bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALOX5AP Gene Variants and Risk of Coronary Artery Disease in Italy. An Angiography-Based Study.
Authors: Girelli Domenico , Martinelli Nicola , Trabetti Elisabetta , Olivieri Oliviero , Cavallari Ugo , Malerba Giovanni , Busti Fabiana , Friso Simonetta , Pizzolo Francesca , Pignatti PierFranco , Corrocher Roberto 
Published: October 2019

Abstract
The gene encoding Arachidonate 5-Lipoxygenase-Activating Protein (ALOX5AP; GeneID: 241; chromosome: 13q12) represents the paradigm of a new class of promising genes identified by powerful genome-wide investigations (Helgadottir A, Nature Genetics 2004), that are currently object of intense studies to confirm their role as possible susceptibility factors for atherothrombosis. Indeed, ALOX5AP encodes the 5-Lipoxygenase-Activating Protein (FLAP; Miller DK, Nature 1990), an essential regulator of the 5-LO/leukotriene pathway, that has been recently implicated in the pathogenesis of atherothrombosis (Funk CD, Nature Review Drug Discovery 2005). We studied a total of 1,431 subjects with or without angiographically documented coronary artery disease (CAD). Seven ALOX5AP single-nucleotide polymorphisms (SG13S25, SG13S377, SG13S114, SG13S89, SG13S32, SG13S41, SG13S35) were examined simultaneously, allowing reconstruction of the at-risk haplotypes “HapA” and “HapB” previously identified in the Icelandic and in the British populations, respectively (Helgadottir A, Nature Genetics 2004). Using a haplotype-based approach, HapA was not associated with either CAD or myocardial infarction (MI). On the other hand, HapB and another haplotype within the same region (that we named “HapC”) were significantly more represented in CAD versus CAD-free subjects, and these associations remained significant after adjustment for traditional cardiovascular risk factors by logistic regression (HapB: OR 1.67, 95% CI 1.04 to 2.67; P=0.032; HapC: OR 2.41, 95% CI 1.09 to 5.32; P=0.030). No difference in haplotype distributions was observed between CAD patients with or without a previous documented MI. Adding our data to current knowledge, some evidence on ALOX5AP as a genetic susceptibility factor for CAD has now emerged in several independent populations (Icelandic, British, Japanese, and Italian). Our study, the first angiography-based to our knowledge, points out a possible role of ALOX5AP in the development of the atheroma rather than in its late complications such as MI.
Double Delayed Intensification (DDI) Is Equivalent to Single DI (SDI) in Children with National Cancer Institute (NCI) Standard-Risk Acute Lymphoblastic Leukemia (SR-ALL) Treated on Children’s Cancer Group (CCG) Clinical Trial 1991 (CCG-1991).
Authors: Matloub Yousif , Angiolillo Anne , Bostrom Bruce , Hunger Stephen P. , Nachman James , Sather Harland , Carroll William L. , Winick Naomi , Gaynon Paul S. 
Published: October 2019

Abstract
Intensification of therapy has improved outcome of children with ALL. CCG 1891 demonstrated that children with intermediate risk ALL (a subset of SR-ALL) had a superior outcome with DDI vs SDI using a modified Berlin-Frankfurt-Muenster (BFM) backbone therapy that included prednisone, in a 3 drug induction (Blood.2002;99:825–33). This benefit was limited to patients with > 5% marrow blasts on Day 7 of induction. CCG-1921 best arm had similar outcome with dexamethasone in induction, and SDI (Blood.2003;101:3809–17). The question remained as to whether DDI would benefit SR patients if they received dexamethasone in induction. Therefore, one hypothesis tested by CCG-1991 was that a regimen with DDI phases would have a superior event free survival (EFS) and overall survival (OS) compared with one that had a SDI phase in children with SR-ALL treated with a modified BFM backbone therapy that included dexamethasone in induction. SR-ALL patients with an unfavorable early response (> 25% marrow blasts at day 14, or >25% marrow blasts at day 7 and >5% marrow blasts at day 14) were not eligible for randomization and were assigned to receive augmented therapy. CCG-1991 used a 2 X 2 factorial design to compare outcome in patients who received SDI vs DDI phases, and oral vs escalating intravenous methotrexate without leucovorin rescue during the interim maintenance phases of therapy. The results of the methotrexate question remain blinded at this time. There were 52 relapses among the 1029 patients randomized to the SDI regimens vs 58 among the 1021 patients randomized to the DDI regimens. Four year EFS was 88.3% (SE = 3.6) for the SDI regimens, and 88.1% (SE = 3.9) for the DDI regimens, p = 0.45, RHR 1.15. The 4 year OS estimate is 96.2% for the SDI, and 94.2% for the DDI; p = 0.25, RHR 1.41. We conclude that there are no benefits to DDI vs SDI in children with SR-ALL and a favorable early marrow response to induction chemotherapy.
