bluuebunny/crossref_metadata_2025 huggingface dataset:
STUDIES ON THE ADHESION OF HUMAN BLOOD PLATELETS AND BACTERIA
Authors: HOULIHAN RAPLH B.
Published: October 2019

1. Platelet counts decreased progressively in heparinized blood which had been stored in the icebox, then rotated in glass tubes. The platelets in similarly treated citrated human blood were stable.

2. Platelets and bacteria did not adhere in rotated heparinized and oxalated plasma from normal persons, or in citrated plasmas containing high concentrations of placenta or artery juice, purified fibrinogen, albumin, or gamma globulin, or in citrated plasmas from cases of subacute bacterial endocarditis.

3. Platelet-bacteria mixtures were found in rotated citrated plasmas containing saline extracts of human heart, heart valve, and vein tissues.

4. The degree of platelet-bacteria adhesion induced by sedimentation of these elements was variable. The degree of platelet-bacteria mixed clumping was enhanced by addition of purified gamma globulin and juices from human placenta, heart, heart valve, and vein, but not in plasma containing artery juice or purified fibrinogen.

5. The data indicated that bacterial agglutinins are not responsible for the adhesion of human platelets to bacteria.

6. The metabolic in vitro products of the alpha, beta, and gamma streptococci did not cause alterations in the morphology or adhesiveness of platelets.

7. Saline extracts of the human placenta, heart, heart valve, vein and artery used in these studies exhibited thromboplastic and prothrombic activity, but no thrombic activity.

8. The nature and relationship of the plasmatic factors responsible for the adhesion of platelets to bacteria, and for the agglutination of platelets, was discussed.
STUDIES ON PLATELETS
Authors: COPLEY ALFRED L. , GLASER DANIEL F.
Published: October 2019

1. Washed isolated platelets added to physiologic saline produce fall in surface tension.

2. Higher concentrations of platelets in saline cause a greater fall in surface tension than lower concentrations.

3. After centrifugation of platelets suspended in saline, the supernatant may show a fall in surface tension as compared to saline in which no platelets have been suspended. In the higher concentrations of platelets, the fall is much greater than in the lower concentrations.

4. When platelets are suspended in heparinized plasma, they exhibit either no change or a higher surface tension than do either their supernatants following centrifugation or the heparinized plasma alone.

5. No full explanation for the observed phenomena can be given.
STUDIES ON HYPOPROTEINEMIA. I. HYPOPROTEINEMIA IN PATIENTS WITH GASTRIC CANCER; ITS PERSISTENCE AFTER OPERATION IN THE PRESENCE OF BODY TISSUE REPLETION
Authors: HOMBURGER F. , YOUNG N. F. , FORBES IRIS
Published: October 2019

1 . The existence of hypoproteinemia in patients with gastric cancer has once again been observed.

2. The intractability of this type of hypoproteinemia in the postoperative phase to treatment with high protein diets and in the presence of positive nitrogen balance has been demonstrated.

3. Long-term studies in two patients, for 28 and 108 days respectively, suggest that the persistence of hypoproteinemia in patients with gastric cancer in positive nitrogen balance is probably not due to a marked degree of depletion of tissue protein stores alone. These patients retained more protein than would have been necessary to replenish depleted tissues.

4. It seems more likely that while such patients are capable of tissue protein synthesis, they fail to shift new protein into the blood stream.
THE EFFECT OF URETHANE ON THE NUCLEAR MORPHOLOGY OF CELLS OF THE GRANULOCYTE SERIES AS OBSERVED IN MARROW CULTURES AND LEUKEMIC BLOOD
Authors: OSGOOD EDWIN E. , CHU I. T.
Published: October 2019

In cultures by the marrow culture technic of human marrow and leukemic blood containing concentrations of urethane from 1:200 to 1:40,000, marked changes in the morphology of the cells of the granulocyte series were noted.

These changes were not noted in the control nor in duplicate cultures containing the methyl-bis (B-chloroethyl) amine hydrochloride form of nitrogen mustard in concentrations from 1:500,000 to 1:40,000,000, nor were they noted in previous studies of cultures containing colchicine or exposed to 200 kilovolt or million volt x-rays, neutron rays or radioactive phosphorus, nor in the bloods or marrows of patients with untreated chronic granulocytic leukemia, of healthy individuals or of persons with miscellaneous diseases.

The changes consisted of an early increase in number of normal mitoses in the progranulocytes; a steadily rising percentage of granulocytes and progranulocytes showing condensation of the chromatin in the nucleus into dense fragments separated by clear spaces; a progressive increase in the number of cells of the granulocyte series with double nuclei, affecting all cells from the progranulocytes to the neutrophil lobocytes but appearing to be most numerous in the granulocyte stage; and the appearance in the cultures by 4 to 5 days of cells containing separated fragments of structureless material staining like basichromatin, which probably represents a karyorrhexis of the nucleus.

