bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Hepcidin, Ferritin, and Iron Deprivation on Erythroid Colony Formation in Vitro.
Authors: Means Robert T. , Dallalio Gail A. , Fleury Thomas W. 
Published: October 2019

Abstract
The anemia of chronic disease (ACD) results from a combination of three pathologic processes. In ACD, a modest shortening of red cell survival creates an increased demand for red cell production, which is not met because of an impaired erythropoietic response and defects in reticuloendothelial iron mobilization and utilization. The impaired erythropoietic response, in turn, has two components: a blunted erythropoietin response, and an impaired response of erythroid progenitors to erythropoietin. Recombinant human erythropoietin (rhEPO) can reverse this impaired progenitor response in vitro, and can also correct ACD in patients. These processes have generally been considered effects of the cytokines which mediate the immune and inflammatory response, such as tumor necrosis factor, interleukin-1, and the interferons. It has recently been proposed that hepcidin, a mediator of innate immunity with the iron regulatory properties, is the factor responsible for ACD. If this is the case, then hepcidin should be able to induce the pathophysiologic mechanisms implicated in ACD. We therefore evaluated the effects of hepcidin and associated phenomena on human CFU-E colony formation in vitro. All CFU-E cultures were performed in plasma clots in serum-containing medium with rhEPO 1 U/mL. Hepcidin at concentrations 10 ng/mL -10 μg/mL had no effect on CFU-E colony formation. A number of studies have demonstrated that increased hepcidin message expression and protein production are strongly associated with increases in serum ferritin concentrations, and so the effect of added ferritin on erythroid colony formation was studied. Neither ferritin nor apo-ferritin 10 – 1000 ng/mL had inhibitory effects on CFU-E colony formation. The effect of iron deprivation on erythroid colony formation was evaluated with using desferrioxamine. Desferrioxamine 0.01mM decreased CFU-E colony formation to 60% of control values, while higher concentrations completely ablated colony growth. In summary, hepcidin does not appear to inhibit CFU-E colony formation directly or indirectly through ferritin. It may exert such an effect by decreasing availability of iron for erythropoiesis; however, such a finding would be difficult to reconcile with the observed clinical response of ACD to rhEPO, given that iron availability is typically a limiting factor in the erythropoietic response to rhEPO. The role of hepcidin in the overall pathogenesis of ACD remains to be fully determined.
Molecular Basis of Congenital Dyserythropoietic Anemia Type I in French Patients.
Authors: Tamary Hannah , Dgany Orly , Proust Alexis , Krasnov Tanya , Avidan Nili , Tchernia Gil , Geneviève David , Comier-Darre Valérie , Le Merrer Martine , Bader-Meunier Brigitte , Ferrero-Vacher Corinne , Yaniv Isaac , Delaunay Jean 
Published: October 2019

Abstract
Congenital dyserythropoietic anemia type I (CDA I) is an inherited disorder characterized by macrocytic anemia and occasionally also by distal bone malformations. The disease has recently been shown to be caused by mutations in the CDAN1 gene, encoding codanin-1. The aim of the study was to characterize the CDAN1 mutations in 12 French patients with CDA I. The clinical data of the 12 French patients (10 kindreds) with CDA I were reviewed. Each of the 28 CDAN1 exons was amplified and sequenced. Half of the patients had a severe disease with prominent neonatal manifestations, complex bone disease, or both. Nine disease-causing mutations were identified: 6 described previously (P1130L, P671L, F869I, R681X, R713W, S1034F) and 3 novel mutations (R687W, F52L and IVS 8 G to A). Seven were missense mutations located in exons 14 to 28. Twenty seven per cent were identified in exon 14. No patient was homozygous for null type mutations. Only in two monozygotic twin patients did we fail to uncover a mutation. Mutations P671L, F52L and R713W were found on four, two and two alleles, respectively. One of the P671L alleles carried a second mutation (R687W). In conclusion the CDAN1 gene is apparently involved in most cases of CDA I in the French patients explored. Our study supports the previous findings that homozygosity for the null type mutations may be lethal, and that CDAN1 mutations are localized mainly in exons 12–28. In the present small group of patients, no apparent phenotype-genotype correlations were observed, in particular concerning abnormalities of the bones. Analysis of a larger number of patients from different ethnic groups is required to further characterize phenotype-genotype correlation in CDA I.
Quantity and Functional Changes of Subsets of Th Cells in the Bone Marrow of Severe Aplastic Anemia Patients.
Authors: He Guangsheng , Shao Zhonghong , Wu De Pei , Ma Xiao , Sun Aining 
Published: October 2019

