bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells
Authors: Albiñana Virginia , Bernabeu-Herrero Maria , Zarrabeitia Roberto , Bernabeu Carmelo , Botella Luisa 
Published: February 2010

SummaryHereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploin-sufficiency of ENG and ALK1.
Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development
Authors: Ufer Mike 
Published: February 2010

SummaryTherapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the factor Xa inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and apixaban throughout preclinical and clinical development.
Antithrombotic treatment and the risk of death and stroke in patients with atrial fibrillation and a CHADS2 score=1
Authors: Gorin Laurent , Nonin Emilie , Labriolle Axel de , Haguenoer Ken , Cosnay Pierre , Babuty Dominique , Charbonnier Bernard , Fauchier Laurent 
Published: February 2010

SummaryIn patients with atrial fibrillation (AF) and an intermediate risk of stroke (CHADS2 score =1), available evidence from clinical trials is inconclusive and the present guidelines for the management of AF indicate that the choice between oral anticoagulant and aspirin in these patients is open. Our goal was to evaluate whether, in patients with AF and only one moderate risk factor for thromboembolism, treatment with an oral anticoagulant is appreciably more beneficial than treatment with an antiplatelet agent. Among 6,517 unselected patients with AF, 1,012 of them (15.5%) had a CHADS2 score of 1 and were liable to treatment with an antiplatelet agent or an anticoagulant. An oral anticoagulant was prescribed for 606 patients (59.9%) and an antiplatelet agent or no antithrombotic treatment for 406 (40.1%). During follow-up (median=793 days, interquartile range=1,332 days), 105 deaths (10.4%) and 19 strokes (1.9%) were recorded. The administration of an anticoagulant was associated with a lower rate of events (relative risk=0.42, 95% confidence interval 0.29–0.60, p<0.0001) than when no anticoagulant was prescribed. Results remained similar after adjustment for age and other confounding factors. In contrast, prescription of an antiplatelet agent was not associated with a lower risk of events. Factors independently associated with an increased risk of events were older age (p<0.0001), concomitant heart failure (p=0.0002), diabetes (p=0.0025), lack of prescription of an anticoagulant (p<0.0001) and permanent AF (p=0.04). Thus, prescription of an anticoagulant is independently associated with a decreased risk of death or stroke among patients with AF and a CHADS2 score =1.
Tools for Building Clinic-Community Partnerships to Support Chronic Disease Control and Prevention
Authors: Barnidge Ellen K. , Brownson Carol A. , Baker Elizabeth A. , Shetty Gowri 
Published: February 2010

Purpose Developing partnerships among health care clinics and community organizations is an important strategy for increasing resources and supports for chronic disease care and management. Although several tools assessing partnership characteristics exist, tools to assess the progression from partnership development to the achievement of specific short-term, intermediate, and long-term outcomes have not been developed to date. The purpose of this article is to introduce tools developed by the Diabetes Initiative of the Robert Wood Johnson Foundation to fill that gap. Conclusion The Diabetes Initiative used a group process with program grantees to better delineate the phases of partnership development that contribute to the achievement of a shared long-term goal. The Framework for Building Clinic-Community Partnerships to Support Chronic Disease Control and Prevention presented in this article was developed as a result of this process. To apply the framework, 3 checklists were created to correspond to each stage of the framework. The final tools include the framework; 3 checklists with items to assess partnership development, agency capacity within and between agencies, and intermediate and long-term outcomes; and a form to facilitate changes to improve the partnership. Overall, these tools seek to aid partnerships in achieving the best possible chronic disease outcomes.
Leukemogenic transformation by HOXA cluster genes
Authors: Bach Christian , Buhl Sebastian , Mueller Dorothée , García-Cuéllar María-Paz , Maethner Emanuel , Slany Robert K. 
Published: February 2010

