bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Localization and Conditioned Release of Pro- and Anti-Angiogenic Cytokines from Resting and Stimulated Platelets.
Authors: Brill Alex , Zelikowitz Tali , Shlomai Gad , Kalchenco Vladislav , Shai Ela , Shinder Vera , Varon David 
Published: October 2019

Abstract
Mechanisms regulating a selective release of pro- or anti-angiogenic cytokines from platelets have not been yet established. In this work, we studied the potential regulative role of shear and collagen in the release of VEGF and endostatin from human platelets. We present data suggesting that subjection of platelets to adhesive proteins under shear, results in selective secretion of VEGF but not endostatin. Furthermore, we demonstrate compartmentalized distribution of these cytokines inside platelets. Platelets subjected to flow (shear rate of 200–2000 s−1) for 4 min on surface-immobilized collagen, selectively released VEGF (from undetectable level to more than 80 pg/ml), whereas the endostatin level remained unchanged (about 65 ng/ml). The release of VEGF was independent of the presence of RBCs or plasma as was demonstrated in experiments with WBC-depleted whole blood, PRP, or washed platelets. A similar yet moderate effect was observed on fibrinogen-coated surface, whereas application of shear force only or incubation of platelets on immobilized collagen or fibrinogen under static conditions did not induce the cytokine release. Soluble collagen promoted release of VEGF that could be inhibited by aspirin in a dose-dependent fashion ranging below effective anti-aggregation doses, which is in accordance with the observed anti-angiogenic effect of NSAIDs. VEGF release was Ca2+-dependent and could be prevented by EDTA or PGE1. In contrast to its inhibitory effect on VEGF release, EDTA markedly increased secretion of endostatin suggesting that calcium depletion confers an anti-angiogenic profile to platelets. The difference in the release regulation of these two cytokines led us to examine their localization in platelet granules. Confocal microscopy evaluation of permeabilized fluorescently double-stained (for VEGF and endostatin) platelets showed a distinct staining of each cytokine with almost no co-localization. For better resolution we prepared sections of resting gluteraldehyde-fixed platelets for electron microscopy. Immunogold labeling of the two cytokines revealed localization of VEGF in α granules and of endostatin in sub granular structures. This differential localization of VEGF and Endostatin is consistent with thier conditioned and constitutive release patterns respectively. In conclusion, we propose a novel phenomenon of selective cytokine release from cytokine-dedicated platelet granules according to environmental signals, which further elucidates the control over the pro and anti angiogenic roles of platelets.
Sliding-Rebinding Mechanism Governs Glycoprotein Ib/von Willebrand Factor Catch Bonds.
Authors: Lou Jizhong , Zhu Cheng 
Published: October 2019

Abstract
The interaction of platelet receptor Glycoprotein Ib (GPIb) and the plasma protein von Willebrand factor (VWF) initiates platelet adhesion and agglutination at the site of vascular injury. The binding sites of GPIb and vWF have been mapped to be the N-terminal domain of GPIb α subunit (GPIbαN) and the A1 domain of VWF respectively. The co-crystal structure of wild-type GPIbαN and VWF-A1 complex is solved and two separated binding interfaces have been identified. One is between the β-switch region of GPIbαN and the central β sheet of A1, another is between the β-finger region of GPIbαN and the loops on the bottom of A1. It has been demonstrated that flow enhances GPIb-VWF binding. Moreover, recent single-molecule experiments with atomic force microscopy (AFM) have shown that GPIb forms catch bonds with VWF. Using GPIbαN/VWF-A1 crystal structure, we studied the dissociation of GPIbαN from VWF-A1 with steered molecular dynamics (SMD) simulations. Our results show that the sliding-rebinding mechanism we proposed previously for selectin/ligand catch bonds also operates for the GPIb/VWF system. When force is applied to GPIbαN/VWF-A1 complex, the interactions between GPIbαN β switch and A1 central β sheet dissociate first, this may lead to the sliding of GPIbαN β finger on the A1 bottom surface to allow new interactions formation. The sliding and forming new interactions will in turn enhance the rebinding of GPIbαN β switch and A1 central β sheet and prolong bond lifetime. The N- and C- terminal flanking sequence of A1 serves as a flexible hinge to regulate catch bonds. As shown in the crystal structure, the A1 N-terminal residue D506 interacts with R543 and R687. The presence of these interactions favors the fast-dissociation pathway, while their dissociation signifies the transition to the sliding pathway. Our results have provided an explanation for the AFM experimental data showing that catch bonds were eliminated by two A1 gain-of-function mutants R543Q and R687E, because these single residue replacements eliminate their interaction with D506, making the transition to occur at much lower forces and prolonging bond lifetime at low forces. R543Q mutant naturally occurs in some patients with type 2B von Willebrand disease (VWD) and R687E mutant also exhibits type 2B VWD phenotype. Our results may provide an explanation for type 2B VWD based on the mechanically regulated nonequilibrium structure-function relationship of GPIb/VWF interaction.
Iron Deficiency and the Role of Nutrition among Female Military Recruits.
Authors: Israeli Eran , Merkel Drorit , Constantini Naama , Yanovich Ran , Evans Rachel K. , Shahar Danit , Moran Daniel S. 
Published: October 2019

