bluuebunny/crossref_metadata_2025_split huggingface dataset:
Helixate®Nexgen in the Treatment of Patients with Hemophilia A: A Long-Term Pharmacovigilance Surveillance.
Authors: Haertel Sabine , Zacharias Claudia , Brackmann Hans-Herrmann , Roland Zimmermann , Harald Lenk 
Published: October 2019

Abstract
Comprehensive large-scale pharmacovigilance surveillances are very effective tools to collect data on products in the post authorization period. The evaluation presented here was set up to assess the long-term efficacy, safety and tolerability of the recombinant FVIII concentrate, Helixate®NexGen (in the US: Helixate®FS). Sixty-five hemophilia centers in Germany, Austria, Italy, France, and Sweden are participating in this ongoing international project. Previously untreated (PUP) and previously treated patients (PTP) at any age suffering from hemophilia A treated with Helixate®NexGen were eligible for the surveillance. Based on the standard schedule preferred at the centers, patients are routinely screened every 3 to 12 months. At these visits, the following parameters, as used routinely for these patients, were documented (non-interventional design): overall clinical response, pharmacokinetics, occurrence of bleedings, adverse drug reactions including the incidence of inhibitors, other laboratory safety parameters, coagulation parameters, relevant concomitant diseases, and medication. To determine the level of exposure, treatment modalities with Helixate®NexGen, including average factor consumption per month and exposure days are recorded. One hundred and ten patients have been included into the investigation up to now; data from 104 patients were available for this interim analysis including 2 PUPs. The median age was 25 years (range: 8 months – 68 years). One patient suffered from mild, eleven from moderate, and 89 from severe hemophilia A; in three patients the information on severity was missing. Most of the patients were treated prophylactically (92%, at least one infusion per week). Exposure to Helixate®NexGen during the pharmacovigilance ranged between 5 and 703 days. A total of 112 bleedings were documented during the observation period, with a range of 0 to 20 bleedings per patient per year. Efficacy of Helixate®NexGen was assessed as good or excellent in 97% of all cases. There were no cases of inhibitor development during the 2-year observation period, especially no cases of inhibitors when patients were switched from products produced in Chinese hamster ovary (CHO) cells to Helixate®NexGen, which is produced in baby hamster kidney (BHK) cells. The good tolerability of Helixate®NexGen was further supported by the fact that there were no other relevant side effects documented. In summary this pharmacovigilance supports the good tolerability and good/excellent efficacy data of Helixate®NexGen.
Comparison of aPTT (Platelin LS®) and Dilute Russell’s Viper Venom (Viperquik LA Test®) for the Screening of Lupus Anticoagulant in Patients with Venous Thromboembolism.
Authors: Roprigues Celso A. , Martinez Aline A. , Morelli Vania M. , Silveira Raniely C. , Noguti Maria Aparecida E. , Lourenco Dayse M. 
Published: October 2019

Abstract
INTRODUCTION: To rule out the presence of LA antibodies, two or more assays that are sensitive to these antibodies must be negative. The dilute Russell’s Viper Venom Time (dRVVT) and the activated partial thromboplastin time (aPTT) using sensitive reagents have been employed to detect LA. The aim of this study was to assess the concordance level of aPTT using Platelin LS and dRVVT as screening tests to identify LA in patients with venous thromboembolism (VTE).
METHODS: 94 patients (58 women, 62%) with VTE were evaluated. The detection of circulating inhibitor with Platelin LS and dRVVT was based on a prolonged clotting time and a prolonged 1:1 mixture of sample plasma and normal pooled plasma. The confirmation of the phospholipid dependency was performed only with dRVVT.
RESULTS: Among the 94 patients, an abnormal test was found in 24 patients (26%) with aPTT and in 61 patients (65%) using dRVVT. After mixing tests, aPTT ratio remained long in 25% of patients with abnormal aPTT, and in 9.8% with long dRVVT. Five patients had a prolonged mixing study identified by both tests, which resulted in a substantial agreement between the two tests (Kappa= 0.78). Confirmatory tests for LA were positive in 5 out of the 6 patients with long dRVVT mixture, resulting in a prevalence of LA detected by dRVVT of 5.3%. The 5 patients with LA detected by dRVVT also had prolonged mixture with aPTT.
CONCLUSION: Our results indicate that aPTT with Platelin LS is highly associated with the presence of LA detected by dRVVT and may be suitable as a screening test for LA in patients with VTE.
Isolated, Idiopathic Splenic Vein Thrombosis, Presenting with Massive Lower GI Bleeding.
Authors: Agheli Aref , Arora Alka , Khalil Maged , Naik Seema , Dumlao Theresa , Steier William , Kalavar Madhumati 
Published: October 2019