Abstract
HOX homeobox genes are important regulators of normal and malignant hematopoiesis. Abdominal-type HOXA genes like HOXA9 are highly leukemogenic. However, little is known about transformation by anterior HOXA genes. Here we performed a comprehensive assessment of the oncogenic potential of every HOXA gene in primary hematopoietic cells. With exception of HOXA2 and HOXA5, all HOXA genes caused a block or delay of hematopoietic differentiation and cooperated with Meis1. No evidence for the alleged tumor-suppressor function of HOXA5 could be found. Whereas all active HOXA genes immortalized mixed granulocytic/monocytic populations, HOXA13 preferentially specified monocytoid development. The anterior HOXA genes HOXA1, HOXA4, and HOXA6 transformed cells, generating permanent cell lines, although they did so less potently than HOXA9. Upon transplantation these lines induced myeloproliferation and acute myeloid leukemia in recipient animals. Kinetic studies with inducible HOX derivatives demonstrated that anterior HOXA genes autonomously contributed to cellular transformation. This function was not mediated by endogenous Hoxa9, which was persistently expressed in cells transformed by anterior HOX genes. In summary our results demonstrate a hitherto unexpected role of anterior HOXA genes in hematopoietic malignancy.
Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia
Authors: Zaja Francesco , Baccarani Michele , Mazza Patrizio , Bocchia Monica , Gugliotta Luigi , Zaccaria Alfonso , Vianelli Nicola , Defina Marzia , Tieghi Alessia , Amadori Sergio , Campagna Selenia , Ferrara Felicetto , Angelucci Emanuele , Usala Emilio , Cantoni Silvia , Visani Giuseppe , Fornaro Antonella , Rizzi Rita , De Stefano Valerio , Casulli Francesco , Battista Marta Lisa , Isola Miriam , Soldano Franca , Gamba Enrica , Fanin Renato 
Published: February 2010

Abstract
Previous observational studies suggest that rituximab may be useful in the treatment of primary immune thrombocytopenia (ITP). This randomized trial investigated rituximab efficacy in previously untreated adult ITP patients with a platelet count of 20 × 109/L or less. One hundred three patients were randomly assigned to receive 40 mg/d dexamethasone for 4 days with or without 375 mg/m2 rituximab weekly for 4 weeks. Patients who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab. Sustained response (ie, platelet count ≥ 50 × 109/L at month 6 after treatment initiation), evaluable in 101 patients, was greater in patients treated with dexamethasone plus rituximab (n = 49) than in those treated with dexamethasone alone (n = 52; 63% vs 36%, P = .004, 95% confidence interval [95% CI], 0.079-0.455). Patients in the experimental arm showed increased incidences of grade 3 to 4 adverse events (10% vs 2%, P = .082, 95% CI, −0.010 to 0.175), but incidences of serious adverse events were similar in both arms (6% vs 2%, P = .284, 95% CI, −0.035 to 0.119). Dexamethasone plus rituximab was an effective salvage therapy in 56% of patients refractory to dexamethasone. The combination of dexamethasone and rituximab improved platelet counts compared with dexamethasone alone. Thus, combination therapy may represent an effective treatment option before splenectomy. This study is registered at http://clinicaltrials.gov as NCT00770562.
Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion
Authors: Hu Siyi , Delorme Nathalie , Liu Zhenzhen , Liu Tao , Velasco-Gonzalez Cruz , Garai Jone , Pullikuth Ashok , Koochekpour Shahriar 
Published: February 2010