Abstract
The impact of iron deficiency is considerable when enhanced physical fitness is required. Female military recruits represent a unique population faced with intense physical and cognitive demands.
Purpose: To examine the prevalence of iron deficiency and the impact of dietary habits among female recruits in the Israel Defense Forces (IDF).
Methods: 348 recruits completed the study (188 female combatants, 58 male combatants, 92 non-combat females). Dietary intake was assessed using a Food Frequency Questionnaire (FFQ). Blood samples were collected for CBC, iron indices and vitamin B12. The common definitions for anemia and iron store deficiency were used as follows: Hemoglobin (Hgb) < 12gr/dl for females and <14gr/dl for males; Serum ferritin < 12 mg/dl.
Results: The prevalence of iron deficiency and iron deficiency anemia was 29.8% and 12.8%, respectively, among female combatants. Similar data were found among non-combat females (27.2% and 17.4% respectively) as compared to 5.2% and 0%, among males. No significant difference in iron or total calorie intake was detected between subjects with iron deficiency (with or without anemia) when compared to subjects with normal iron status in the same study group. Plant sources constituted 85% of dietary iron source for females, in comparison to 73% for males.
Conclusions: A high prevalence of iron deficiency was found among female recruits. Coupled with the iron loss during menstruation, inadequate iron intake may have a permissive role for iron deficiency in female recruits, and is an important issue facing females in the military.
Population-Based Prevalence of Anemia, Iron, Folic Acid and Vitamin B12 Deficiency among Young Adults in Israel.
Authors: Merkel Drorit , Balicer Ran , Davidovitch Nadav , Grotto Itamar , Zarka Salman , Huerta Michael 
Published: October 2019

Abstract
Background: The prevalence of anemia and iron deficiency among adolescents and young adults in Israel has not yet been assessed. Studies performed among specific populations in Israel demonstrated highly variable rates of anemia of 6–58%, with iron deficiency rates of 13–38%. We have set out to investigate the prevalence of anemia, iron, folic acid and vitamin B12 deficiency among young males and females that are requited to the army in Israel (IDF).
Methods: A random sample of 366 new recruits to the IDF (270 males and 96 females) participated in the study and undergone blood testing for Hemoglobin, Iron, Transferrin, Ferritin, Vitamin B12, Folic acid on recruitment day.
Results: Anemia among females (Hb<12 gr/dl), was 15.1% compared with 11.4% among males (Hb<14 gr/dl). Transferrin saturation values indicating iron deficiency (15%>) were also more prevalent among females compared with males (28.1% and 9.7%, respectively), as were low ferritin rates (37.2% and 14.3%, respectively). Vitamin B-12 deficiency (<180 pg/ml) was found in 6.6–9.6% of the subjects, and folic acid deficiency was detected in 6.4–11.7% of the subjects. Low-level paternal education and immigration were two factors found to be negatively associated with anemia. Smoking was associated with low ferritin levels in males. Anemia and iron levels were not affected significantly by the type of service designed, as combat soldiers or for clerical work.
Conclusions: Anemia and iron deficiency occur frequently among young adults requited to the IDF. They were more prevalent among females; but in males the prevalence is higher than expected. Low content of iron in the diet, infection like H Pylori and engaging in strenuous exercise preparing to service, may contribute to depleted iron stores. Low-level paternal education and immigration was surprisingly protecting factor, may be as a result of different eating habits. Anemia and iron deficiency, are known to reduce physical work capacity and mental performance, therefore it is important to perform more research to identify possible etiologies for intervention like education for proper nutrition, and adjustment of the diet in the military to tackle this prevalent problem.
Utilization of Darbepoetin alfa in Relation to Cancer Patients’ Hemoglobin Levels.
Authors: Hess Gregory , Hill Jerrold , Hulnick Scott , Nordyke Robert 
Published: October 2019

