bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enalapril Therapy Prevents Cardiac Remodelling of Sickle Cell Disease Patients.
Authors: Saad Sara T. , Lima Carmen S. Passos , Ueti Osvaldo M. , Ueti Adriana A. , Franchini Kleber G. , Costa Fernando F. 
Published: October 2019

Abstract
Angiotensin-converting enzyme (ACE) inhibitors are capable of decreasing cardiac remodelling in patients with cardiac dysfunction, however their effects on sickle cell disease (SCD) are unknown. Thus, this study aimed to investigate the cardiac effects of enalapril on SCD patients. Thirteen adult patients with sickle cell disease (SCD) and microalbuminuria (3M/10F); 11 sickle cell anemia patients (SCA), 1 Sβ thalassemia patient (Sβ) and 1 patient with hemoglobin SC (SC) were treated with enalapril. Thirteen other SCD patients (4M/9F) without microalbuminuria, matched according to age, diagnosis (11 SCA, 1 Sβ and 1 SC), and levels of hemoglobin, hematocrit and fetal hemoglobin, did not receive enalapril and were followed up as the control group in the same period of study. In the treated group, enalapril (5mg) was administered to 9 SCD patients during the entire study period. One patient did not complete follow-up, and higher doses (7.5mg to 20mg) were administered to 3 patients who developed systolic BP over 120 mmHg during the study period. Median age (28.5 vs 29.0; P= 0.580), baseline values of hemoglobin (8.5 vs 8.4g/dL, P= 0.600), hematocrit (25.0 vs 23.5%, P= 0.500), fetal hemoglobin (4.4 vs 4.1%, P=0.720) and mean blood pressure (MBP; 80 vs 93mmHg, P= 0.13) were similar in treated and untreated patients Echocardiograms were performed before the study entry and once a year in patients and controls. Comparisons of groups were performed at the beginning of the study and after 36 months of follow-up using the Wilcoxon-signed rank test and Spearman coefficient. At 36 months of follow-up, MBP was lower than the baseline value (93 mmHg vs 87 mmHg, P= 0.018) in the treated group. Significant increases in left ventricular mass (192 vs 231g, P= 0.005), posterior left ventricular wall thickness in end-diastole (8.5 vs 10.0mm, P= 0.013), left ventricular mass index (114.4 vs 131g/m2, P= 0.043), interventricular septal wall thickness in end-diastole (9.0 vs 9.5mm, P= 0.036) and aortic root dimension (28 vs 32mm, P= 0.009) values were seen in untreated, but not in enalapril treated patients. No major changes were seen in left ventricular ejection fraction, left ventricular systolic diameter, left ventricular diastolic dimension and left atrial diameter, in both groups, along the observational period. No significant correlation was detected between the data here presented. At the end of the study, no symptoms or signals related to cardiac failure were found in any of the enrolled patients. These results indicate a trend toward cardiac and aortic root remodeling in untreated SCD patients and suggest that long-term treatment with ACE inhibitors has beneficial effects on the cardiac remodeling of SCD patients and could be indicated for adult patients, if an increase in baseline blood pressure occurs.
A New Sequence Change in the Hs2-Lcr (G→A − 10.677) and Gg-Globin Gene Promoter Region (T→C − 157 and a 4 Bp Deletion − 222 to − 225) in Sickle Cell Anemia Patients with Fetal Hemoglobin Level and bS-Globin Gene Haplotypes Diversity.
Authors: Adorno Elisangela V. , Neto Jose P. Moura , Lyra Isa , Zanette Angela D. , Santos Leandro F. , Seixas Magda O. , Reis Mitermayer G. , Costa Fernando F. , Goncalves Marilda S. 
Published: October 2019