Abstract
Isolated, also called idiopathic, splenic vein thrombosis (SVT) is a very rare clinical condition, which usually results in left-sided portal hypertension and isolated fundal varices. This syndrome is a rare cause of mostly upper, gastrointestinal bleeding. There are only a few hundreds of cases reported in the literature. Colonic varices are even much rarer, 0.07% post mortem autopsies, and 0.2% in a prospective large endoscopic trials. Pancreatic disorders, including malignancies are the most common underlying causes for SVT. Congenital aneurysm of the splenic vein is one of the theoretical explanations of the Isolated, Idiopathic SVT.
Case report: A 53 year old Caucasian female with history of hypertension, and no history of smoking or alcohol abuse, presented with chronic lower gastrointestinal bleeding. Upper endoscopy and flexible colonoscopy revealed perigastric varices without any source of acute bleeding. A bleeding scan demonstrated marked splenomegaly and source of bleeding from left colon. Mesenteric angiogram during venous phase showed splenic vein thrombosis and extensive perigastric varices. In addition, a single large left colonic varix from the lower pole of the spleen was identified as the source of bleeding. The patient was treated with splenic artery embolization with coils, followed by splenectomy, without any major complication. Coagulation studies 8 weeks after the procedure did not show any hypercoagulable state.
Conclusion: The Isolated, Idiopathic SVT, itself is a very rare syndrome. Our center has reported four cases of SVT, secondary to medical conditions, such as; pancreatic malignancy, MRSA sepsis, and multi-organ failure. Upper gastrointestinal bleeding has been more frequently reported than lower bleeding. Interestingly, in our case report, a single colonic varix secondary to SVT was proved to be the cause of chronic lower gastrointestinal bleeding. SVT should be suspected in any patient with a triad of gastric varices, splenomegaly, and normal liver function tests, who presents with gastrointestinal bleeding secondary to left sided or so called “sinistral” portal hypertension. Mesenteric angiography with venous phase is the gold standard for the diagnosis of SVT, as endoscopic studies may not be diagnostic of this syndrome. Splenectomy is the only and definitive procedure of choice in the patients with isolated SVT, followed by post splenectomy vaccination.
Interaction between Paracetamol and Warfarin: A Double-Blind Placebo-Controlled Randomised Study.
Authors: Mahe Isabelle , Bertrand Nathalie , Drouet Ludovic , Simoneau Guy , Sollier Claire Bal dit , Mazoyer Elizabeth , Caulin Charles , Bergmann Jean-François 
Published: October 2019

Abstract
Background: Paracetamol is the gold standard antalgic and antipyretic therapy for patients receiving oral anticoagulants. Paracetamol and anticoagulant are therefore often concomitantly prescribed. The literature reports conflicting data about this association, concluding sometimes to the existence of an interaction and sometimes not. The primary objective of the study is to assess the effect of paracetamol on the anticoagulant effect of warfarin in usual conditions.
Methods: Patients on stable oral anticoagulation (warfarin with a target INR between 2 and 3) for at least 1 month have been included in a prospective randomised double blind study, cross-over controlled versus placebo. They randomsuccessively received for a 14 days-period paracetamol (at 1g four times daily) and placebo. Both periods were separated by a wash-out period lasting at least 2 weeks. INR, factors II, V, VII, X were measured during each period before the intake of the study-treatment and 12h after the intake at day 2, 4, 7, 9, 11 and 14.
Results: 20 patients were included. On paracetamol, the mean maximal INR increase observed was 1.01 ± 0.45 versus 0.27 ± 0.28 on placebo, p=0.003. The mean maximal INR was higher on paracetamol than on placebo (3.45 vs 2.66, p=0.01). A clinically significant increase of INR (above 0.5) was observed in 17 out of 19 patients on paracetamol as compared to 3 out of 19 patients on placebo. Factor II, VII, X levels were significantly decreased on paracetamol while there was no difference in factor V levels.
Discussion: Paracetamol at 4g/d induced a significant increase in INR in patients on a stable anticoagulation with warfarin. It results in an increase in the risk of bleeding of the warfarin. The mechanism of the interaction may be a metabolit of the paracetamol, inhibiting of enzymes involved in the synthesis of the vitamino-K dependent clotting factors.
Identification, Characterization of a Novel Zinc Finger Protein (HZF1) Gene and Its Roles in Erythroid Differentiation and Megakaryocyte Differentiation.
Authors: Zhang Jun-Wu , Peng Han , Du Zhan-Wen 
Published: October 2019