Abstract
Background: Prevailing guidelines through 2006 recommended initiating erythropoiesis stimulating agents (ESAs) for chemotherapy-induced anemia (CIA) at hemoglobin (Hb) levels <11 g/dL, maintaining near 12 g/dL, and withholding at >13 g/dL.
Objective and Purpose: To determine darbepoetin alfa (DA) administration patterns in cancer patients and selected factors related to such use.
Methods: A retrospective ESA administration-level analysis of Varian Medical Systems electronic medical records (EMRs), which includes 122,985 cancer patients across 13 states and 82 physical sites of care. The study period was 1/1/2005 – 11/30/2006. All DA administrations were recorded with the most recent Hb (day of or up to 7 days prior to administration). The proportion of DA administrations at Hb ≥ 12 and Hb ≥ 13 g/dL were the primary outcome measures. Utilization by Hb level was analyzed for all administrations, stratifying by year, gender, and anemia type. The types of anemia assessed were CIA, anemia of cancer (AOC), and myelodysplastic syndrome (MDS).
Results: During the 23 month period, there were 33,923 DA administrations associated with Hb results in 5,252 patients. The proportion of all DA administrations given at Hb≥12 was 7.7%, for Hb≥13 g/dL it was 1.1%; proportions for CIA, AOC, and MDS were 8.1 /1.2% (N = 25,638 administrations), 7.5 /1.0% (N = 7,054), and 2.3 /0.2% (N = 1,231) for Hb ≥12 and ≥13 g/dL respectively. The difference across all three indications was statistically significant (P < 0.005) for both Hb thresholds. Overall, the proportion of all DA administrations at Hb ≥12 g/dL and ≥13 g/dL declined from 8.6% to 7.1% (p<.0001) and from 1.3% to 1.0% (p<.06) respectively in 2005 vs. 2006.
Conclusions: In this population, DA administration at Hb ≥ 12 and Hb ≥ 13 occurred in approximately 7.7% and 1.1% of administrations, respectively. The results suggest that for the majority of administrations the prevailing guidelines at the time were adhered to by clinicians. Further research is required to understand dose titrations at Hb from 12 – 13 g/dL.
Inflammatory Cytokines: TNFα, IL-1β, IL-6 and IL-8 in Pulmonary Hypertension of Sickle Cell Disease.
Authors: Vicari Perla , Noguti Maria Aparecida E. , Morelli Vania M. , Cançado Rodolfo D. , Figueiredo Maria Stella 
Published: October 2019

Abstract
Background: Although pulmonary hypertension (PHT) is a common complication in patients with sickle cell disease (SCD), the rate of development of PHT and the factors that affect disease progression are unknown.
Objectives: To evaluate the plasma levels of cytokines in SCD comparing with healthy subjects and to find out if there is a relationship among cytokines and PHT.
Patients and methods: Dosage of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), interleukin-8 (IL-8) and interleukin-1 beta (IL-1β) had been evaluated in 107 steady-state sickle cell patients, from the UNIFESP/EPM and College of Medical Sciences of the Santa Casa de Misericórdia, and in 108 blood donors. The presence of PHT was evaluated in sickle cell patients by transthoracic Doppler echocardiogram and the results were associated with age, hemoglobin and fetal hemoglobin, lactic dehydrogenase and cytokines levels.
Results: The presence of PHT was significantly related with age, low hemoglobin and high lactic dehydrogenase levels. There were no difference of plasma levels of IL-6, IL-1β and TNFα between patients and controls. The IL-8 levels were predominantly higher in patients than in controls (p=0.0001). Among patients with SCD, IL-8 levels were significantly higher in those with PHT (p=0.02). In addition, increased levels of IL-8 (>95th percentile of the control group) were detected in 33.3% in patients with PHT in comparison with 10.8% in those without (OR: 4.1; 95%CI 1.3–12.7).
Conclusion: These results indicate that age, hemoglobin, lactic dehydrogenase levels, and elevated levels of IL-8 could be risk factors of PHT in SCD. However a larger study with SCD patients with PHT is required to clarify this question. (Funded by Fapesp 04/04498–4).
Procoagulant Activity in Sickle Cell Anemia.
Authors: Vicari Perla , Lourenço Dayse M. , Morelli Vania M. , Noguti Maria Aparecida E. , Figueiredo Maria Stella 
Published: October 2019