Abstract
The sickle cell anemia has a very high prevalence in Bahia, a state of Brazil. The HbF levels and bS-globin gene haplotypes of 125 sickle cell anemia patients were investigated and the Gγ and Aγ gene promoter and HS2-LCR regions of ten patients were selected for DNA sequence. The study was approved by the Oswaldo Cruz Research Foundation’s human research ethics committee. The bS- globin gene haplotypes were investigated using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques; the HbF levels were estimated by high performance liquid chromatography (HPLC). The Gg and Ag-globin gene promoter and HS2-LCR regions were sequenced in an automatic sequencer. The distribution of bS- globin gene haplotypes showed 64 (51.2%) patients with genotype CAR/Ben; 36 (28.8%) Ben/Ben; 18 (14.4%) CAR/CAR; two (1.6%) CAR/Aty; two (1.6%) Ben/Cam; one (0.8%) Car/Cam; one (0.8%) CAR/Arab-India and one (0.8%) Sen/Aty. Among these patients, four CAR/CAR had HbF ≥10.0%; three Ben/Ben had HbF ≤ 5.0%; 11 CAR/Ben had HbF ≥15.0% and 18 had HbF ≤ 5.0%; two Cam/Ben patients had HbF levels ≥15.0%. Ten individuals presenting HbF and bS-globin gene haplotypes diversity were selected to sequence the Gg and Ag-globin gene promoter and HS2-LCR regions. The HS2-LCR sequence analyses demonstrated a G→A change (−10.677) (GeneBank DQ873522) in five sickle cell anemia patients with Ben haplotype and high HbF levels (Table 1); the CAR/Ben and Ben/Ben patients with low HbF levels did not have this sequence variation; among the small patient group investigated, there were two CAR/CAR patients with high HbF levels without this substitution. The Gg gene promoter sequence analyses showed a T→C substitution (−157) (GeneBank DQ873521) among all patients and a 4 bp deletion (−222 to −225) (GeneBank DQ873519) related to Cam haplotype (Figure 1). The HS2-LCR sequence change reported here is located in the proximity to a binding site of the GATA-1 and a ubiquitous trans-acting factor and can constitute a motif associated to the Ben chromosome and may play an important role in g-globin gene transcription regulation. The polymorphic site on Gg-globin gene promoter region can be a common sequence characteristic among the Brazilian sickle cell anemia patients. The results described here suggest new polymorphisms in the HS2-LCR and Gg gene promoter and confirms the genotypic heterogeneity among Brazilian sickle cell anemia patients, justifying further studies to investigate its correlation with HbF synthesis and clinical profile in sickle cell anemia patients.
Figure Figure
Correlation between Dose-Dependent Reductions in Serum Transaminase (ALT) and Serum Ferritin Levels during Long-Term Chelation Therapy with Deferasirox (Exjade®, ICL670).
Authors: Brissot P. , Deugnier Y. , Cianciulli P. , Cario H. , Jeng M. , Rabault B. 
Published: October 2019

Abstract
Introduction: Hepatic siderosis, a result of chronic transfusion therapy, leads to hepatocellular injury and progression to chronic liver disease. Increases in serum transaminase levels are indicative of progressive liver damage. The effect of deferasirox (Exjade®, ICL670), a novel, once-daily oral chelator, on liver iron content and pathology in chronically transfused patients has been assessed in Phase II and III clinical studies. A sub-analysis of pooled data from the planned 4-year extension of two pivotal studies sought to correlate the long-term changes in serum ALT levels with those of serum ferritin in iron-overloaded patients during treatment with deferasirox.
Methods: In these two clinical studies, 480 patients with β-thalassemia (β-thal), myelodysplastic syndromes (MDS), Diamond-Blackfan anemia (DBA), and other transfusion-dependent anemias received deferasirox at 5, 10, 20 or 30 mg/kg/day according to baseline liver iron concentrations for 12 months. In the extension phases, doses were titrated according to patient response, with dose escalation for patients who did not receive sufficient drug in the core study to reduce iron burden. Serum ferritin and ALT levels were assessed at baseline and monthly during the core and extension phases. For this analysis, serum ferritin and ALT levels were analyzed in the combined patient groups who received deferasirox 5 and 10 mg/kg/day, and in those who received 20 and 30 mg/kg/day.
Results: Throughout the entire period, deferasirox at 20 and 30 mg/kg/day resulted in a negative iron balance in transfused patients with secondary iron overload. Changes from baseline to week 128 (2.5 years) for serum ferritin and ALT levels are presented. The figure shows that deferasirox at 20 and 30 mg/kg/day decreased median serum ferritin. These decreases were mirrored by decreases in ALT, with a Spearman’s rank-correlation 0.67. Patient numbers shown are baseline/week 128. A number of patients had not reached week 128 of treatment at the time of data cut-off.
Figure Figure
Decreases in ALT were also observed after dose escalation in the extension phase in patients originally assigned deferasirox 5 and 10 mg/kg/day. There were no consistent relevant changes in other biochemical liver parameters, such as serum aspartate transaminase, in this patient population.
Conclusions: With long-term follow-up of this large patient population, correlation between decreases in serum ferritin and ALT levels was high, indicating an association between iron burden and liver dysfunction, and further emphasizing the potential beneficial effect of deferasirox on hepatic function.
Thrombogenicity of Microparticles Derived from Vascular Cells.
Authors: Isobe Hirotaka , Perkmann Thomas , Oskolkova Olga , Bochkov Valeri , Binder Bernd R. 
Published: October 2019