Abstract
Objective To evaluate the quantity and functional changes of subsets of Th cells in the bone marrow of severe aplastic anemia (SAA) patients and the relationship between these changes and the patient hematopoietic function.
Methods By FACS, the quantity and ratio of Th1 cells and Th2 cells, the percentage of CD3+CD8+ cells in the bone marrow were detected in 24 patients with SAA at active phase, 15 patients with SAA at recovery phase, and 16 normal controls respectively. By radioimmunoassay, the levels of cytokines of Th1 type (TNF-α), or Th2 type (IL-4) in the serum of 20 patients with SAA at active phase, 12 patients with SAA at recovery phase, 16 normal controls were measured respectively. The relationships between CD3+CD8+ cells, TNF-α and Ret, ANC were evaluated; the relationships between Th1 cells and CD3+CD8+ cells, TNF-α or Ret, ANC were evaluated; the relationships between IL-4, balance of Th1/Th2 and Ret, ANC were also evaluated.
Results The percent of Th1 cells, Th2 cells, and ratio of Th1/Th2 in bone marrow of patients with SAA at active phase was: 4.87±2.64%, 0.41±0.26%, 21.22±5.07, were higher than those of normal controls: 0.42±0.30% (p<0.01), 0.24±0.17% (p<0.05), 1.57±0.93(p<0.01) respectively, and all of these decreased to normal levels at recovery phase (p>0.05); the percent of CD3+CD8+ cells decreased from 32.32±18.69% at active phase to 13.76±2.96% at recovery phase significantly (p<0.01); the serum levels of TNF-α, IL-4 at active phase was 4.29±3.15ng/ml and 1.24±0.73 ng/ml respectively, higher than those of normal controls(1.21±1.16 ng/ml, 1.18±0.97 ng/ml), but only the difference of TNF-α was significant (p<0.01); in recovery SAA patients, the serum levels of TNF-α significantly decreased to 1.46±1.41 ng/ml (p<0.01), and the levels of IL-4 increased continually markedly to 3.05±1.94 ng/ml; the CD3+CD8+ cells and TNF-α of patients correlated with Ret (p<0.05;p<0.05) and ANC (p<0.05;p<0.05) negatively, Th1 cells correlated with CD3+CD8+ cells and TNF-α positively (p<0.01;p<0.05), the Ret and ANC negatively(p<0.01;p<0.01), IL-4 and the balance of Th1/Th2 correlated with Ret and ANC positively (p<0.05;p<0.01) (p<0.01;p<0.01).
Conclusion The formation of bone marrow failure in SAA might be caused not only by the increase of Th1 cells, Th1 type effective cells and cytokines, but also by unsufficient compensation of Th2 cells and Th2 type cytokines, which shifted the balance of Th1/Th2 to Th1.
Transcranial Doppler in Sickle Cell Anemia Adult Patients: Brazilian Experience.
Authors: Silva Gisele S. , Figueiredo Maria S. , Vicari Perla , Massaro Airton R. , Filho Adauto Castelo , Gabbai Allan A. , Bordin Jose Orlando 
Published: October 2019

Abstract
Sickle cell anemia (SCA) may cause a variety of neurological complications, including stroke and headaches. Stroke occurs in up to 9% of children with SCA, and transcranial Doppler (TCD) studies have demonstrated that increased velocities are related to higher stroke risk. Throbbing headache occurs in SCA but its cause, frequency, and relationship to TCD velocities have received little attention. On the other hand, there are few TCD studies in adult patients. Our aims were: 1) to describe the main features of TCD in adult SCA patients, and 2) to investigate if there were correlation between TCD features and presence of headache. TCD was performed in 56 adult SCA patients (≥ 16 years old) and in 56 healthy individuals (HI), matched by age and race. There were 6 patients with a remote history of stroke but none were on chronic transfusion. The SCA group was submitted to a neurological evaluation and specifically asked about the occurrence of headache and its characteristics. The highest flow velocity (maxFV) recorded for each artery was considered the most representative. We analyzed the frequency of FV asymmetry (side-to-side difference > 20%) and focal FV changes. The mean maxFV was significantly higher in patients (117.7 ± 21.6 cm/s) than in HI (72.45 ± 11.48 cm/s) (p<0.005). Only one patient had maxFV higher than 170 cm/s. The frequencies of asymmetry and of focal FV changes were significantly higher in SCA. Forty-one patients (73.2%) reported having headaches. Twenty-eight patients (50%) had severe (= 5 for pain intensity at a 1–10 scale) and frequent headaches (at least once a month). This group of patients presented TCD velocities significantly higher than patients without or with milder headaches (p=0.035). In conclusion, TCD maxFV was significantly higher in adult patients with SCA than HI, however, only one patient was considered at risk of stroke according to TCD criteria described in children. FV asymmetry and focal FV changes may be markers for arterial disease in adult SCA patients, and need to be further confirmed by neuroimaging and clinical follow up studies. The patients with severe headaches presented TCD velocities significantly higher than patients without or with milder headaches, but this finding needs to be confirmed by more and larger studies.
Global Gene Expression Profile of Human Bone Marrow before and after Hydroxyurea Administration in Sickle Cell Anemia.
Authors: Costa Flavia C. , Cunha Anderson F. , Fattori Andre , Peres Tarcisio S. , Costa Gustavo G.L. , Saad Sara T.O. , Costa Fernando F. 
Published: October 2019