Note: Nothing in this article is to be construed as a recommendation of urethane for the clinical treatment of leukemias. While many years must elapse before its place in therapy can be evaluated, it does seem worthwhile to give urethane a trial for metastatic malignant tumors. Our present impression is that either radioactive phosphorus or total body irradiation with x-rays given in small regularly spaced doses is far superior to urethane in the treatment of leukemias.17 When the cells become resistant to radiation therapy, urethane may be worthy of a trial.
LIVER EXTRACT REFRACTORY MEGALOBLASTIC ANEMIA
Authors: MUELLER JOHN F. , HAWKINS V. R. , VILTER RICHARD W.
Published: October 2019

1 . The patient described in this report had macrocytic anemia, megaloblastic maturation arrest in the bone marrow, glossitis, hyper-reflexia and diminished vibration perception in the feet. None of these abnormalities was improved by liver extract or vitamin B12 but all responded rapidly to folic acid except the neurologic signs.

2. This patient appears to have had a megaloblastic anemia which has been described in European clinics under the names "achrestic anemia" and "refractory megaloblastic anemia." It appears to be similar to "Wills" factor deficiency anemia" and some cases of pernicious anemia of pregnancy.

3. This patient did not appear to have a primary deficiency of folic acid since the excretion of this substance in the urine was within normal limits. A deficiency of an unknown factor probably equivalent to "the Wills’ factor" is suggested.

4. It seems likely that folic acid induced a remission in this case by a "mass action" effect. The possible relationship of folic acid, vitamin B12, the unknown factor and liver extract to nucleo-protein synthesis is discussed.
ACQUIRED HEMOLYTIC ANEMIA
Authors: EVANS ROBERT S. , DUANE ROSE T.
Published: October 2019

1. Observations of 11 patients with acquired hemolytic anemia are reported.

2. In contrast to patients with congenital hemolytic jaundice, all patients in this group exhibited evidence of sensitization of their erythrocytes by an antibody-like agent. In all patients studied there was abnormal destruction of transfused cells in vivo.

3. The sensitizing agent was found to be adsorbed on the erythrocytes when it could not be demonstrated in the serum. A rough method of assay of the amount adsorbed was devised by making serial dilutions of the anti-globulin serum. With this technic a fairly consistent correlation was found between the amount of antibody on the cell and activity of the disease.

4. Splenectomy when successful appears to exert a curative effect by sharply reducing the amount of antibody substance on the cell. Patients who had not responded to splenectomy in the past showed evidence of saturation of their cells with adsorbed antibody. The erythrocytes of patients who had responded to splenectomy and were in remission when studied showed distinctly less antibody on the cell by the same technique.

5. Two patients were observed to enter spontaneous remission after a long period of activity. The onset of remission in both was associated with a decrease in the amount of adsorbed immune body. However, one patient has shown evidence of return of antibody production without immediate recurrence of the hemolytic anemia. This inconsistency is not explained.

6. The tendency toward spherocytosis as measured by increased osmotic fragility may or may not be present in acquired hemolytic anemia. Prior to splenectomy the most marked increase in hypotonic fragility was observed in the patient with the most active disease. Continued activity of the disease following splenectomy was productive of the most extreme increases in spherocytosis. This suggests that the spherocytic cells are removed from the circulation by the spleen.

7. Agglutination of red cells when the amount of adsorbed antibody reaches a critical level, together with such other phenomenon as stasis, spherocytosis, increased mechanical fragility and possibly phagocytosis probably explain the increased cell destruction.

8. The occurrence of definite and sustained leukopenia with neutropenia and thrombocytopenia in several patients with hemolytic disease due to an immune body agent raises questions as to the etiology of classic thrombocytopenic purpura and of splenic neutropenia. Patients have been observed who seem to represent transition forms between acquired hemolytic anemia and thrombocytopenic purpura. Abnormal immune mechanisms could account for both excessive destruction of platelets and deficient formation.
FAMILIAL PANMYELOPHTHISIS
Authors: ROHR KARL
Published: October 2019

An account is given of a similar and hitherto unknown clinical-hematologic syndrome in two adult brothers with marked hemorrhagic diathesis, diffuse pigmentation of the skin, violent pain in the bones and panhemocytopenia. In the younger brother, there is also a certain degree of infantilism. The elder brother died with all the symptoms of an intensive aplastic anemia; in the younger brother, the condition was stabilized after splenectomy. The blood picture in both patients was characterized by a hyperchromic anemia with remarkable micro- and macrocytosis, and an increased number of reticulocytes. In the younger brother, increased fragility of the red blood cells and an elevated serum iron content were observed. In both cases, an unusual increase of the plasmocytic and reticular cells and of the tissue mast cells was noticed in the bone marrow and, in the final stages of the disease, the marrow showed marked fibrosis.

The disease is believed to be a variety, in adults, of the syndrome first described by Fanconi as a constitutional panmyelopathy occurring in children. The illness is the result of a hereditary pathologic reaction of the reticulo-histiocytic system and seems to have been caused by an anaphylactic-allergic phenomenon. The possibility is discussed that genetic connections may exist between this condition and other diseases, such as certain osteoscleroses and Cooley’s anemia, which are characterized by simultaneous disturbances of the bone and bone marrow and by a similar blood morphology.
Cytogenetic studies in a patient with acute granulocytic leukemia of seven and one-half years duration
Authors: Littlefield LG , Vodopick HA
Published: October 2019