Abstract
Microparticles (MPs) are released from cells during processes such as apoptosis or during cell activation. These MPs contain phospholipids, proteins and even nucleic acids derived from their parent cells. They are found circulating in plasma but also in tissues such as atherosclerotic plaques. It is thought that MPs contain and transfer tissue factor and can thereby induce blood clotting.
In this study we analyzed clot promoting properties of MPs generated from vascular cells in vitro. MPs were generated from endothelial cells (EC), smooth muscles cells (SMC), monocytes (U937), erythrocytes (RBC) or platelets (Pl) by inducing apoptosis or by calcium ionophore activation; they were subsequently isolated by differential centrifugation. Thrombogenicity of the MPs was evaluated using a thrombin generation assay (Technothrombin® TGA) and MP free plasma as substrate. MPs displayed a different thrombin generating potential depending on the parent cells. MPs derived from RBCs (~400nM peak thrombin/105 MPs/ml plasma), ECs (~300nM), SMCs (~300nM) and Pls (~300nM) were more thrombogenic than MPs derived from U937 (~200 nM). In addition EC, SMC and U937 MPs all expressed tissue factor but EC MPs induced thrombin generation in a tissue factor and FVII independent manner. EC MPs even expressed active tissue factor pathway inhibitor and functionally inhibited tissue factor dependent thrombin generation. Since the higher thrombin generation induced by MPs derived from EC as compared U937 derived MPs could not be explained by a different activity of tissue factor, we were interested whether lipids contained in the microparticles could account for the differences in thrombin generation. We therefore analyzed thrombin generation induced by lipids isolated from MPs and parent cells and could show that lipids from EC MPs and SMC MPs exhibited higher thrombin generation than those from U937 MPs. Upon analysis of lipids by thin layer chromatography and mass spectrometry we found that in general microparticles are enriched in cholesterol, sphingomyeline and phosphatidylserine over the parent cells and that EC and SMC MPs were enriched in negatively charged phospholipids (different species of phosphatidylserine and phosphatiylglycerol) as compared to MPs derived from U937 cells. When thrombogenicity was, however, evaluated in vivo by injecting MPs into mice it was found that the highest capability to induce thrombin-antithrombin (TAT) complexes had MPs derived from SMCs; also U937 MPs induced an increase in TAT levels, while EC MPs – although more thrombogenic than U937 MPs in vitro – did not induce TAT complex formation by themselves but were only synergistic in vivo.
From these data we conclude that thrombin formation in vivo depends on the initiation of the tissue factor FVII pathway, while the extent of thrombin formation is dependent on negatively charged phospholipids contained to a higher extent in MPs derived e.g. from ECs.
S-MRI Score as a Simple Method To Assess Bone Marrow Involvement in Gaucher Disease.
Authors: Roca Mercedes , Mota Juan , Alfonso Pilar , Giralt Manuel , Pocovi Miguel , Giraldo Pilar 
Published: October 2019