Upregulation of Tissue Factor in Polymorphonuclear Leukocytes from Patients with Myeloproliferative Disorders and Inhibition by Hydroxyurea Treatment.
Authors: Maugeri Norma , Cerletti Chiara , Giordano Giulio , Petrilli Maria P. , Fraticelli Vincenzo , de Gaetano Giovanni , Leone Giuseppe , Storti Sergio , Donati Maria B. 
Published: October 2019

Abstract
Polymorphonuclear leukocytes (PMN) from healthy subjects can produce and store tissue factor (TF), which is expressed on PMN surface upon in vitro stimulation with P-selectin. We report here that platelets and PMN from 12 patients with myeloproliferative disorders (MPD) (6 Polycytemia Vera, 6 Essential Thrombocythemia) show up regulation of P-selectin and TF, respectively, in the absence of any in vitro challenge, in comparison to healthy subjects (31±5 vs. 2.8±0.4 percent of P-selectin-positive platelets and 6.4±1.3 vs. 0.8±0.3 percent of TF-positive PMN, both differences P<0.05). The number of circulating mixed platelet-PMN aggregates was also increased (15.1±4.4 percent of platelet-PMN aggregates in MPD vs 2.6±0.5 in healthy, P<0.05). PMN TF expression as well as mixed platelet-PMN aggregates, but not platelet P-selectin, were significantly reduced in six MPD patients after three weeks treatment with hydroxyurea (HU) (6.3±1.7 vs. 1.4±0.2 percent of TF-positive PMN and 25.1±6.3 vs. 4.7±1.1 percent of platelet-PMN aggregates, before and after HU, respectively; both differences P<0.05). In vitro studies performed on PMN separated from healthy donors confirmed HU effects (0–1,400 microM). HU prevented both P-selectin-induced TF expression and mixed cell aggregate formation. The inhibitory effect of HU was specific for P-selectin induced PMN activation, as it did not affect fMLP-induced PMN TF expression. Thus, in MPD patients, platelet P-selectin-mediated TF expression on circulating PMN may play a role in thrombus formation and represents a novel target for the antithrombotic activity of HU.
Cell-Derived Microparticles (C-MP) Are Elevated in Splenectomized Patients and Depressed in Those with Hypersplenism, Suggesting Spleen as Scavenger of C-MP.
Authors: Fontana Vincenzo , Jy Wenche , Dudkiewicz Pamela , Horstman Lawrence L. , Bidot Carlos , Ahn Yeon-Soong 
Published: October 2019

Abstract
BACKGROUND: Cell-derived microparticles (C-MP) are microvesicles released during activation and apoptosis from platelets (PMP), leukocytes (LMP), endothelial cells (EMP) and red cells (RMP). They commonly express phosphatidylserine (PS) judged by binding annexin V (AnV) and carry markers of parent cells. C-MP are involved in thrombosis, inflammation and angiogenesis. Little is known how C-MP are cleared from circulation. To test that the spleen might be involved, we investigated C-MP profiles in patients who underwent splenectomy for various causes (group A), those with hypersplenism (group B), and healthy controls with spleen (group C).