Abstract
A significant number of transcription factors contain evolutionarily conserved zinc finger motifs. The classical C2H2 zinc finger motif, which employs two cysteine and two histidine residues to coordinate a single zinc ion, is a maim type of the zinc finger proteins. Many of the identified C2H2 type zinc protein have been demonstrated to be transcription factors that play important roles in differentiation and development of cells and tissues of higher organisms. In this study, we obtained some novel expression sequence tags (ESTs) containing C2H2 type motifs by reverse transcription-polymerase chain reaction (RT-PCR) using RNAs derived from hemin-induced K562 cells. A cDNA encoding novel zinc finger protein (designed as HZF1) was obtained by screening the human bone marrow cDNA library using one of the ESTs as the probe. The cDNA sequences (2013 nucleotides) have been submitted to the GenBank databases under accession No. AF244088.1). Three transcripts of HZF1 gene were explored by PCR amplification of cDNAs derived from hemin-induced K562 cells. The cDNA sequences (2632 nucleotides) of the longest transcript have been submitted to the GenBank databases under accession No. DQ117529). These transcripts may result from different splicing of the pre-mRNA of HZF1 but the differences between them are only involved in 5′ non-translation region of HZF1 mRNA. BLASTN analysis revealed that HZF1 gene has four exons and three introns. The putative protein consists of 670 amino acid residues including continuous 15 C2H2 and 2 C2RH zinc finger motifs. This structure characterization and the nuclear location of the protein suggest that HZF1 may function as a transcription factor. HZF1 mRNA was detected in ubiquitous tissues and various hematopoietic cell lines. Increased HZF1 mRNA expression was observed following hemin-induction or phorbol myristate acetate (PMA)-induction of K562 cells. Both of the antisence method and RNA interference assay revealed that repression of the intrinsic expression of HZF1 blocked the hemin-induced erythroid differentiation and reduced the PMA-induced megakaryocytic differentiation of K562 cells, which suggested that HZF1 play an important part in erythroid differentiation and megakaryocytic differentiation.
NCoA4 Containing Transcriptional Complexes Modulates Response of Myelomonocytic Leukemic Cell Line to Retinoids and VD3.
Authors: Baudet Aurelie , Delva Laurent , Balaguer Patrick , Piquemal David , Marti Jacques , Commes Therese 
Published: October 2019