Abstract
Background: Semiquantitative MRI is a very useful procedure to evaluate the bone marrow burden in Gaucher disease (GD). Score systems have been applied to obtain a parameter to evaluate the severity of bone disease. Our purpose was applied a simple, reproducible and accurate score to evaluate completely bone marrow involvement in GD patients
Patients and Methods: MRI was performed in spine, pelvis and femora at diagnosis in 54 adult consecutively diagnosed as GD1, 61.1% females. Three MRI patterns and punctuation in each location were defined: normal: 0; non-homogeneous infiltration subtypes reticular:
mottled: diffuse: and homogeneous infiltration: This score was called as Spanish-MRI (S-MRI):
Two independent observers applied the S-MRI and Bone Marrow Burden (BMB) score and to compare the differences between both systems by using non parametric Mann-Whitney test. Correlation rank test was calculated.
Results: In 46 patients (85.2%) bone involvement was observed, 39 (72.3%) has spine affected, 35 (64.8%) pelvis and 33 (61.2%) femorae, 14 patients had bone infarcts, 14 avascular necrosis, 2 vertebral fracture and 2 bone crisis. Correlation analysis between S-MRI and BMB was significant (r2:.675; p= .0001). No evidence of correlation was observed between CT activity and S-MRI and neither between CT activity and BMB. We have analysed the relationship between the patient genotype and bone infiltration according S-MRI, the location and complications. Patients with genotype N370S/rare allele (n=22), have more bone complications (90.1%) Infarcts: 9; AVN: 8, Bone crisis: 2; and vertebral fracture: 1. The mean S-MRI in this group was 7.9. Patients N370S/L444P (n=16) were the higher group with spine involvement (87.5%) mean S-MRI: 8.7. By contrast all patients homozygous for N370S (n=8), have femorae involvement, but a low S-MRI 7.5. The remaining 5 patients have complex genotypes (rare/rare), nevertheless they are not significant data(p=.335, p=.795)
Conclusions: S-MRI is a simple method that provides useful information to evaluate bone infiltration and detect silent complications. Our results were correlated with the BMB score with higher sensitivity and specificity and provide accuracy to classify the degrees of the bone disease
This work has been performed with the collaboration of the Spanish Group on Gaucher Disease and partially sponsored by a grant from FEETEG.
Toll-Like Receptor 2 Signalling Regulates Oxidative Burst of Human Neutrophils, but Not Cytokine Response of Dendritic Cells after Contact with Aspergillus fumigatus.
Authors: Loeffler Juergen , Mezger Markus , Wozniok Iwona , Kurzai Oliver , Einsele Hermann 
Published: October 2019

Abstract
Toll-like receptors (TLRs) play a crucial role for detecting conserved pathogen-associated molecular patterns comprising fungal structures. Activation of polymorphonuclear granulocytes (PMNs) as well as mobilization of antigen presenting cells is important for successful clearance of fungal infections. Here, the role of TLR2 and TLR4 for activation of PMNs and immature dendritic cells (iDCs) through Aspergillus fumigatus was analyzed.
Generation of iDCs was achieved by cultivating monocytes in the presence of GM-CSF and IL-4. PMNs were obtained from fresh blood. In blocking studies, cells were preincubated with anti-TLR2 and / or anti-TLR4 antibody before stimulation with Aspergillus fumigatus germinating conidia. For RNA interference (RNAi) experiments, iDCs were transfected with short-interfering RNA (siRNA) via electroporation and gene expression was controlled by quantitative real-time PCR.
Oxidative burst of PMNs was induced after contact with Aspergillus or TLR2 ligand zymosan. Release of oxygen intermediates could be significantly reduced if PMNs were preincubated with anti-TLR2 antibody.
In contrast to monocytes, cytokine secretion (IL-12 and TNF-α) of iDCs was not altered if anti-TLR antibodies were used. To study the role of TLR2 and TLR4 more detailed, an RNAi system for iDCs was established to downregulate gene expression. Determination of siRNA transfection rate revealed an efficiency of about 85% and allowed significant downregulation of TLR2 and TLR4 (> 90%). In accordance to blocking studies, expression of IL-10, IL-12 and TNF-a was not reduced after TLR2 or TLR4 siRNA transfection and stimulation with Aspergillus.
We conclude that TLR2 plays an important role in the induction of the oxidative burst of PMNs whereas cytokine release of iDCs seems to be independent of TLR2 / TLR4 signalling. The established siRNA system allows the detection of receptors responsible for activation of iDCs.
The Acute-Phase Protein Serum Amyloid A Induces G-CSF Expression.
Authors: He Rong , Zhou Jian , Ye Richard D. 
Published: October 2019

Abstract
Host response to injury and infection is accompanied by a rapid rise of acute-phase proteins in the blood. Serum amyloid A (SAA) is a major acute-phase protein, and has been used as a marker for inflammatory diseases. However, its precise role in inflammation has not been defined. In our previous study, we found that SAA can induce IL-8 and TNF-alpha secretion from peripheral blood neutrophils, which indicates that SAA has cytokine-like functions. We have also identified SAA as an endogenous ligand that induces the expression of interleukin-23 (IL-23), a hetero-dimeric cytokine that promotes autoimmune inflammation. In this study, we reported that SAA stimulates monocytes to secret granulocyte colony-stimulated factor (G-CSF), a cytokine and a major hematopoietic growth factor. Injection of SAA into mouse peritoneum significantly increases the number of neutrophils in both peritoneal cavity and blood circulation. These results suggest that SAA can induce granulocytosis during infection and inflammation. We hypothesize that during the inflammation, locally or systematically produced SAA can increase the number of neutrophils in blood circulation and recruits them to injured or infected sites through induction of G-CSF.
Evaluation of Ethnic Differences in Mannose-Binding Lectin (MBL) Level or MBL Genotype.
Authors: Buchbinder Aby , Basile Thomas , Ding Cliff , Hester Jeff , Yu Jing , Eckhardt Thomas , Conover Charles , Horak Ivan 
Published: October 2019