MATERIAL AND METHODS: Group A (Gr A) consisted of 44 patients (18 M and 26 F, mean age 57.2 yr) with splenectomy; group B (Gr B) consisted of 25 patients (12 M and 13 F, mean age 61.6 yr) with hypersplenism. Gr A had 25 ITP, 7 myeloproliferative disorders, 4 lymphoma, 3 hemolytic anemias, 4 trauma related splenectomy, 1 unknown reason. Group B had 19 chronic hepatitis C, 2 alcoholic, 2 idiopathic and 1 autoimmune hepatitis, 1 portal vein thrombosis. Group C (Gr C) were healthy controls with spleen (n=109). Flow cytometry was used to assay C-MP. PMP were identified by CD41+, LMP by CD45+, EMP by CD31+/CD41−, and RMP by glycophorin+. Profile of C-MP and blood counts were compared among the 3 groups.
RESULTS: Table 1 summarizes C-MP data among the 3 groups. Gr A and B were well matched for ages and sex. Mean values of WBC and Hgb were normal in all groups while the platelet count was low in Gr B. Mean values of LMP, EMP and RMP were significantly higher in Gr A compared to Gr B and C, but PMP were not. All species of C-MP (PMP, LMP, EMP, RMP) in Gr B were significantly lower than Gr C (healthy control) and were markedly depressed compared to Gr A (see Table 1). Correlation analysis revealed that PMP correlated with platelet count (p<0.0001) but no correlation between LMP and WBC was seen, or between RMP and Hgb. Accordingly, high LMP and RMP in Gr A cannot explain the relatively high Hgb and WBC levels in this group.
DISCUSSION/COMCLUSIONS: Our data suggest that spleen sequesters and/or clears C-MP of all types (PMP, LMP, EMP, RMP). C-MP express PS (bind AnV), which is known to promote clearance from circulation. Splenectomy is known to be associated with thrombosis but its mechanism in not well elucidated. Elevated C-MP in splenectomized patients may contribute to their increased risk of thrombosis.
Table 1 Gr A (Splntomy) Gr B (Hyperspln) Gr C (Control) p value (A-C) p value (B-C) Patient no. 44 25 109 PMP 13858 7073 15992 n. s. <0.0001 LMP 2043 1180 1385 <0.0001 <0.001 EMP 857 238 436 <0.001 <0.0001 RMP 2964 926 1138 <0.0001 <0.005
Changes in ADAMTS 13 Activity and Von Willebrand Factor Parameters during Acute Dengue Infection.
Authors: Sosothikul Darintr , Seksarn Panya , Pongsawaluk Sureeporn , Lusher Jeanne M. 
Published: October 2019

Abstract
Dengue virus causes febrile illnesses: Dengue Fever (DF) and less frequently a life-threatening illness, Dengue Hemorrhagic Fever (DHF). The pathophysiology of hemostatic defect in dengue infection is thought to relate to the direct effect of virus or cytokines on endothelial activation. To study the state of endothelial activation during dengue infection, we measured plasma levels of von Willebrand factor antigen (vWF:Ag), vWF-collagen binding assay (vWF:CBA), and ADAMTS 13 activity in 42 children (20 with DF and 22 with DHF) during 3 phases of illness: febrile, toxic, and convalescent phase. 38 healthy children comprised as controls. Our data shows that both VWF:Ag and vWF:CBA levels were significantly higher in dengue patients (p ≤ 0.001 in both DF and DHF patients) versus controls. DHF patients had significantly higher of VWF: Ag (p = 0.01, versus DF). ADAMTS 13 activity levels were significantly decreased only in DHF patients during 3 phases of the illness (febrile; mean 78%; p = 0.016, toxic; mean 68%; p<0.001 and convalescent; mean 69%; p<0.001 compared to mean 104% of the controls). Compared to DF patients, DHF patients had significantly lower plasma concentrations of ADAMTS 13 activity during the febrile, toxic and convalescent phase (p = 0.039, p = 0.002 and p =0.003, respectively). Endothelial cell activation is a hallmark of dengue infection especially in DHF patients; indicated by a significant rise in VWF:Ag and vWF:CBA and a reciprocal decline in ADAMTS 13 activity.