Abstract
Large scale analyses of transcriptome improve comprehension of complex processes such as differentiation or cell proliferation. SAGE libraries construction of the AML model U937 allowed the identification of new markers of myelomonocytic differentiation induced by retinoids and vitamin D3 (VD3) (Piquemal et al., 2002). Those molecules act through ligand-dependent transcription factors of the nuclear receptors family: RAR, RXR and VDR. Among differentially expressed members of transcriptional complexes, the most relevant was the co-regulator NCoA4 (Nuclear receptor Coactivator 4). This protein that modulates interactions between transcription factors, RNA polymerase II and chromatin remodeling factors, was initially described as a co-activator of the androgen receptor (AR). Its activity has been extended to receptors of estrogens (ER), peroxisome-proliferating activators (PPAR), retinoid X (RXR) and recently to VD3 receptor (VDR).
Using real-time semi-quantitative PCR, we found that NCoA4 is specifically expressed during the monocytic differentiation of U937 but not during the granulocytic differentiation of NB4 cell lines. These results were confirmed by analysis on normal and in vitro-differentiated leukemia primary cells. Moreover, its early induction, within 6 hours of retinoids and VD3 treatment on U937 cells, suggests that its expression may be controlled by one or several nuclear receptors. Because of cross-talks between retinoids and VD3 pathways, we used NB4-LR2 cells in which RAR is knock-down. In this cell line, NCoA4 is expressed in a VDR-dependent fashion reinforcing the hypothesis that the coregulator is specifically involved in the VD3-monocytic differentiation of leukemic cells.
Next, to explore the role of NCoA4, U937 cells were stably transfected to constitutively over-express the protein. The doubling time of this cell line (U-NCoA4) reaches to 48 hours against 24 hours in U937 cells. Concerning ligand-induced growth arrest, these cells are particularly sensitive to the RXR and VDR agonists while no significative difference was observed after treatment by the RAR agonist or by any combination. In addition, over-expression of NCoA4 induces a slow down of differentiation, as shown by expression of CD11b and CD14 myelomonocytic markers. Thus, in U-NCoA4, except for the RAR agonist, treatment for 72 hours corresponds to treatment for 48 hours levels of U937 cells.
To conclude, in term of growth arrest, NCoA4 over-expressing cells are particularly sensitive to RXR and VDR agonists. Thus, natural ligands present in the culture medium might reduce or delay proliferation, inducing the same effect on differentiation. In order to have a large view of networks, transcriptome of U-NCoA4 was analyzed by real time PCR on Low Density Array composed of a hundred messengers extracted from U937 SAGE libraries. Analysis is currently in progress.
Insulin-Like Growth Factor 1 Induced Expression of Vascular Endothelial Growth Factor, Which Is Dependent on MAP Kinase and Phosphatidylinositol 3-Kinase Signaling in Human Bone Marrow Stromal Cells.
Authors: Liu Gexiu , Tang Guangxiao 
Published: October 2019

Abstract
INTRODUCTION: Administration of bone marrow stromal cells after traumatic brain injury provides functional benefit. Its protective mechanisms include neurogenesis and angiogenesis. Different traumatic brain injuries have shown that vascular endothelial growth factor (VEGF) induced neuroprotection, neurogenesis, and angiogenesis. Insulin-like growth factor 1 (IGF-1) is a 7.5-kDa peptide with structural homology to proinsulin. In the adult organism, the liver is the major source of IGF-1. Although IGF-1 is very low in the normal adult rat brain, a number of studies have shown that IGF-1 is strongly induced in the CNS, and exerted its mitogenic and trophic effects on a variety of cell-types after different traumatic brain injuries, suggesting its repair roles after brain damage. We tested the hypothesis that IGF-1 induces expression of VEGF in human bone marrow stromal cells, and its signaling pathway.
METHODS: Human bone marrow adherent cells were cultured, and were passaged in DMEM/F12 containing 10% FBS. The fifth passage cells were identified as stromal cells. Subconfluent cells were used, and were washed twice in PBS, then cultured in serum-free DMEM/F12. After overnight incubation, cells were exposed to IGF-1 (100 ng/ml) in the presence of no kinase inhibitor or a 1 h pretreatment with 50 μM PD98059, or 200 nM wortmannin. Cells were harvested after 2 h for analysis of active phosphorylated kinases (Akt and MAPK) or after 24 h for analysis of VEGF protein and mRNA. VEGF mRNA was detected by semi-quantitative RT-PCR, and VEGF protein by ELISA, and kinases by Western blot.
RESULTS: 100 ng/ml IGF-1 increased significantly both VEGF mRNA and VEGF protein, which were very low level in control cells. 24 hours after treatment, ratio of RT-PCR product between VEGF and β-actin reach to (38.93±6.73)% from (18.61±4.25)% of control cells (P<0.01). VEGF protein increased to (123.45±20.86)pg/ml from (46.97±8.91)pg/ml (P<0.01). Moreover, IGF-1 induced active phosphorylated kinases (Akt and MAPK). And PD98059 or wortmannin inhibited effects of IGF-1.
CONCLUSION: IGF-1 enhanced expression of VEGF mRNA and VEGF protein in human bone marrow stromal cells, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling. These results suggest that VEGF be involved in therapeutic effects of bone marrow stromal cells in ischemic disorders, including stroke.
Molecular Diagnosis of Invasive Fungal Infections: Species Identification and Quantitative Analysis by Broad-Spectrum PCR Assays.
Authors: Baskova Lenka , Preuner Sandra , Lion Thomas 
Published: October 2019