During a 7 1/2-yr period we monitored a chromosomally aberrant cell line in a woman with acute granulocytic leukemia (AGL) whose disease followed a rather unusual course. Her initial remission induced with 6- mercaptopurine (6-MP) and prednisone was maintained for 52 mo with biweekly doses of methotrexate (MTX) given orally. Because signs of liver dysfunction occurred, maintenance therapy was stopped. After 15 mo without chemotherapy, she suffered her first relapse (5 yr 7 mo after the initial diagnosis). A second remission, again induced with 6- MP and prednisone, was maintained for 1 yr, after which a second relapse occurred. Another remission lasting for only 4 mo was followed by a relapse of the leukemic process which led to her death. Cytogenetic studies of marrow cells and peripheral blood at the time of her initial diagnosis showed abnormal stem lines with characteristic chromosome markers. A small percentage of malignant cells bearing these markers persisted in her marrow during the years of her prolonged remission. At the time of her first relapse, 75% of her marrow cells had the marker karyotype, and at the time of her death (7 1/2 yr after the leukemia was diagnosed) all analyzable marrow metaphases had the characteristic chromosome changes.
Platelet release reaction and intracellular cGMP
Authors: Weiss A , Baenziger NL , Atkinson JP
Published: October 2019

Enchanced cAMP concentrations inhibit the aggregation and release reaction of isolated human platelets and platelet-rich plasma to all known inducing agents. An opposing role for cGMP in this phenomenon has been proposed by some but not by others, and the function of cGMP in this secretory process is unclear. To further elucidate the role of cGMP in the release reaction, the effect of increased concentrations of this cyclic nucleotide on 14C-serotonin release was evaluated utilizing isolated human platelets and highly purified human thrombin or commercially available bovine thrombin. Several recently described stimulators of guanylate cyclase, including sodium nitroprusside, sodium azide, nitrosoquanidines, and ascorbic acid, were found to markedly augment platelet cGMP levels. Enhanced platelet cGMP concentrations produced by these drugs or by the exogenous addition of cGMP and its analogues neither caused these cells to secrete nor modulated the thrombin-induced serotonin release reaction. The inhibition of serotonin release by increased cAMP concentrations was not counteracted by increased cGMP levels. Platelet cGMP concentrations were unaltered by thrombin. These data indicate that cGMP is not an obligatory signal or a modulator of the thrombin-induced platelet release reaction.
Platelet arachidonic acid metabolism and platelet function in ten patients with chronic myelogenous leukemia
Authors: Jubelirer SJ , Russel F , Vaillancourt R , Deykin D
Published: October 2019

We have compared the pathways of arachidonic acid (C 20:4) metabolism in platelets from ten patients with Philadelphia chromosome-positive CML with those of seven normal subjects. Platelets were incubated with 3H-arachidonic acid, gel-filtered, and treated with thrombin (5 U/ml). The cyclooxygenase and lipoxygenase-derived products and free arachidonic acid released from the platelets were separated by high pressure liquid chromatography and their radioactivity determined. The total uptake of 3H-C 20:4 by platelets from CML patients did not differ from controls, but the release of radioactivity in response to thrombin was significantly lower (p < 0.01) in CML patients (32.3% +/- 4.9% of total radioactivity was released from control platelets; 19.0% +/- 7.4% from CML platelets). Both cyclooxygenase and lipoxygenase-derived products were reduced, but there was no specific pattern of abnormality. Although there was no direct correlation between either the WBC or platelet count and impairment of platelet C 20:4 metabolism, the platelets from three patients with accelerated disease released the lowest total amount of 3H-C 20:4 metabolites. In a single patient, studied before and after successful chemotherapy (hydroxyurea), severe abnormalities in platelet arachidonic acid metabolism returned to normal after treatment.
A cytokine receptor gene cluster in the X-Y pseudoautosomal region?
Authors: Kremer E , Baker E , D'Andrea RJ , Slim R , Phillips H , Moretti PA , Lopez AF , Petit C , Vadas MA , Sutherland GR
Published: October 2019

The receptors for interleukin-3 (IL-3), IL-5, and granulocyte- macrophage colony-stimulating factor (GM-CSF) are heterodimers comprised of ligand specific alpha chains and a common beta chain. The genes encoding the IL-5 receptor alpha chain and the common beta chain reside on chromosome 3 and 22 respectively, while the GM-CSF receptor alpha chain gene (CSF2RA) has been mapped to the pseudoautosomal region (PAR) of the sex chromosomes, which is a 2.6-Mb stretch of homologous sequence at the tips of the short arms within which a single obligatory recombination occurs during male meiosis. We have mapped the gene encoding the IL-3 receptor alpha chain (IL3RA) to the sex chromosomes by polymerase chain reaction (PCR) analysis of human-mouse or human- chinese hamster cell hybrids, and to Yp13.3 and Xp22.3 using fluorescence in situ hybridization. To explore the possibility that IL3RA is located within the pseudoautosomal region we screened the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees for an informative-restriction fragment-length polymorphism (RFLP) that showed male meiotic recombination. Two informative CEPH pedigrees were identified that displayed this phenomenon, confirming the psuedoautosomal location of IL3RA. Using long-range restriction mapping we have found that IL3RA maps to the same 190-kb restriction fragment as CSF2RA, suggesting that a cytokine receptor gene cluster may reside in the PAR.
Splenectomy is safe and effective in human immunodeficiency virus- related immune thrombocytopenia [see comments]
Authors: Oksenhendler E , Bierling P , Chevret S , Delfraissy JF , Laurian Y , Clauvel JP , Seligmann M
Published: October 2019