Abstract
Sickle cell anemia (SCA) is associated with a hypercoagulable state that may contribute to the vaso-occlusive episodes observed in the disorder. Although numerous studies have been conducted to elucidate the mechanisms responsible for the prothrombotic state, the role of thrombogenisis in SCA complications remains controversial. We measured D-Dimer, thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2 (F1+2), plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF) and factor VIII (FVIII), in 42 homozygous sickle cell patients (HbSS), 26 women and 16 men, aged 14 to 48 years (mean age 26.8 years), 9 with hydroxyurea (HU) therapy, and correlated these data with clinical manifestations. Among the 42 studied patients, we found elevated plasma level (above the normal range) of these markers in 36 patients for D-Dimer (mean = 1481, range 280 – 5145 ng/mL), in 29 patients for TAT (mean = 7.35, range 2.2 – 45.0 microg/L) and FVIII (mean = 173, range 22.6 – 310.6%); in 25 patients for F1+2 (mean = 1.12, range 0.3 – 2.65 mM/L), in 21 patients for vWF (mean = 175, range 58 – 280%), and in 7 subjects for PAI-1 (mean = 41, range 11.5 – 103 ng/mL). There was no significantly correlation between hemostatic markers and the presence of leg ulcers or retinopathy in SCA patients. Factor VIII levels were significantly elevated in the 19 subjects with pulmonary hypertension, in the 5 with stroke and in the 33 patients who had not been treated with HU (p<0.05). TAT levels were also significantly elevated in the patients without HU (p<0.05). These findings confirmed the presence of a hypercoagulable state in patients with sickle-cell anemia, which could be driven by disease severity. (Supported by Fapesp 02/13801–7)
Hemoglobin San Martin: A New Unstable Variant Associated with Hemoglobin S in an Argentinean Boy.
Authors: Feliu-Torres Aurora , Eandi-Eberle S. , Calvo K. , Bragós I. , Ojeda M. , Voss M. , Pratti A. , Milani A. , Targovnik H. , Sciuccati G. , Bonduel M. , Diaz L. , Staciuk R. , Noguera N. 
Published: October 2019

Abstract
A new unstable hemoglobin (Hb) detected in a 10 year-old boy from San Martin, Buenos Aires, Argentina, is hereby described. The patient (pt) was born at term, after a normal pregnancy, by cesarean section. He had a history of multiple episodes of pallor, jaundice and dark urine related to infections, since 6 months of age. The physical examination only revealed pallor and icterus, with no hepatosplenomegaly. The pt and his mother showed the presence of an anomalous band on both alkaline and acid pH electrophoresis. Isopropanol and sickling tests were positive. In order to identify the abnormal Hb variant the β globin gene was analysed. Three exons were amplified and automatically sequenced with direct and reverse probes.
Table 1. Hematological data Patient Mother Hb g/dl/PCV % 10.9/36 10.5/34 MCV fl/MCH pg 79.4/24.1 80.7/24.6 RDW % 15.7 18.2 Reticulocyte count % 5.2 8.0 Electrophoresis (pH 9) A/X/A2 A/X/A2 Electrophoresis (pH 5) X/A-A2 X/A-A2 Sickling/Isopropanol tests Positive/Positive Positive/Positive Inclusion bodies Positive Positive
Two mutations were identified in the same β globin gene. One in Exon 1, corresponding to Hb S [Ex1 β6 Glu→Val (GAG→GTG)]; and the second one in Exon 2 [Ex2 β85 (F1) Phe→Leu (TTT→CTT)]. This second mutation is responsible for a new unstable Hb that has not been described so far, in association with Hb S. The substitution occurs in an external position between two hydrophobic residues of different size.
The BLyS/BAFF Receptor-Ligand System in HCV Induced B-Cell Clonal Disorders.
Authors: Landau Dan Avi , Rosenzwajg Michelle , Saadoun David , Klatzmann David , Cacoub Patrice 
Published: October 2019

