bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Regulates Activated Complement C5a in Vivo.
Authors: Nishimura Toshihiko , Myles Timothy , Nagashima Mariko , Morser John , Pearl Ronald G. , Leung Lawrence L.K. 
Published: October 2019

Abstract
The latent plasma carboxypeptidase thrombin-activatable fibrinolysis inhibitor (TAFI) is activated by thrombin/thrombomodulin on the endothelial cell surface, and functions in dampening fibrinolysis. We recently showed that TAFIa efficiently inactivates bradykinin, C5a, and thrombin-cleaved osteopontin, suggesting that it may have a broad anti-inflammatory role. In this study, we examined the pulmonary inflammatory responses in a C5a-induced alveolitis model in wild-type (WT) and TAFI deficient mice. TAFI deficient mice had been backcrossed into a pure C57/B6 background. C5a was instilled into the trachea of anesthetized mice, which were then allowed to recover. Six hours later, bronchiole alveolar lavage (BAL) was performed and the extent of pulmonary inflammation determined. C5a caused a dose-dependent increase in cell counts (WBC/ul) in the BAL fluids in WT mice (saline control, 5.3±4.1 (mean±SD); C5a at 0.05 mg/ml, 28.7±8.5, C5a at 0.1 mg/ml, 60.4±23.8; n=6 for saline and low-dose C5a, n=12 for high dose C5a; p < 0.0005 and < 0.0001 for low-dose and high-dose C5a compared to saline control respectively). Significantly increased BAL cell counts in the TAFI deficient mice in response to C5a stimulation were noted (saline control, 3.3±3.9; low-dose C5a 70±11.2; high-dose C5a 159.6±58.7; n=6 for saline and low-dose C5a, n=12 for high dose C5a; p < 0.00001 and < 5E-0.6 respectively), representing ~2.4–2.6 fold increase in BAL cell counts in the TAFI deficient mice. Determinations of the wet/dried lung weight ratios, an index of pulmonary edema, showed similarly significant results (WT mice: 4.1±0.14, 4.25±0.1, 4.52±0.15 and TAFI-deficient mice: 4.27±0.41, 5.3±0.53, 5.77±0.62 for saline control, low- and high-dose C5a respectively). Our data indicate that in the absence of TAFI, the chemotactic and inflammatory effects of C5a in pulmonary inflammation were enhanced. We are in the process of testing whether E229K thrombin, which selectively activates protein C and TAFI, will ameliorate the C5a alveolitis response in WT mice. Our results support our thesis that the function of TAFIa is not restricted to fibrinolysis. It has a broad anti-inflammatory role and may serve as a homeostatic counterbalance to thrombin’s inflammatory functions.
Randomized Multicenter Trial of Cladribine Alone (C) or in Combination with Cyclophosphamide (CC), and COP in Previously Untreated Low Grade B-Cell Non-Hodgkin Lymphoma Patients: The First Interim Analysis.