Sixty-eight patients, followed in a prospective cohort study of 185 human immunodeficiency virus (HIV)-infected patients with severe immune thrombocytopenia (platelets < 50 x 10(9)/L), underwent splenectomy, 2 to 41 months (median: 10 months) after immune thrombocytopenic purpura (ITP) was diagnosed. The mean platelet count increased from 18 x 10(9)/L to 223 x 10(9)/L with a persistent increase in 56 (82%). It also led to a significant increase of the mean CD4 cell count from 475 x 10(6)/L to 725 x 10(6)/L within a mean delay of 10 months. In the whole cohort, with a mean follow-up of 63 months (range, 6 to 126), the 5-year estimated rate for progression to acquired immunodeficiency syndrome (AIDS) was 23% (95% confidence interval [CI], 15% to 31%) and the AIDS-free survival was 69% (95% CI, 61% to 77%). To investigate the potential impact of splenectomy, a Cox's multiple regression model was used; as splenectomy was not randomly assigned, it was incorporated as a time-dependent covariate. After adjustment on the CD4 cell count, no statistically significant differences were observed between the splenectomized and the nonsplenectomized patients: AIDS progression rate (P = 0.23), survival (P = 0.64) and AIDS-free survival (P = 0.72) were not influenced by splenectomy. Splenectomy is both effective and safe in the treatment of severe, refractory ITP associated with HIV infection.
Direct comparison by limiting dilution analysis of long-term culture- initiating cells in human bone marrow, umbilical cord blood, and blood stem cells
Authors: Pettengell R , Luft T , Henschler R , Hows JM , Dexter TM , Ryder D , Testa NG
Published: October 2019

Limiting-dilution analysis of long-term culture-initiating cells (LTCIC) is a quantitative method of estimating hematopoietic stem cell activity in clinical samples. We compared the numbers of LTCIC in bone marrow (BM), umbilical cord blood, and blood progenitor cells (obtained from patients with solid tumors at leukapheresis after mobilization with induction chemotherapy and filgrastim administration), using a two- stage long-term culture system and a limiting-dilution technique, scoring cobblestone areas of greater than 15 hematopoietic cells weekly for up to 8 weeks. Samples were obtained from 30 normal BMs, 20 human umbilical cords, and 32 leukapheresis products. Direct comparison of LTCIC in the three sources showed that the median proportions of cells generating hematopoietic foci from unfractionated mononuclear cells at 5 and 8 weeks, respectively, were 1:13,314 and 1:33,949 for BM, 1:12,506 and 1:34,546 for umbilical cord blood, and 1:10,302 and 1:12,891 for leukapheresis product. The estimated proportions of LTCIC from unfractionated mononuclear cells and CD34+ cells were similar in experiments with leukapheresis product. Leukapheresis product was superior to umbilical cord blood and cord blood to BM at 5 and 8 weeks of culture (P = .01). In two-stage long-term cultures, more colonies per flask and CD34+ cells were found in assays of leukapheresis product than in BM or umbilical cord blood cultures (P = .0005). Results obtained by this simplified limiting-dilution analysis correlated well with standard long-term cultures and can be used as a measure of the stem cell population. These data suggest that the incidence of putative stem cells in leukapheresis product and umbilical cord blood are at least comparable with that of BM.
The human cardiac mast cell: localization, isolation, phenotype, and functional characterization
Authors: Sperr WR , Bankl HC , Mundigler G , Klappacher G , Grossschmidt K , Agis H , Simon P , Laufer P , Imhof M , Radaszkiewicz T
Published: October 2019

We have isolated and characterized the human cardiac mast cell (CMC) and compared this novel mast cell (MC type with MC obtained from uterus, skin, and lung. Heart tissue was obtained from 14 patients with cardiomyopathy (CMP, heart transplantation). CMC were isolated by enzymatic digestion using collagenase, pronase-E, hyaluronidase, and DNAse. Substantial amounts of CMC (0.5% to 1.5% of isolated cells) were found in the atrial appendages but not in ventricular digests or other sites of the heart (< 0.1%). In situ staining of atrial tissue revealed the presence of CMC in the myocardium (2.16 +/- 0.7 MC/mm2), endocardium (2.24 +/- 0.9 MC/mm2), and epicardium. As assessed by combined toluidine blue/immunofluorescence staining with monoclonal antibodies (MoAbs), isolated CMC expressed surface IgE, the receptor for stem cell factor (c-kit receptor/CD117), the p24 antigen (CD9), the Pgp-1 homing receptor (CD44), the pan leukocyte antigen (CD45), and the ICAM-1 antigen (CD54). CMC were not recognized by MoAbs to lymphocyte function associated antigen 2 (LFA-2; CD2), T-cell receptor (TcR; CD3), T4 antigen (CD4), LFA-1 alpha-chain (CD11a), C3biR alpha-chain (CD11b), CR4 alpha-chain (CD11c), LPS-R related Ag (CD14), 3-FAL/x-hapten (CD15), Fc gamma RIII (CD16), lactosylceramid (CDw17), the B-cell antigen CD19, or CR1 (CD35). In situ expression of leukocyte antigens on CMC was demonstrable by indirect immunoperoxidase staining technique and double-labeling immunohistochemistry. Almost all CMC (90%) reacted with MoAbs against tryptase and chymase and thus were MCTC. Cardiac mast cells were also stained by the heparin-binding dye Berberine sulfate and expressed measurable amounts of histamine (4.6 +/- 1.4 pg per cell). Cross linking of either IgE receptor or SCF receptor (c-kit) on CMC resulted in histamine secretion (non-specific release: < 6% of total histamine, alpha IgE induced: 12% to 52%; SCF-induced release: 9% to 18%), whereas neither substance P (a skin MC agonist) nor the basophil agonist FMLP showed an effect on CMC. Together, the CMC is an MCTC primarily located in the appendage of the atrium. This novel type of MC exhibits surface membrane antigen and functional properties similar to those of lung and uterus MC.
Blood clotting in minimally altered whole blood
Authors: Rand MD , Lock JB , van't Veer C , Gaffney DP , Mann KG
Published: October 2019