Portal Vein Thrombosis Following Splenectomy for Hematologic Diseases: Prevalence and Risk Factors.
Authors: Ciapanna Denis , Nosari Annamaria , Gargantini Livio , Mostarda Giovanni , Nichelatti Michele , Turrini Mauro , Morra Enrica 
Published: October 2019

Abstract
Portal vein thrombosis (PVT) is a potentially fatal complication of splenectomy; the prevalence of PVT remains up till now controversial, such as the related-risk factors. The hematologic patients who underwent splenectomy in Niguarda Hospital, Milan, Italy, between January 1995 and November 2004 were retrospectively reviewed to identify the prevalence of post-splenectomy PVT and risk factors associated with its development. Splenectomy was performed because of malignant (n = 41) or non-malignant (n = 44) hematologic diseases. Indications for splenectomy in the groups with and without PVT were compared with Fisher’s exact test. We tested the reliability of platelet count as a marker of PVT, analysing the receiver operator characteristic (ROC) curve. Cut-off level was chosen for best prediction in term of sensitivity and specificity.
Among 85 patients who underwent splenectomy, the associated non-malignant diseases were immune thrombocytopenic purpura (n = 40), hemolytic anemia (n = 2), Evan’s syndrome (n = 1), cryoglobulinemia (n = 1); malignant diseases were lymphoproliferative (n = 39) and myeloproliferative disorders (n = 2). Four cases of PVT (4,71%) were diagnosed. One of 2 patients with a myeloproliferative disorder had PVT. PVT was also present in 3/39 (7.69%) patients with lymphoproliferative malignancies, all with splenic marginal zone B-cell variety non-Hodgkin’s lymphoma (3/16) . The median splenic weight in patients who developed PVT was 1800 g (range 1500–1980 ) and the median post-surgery platelet count was 661 x 109/liter (range 211–1250). No patient with non-malignant diseases had portal vein thrombosis. The incidence of the event was of 0.0000523 new cases for day-patient, with a 0.005% new incidental case probability. Splenic weight, with a cut-off value of 500 grams for the risk analysis (p=0.029), was significantly correlated to thrombosis. PVT was also significantly correlated to the entity of the post-surgery thrombocytosis (p=0.024), setting the threshold value of thrombosis risk at 850.000/uL (Sensibility 0.50 - Specificity 0.95).
Patients with myeloproliferative and lymphoproliferative disorders seem at higher risk for the development of PVT than those with non-malignant diseases. A splenic weight over 500 grams and a post-surgery thrombocytosis over 850.000/uL are significantly associated with the occurrence of PVT. The presence of these two risk factors should require the prophylactic use of adequate doses of low molecolar weight heparin.
Amplified Expression Profiling of Platelet Transcriptome Reveals Global Activation of Arginine Metabolic Pathways in Patients with Sickle Cell Disease.
Authors: Raghavachari Nalini , Xu Xiuli , Villagra Jose , Kato Greg , Munson Peter J. , Morris Sidney , Gladwin Mark T. 