Authors: Kalinka Ewa E. , Wajs Jaroslaw J. , Sulek Kazimierz , Robak Tadeusz , Blasinska-Morawiec Maria , Holowiecki Jerzy , Sawczuk-Chabin Joanna , Ceglarek Bernadeta , Konopka Lech , Mazur Grzegorz , Federowicz Irena , Jerdrzejczak Wieslaw , Watek Marzena , Kisiel Elzbieta , Meder Janusz , Centkowski Piotr , Seferynska Ilona , Czyz Jaroslaw , Warzocha Krzysztof ,   for the Polish Lymphoma Research Group
Published: October 2019

Abstract
To comparatively assess first-line treatment with cladribine alone (C) or in combination with cyclophosphamide (CC), and COP (cyclophosphamide, vincristine, prednisone) in low grade B-cell non-Hodgkin lymphoma (NHL), previously untreated patients (pts) with Ann Arbor stage II–IV were randomly allocated to receive 6 monthly courses of either C, CC, or COP. End points were treatment response, freedom from progression (FFP) and overall survival (OS), and tolerance. From June 1, 2000, 165 pts were randomized in 17 centers. The first interim analysis performed at July 1, 2004 included 105 out of 165 randomized pts (63.6%) who have completed at least six cycles of the scheduled chemotherapy. Of 105 analyzed pts, 38 (36.2%) were diagnosed as small lymphocytic, lymphoplasmocytoid 8 (7.6%), marginal-zone 22 (21%), follicular 33 (31.4%), and not otherwise specified low grade B-cell NHL 4 (3.8%). Randomization constituted comparable groups, including international Prognostic Index variables. Compared to C and CC, COP induced lower overall response rates (75%, 85%, 51%, χ2 test p<.005), including lower complete remission rates (43%, 62.5%, 5.5%, χ2 test p<.001). With a median follow-up of 10 months, median FFP was superior in patients receiving cladribine containing regimens (8 versus 11 versus 6 months, respectively, χ2= 15.1, log-rank test p<.001). No difference in median OS was detected (9 versus 12 versus 7 months, respectively, χ2= 1.15, log-rank test p=.56). Incidences of infections (7% versus 15% versus 11%) and non-hematological side effects (7% versus 7.5% versus 16%) were similar in the randomize groups, whereas CC but not C induced more frequent cytopenias compared to COP (30% versus 11%, χ2 test p<.05). This resulted in more frequent intervals’ prolongation between CC versus COP cycles (respectively 32.5% and 11%, χ2 test p<.05) but dose reductions because of hematological or other toxicity were comparable in C, CC, and COP groups (11% versus 17.5% versus 5.5%). In pts with low grade B-cell NHL, first line C and CC regimens provided similar response rates, FFP, and OS, which were superior to those obtained with COP. The first interim analysis has resulted in discontinuation of accrual in the COP arm. An observed trend toward a better tolerance of C over CC, which may influence the choice between these regimens as front-line treatments, warrants larger number of pts and longer follow-up.
Effects of a New Pathogen-Reduction Technology (Mirasol PRT) on Platelet Function.
Authors: Diaz-Ricart Maribel , Perez-Pujol Silvia , Tonda Raul , Lozano Miguel , Fuste Berta , Lopez-Vilchez Irene , Galan Ana M. , Li Junzhi , Goodrich Raymond , Escolar Gines 
Published: October 2019

Abstract
Several strategies for pathogen reduction are being developed to reduce the risk of pathogen transmission associated with platelet transfusion. There is concern that these techniques could have a deleterious effect on platelet integrity and functions. We evaluated the impact of a new technology for pathogen reduction based on riboflavin + illumination at 6.2 and 12.3 J/ml (Mirasol PRT) on functional and biochemical characteristics of platelets. Platelet concentrates (PCs) obtained by apheresis (n=8) were treated with Mirasol PRT and then stored at 220 C. Modifications in major platelet glycoproteins (GPIb, GPIV, and GP IIbIIIa), adhesive ligands (vWF, Fg, and Fn), activation dependent antigens (P-selectin and LIMP), and apoptotic markers (Annexin V binding and factor Va) were analyzed by flow cytometry. Adhesive and cohesive functions of platelets in the concentrates were evaluated using well-established models with circulating human blood. Studies were performed the preparation day (day 0) and along storage (days 3 and 5) of PCs. Aliquots were taken for aerobic and anaerobic microbiologic cultures. No bacterial growth was observed. Exposure to PRT treatment results in very mild modifications in platelet counts. Levels of GPIb, GPIIb-IIIa and GPIV remained stable during storage in PCs treated with PRT 6.2J/ml and in the same range as those observed in non treated PCs. However, when PRT 12.3 J/ml was applied, levels of GPIb moderately decreased along days of storage 3 and 5. VWF, Fg, and factor Va did not modify their expression, neither by treatment nor by storage period. Fn appeared more elevated in all PRT samples when compared with non-treated samples. A progressive increase in P-selectin and LIMP expression and in Annexin V binding was observed during storage of PRT-treated PCs. Functional studies in perfusion models indicated that Mirasol PRT 6.2 J/ml treated platelets preserved adhesive and cohesive function to levels compatible with those observed in the respective control PCs. In conclusion, platelet function was well preserved in PCs treated with Mirasol PRT 6.2 J/ml and stored for 5 days.