The sequences of events regulating thrombin generation during tissue factor-initiated clotting in whole blood at 37 degrees C in which the contact pathway was suppressed with corn trypsin inhibitor are studied using quantitative Western blotting of factor V, prothrombin, platelet factor 4, antithrombin III, and fibrinogen. In addition, fibrinopeptide A (FPA), thrombin-antithrombin III (TAT) complex formation, and prothrombin fragment 1.2 (F1.2) were measured via commercially available enzyme-linked immunosorbent assays (ELISAs). In a typical experiment initiated with 40 pmol/L recombinant tissue factor, visual clot time (4.5 minutes), was preceded by significant cleavage of factor V resulting in 65% factor Va heavy-chain generation but only 10% light-chain formation. At this point, 50% of the platelet factor 4 is released, suggesting that half (approximately 700 pmol/L) of the platelet prothrombinase sites available have been generated. At clot time, approximately 15 nmol/L thrombin B-chain is present; however, analyses of FPA release demonstrate that only 15% of the thrombin is acting on fibrinogen. This thrombin is produced by the action of 7 pmol/L prothrombinase. The maximum rate of thrombin production is reached well after clot time and is consistent with the presence of approximately 150 pmol/L prothrombinase (at about 7 minutes). These results suggest that factor Xa is the limiting factor for thrombin generation. After 60 minutes, 75% of the initial prothrombin (1.24 mumol/L) is consumed yielding 400 nmol/ L prethrombin 2 and 360 nmol/l thrombin (B-chain) products. The sum of these values (800 nmol/L) is similar to the (corrected) F1.2 concentration determined by ELISA. The incomplete cleavage of prothrombin indicates both the prothrombinase complex and the formation of prothrombinase are inhibited in the reaction. TAT complex measured by ELISA is almost equivalent to B-chain concentration, but sodium dodecyl sulfate stable thrombin-antithrombin III complexes are not observed until well after clot formation and are never equivalent to ELISA-TAT values. At the point of clot formation, 80% of the fibrinogen is depleted from the fluid phase, whereas only 35% to 45% of the FPA is released, suggesting a significant incorporation of uncleaved fibrinogen into the initial clot formed.
Telomerase Regulation, Cell Cycle, and Telomere Stability in Primitive Hematopoietic Cells
Authors: Engelhardt Monika , Kumar Rakesh , Albanell Juan , Pettengell Ruth , Han Wei , Moore Malcolm A.S.
Published: October 2019

Low levels of telomerase activity have recently been detected in human primitive hematopoietic cells, however, blood cells exhibit telomere shortening on cell proliferation. This challenging observation led us to study telomerase regulation and telomere length in human hematopoietic progenitor cells from fetal liver (FL), cord blood (CB), peripheral blood (PB), and bone marrow (BM). We found telomerase activity in CD34+/CD38+ cells exceeding levels in CD34+/CD38−, CD34−, and mononuclear cells (P < .05). Baseline telomerase activity was highest in BM (n = 5) CD34+ cells, followed by PB (n = 20), CB (n = 11), and FL (n = 1). Within 48 hours to 72 hours of in vitro culture of CD34+ cells in the presence of cytokines (KL, interleukin-3 [IL-3], IL-6, erythropoietin, granulocyte colony-stimulating factor), telomerase activity was upregulated, peaked after 1 week of culture, and decreased to baseline levels or below detection after 3 to 4 weeks. Stimulation of CD34+ cells with single cytokines resulted in no or minor telomerase upregulation, whereas cytokine combinations resulted in a significant telomerase increase (P < .001). There was a correlation between telomerase activity, cell cycle status by BrdU incorporation, and induction of phosphorylated retinoblastoma protein, CDC2, CDK2, cyclin D1, and cyclin A, but not cyclin E and B1 after 72 hours with multiple (but not single) cytokines. In nonexpanding CD34+ cells, telomerase was low or undetectable. Secondary CD34+ cells showed a reduced ability to upregulate telomerase activity. Antiproliferative cytokines such as transforming growth factor-β1 and high concentrations of all-trans–retinoic acid in cytokine-supported CD34+ cultures downmodulated telomerase activity. Average telomere lengths were 10.4 kbp, 7.4 kbp, and 7.6 kbp in CB, PB, and BM CD34+ cells, respectively. In ex vivo expansion cultures, an average telomeric DNA loss of 1 to 2 kbp over 4 weeks was observed. However, the rate of base pair loss per population doubling was significantly lower during the first 2 weeks, when telomerase was upregulated, than during weeks 3 and 4 of culture. In summary, telomerase is upregulated in response to cytokine-induced proliferation and cell cycle activation in primitive hematopoietic cells. Telomerase is downregulated between weeks 3 and 4 of ex vivo expansion culture linked with decreased proliferation and greater expansion of more mature cell subsets. Our data suggest that telomerase activity in hematopoietic cells reduces, but does not prevent, telomere shortening on proliferation.
Vitamin E Reduces Monocyte Tissue Factor Expression in Cirrhotic Patients
Authors: Ferro Domenico , Basili Stefania , Praticó Domenico , Iuliano Luigi , FitzGerald Garret A. , Violi Francesco
Published: October 2019