Published: October 2019

Abstract
In sickle cell disease, ischemia-reperfusion injury and intravascular hemolysis produce endothelial dysfunction and vasculopathy characterized by reduced nitric oxide (NO) and arginine bioavailability. Recent functional studies of platelets in patients with sickle cell disease reveal a basally activated state, suggesting that pathological platelet activation may contribute to sickle cell disease vasculopathy. Studies were therefore undertaken to globally examine transcriptional signaling pathways in platelets that may be dysregulated in sickle cell disease. We demonstrate and validate here the feasibility of comparative platelet transcriptome studies on clinical samples from single donors, by the application of RNA amplification followed by microarray-based analysis of 54,000 probe sets. Data mining for platelet specific or abundant genes identified 118 genes that showed more than a 100-fold increase in transcript expression level compared to all other cells in the database. Most of these genes were clearly annotated as platelet-specific and 84% of these transcripts overlapped with the platelet abundant genes identified in previous gene expression studies. On comparing the platelet gene expression profiles in 18 patients with sickle cell disease in steady state to 12 African American controls, at a 3-fold cut-off and 5% false discovery rate, we identified >100 differentially expressed genes, including multiple genes involved in arginine/NO metabolism and redox homeostasis. Further functional characterization of these pathways using Gene Set Enrichment Analysis, real time PCR, arginase enzymatic assay, and polyamine quantification revealed arginase II-mediated catabolism and diversion of arginine from NO signaling and polyamine synthesis to proline formation. These studies suggest a potential pathogenic role for platelet arginase and ornithine decarboxylase antizyme and provide a novel framework for the study of disease-specific platelet biology.
Symptoms and Signs of Hemochromatosis in HFE C282Y Homozygotes Identified by Screening in Primary Care.
Authors: McLaren Gordon D. , McLaren Christine E. , Adams Paul C. , Barton James C. , Reboussin David M. , Gordeuk Victor R. , Acton Ronald T. , Harris Emily L. , Speechley Mark , Sholinsky Phyliss , Dawkins Fitzroy W. , Snively Beverly M. , Vogt Thomas , Eckfeldt John H. 
Published: October 2019

Abstract
Some patients with hemochromatosis (HC) experience fatigue, heart failure or arrhythmias, diabetes mellitus, liver damage, impotence, or arthritis. We examined self-reported symptoms and clinical conditions in persons homozygous for HFE C282Y, the major HC-associated gene mutation, identified in the Hemochromatosis and Iron Overload Screening (HEIRS) Study, a multi-center, multi-ethnic study in which 101,168 adults were recruited from primary care settings. Non-Hispanic Caucasian C282Y homozygotes were compared to participants without HFE C282Y or H63D alleles (controls) with transferrin saturation (TfS) and serum ferritin (SF) levels in the middle half of gender-specific distributions. Evaluation included a medical history, focused physical examination, and repeat SF. Among 44,082 non-Hispanic Caucasian participants screened at five Field Centers in the United States and Canada, 282 persons homozygous for C282Y were identified, comprising three groups: newly-diagnosed cases with normal (N=64) or elevated (N=131) SF (>200 μg/L in women, >300 μg/L in men), and previously-diagnosed cases (N=87). There were 364 non-Hispanic Caucasian controls. Significant differences were observed for six of 38 outcomes. Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF reported significantly more chronic fatigue than controls (p=0.002). All groups of C282Y homozygotes reported weight loss more often than controls (p<0.001). Excessive thirst was reported more often than controls by newly diagnosed C282Y homozygotes, regardless of SF level (p=0.004), but there was no difference in self-reported history of diabetes. Joint stiffness was more common among newly diagnosed C282Y homozygotes with elevated SF than among control subjects (p<0.001). Swelling or tenderness of the second and third metacarpophalangeal joints and increased pigmentation were also more common among previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF than among controls (p=0.001 and p=0.002, respectively). The prevalences of manifestations related to liver or heart disease among C282Y homozygotes were not significantly different from controls. There were no differences among the three groups of C282Y homozygotes in the prevalences of any symptoms or clinical conditions. In summary, some symptoms and conditions associated with HC were more prevalent among C282Y homozygotes than among controls. However, C282Y homozygotes identified by screening in primary care settings did not have a higher prevalence of most symptoms and signs associated with HC than control subjects.
Dietary Iron, Alcohol Consumption and Serum Ferritin Concentrations in African Americans.
Authors: Gordeuk Victor R. , Diaz Sharmin F. , Onojobi Gladys O. , Debebe Zufan , Edossa Amanuel , Nekhai Sergei , Taylor Robert E. 
