Authors: Goltry Kristin L. , Patel Vikram P. 
Published: October 2019

AbstractThe binding of late stage erythroid cells to fibronectin (FN) has been well characterized and is believed to be critical for the terminal stages of erythroid differentiation, but the adhesive properties of more primitive murine erythroid progenitors and the role of these interactions during earlier stages of erythropoiesis has not been determined. Using chymotryptic fragments and inhibitory probes, we have tested the ability of each of the major cell binding domains of FN; the RGDS sequence, the CS-1 sequence, and the carboxy-terminal heparin-binding domain (HBD), to promote adhesion of primitive burst-forming unit-erythroid (BFU-E), mature BFU-E, and colony-forming unit-erythroid (CFU-E). We found that only 10% to 15% of BFU-E bound to FN or to the RGDS sequence in contrast to 75% to 85% of CFU-E. Approximately 50% to 70% of BFU-E and 60% to 80% of CFU-E bound to the carboxy-terminal HBD and to the CS-1 sequence. The binding of BFU-E and CFU-E to the RGDS and CS-1 sites was blocked by β1 integrin antibodies. These results suggest that binding to FN determinants is developmentally regulated during early erythroid differentiation. Erythroid progenitor migration within the bone marrow is thought to be important for the eventual release of reticulocytes into the circulation. A correlation between FN binding and the migratory capacity of erythroid cells has been suggested, although the ability of FN to promote migration of erythroid progenitors has not been directly measured. We measured migration of CFU-E on fragments of FN containing each cell binding region. CS-1–containing fragments, in addition to promoting adhesion of both BFU-E and CFU-E, supported the highest levels of CFU-E migration (11-fold above background). Migration was sixfold above background on intact FN and only threefold above background on RGDS-containing fragments. Fragments containing HBD alone, although they promoted adhesion of CFU-E, failed to support significant levels of migration. These results show that specific domains of FN possess distinct adhesion- and migration-promoting properties for murine erythroid progenitors. Regulation of the adhesive properties during erythroid differentiation may alter the ability of progenitors to migrate in the bone marrow and thus play an important role in normal murine erythroid differentiation.
Downregulation of c-kit Expression in Human Endothelial Cells by Inflammatory Stimuli
Authors: König Andrea , Corbacioglu Selim , Ballmaier Matthias , Welte Karl 
Published: October 2019

AbstractIn recent studies we have shown that the expression of stem cell factor (SCF ) in human endothelial cells is regulated by inflammatory processes. Gram-negative bacteria, interleukin-1 (IL-1), and lipopolysaccharide were able to upregulate the expression of SCF in human umbilical vein endothelial cells (HUVEC) (Blood 83:2836, 1994). Interestingly enough c-kit, the receptor of SCF, is coexpressed on HUVEC, suggesting an autoregulatory mechanism. To investigate the relation of c-kit and inflammatory processes we stimulated HUVEC with IL-1α and we established an in vitro model of inflammation. Binding experiments with 125I-SCF were performed to study the c-kit receptor expression on HUVEC. Scatchard analysis revealed both high-affinity receptors (Kd ≈0.36 nmol/L) and low-affinity receptors (Kd ≈2.9 nmol/L). Exposure to IL-1α led to a significant 50% reduction of c-kit high-affinity receptors, whereas the number of low-affinity receptors was not affected, in comparison to a control group of untreated HUVEC. Furthermore, using Northern blot analysis we studied the regulation c-kit mRNA expression in HUVEC after stimulation with IL-1α. Kinetic experiments showed a time-dependent downregulation of c-kit specific transcripts. In addition, we cocultured HUVEC with diverse bacterial strains. Experiments were performed over time with 1 × 106 bacteria/mL. Our data showed that, in contrary to the previously reported upregulation of SCF mRNA expression, stimulation with Yersinia enterocolitica or with Neisseria meningitidis led to a significant time-dependent downregulation of c-kit mRNA within 3 hours. These data indicate that inflammatory stimuli such as IL-1 or living bacteria activate a mechanism that downregulates c-kit receptor expression in human endothelial cells during the state of inflammation.