Abstract
The levels of HbF in sickle cell disease (SCD) can be increased by pharmacological agents such as hydroxyurea (HU), which has been shown to reduce the frequency of pain crises, hospitalizations and acute chest events requiring blood transfusions in adults with SCD. However, there is some evidence to suggest that some SCD patients show benefits from HU treatment without increase in their HbF levels. Thus, the molecular mechanism by which HU increases HbF levels and improves the clinical evolution in SCD remains unclear. This study aims to provide the global gene profile of human bone marrow of a homozygous patient three months before beginning treatment and after the initial administration of HU and to investigate groups of differentially expressed genes that could be involved in the pathways by which HU improves the clinical evolution in SCD. Using the Serial Analysis of Gene Expression (SAGE) technique, two libraries, before HU administration (HbS profile) and after HU administration (HbSHU) were performed. A total of 47.192 and 46.697 tags were analyzed for the HbS and HbSHU profiles and represented 15.735 and 15.901 distinct tags, respectively. Among these, 4.151 and 3.817 tags were no match tags that could represent new genes that remain to be identified. When both profiles were compared, 518 transcripts were determined to have statistically significant differential levels of expression (P value < 0.05). The functional annotation of transcripts, according to the Gene Ontology Consortium, showed that the categories of binding and structural molecule activity were up-regulated following HU treatment. For example, genes associated with nucleic acid binding such as Signal Transducer and Activator of Transcription 5 A, v-fos FBJ murine osteosarcoma viral oncogene homolog, Early Growth Response 1 and several ribosomal and zinc finger proteins were induced by HU treatment. Conversely, the transporter activity category was down regulated by HU treatment. Genes associated with oxygen transporter activity and other genes associated with ion binding, like S100 calcium binding protein A8 (calgranulin A) and transferrin were found to be down regulated by HU treatment. Taken together, these results strongly suggest that HU produces a significant change in the expression of bone marrow cells. Future studies of these described genes that are differentially expressed during HU treatment may contribute to further the understanding of the mechanism by which HbF acts in SCD and improves the clinical evolution of the disease. The description of new genes involved in these pathways may also represent a potential tool to identify new targets for the therapy of SCD.
Study on Hepatitis C Treatment Using Ribavirin and Pegylated Interferon in Thalassemia Patients (SCRIPT): One Year Report.
Authors: Inati Adlette , Sharara Ala , Ghorra Sandy , Aoun Elie , Taha Marwan , Koussa Suzanne , Taher Ali 
Published: October 2019