Clotting activation may occur in liver cirrhosis, but the pathophysiological mechanism has not been fully elucidated. Because a previous study demonstrated that lipid peroxidation is increased in cirrhosis, we analyzed whether there is a relationship between lipid peroxidation and clotting activation. Thirty cirrhotic patients (19 men and 11 women; age, 34 to 79 years) and 30 controls matched for sex and age were investigated. In all subjects, monocyte expression of tissue factor (TF) antigen and activity; plasma levels of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation; and urinary excretion of Isoprostane-F2-III, a marker of lipid peroxidation, were measured. Furthermore, the above-reported variables were re-evaluated after 30 days of treatment with standard therapy (n = 5) or standard therapy plus 300 mg vitamin E twice daily (n = 9). In addition, we analyzed in vitro if vitamin E (50 μmol/L) influenced monocyte TF expression and F1+2 generation. Cirrhotic patients had higher values of Isoprostane-F2-III (P < .0001), F1+2 (P < .0001), and monocyte TF antigen (P < .0001) and activity (P < .03) than controls. Isoprostane-F2-III was significantly correlated with F1+2 (Rho = 0.85; P < .0001) and TF antigen (Rho = 0.95; P < .0001) and activity (Rho = 0.94;P < .0001). After vitamin E treatment, Isoprostane-F2-III (P = .008), F1+2 (P < .008), and monocyte TF antigen (P = .012) and activity (P = .008) significantly decreased; no changes of these variables were detected in patients not receiving vitamin E. In vitro, vitamin E significantly reduced the expression of monocyte TF antigen (−52%; P = .001) and activity (−55%; P= .003), as well as F1+2 generation (−51%; P = .025). This study shows that vitamin E reduces both lipid peroxidation and clotting activation and suggests that lipid peroxidation may be an important mediator of clotting activation in liver cirrhosis.
Progenitor B-1 B-cell acute lymphoblastic leukemia is associated with collaborative mutations in 3 critical pathways
Authors: Gough Sheryl M. , Goldberg Liat , Pineda Marbin , Walker Robert L. , Zhu Yuelin J. , Bilke Sven , Chung Yang Jo , Dufraine Joseph , Kundu Subhadip , Jacoby Elad , Fry Terry J. , Fischer Susanna , Panzer-Grümayer Renate , Meltzer Paul S. , Aplan Peter D.
Published: October 2019

Key Points

An NUP98-PHF23 fusion collaborates with acquired Bcor and Jak/Stat mutations to produce a pro–B-1 ALL. Gene expression profile of murine pro–B-1 ALL resembles that of a subset of human ALL, suggesting some human ALLs arise from pro–B-1 B cells.
Standard measures for sickle cell disease research: the PhenX Toolkit sickle cell disease collections
Authors: Eckman James R. , Hassell Kathryn L. , Huggins Wayne , Werner Ellen M. , Klings Elizabeth S. , Adams Robert J. , Panepinto Julie A. , Hamilton Carol M.
Published: October 2019

Key Points

The PhenX Toolkit recommends standard SCD measures for use in clinical, epidemiologic, and genomic studies. Widespread use of PhenX measures will accelerate translational research to elucidate the etiology, epidemiology, and progression of SCD.
Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex: a meta-analysis of 40-year published data
Authors: Rota Matteo , Cortesi Paolo A. , Crea Roberto , Gringeri Alessandro , Mantovani Lorenzo G.
Published: October 2019

Key Points

AICC has been used since 1977 to control bleeding in patients with hemophilia with inhibitors. AICC is associated with a low incidence of TEEs, especially when administered prophylactically.
Prothrombin conversion is accelerated in the antiphospholipid syndrome and insensitive to thrombomodulin
Authors: Kremers Romy M. W. , Zuily Stéphane , Kelchtermans Hilde , Peters Tessa C. , Bloemen Saartje , Regnault Véronique , Hemker H. Coenraad , de Groot Philip G. , Wahl Denis , de Laat Bas
Published: October 2019

Key Points

The rate of prothrombin conversion is elevated in APS patients, causing a hemostatic imbalance. TG and prothrombin conversion are higher in APS patients with prior thrombosis than in patients without thrombosis.
Defining autoimmune hemolytic anemia: a systematic review of the terminology used for diagnosis and treatment
Authors: Hill Quentin A. , Hill Anita , Berentsen Sigbjørn
Published: October 2019