ADAMTS13 Activity in Sickle Cell Disease: A Role in the Development of Clinical Vaso-Occlusion?.
Authors: Schnog John-John B. , Kremer-Hovinga Johanna , Akin Sakir , Ozveren Ernan , Krieg Soraya , Lammle Bernhard , Brandjes Dees , Mac Gillavry Melvin R. , Muskiet Fred D. , Duits Ashley J. 
Published: October 2019

Abstract
Endothelial cell activation occurs continuously in sickle cell disease (SCD). As VWF and especially the ultra large VWF multimers, released from activated endothelial cells, can serve as bridging proteins between the vessel wall and sickle red blood cells, we determined ADAMTS13 (the vWF-cleaving protease) activity as well as VWF:Rcof and VWF:Ag levels in SCD. Fourteen sickle cell patients (13 HbSS, 1 HbSC; 39 samples collected) and 9 HbAA controls were included. VWF:Rcof and VWF:Ag were assessed by commercially available assays, ADAMTS13 activity was determined by quantitative immunoblotting of proteolysed VWF-substrate. VWF:Rcof and VWF:Ag levels were higher in patients, as compared to controls. ADAMTS13 activity ranged from 45–128% in asymptomatic patients, from 38–205 in patients during acute vaso-occlusive events (VOE) and from 43-75% in controls. The ratios of ADAMTS13 to vWF:Ag levels and activity were lower in patients (SCD asymptomatic: 0.44 [interquartile range 0.34–0.55], SCD acute VOE: 0.29 [0.21–0.43], HbAA: median 0.61 [0.33–1.23], Kruskar Wallis test p=0.003). The ADAMTS13 - VWF:Rcof and the ADATS13 - VWF:Ag ratios dropped during acute vaso-occlusive events in 3 of 6 patients. In patients from whom multiple samples were collected (n=4), ADAMTS13 activity and VWF:Ag levels (and to a lesser extent VWF:Rcof) were inversely related. One patient showed no change in ADAMTS13 activity despite strong increments in VWF:Ag and VWF:Rcof during vaso-occlusive pain crises prior to his death (pulmonary embolism). VWF:Ag levels at initial presentation of acute VOE were related to the duration of pain (rs=0.53, p=0.02), whereas the ratios of ADAMTS13 to VWF:Ag levels and ADAMTS13 to VWF:Rcof were inversely related hereto (rs=−0.67, p=0.002, rs=−0.53, p=0.02 respectively). These data demonstrate that ADAMTS13 activity is related to VWF:Ag levels and VWF:Rcof in SCD and that the role of ADAMTS13 and VWF in the pathophysiology of SCD deserves further evaluation.
A Report of Transplantation of 224 Patients with Beta Thalassemia Major in Tehran, 1991– 2004.
Authors: Ghavamzadeh Ardeshir , Jahani Mohamad , Alimoghaddam Kamran , Iravani Masoud , Bahar Babak , Mousavi Asadolah , Gholibeikian Simin , Pejhan Shervin , Orouji Zahra , Babhadiashar Nima , Ashouri Asieh 
Published: October 2019

Abstract
Introduction: Beta Thalassemia Major is one of the most common single gene disorders and the most common type of hemoglobinopathies in Iran, with more than 20,000 patients. North and South parts of Iran have the highest prevalence, although it exists all over the country. In Iran, the first thalassemic patient was transplanted in our center, in 1991.