Abstract
Invasive fungal infections (IFI) play an increasingly important role as life-threatening complications in immunocompromised patients. Early application of antimycotic agents is an essential prerequisite for successful therapy. However, standardized diagnostic techniques permitting rapid, sensitive and, no less importantly, economic screening for the clinically relevant fungi have been lacking. We have developed two different real-time PCR systems for quantitative analysis of pathogenic fungi. The Pan-AC assay* permits in a single reaction the detection of all important Aspergillus and Candida species, which are responsible for the great majority of IFI in immunosuppressed individuals. In view of the increasing incidence of invasive infections caused by hitherto uncommon fungal species, new diagnostic tests with very broad specificity are required. We have therefore developed an additional two-reaction Pan-fungus assay*, which facilitates quantitative detection of a wide spectrum of fungal species (n>50), including also the newly emerging pathogenic fungi. The assays display high sensitivity and show no cross-reactivity with non-fungal pathogens or human DNA sequences. We have established an additional rapid molecular assay based on PCR fragment length analysis of a variable region in the fungal genome permitting rapid identification of the fungal species present, in order to facilitate selection of the most appropriate antifungal treatment. Correct identification of specific fungal pathogens including different Aspergillus, Candida and Fusarium species detected by the above assays in patients with febrile neutropenia has been confirmed by sequence analysis. The new assays are readily applicable to routine clinical diagnosis and provide a rapid and economic approach to the screening and monitoring of invasive fungal infections.
Early “Mini” Donor Lymphocyte Infusions after Reduced-Intensity Conditioning in Allogeneic Transplant of Highly Purified CD34+ Cells from HLA-Identical Donors in Pediatric Leukemia Patients.
Authors: Diaz Miguel A. , Gonzalez-Vicent Marta , Ramirez Manuel , Perez Antonio , Garcia-Castro Javier , Sevila Julian , Madero Luis 
Published: October 2019

Abstract
To maximize graft-versus-leukemia (GvL) effect while minimizing transplant-related morbidity and mortality (TRM), we designed a study of allogeneic CD34+ selected PBSC transplantation followed by donor lymphocyte infusion (DLI). PBSC CD34+ selection was performed with the CliniMACS device. Between June 2004 and July 2005, fifteen consecutive patients (5 females and 10 males) aged between 1–16 years (median 5 years) diagnosed of AML (6) and ALL (9) were conditioned with fludarabine 30 mg/m2/day x 5 days and melphalan 140 mg/m2/day x 1 day. Status at transplantation was 1st CR 10, 2nd CR 4 and 3th CR 1. GvHD prophylaxis consisted of CsA + short Mtx in 13 cases and CsA in 2. Patients were grafted with a median number of 6.9 x 106/Kg CD34+ cells (range: 1.5–30.9 x 106/Kg) and 15.6 x 103 CD3+ cells (range: 2–59.2 x 103/Kg). All patients engrafted. Median time to neutrophil and platelet engraftment was 12 days (range: 9–15 days) and 13 days (range: 9–42 days), respectively. DLI of 0.5 x 105/Kg CD3+ cells were scheduled on day +15, +30 and +60. A total of 40 DLI were performed. One patient had acute GvHD grade I after the 2nd DLI that resolved with topical steroid treatment and another one developed graft hypoplasia after first DLI resolved after G-CSF treatment. One patient died of a sepsis on day +15 (TRM 6% ± 5%). Two patients relapsed, one with an isolated CNS relapse (6 months postransplant) and the other with a medullar relapse (3 months). With a median follow-up of 6 months (range: 3–13 months) the disease free survival was 75% ± 13% and overall survival 87% ± 8%. The preliminary results of our transplantation strategy are encouraging. A large prospective study is needed to substantiate these results.