Abstract
BACKGROUND: Treatment of thalassemia patients with HCV using combination interferon and ribavirin is limited to few case series.
DESIGN: Multicenter randomized single-blinded trial comparing PEG-IFN a-2a +/− ribavirin in thalassemia major patients with chronic HCV.
METHODS: 20 patients with HCV genotypes 1 and 4 were randomized into Group A (PEG-IFN 180 mg SC once weekly) and B [PEG-IFN and ribavirin (≥10.6 mg/kg/d)] for 48 weeks. Baseline studies included liver biopsy (histology and iron concentration), quantitative PCR, and HCV genotyping. The primary end point was a SVR 24 weeks post-treatment. Secondary end points were transfusion requirements, EVR, ETR, and biochemical response.
RESULTS: Baseline characteristics of both groups were comparable. The mean age was 21.6 ± 11 years in group A and 16.5 ± 3.9 in group B. Fibrosis grade >1 was present in 42% in group A and 50 % in group B. Mean viral load was 137,570 IU/ml and 178,087 IU/ml respectively. Genotype 1 was found in 66% in group A and 87% in group B. EVR occurred in 8/12 in group A and 6/8 in group B (67 and 75% respectively). ETR was observed in 7/12 in group A and 6/8 in group B (59.3% and 75% respectively). Transfusion requirements increased by 55% in group B versus 21% in group A (p=0.08). Adverse events were not significantly different between treatment groups.
CONCLUSIONS: This interim report suggests that combination PEG-IFN and ribavirin is effective at achieving ETR in thalassemics, is associated with an increase in transfusion requirements but no other significant side effects. Additional follow up and patient recruitment is needed to evaluate long term safety and sustained viral response.
HB Florida: A New Elongated C-Terminal β-Globin Variant Causing Dominant β-Thalassemia.
Authors: Sonati Maria F. , Weinstein Beatriz I. , Erramouspe Beatriz , Albuquerque Dulcineia M. , Kimura Elza M. , Oliveira Denise M. , Costa Fernando F. 
Published: October 2019

Abstract
An elongated C-terminal β-globin variant, due to the deletion of one nucleotide (-C) in between codons 140/141 (GCC/CTG→GCC/TG), which modified the C-terminal sequence and added 10 more residues to the β-chain [(141)Trp-Pro-Thr-Ser-Ile-Thr-Lys-Leu-Ala-Phe-Leu-Leu-Ser-Asn-Phe-(156)Tyr-COOH], was found in an 8-year-old Argentine girl of Spanish descent with clinical picture of β-thalassemia intermedia. The patient presented chronic moderate hemolytic anemia (RBC=3.8x10¹²/L, Hb=8.6 g/dL, Hct=28%), with pallor, jaundice and liver and spleen enlargement, having required blood transfusion for 5 times, during viral and bacterial infections; peripheral blood analysis revealed a remarkable degree of anisocytosis with microcytosis (RDW=28%, MCV=73.0 fl), poikilocytosis (with ovalocytes and schistocytes), hypochromia (MCH=22.6pg), 13% of reticulocytes and 2% of erythroblasts, punctate basophilia, elevated Hb A2 and Hb F levels (5% and 13%, respectively), without any detectable abnormal Hb (Hb and globin chain electrophoreses/HPLC). Tests for unstable hemoglobins were weakly positive, but the staining of the bone marrow cells with methyl violet allowed the visualization of many inclusion bodies, suggesting that this is probably a hyperunstable variant whose proteolysis in the bone marrow precursors results in dominant β-thalassemia phenotype, since the other β-locus showed no alteration. Mother’s carrier was completely normal and the father, although not available for studying, was also probably normal.
Pegfilgastrim in Autoimmune Neutrophenia.
Authors: Hopkins Tamara V. , Floyd Justin D. , Mirza Irfan A. , Lobins Raymond L. , Bashir Qaiser , Shahab Nasir 
Published: October 2019

Abstract
A 50-year-old Caucasian male with chronic renal failure with two failed cadavaric kidney transplants was evaluated after multiple admissions for life-threatening febrile neutropenia. The absolute neutrophil counts (ANC) had ranged from 165–988/mm3 in the previous year. No cause was identified. A bone marrow aspirate revealed normal trilineage hematopoiesis without dysplasia and cytogenetic analysis demonstrated 46 XY. Core biopsy revealed adequate cellularity. A blood antineutrophil antibody test was positive confirming a diagnosis of autoimmune neutropenia (AIN). Treatment with prednisone was initiated. Although the patient responded to prednisone (100mg/day), evidenced by the ANC increasing to 5544/mm3, he developed massive shifts in weight secondary to fluid retention which complicated dialysis. Additionally he had mild to moderate steroid induced psychosis and sleep disturbances. Attempts at decreasing the dose of prednisone resulted in a decrease in the ANC as well. Therefore, treatment with filgastrim at 300 mcg SQ daily was initiated. The ANC rapidly increased from 571 to 16,578/mm3. Treatment was then switched to pegfilgastrim 6 mg SQ every 3 weeks for ease of administration. An initial ANC increase to 16,000/mm3 was noted; however, by week 3 the ANC had decreased to 448mm3. As a result, the treatment schedule was changed to pegfilgastrim 6 mg SQ every 2 weeks. Since this adjustment, the ANC has consistently ranged from 1500–20,000/mm3. Additionally, there have been no other infections. Pegfilgastrim has already been shown to be as effective as filgastrim in cancer chemotherapy patients, providing a more convenient and tolerable alternative to filgastrim. To date there have been no documented uses of pegfilgastrim in AIN patients. It is logical to assume that pegfilgastrim would have similar efficacy in AIN as well. It was this assumption that first lead to its use in our patient. However, dosing every two weeks rather than the standard every 3 weeks was necessary to achieve the desired effect.
Extracellular Nucleotide UTP Regulate Lipopolisaccharide-Induced Cytokine Production in Human Neutrophils.
Authors: Garcia Analia E. , Tuluc Florin , Meshki John , Bredetean Ovidiu , Kunapuli Satya P. 
Published: October 2019