Published: October 2019

Abstract
We investigated the relationship of dietary iron and alcohol consumption with serum ferritin concentration among 143 inner-city African-Americans from the community. Seventy-one of the participants reported consuming an average of more than four alcoholic drinks per day and 72 less than two alcoholic drinks per week. The mean age was 47 years for the high alcohol group and 49 years for the low alcohol group. Thirteen (18%) of the participants in the high alcohol group were women compared to 27 (38%) in the low alcohol group. Body mass index and rates of positivity for HIV and hepatitis C virus were similar. Typical daily dietary iron and alcohol consumption was calculated based on a dietary questionnaire that has been validated for use among various ethnic groups (University of Hawaii). The relationship of dietary iron content and alcohol consumption with log10 serum ferritin concentration and with log10 ratio of serum ferritin to AST (ferritin/AST) was examined in multivariate linear regression models that adjusted for age, sex, ferroportin Q248H status, caloric intake and serum concentrations of CRP and ALT. Ferritin/AST has been shown to correlate with hepatic iron concentration in the setting of alcoholic liver disease. Both average daily dietary iron from meat, poulty and fish (P = 0.013) and average daily alcohol consumption (P = 0.015) correlated positively with log10 serum ferritin, but average daily non-heme iron content did not (P = 0.9). Similar findings obtained for log10 ferritin:AST. According to this modeling and holding other variables constant, a 70 kg individual with serum ferritin of 100 ng/ml associated with dietary iron from meat, poultry and fish of 3.5 mg/day would have serum ferritin of 135 ng/ml (95% c.i. 107–172) associated with dietary iron from meat, poultry and fish of 7.0 mg/day. Similarly, a 70 kg individual with serum ferritin 100 ng/ml associated with no alcohol intake would have serum ferritin 124 ng/ml (105–148) associated with alcohol consumption of 56 g/day. Our results are consistent with the hypothesis that the amount of dietary heme iron and the degree of alcohol consumption influence the amount of storage iron in the body as reflected by serum ferritin concentration.
Down Regulation of Hepcidin and Haemojuvelin Expression in the Hepatocyte Cell-Line HepG2 Induced by Thalassaemic Sera.
Authors: Weizer-Stern Orly , Adamsky Konstantin , Amariglio Ninette , Levin Carina , Koren Ariel , Breuer William , Rachmilewitz Eliezer , Gardenghi Sara , Rivella Stefano , Cabantchik Yoav , Rechavi Gideon 
Published: October 2019

Abstract
β-thalassaemia represents a group of diseases, in which ineffective erythropoiesis is accompanied by iron overload. In a mouse model of β-thalassaemia we observed that the liver expresses relatively low levels of hepcidin, which is a key factor in the regulation of iron absorption by the gut and of iron recycling by the reticuloendothelial system. We hypothesized that despite the overt iron overload, a putative plasma factor found in β-thalassaemia might suppress liver hepcidin expression. We therefore compared sera from β-thalassaemia and haemochromatosis (C282Y mutation) patients with those of healthy individuals in terms of their capacity to evoke changes in expression of key genes of iron metabolism in human HepG2 hepatoma cells. Sera from β-thalassaemia major patients evoked a major decrease in hepcidin (HAMP) and lipocalin2 (oncogene 24p3) (LCN2) expression, as well as a moderate decrease in haemojuvelin (HFE2) expression, compared to sera from healthy individuals. Significant correlation was found between the degree of downregulation of HAMP and HFE2 evoked by b-thalassaemia major sera (r=0.852, p<0.0009). Decreased HAMP expression was also found in HepG2 cells treated with sera collected from β-thalassaemia intermedia patients. In contrast, the majority of sera from hereditary haemochromatosis patients evoked an increase in HAMP expression, which correlated with their transferrin saturation (r=0.765, p<0.0099). Our results suggest that in β-thalassaemia, serum factors might override the potential effect of iron overload on HAMP expression, thereby providing an explanation for the failure to arrest excessive intestinal iron absorption.