The terminology applied to autoimmune hemolytic anemia (AIHA) seems inconsistent. We aimed to evaluate the consistency of definitions used for diagnosis and treatment. In this systematic review of literature from January 2006 to December 2015, we assessed heterogeneity in the definition of AIHA and its subtypes, refractory disease, disease phase, severity, criteria for treatment response, and response durability. A Medline search for anemia, hemolytic, autoimmune was supplemented with keyword searches. Main exclusions were conference abstracts, animal and non-English studies, and studies with <10 cases. Of 1371 articles retrieved, 1209 were excluded based on titles and abstracts. Two authors independently reviewed 10% and 16% of abstracts and full papers, respectively. After full-paper review, 84 studies were included. AIHA was most frequently (32 [52%] of 61) defined as hemolytic anemia with positive direct antiglobulin test (DAT) and exclusion of alternatives, but 10 of 32 also recognized DAT-negative AIHA. A lower threshold for diagnosis of DAT-negative AIHA was observed in literature on chronic lymphocytic leukemia. Definitions of anemia, hemolysis, and exclusion criteria showed substantial variation. Definitions of primary/secondary cold agglutinin disease/syndrome were not consistent. Forty-three studies provided criteria for treatment response, and other than studies from 1 center, these were almost entirely unique. Other criteria were rarely defined. Only 7, 0, 3, 2, 2, and 3 studies offered definitions of warm AIHA, paroxysmal cold hemoglobinuria, mixed AIHA, AIHA severity, disease phase, and refractory AIHA, respectively. Marked heterogeneity in the time period sampled indicates the need to standardize AIHA terminology.
Characteristics and treatment regimens across ERS SHARP severe asthma registries
Authors: van Bragt Job J.M.H. , Adcock Ian M. , Bel Elisabeth H.D. , Braunstahl Gert-Jan , ten Brinke Anneke , Busby John , Canonica Giorgio W. , Cao Hui , Chung Kian Fan , Csoma Zsuzsanna , Dahlén Barbro , Davin Elizabeth , Hansen Susanne , Heffler Enrico , Horvath Ildiko , Korn Stephanie , Kots Maxim , Kuna Piotr , Kwon Namhee , Louis Renaud , Plaza Vicente , Porsbjerg Celeste , Ramos-Barbon David , Richards Levi B. , Škrgat Sabina , Sont Jacob K. , Vijverberg Susanne J.H. , Weersink Els J.M. , Yasinska Valentyna , Wagers Scott S. , Djukanovic Ratko , Maitland-van der Zee Anke H.
Published: October 2019

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.

This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.

Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2(the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the NetherlandsversusHungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1between those from SloveniaversusPoland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1in those starting anti-IgE (SloveniaversusSpain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.

The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
LncRNA AB209371 up-regulated Survivin gene by down-regulating miR-203 in ovarian carcinoma
Authors: Zheng Zi-Hui , Wu Dong-Mei , Fan Shao-Hua , Wen Xin , Han Xin-Rui , Wang Shan , Wang Yong-Jian , Zhang Zi-Feng , Shan Qun , Li Meng-Qiu , Hu Bin , Zheng Yuan-Lin , Lu Jun
Published: October 2019

AB209371 gene has been characterized as an oncogenic lncRNA in liver cancer. However, its involvement in ovarian carcinoma (OC) is unknown. In the present study, we analyzed the roles of AB209371 in OC. We found that AB209371 gene and Survivin gene were up-regulated in OC and positively correlated with OC development. AB209371 over-expression led to up-regulated Survivin in OC cells, while Survivin over-expression failed to affect AB209371. In addition, AB209371 over-expression led to down-regulated miR-203. However, miR-203 over-expression failed to affect AB209371, but down-regulated the expression of Survivin. In addition, over-expressions of AB209371 and Survivin resulted in the increased proliferation rate of OC cells. Over-expression MiR-203 played the opposite role and attenuated the effects of AB209371 over-expression. Therefore, AB209371 may down-regulate miR-203 to up-regulate Survivin, thereby promoting OC cell proliferation. Our study provided novel insights into the pathogenesis of OC.
Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance
Authors: Huang Peisen , Wang Li , Li Qing , Xu Jun , Xu Junyan , Xiong Yuyan , Chen Guihao , Qian Haiyan , Jin Chen , Yu Yuan , Liu Jiandong , Qian Li , Yang Yuejin
Published: October 2019

Background

Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs.

Methods

Exo was isolated from MSCs and delivered to an acute myocardial infarction (AMI) rat heart through intramyocardial injection with or without intravenous infusion of atrovastatin-pretreated MSCs on day 1, day 3, or day 7 after infarction. Echocardiography was performed to evaluate cardiac function. Histological analysis and ELISA test were performed to assess angiogenesis, SDF-1, and inflammatory factor expression in the infarct border zone. The anti-apoptosis effect of Exo on MSCs was evaluated using flow cytometry and Hoechst 33342 staining assay.

Results

We found that intramyocardial delivery of Exo followed by MSC transplantation (in brief, Exo+MSC treatment) into MI hearts further improved cardiac function, reduced infarct size, and increased neovascularization when compared to controls treated with Exo or MSCs alone. Of note, comparing the three co-transplanting groups, intramyocardially injecting Exo 30 min after AMI combined with MSCs transplantation at day 3 after AMI achieved the highest improvement in heart function. The observed enhanced heart function is likely due to an improved microenvironment via Exo injection, which is exemplified as reduced inflammatory responses and better MSC recruitment and retention. Furthermore, we demonstrated that pre-transplantation injection of Exo enhanced survival of MSCs and reduced their apoptosis both in vitro and in vivo.