Methods and patients: Till now (August 2004) 224 Beta Thalassemia Major Patients have been transplanted in this center. Age range =2–17 years, M/F=123/101, Class I=99, class II=81 and class III= 44. 124 patients (55.4%) received Bone Marrow, 94 (42%) Peripheral Blood stem cell and 6 (2.7%) Cord Blood for transplantation. Their conditioning regimen in class I and II included Busulfan 3.5mg/kg for 4days, Cyclophosphamide (CY) 50mg/kg for 4 days and their GVHD prophylaxis regimen was Cyclosporine (CYX) 3mg/kg (IV from day −2 till day +5) and 12.5mg/kg (PO after then) and in class III, included Busulfan 4mg/kg for 4days and CY 40mg/kg for 4days and their GVHD prophylaxis regimen was CYX plus MTX 10mg/m2 on day +1 and 6mg/m2 on days +3 and +6.
Results:188 (84%) patients are alive and 36(16.1%) deceased.188 (84%) patients have passed 100 days after transplantation.168 (75%) patients had developed clinical acute GVHD after transplantation (grade II–IV= 57.1%). 67(35.6%) patients developed chronic GVHD (44 limited, 23 extensive). Three to ten year overall survival was 81% and disease free survival was 70 %.
Conclusion: Blood and marrow transplantation (based on other documented studies and our experience) is the treatment of choice for class I& II and is indicated in class III thalassemic patients.
Smoking as a Cause for Mild Chronic Neutrophilia.
Authors: Stemmelin German R. , Doti Carlos A. , Shanley Claudia M. , Ceresetto Jose M. , Rabinovich Oscar M. , Vicente Reparaz Maria A. , Vukovic Matias Gonzalez , Bullorsky Eduardo O. 
Published: October 2019

Abstract
Mild chronic neutrofilia is a frequent reason for hematologic consultation and in 70% of the cases there is no identifiable cause.
Objective: to determine if smoking habit could be the etiology for leucocytosis with neutrophilia in smokers with no other pulmonary associated disease.
Materials and Methods: We questioned 300 consecutive blood donors from our institution, elaborating a complete record of smoking habit. Immediately before blood donation an automated complete blood count was performed. Leucocytosis was defined as a white cell count above 11 x 109/L, and neutrophilia as a neutrophil count over 7.7 x 109/L. All data is stated as mean value ± 1 SD.
Results: we studied 195 (65%) men and 105 (35%) women (n=300). Mean age was 36.5 y.o. (18–69). Fifty-five percent (165/300) smoke or were previous smokers; 8.4% (14/165) of these, did not smoke at the time of this investigation, and only two have quit smoking a year prior to questioning. Mean time of duration of smoking habit was 16.4 years ± 10.6 and the average amount of cigarettes smoked through life (estimated from data referred along different phases of each subject’s history) was 1.26 x 105 ± 1.21 x 105. In the following table results from smokers (previous or actual) vs. non-smokers are compared.
Leucocytosis was present in 37/165 (22.4%) of smokers and in 3/135 (2.2%) of non-smokers (p<0.001) and neutrophilia was noted in 19/165 (11.5%) of smokers and in 2/135 (1.5%) of non-smokers (p<0.001). None of the volunteers had a WBC count over 20 x 109/L. A direct association was established for the number of cigarettes smoked and the WBC count and neutrophil count.
Discussion: smoking habit affects ciliar movement, inhibits alveolar macrophage function and produces hyperplasia on mucous glands within bronquial walls. These alterations result in entrapment of mucous secretions that will ultimately lead to bacterial colonization. The neutrophilia observed in smokers would be the result of a normal physiologic response to a potential infectious focus. In conclusion, is our understanding that the smoking habit should be considered as a common etiology for mild leucocytosis and neutrophilia.