Abstract
The study aim was to examine the B-Lymphocytes Stimulator (BLyS) receptor-ligand system in HCV induced B lymphocyte clonal disorders. 94 patients with chronic HCV [including 35 HCV+ mixed cryoglobulinemia (MC)-vasculitis and 9 HCV+ B-non Hodgkin’s lymphoma (B-NHL) patients] and 15 healthy volunteers were included. A 2-fold serum BLyS increase was associated with HCV-induced MC-vasculitis, and a three-fold increase with HCV-induced B-NHL, compared with HCV+ patients without vasculitis or healthy controls (p<0.05). Lower mBLyS expression in HCV-induced MC vasculitis was observed. CD19+ BLyS binding and BR3 staining showed a step wise decrease with highest values in healthy controls and HCV+ without MC, and lowest in B-NHL (p<0.05, p<0.0001, respectively) with a further decrease in Vh1-69+ (heavy chain rearrangement often found in clonal disorders associated with HCV) clonal B-cells. BLyS anti-apoptotic effects were maintained despite this decrease in BR3 staining. Complete clinical remission after anti-viral treatment was associated with a decrease in serum BLyS, and an increase in BR3 staining. Rituximab treatment was associated with a five-fold increase in serum BLyS (p<0.001), mirroring the depletion of CD19+ cells. BR3 staining in repopulating B-cells was significantly decreased (p<0.005). In conclusion, the BLyS ligand-receptor activity is increased in HCV induced B-cell clonal disorders, indicating a possible role for treatment targeting the BLyS receptor-ligand system.
Figure Figure Figure Figure
Clinical and Virological Responses to Anti-Viral Treatment Correlates with Regulatory T-Cells Evolution in Patients with HCV-Induced Cryoglobulinemia Vasculitis.
Authors: Landau Dan Avi , Rosenzwajg Michelle , Saadoun David , Trebeden-Negre Helene , Cacoub Patrice , Klatzmann David 
Published: October 2019

Abstract
Background- Mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder associated with chronic hepatitis C virus (HCV) infection. We previously reported that MC vasculitis is associated with a quantitative defect of peripheral blood regulatory T cells (Tregs). We aimed to prospectively evaluate the evolution of this defect during the course of anti-viral treatment.
Methods- Treg frequencies and numbers were analyzed in 131 HCV chronically infected patients (including 66 with MC vasculitis) and 20 healthy volunteers. Measurements were taken before, during and after treatment with Pegylated Interferon and Ribavirin.
Findings- At baseline, patients with MC vasculitis had significantly lower frequency and number of Tregs than patients without MC vasculitis. Complete remission of MC vasculitis following anti-viral treatment was associated with a significant increase in Treg levels compared to baseline levels. In contrast, Treg levels in non- or partial-responders, which did not differ from those of complete responders at baseline, remained unchanged over the course of the study, and where significantly lower that those of complete responders.
Interpretation- The strong positive correlation between clinical responses and Treg levels provides additional support for the central role of Treg cells in the pathogenesis of HCV-induced MC-vasculitis. Furthermore, it emphasizes the dual role of Treg cells in chronic HCV infection: while they may hinder viral elimination, Treg cells also have a beneficial role in limiting autoimmune tissue injury.
Correlations, in MC-vasculitis patients, between CD4+CD25 high levels and response to anti-viral treatment using clinical (A+B) or laboratory (C+D) measures. CR-complete response, NR/PR-no or partial response. Correlations, in MC-vasculitis patients, between CD4+CD25 high levels and response to anti-viral treatment using clinical (A+B) or laboratory (C+D) measures. CR-complete response, NR/PR-no or partial response.