Abstract
Extracellular nucleotides can function as paracrine and autocrine mediators that signal through P2Y nucleotide receptors. Human polymorphonuclear (PMN) cells express P2Y receptors on the cell surface but the role of these G protein-coupled receptors in human neutrophils is not well established. Interleukin-8 (IL-8), which is a CXC-chemokine that induces adherence of neutrophils to vascular endothelium and extravasation into tissue, is produced by macrophages and endothelium. Additionally, neutrophils can synthesize and release interleukin-8 upon stimulation with lipopolisacharides (LPS) but the intracellular signaling pathways involved in this process are not clearly understood. LPS is a potent activator of macrophages and is responsible for the initiation the septic shock, increasing the secretion of various cytokines. Here we present evidence that LPS (1 ng/ml to 100 ng/ml) causes IL-8 production in a dose- and time- dependent manner and demonstrate that LPS itself is responsible for mitogen-activated protein kinase (MAPK) ERK1/2 phosphorylation. We used an enzyme immunosorbent-linked assay (ELISA) to determinate the amount of IL-8 released by isolated human neutrophils and present evidence that extracellular nucleotide uridine triphosphate (UTP) (1 μM/ml to 100 μM/ml) can inhibit IL-8 production in human neutrophils in a dose- and time- dependent manner. The addition of ATP had a similar inhibitory effect suggesting that nucleotides act on neutrophils via the P2Y2 receptor, which is equally activated by UTP and ATP. A cytokine array was used to detect the release of 42 different cytokines in the extracellular medium. IL-8 and IL-6 ere the major cytokines detected in the medium, though other cytokines were detected in lower concentrations. In the current study, we demonstrated that extracellular nucleotides may have an important role in regulating IL-8 production in neutrophils and potentially modulating the inflammatory response.
The Role of Serum Procalcitonin and Interleukin-6 in the Differentiation and Surveillance of Sepsis and Non-Infectious Systemic Inflammatory Response Syndrome.
Authors: Liu Xiaoli , Du Bin , Pan Jiaqi , Hua Baolai 
Published: October 2019

Abstract
To evaluate the discrimination of serum procalcitonin (PCT) and interleukin-6 (IL-6) between patients with sepsis and non-infectious inflammatory response syndrome (SIRS) and the pridicton power of clinical outcome, a perspective study was performed in 27 patients with sepsis and 30 patients with non-infectious SIRS. The serum concentrations of PCT, IL-6, and C-reactive protein (CRP), white blood cell count, percentage of neutrophil, and maximal body temperature were obtained less than 24 hours after clinical onset of SIRS. The serum levels of PCT and IL-6, and percentage of neutrophil were significantly higher in patients of sepsis than in those of SIRS (PCT 5.54 [1.20, 32.74] μg/L vs 0.77 [0.22, 3.90] μg/L, P=0.001; IL-6 163.66 [33.60, 505.26] ng/L vs 37.72 [22.52,110.78] ng/L, P=0.004; CRP 15.28±8.41 g/L vs 9.51±7.65 g/L, P=0.010; and percentage of neutrophil 91%±4% vs 88%±4%, P=0.010). Receiver operating characteristic curves showed that the power of PCT and IL-6 were the best of all above. There was significant correlation between serum concentrations of PCT or IL-6 and the APACHE II or SOFA score, so was between serum PCT concentration and the ICU length of stay. Serum concentrations of PCT and IL-6 are more reliable indicators to differentiate sepsis and non-infectious SIRS than the conventional inflammatory markers, and correlate with the disease severity. And PCT levels were significantly correlated with ICU length of stay. (Supported by research grants from PUMCH, China)