Smokers (n:165) Non-smokers (n:135) p (t-test) WBC x 109/L 9.6 ± 2.1 6.8 ± 1.3 < 0.001 Neutrophils x 109/L 5.7 ± 1.6 3.9 ± 1.0 < 0.001 Hct % 45.9 ± 3.7 45.2 ± 3.6 NS Platelets 207 ± 48.7 206.4 ± 45.8 NS
Cytokine or Cytokine Receptor Treatment Using Hematopoietic Secretory Lysosomes as Vehicles.
Authors: Hansson Markus , Calafat Jero , Gao Ying , Persson Ann-Maj , Tapper Hans , Olsson Inge 
Published: October 2019

Abstract
Immunological responses are tightly controlled through a balance between stimulatory and inhibitory cytokines. This is used therapeutically in chronic inflammatory diseases such as rheumatoid arthritis or Crohn’s disease, where anti-cytokine therapy has proven to be useful. Furthermore, stimulatory cytokines are used in treatment of some malignant diseases. However, both anti-cytokine therapy and cytokine therapy are systemic treatments with severe side-effects: thus local delivery of the treatment may improve the therapeutic efficacy and reduce the systemic side-effects.
We therefore propose the concept of local delivery using secretory lysosomes of hematopoietic cells as vehicles. A secretory lysosome is a compartment with a dual function of storage and degradation found in secretory cells, e.g. in neutrophils and lymphocytes. The secretory lysosomes are released by degranulation at sites of inflammation or infection. Therapeutically-active protein could be induced for expression and storage in secretory lysosomes and thereby be locally released by degranulation resulting in local delivery of therapeutically active protein.
In support of this concept, we have shown that: I) gene transfer and granule loading can be achieved using the soluble TNF-a receptor (sTNFR1) after cDNA expression in hematopoietic cell lines and hematopoietic progenitor cells; II) endoplasmic reticulum export can be facilitated by the addition of a transmembrane domain; III) constitutive secretion can be prevented by incorporating a cytosol-sorting signal resulting in secretory lysosome targeting; IV) the sTNFR1 is released from the transmembrane domain into the secretory lysosome by proteolytic cleavage; V) regulated sTNFR1-secretion can be triggered by activation or calcium signal.
In vivo investigations are currently determining the feasibility of local protein delivery at sites of inflammation or malignancy.
Intermittent Low Dose Interleukin 11 Can Lead to Transfusion Independence in Patients with Chronic Myelo-Monocytic Leukemia and Thrombocytopenia.
Authors: Shah Chirag , Gentile Teresa C. 
Published: October 2019

Recombinant Interleukin- 11 (IL-11) is a thrombopoietic cytokine that stimulates megakaryocytopoiesis in vitro and platelet production in vivo. It attenuates post chemotherapy thrombocytopenia at a dose of 50 mcg/ kg/ day subcutaneously (SC). Unfortunately, prolonged administration is associated with significant toxicity including peripheral and pulmonary edema at this dose. Administration of low dose IL-11 at 10 mcg/kg/day SC has shown efficacy in bone marrow failure states without significant toxicity. We report two cases of chronic myelo-monocytic leukemia (CMML) with transfusion dependent thrombocytopenia who received intermittent low dose IL-11 without significant toxicity.
Case Reports- Patient 1 is a 79-year-old male with history of CMML with pancytopenia of three years duration. Recently he required transfusion of platelets with his platelet counts falling to less than 15 x 109/L. His cytogenetic study showed normal karyotype, 46 XY. He required platelet transfusion at every 14 days. He initially was started on IL-11 at 10mcg/kg/day, 5 days per week.. His platelet count increased to above 30 x 109/L and he became transfusion independent within two weeks. Unfortunately on this schedule he developed edema and mild CHF. IL-11 was stopped for two weeks and upon resolution of toxicity, restarted at 10 mcg/kg/day on Monday, Wednesday and Friday. He has remained transfusion independent without recurrence of edema at 5 months on this schedule.