Conclusions

Combinatorial delivery of exosomes and stem cells in a sequential manner effectively reduces scar size and restores heart function after AMI. This approach may represent as an alternative promising strategy for stem cell-based heart repair and therapy.
Proposal of a new nomenclature for introns in protein-coding genes in fungal mitogenomes
Authors: Zhang Shu , Zhang Yong-Jie
Published: October 2019

Fungal mitochondrial genes are often invaded by group I or II introns, which represent an ideal marker for understanding fungal evolution. A standard nomenclature of mitochondrial introns is needed to avoid confusion when comparing different fungal mitogenomes. Currently, there has been a standard nomenclature for introns present in rRNA genes, but there is a lack of a standard nomenclature for introns present in protein-coding genes. In this study, we propose a new nomenclature system for introns in fungal mitochondrial protein-coding genes based on (1) three-letter abbreviation of host scientific name, (2) host gene name, (3), one capital letter P (for group I introns), S (for group II introns), or U (for introns with unknown types), and (4) intron insertion site in the host gene according to the cyclosporin-producing fungus Tolypocladium inflatum. The suggested nomenclature was proved feasible by naming introns present in mitogenomes of 16 fungi of different phyla, including both basal and higher fungal lineages although minor adjustment of the nomenclature is needed to fit certain special conditions. The nomenclature also had the potential to name plant/protist/animal mitochondrial introns. We hope future studies follow the proposed nomenclature to ensure direct comparison across different studies.
Investigating effect of Helicobacter pylori treatment on improvement of non-alcoholic fatty liver parameters: a randomized trial
Authors: Kazemifar Amir Mohammad , Shafikhani Ali Akbar , HajiNoormohammadi Elaheh , Azarion Zahra , Hajiaghamohammadi Aliakbar
Published: October 2019

Background and objective

The correlation between the eradication of Helicobacter pylori (HP) and non-alcoholic fatty liver disease (NAFLD) is a controversial one. The aim of this study is to investigate the effect of Helicobacter pylori treatment on liver function tests and lipid profiles and to compare its effects with exercise therapy and diet alone.

Method

This was a double-blind randomized clinical trial conducted at Qazvin University of Medical Sciences. One hundred patients with NAFLD having a positive test for urea breath testing were randomly assigned into one of the intervention and comparison groups. The diet and physical activity program were given to two groups of patients for 8 weeks, three sessions per week. In addition to the above therapy, the patients in the intervention group also received HP treatment for 2weeks. The data corresponding to anthropometric and clinical features before and after the intervention were collected in both groups and compared using appropriate statistical methods.

Results

After the treatment interventions, the variables of weight, BMI, blood glucose, triglyceride, AST, ALT, total cholesterol, and LDL-C were significantly decreased in both groups (p < .05). In the between-group comparisons, only ALT was significantly lower in the intervention group (HP) (p < .05).

Conclusion

Findings of this study showed that the eradication of Helicobacter pylori could significantly improve the ALT index, but it had no additional effect on changes in metabolic indicators.

Trial registration

Registration number: IRCT2015042020951N2

Name of trial registry: The study of treatment of Helicobacter pylori in improvement of non-alcoholic fatty liver disease

The date of registration: 2015-05-12

Where the full trial protocol can be accessed: https://fa.irct.ir/trial/18489
Noncurated Data Lead to Misinterpretation of Treatment Outcomes in Patients With Prostate Cancer After Salvage or Palliative Radiotherapy
Authors: Rutzner Sandra , Ganslandt Thomas , Fietkau Rainer , Prokosch Hans-Ulrich , Lubgan Dorota
Published: October 2019

PURPOSE

Clinical data warehouses (cDWHs) and cancer registry databases have enabled researchers to conduct clinical analytics with structured electronic health record data. However, these secondary electronic health record sources are often limited in scope because they do not capture the clinical information needed to understand complex clinical questions. Thus, we evaluated the effect of additional curation of data.

MATERIALS AND METHODS

Clinical data sets of 149 patients with prostate cancer with biochemical recurrence after radical prostatectomy treated with salvage or palliative radiotherapy between 2008 and 2017 from our institutional cDWH and Gießener Tumor Documentation System (GTDS) were linked (data warehouse [DWH] population) for analyzing treatment outcomes. The linked data sets were manually curated (manual postprocessing [MPP], eg, incorporate data from established urologists). The primary outcomes were the impact on data quality of treatment outcomes and the time spent on data curation.

RESULTS

We obtained significantly more information on disease progression and patient survival (nonsignificant) when using curated data; the biochemical progression-free survival rate at 5 years for the DWH and DWH plus MPP populations was 63% v 30% ( P ≤ .001) and the overall survival rate was 84% v 81% ( P = .479), respectively. The median deviation of completeness and the median concordance of clinical data values were 21.47% (range, 55.38%-100%) and 95.00% (range, 63.40%-100%), respectively. We spent 121 hours, 42 minutes on data curation, with most time required for laboratory values, accounting, for a total of 45 hours, 20 minutes (37.26%).

CONCLUSION

Our analysis indicates that time-to-event outcomes for patients with prostate cancer cannot be extracted using secondary data sources (cDWH plus GTDS) only. Outcomes data differed between the electronic data (DWH) and the second manual extraction (DWH plus MPP) because of a lack of follow-up data. When using such unique database resources, only baseline characteristics can reliably be extracted.