Abstract
Background: MBL is a natural human plasma protein that plays an important role in the humoral innate immune defense. MBL specifically recognizes a broad range of microorganisms, including bacteria, fungi, viruses, and parasites, by binding to common carbohydrate structures located on their surfaces and activating the lectin pathway of complement. The concentration of MBL in plasma is largely genetically determined and ranges from 5 to 10,000 ng/mL. Deficiency is caused by mutations within the mbl2 gene or its promoter region. Individuals heterozygous (A/O) and homozygous (O/O) for these mutations display a reduced level of MBL in plasma. Low levels of MBL have been associated with increased risk of serious infection in situations in which other components of the immune system are compromised. Studies in patients with hematologic malignancies undergoing chemotherapy suggest that low MBL levels or variant MBL genotypes (A/O or O/O) are correlated with infectious complications of chemotherapy and/or duration of febrile neutropenia. The effect of ethnicity on MBL level and genotype was examined as part of the development of recombinant human MBL (rhMBL), a novel molecule that is entering clinical trials.
Methods: The plasma MBL level (protein concentration) and MBL genotype of 80 healthy volunteers were determined by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR), respectively.
Results: No differences in MBL level or genotype were observed among the 3 ethnic groups (see table below). Overall, the plasma MBL level was <100 ng/mL for 10% of the volunteers and <300 ng/mL for 16%. Regarding MBL genotype, 4% had an O/O genotype and 34% had an A/O genotype.
Conclusions: The MBL level and genotype data from 80 healthy volunteers of different ethnic backgrounds were observed to be generally concordant. Further analyses in individuals with other ethnicities are ongoing.
MBL Level and MBL Genotype by Ethnicity White Black Hispanic Total (N=50) (N=15) (N=15) (N=80) n (%) n (%) n (%) n (%) MBL Level (ng/mL) <100 5 (10) 1 (7) 2 (13) 8 (10) 100 to <300 3 (6) 2 (13) 0 5 (6) ≥300 42 (84) 12 (80) 13 (87) 67 (84) MBL Genotype A/A 32 (64) 9 (60) 9 (60) 50 (63) A/O 16 (34) 6 (40) 5 (33) 27 (34) O/O 2 (4) 0 1 (7) 3 (4)
Effects of Protease Inhibiton and Proteasome, Soluble Interleukin-2-Receptor (sIL-2R) in Biclonal Gammopathy-Human Immunodeficiency Virus Patients (BG-HIV).
Authors: McPherson Eugene , Hazel E. , Tassy P. 
Published: October 2019

Abstract
Human immunodeficiency virus-1 (HIV-1) encodes for a protease required for the cleavage of the viral gag-pol polyprotein. HIV-1 protease inhibition (PI) has revolutionized HIV therapy. Recently the 20S proteasome has been shown to cleave the same sites as PI, therefore proteasome inhibition may contribute to some of the effects of PI independent of virus inhibition. Tumor cells of multiple myeloma have been shown to be heavily dependent proteasome regulated proteins for their growth and interaction with stromal cells. Nuclear factor-kb (NF-kb) a transcription factor is an important promoter of myeloma cell growth within bone marrow microenvironment by upregulating IL-6, CRP, VEGF and cell adhesion. We observe a 60+ yo female with HIV-myeloma (biclonal Gammopathy IgG- kappa, IgM-lambda with hypercoagulable state, hyperviscosity syndrome with epistaxis, CHF, fatiqueness, and HIV-1, CD4-728/cumm (22%) but a viral load > 100,000 copies/ml, M-protein IgG of 6.9g/L, IgM of >2 g/L, kappa and lambda (biclonality) respectively. C-reactive protein of 40 mg/dl. With ritonavir-based HAART over 12 weeks lead to over a 50% M-protein reduction and normalization of sIL-2R.
CONCLUSION: HIV-1 protease inhibitors-Ritonavir based therapy-HAART may modulate proteasome activity and cytokines in HIV-myeloma (biclonal gammopathy) patients independent of virus inhibition and reduce tumor mass burden with increase survival and QOL.