Patient 2 was a 63-year-old male with previous history of chronic lymphocytic leukemia and diffuse large B cell lymphoma who developed CMML with severe pancytopenia. His karyotype was 46, XY, −7, +21. His platelet count was consistently less than 10 x 109/L. He required platelet transfusion twice a week. He was started on IL-11 at 10mcg/kg/day for 5 days per week, two weeks on and two weeks off. His platelet count increased to as high as 64 x 109/L after 2nd cycle. His platelet transfusion requirement decreased from every 3rd day to every 10th-14th day. He experienced no peripheral or pulmonary edema.
Conclusion: Administration of low dose IL-11 in other bone marrow failure states has been reported but its use has not been described in CMML. Our observation in these 2 patients suggests that IL-11 has efficacy in CMML and is very well tolerated at low doses on an intermittent administration schedule. IL-11 may decrease the transfusion requirement in transfusion dependent patients. Further studies are needed to evaluate overall impact on larger number of patients who require regular platelet transfusion.
A Simple Technique to Determine Thrombopoiesis in Thrombocytopenic Patients Using Immature Platelet Fraction (IPF).
Authors: Wada Hideo , Sakakura Miho , Matsumoto Takeshi , Kaneko Toshihiro , Nobori Tutomu , Shiku Hiroshi 
Published: October 2019

Abstract
Introduction
Reticulated platelets (RP) were suggested that those cells might contain increased amounts of cytoplasmic RNA, reflecting the rate of thrombopoiesis in bone marrow. The flow cytometric analysis has been used for RP assay, however it was difficult applying to routinely testing due to complicated operations. We developed a new automated RP testing method named as immature platelet fraction (IPF) using XE-2100 automated hematology analyzer equipped with modified software and a polymethine dye. The aim of the study is to evaluate the IPF as indicator to discriminate level of thrombopoiesis in thrombocytopenic patients.
Methods
We have analyzed IPF in 129 healthy volunteers (40 females and 89 males; range, 21–60 years), and in 127 consecutive, unselected patients in Mie University Hospital from June 1, 2002 to March 31 2003. IPF was measured in the patients categorized to three groups which are different level of thrombopoiesis phase as ‘suppressed’ (Chemotherapy-induced hypoplasia (n=80)), aplastic anemia (AA) (n=24)), ‘increased’(idiopathic thrombocytopenic purpura (ITP) (N=51), Thrombotic thrombocytopenic purpura (TTP) (n=9)), the peak value of IPF preceding with platelet recovery (peripheral blood stemcell transplant (N=5)), bone marrow transplant (N=1), chemotherapy (N=101)), liver transplant (N=2))), high of FDP (>10μL/mL) group (N=19)) and ‘normal’(healthy volunteers (N=129)). Peripheral blood was collected in EDTA anti-coagulant. Total platelet counts and IPF were determined by the XE-2100 (Sysmex). Analysis of IPF was performed by special designed software. A receiver operating characteristic (ROC) curve was plotted for choosing optimized cut off value of IPF to discriminate different level of thrombopoiesis.
Results
Mean IPF value in healthy volunteer was 3.3±1.7 (%). IPF in ‘increased’ group was significantly higher than ‘suppressed’ and ‘normal’ group (p<0.01). In ‘increase’ group, IPF was significantly elevated in ITP (especially active phase; 16.5±9.2 %), TTP (13.4±3.1 %) and the peak value of IPF prior platelet recovery (11.4±5.4 %). The best cutoff point of IPF was chosen to discriminate ‘increased’ group from ‘suppressed + normal’ group was 6.15 (%). The sensitivity and specificity of this cutoff value are 80.0% and 90.1% for distinguish ‘suppressed + normal’ group, 80.0% and 83.7 % for distinguish ‘suppressed’ group. The positive predictive value was 89.4%, and negative predictive value was 70.7% to detect the ‘increased’ group from ‘suppressed’ group.
Summary
Our results suggest that the IPF reflects the level of thrombopoiesis in thrombocytopenic disorders. This simple technique of IPF measurement is useful for the differential diagnosis and analysis of platelet kinetics in thrombocytopenic patients.