AbstractBackgroundFactors responsible for invasive and metastatic progression of prostate cancer (PCa) remain largely unknown. Previously, we reported cloning of prosaposin (PSAP) and its genomic amplification and/or overexpression in several androgen-independent metastatic PCa cell lines and lymph node metastases. PSAP is the lysosomal precursor of saposins, which serve as activators for lysosomal hydrolases involved in the degradation of ceramide (Cer) and other sphingolipids.ResultsOur current data show that, in metastatic PCa cells, stable down-modulation of PSAP by RNA-interference via a lysosomal proteolysis-dependent pathway decreased β1A-integrin expression, its cell-surface clustering, and adhesion to basement membrane proteins; led to disassembly of focal adhesion complex; and decreased phosphorylative activity of focal adhesion kinase and its downstream adaptor molecule, paxillin. Cathepsin D (CathD) expression and proteolytic activity, migration, and invasion were also significantly decreased in PSAP knock-down cells. Transient-transfection studies with β1Aintegrin- or CathD-siRNA oligos confirmed the cause and effect relationship between PSAP and CathD or PSAP and Cer-β1Aintegrin, regulating PCa cell migration and invasion.ConclusionOur findings suggest that by a coordinated regulation of Cer levels, CathD and β1A-integrin expression, and attenuation of "inside-out" integrin-signaling pathway, PSAP is involved in PCa invasion and therefore might be used as a molecular target for PCa therapy.
Gene ontology analysis for RNA-seq: accounting for selection bias
Authors: Young Matthew D , Wakefield Matthew J , Smyth Gordon K , Oshlack Alicia 
Published: February 2010

AbstractWe present GOseq, an application for performing Gene Ontology (GO) analysis on RNA-seq data. GO analysis is widely used to reduce complexity and highlight biological processes in genome-wide expression studies, but standard methods give biased results on RNA-seq data due to over-detection of differential expression for long and highly expressed transcripts. Application of GOseq to a prostate cancer data set shows that GOseq dramatically changes the results, highlighting categories more consistent with the known biology.
Potent intestinal Th17 priming through peripheral lipopolysaccharide-based immunization
Authors: McAleer Jeremy P , Liu Bei , Li Zihai , Ngoi Soo-Mun , Dai Jie , Oft Martin , Vella Anthony T 
Published: February 2010

Abstract
The data provide impetus for using TLR-based peripheral vaccination to augment specific Th17 immunity in the gut mucosa.
Lipopolysaccharide (LPS) is a potent natural adjuvant, commonly used to amplify Th1 responses. Here, we report that systemic immunization using LPS generates large numbers of specific Th17 cells in murine small intestinal lamina propria. The priming of these Th17 cells required IL-23p19 production by bone marrow-derived cells. In contrast, IL-23 had no impact on Th1 differentiation or overall numbers of Ag-specific regulatory T cells. Experiments using T-cell adoptive transfers revealed a previously unappreciated mechanism for how Th17 responses are amplified in vivo: stimulation through LPS expanded precommitted Th17 cells rather than causing Th17 differentiation. Second, LPS drove Th17 cell expansion independently of IL-23, demonstrating that this cytokine is not necessary for expansion and possibly functions at an earlier stage in Th17 priming. Our data provide an impetus for using LPS-based peripheral vaccination to augment specific T-cell-mediated immunity in the gut mucosa.
LMNA Mutations, Skeletal Muscle Lipid Metabolism, and Insulin Resistance
Authors: Boschmann Michael , Engeli Stefan , Moro Cedric , Luedtke Angelika , Adams Frauke , Gorzelniak Kerstin , Rahn Gabriele , Mähler Anja , Dobberstein Kerstin , Krüger Antje , Schmidt Saskia , Spuler Simone , Luft Friedrich C. , Smith Steven R. , Schmidt Hartmut H.-J. , Jordan Jens 
Published: February 2010

Abstract
Context: Type 2 familial partial lipodystrophy (FPLD) is an autosomal-dominant lamin A/C-related disease associated with exercise intolerance, muscular pain, and insulin resistance. The symptoms may all be explained by defective metabolism; however, metabolism at the tissue level has not been investigated.
Objective: We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect.
Patients and Methods: Carbohydrate and lipid metabolism was studied on 10 FPLD patients, one patient with limb-girdle muscular dystrophy (LGMD1B, a different lamin A/C disease), and 10 healthy control subjects before and during an oral glucose tolerance test by indirect calorimetry and im microdialysis. Muscle biopsies were taken for in vitro studies.
Results: We observed marked increased skeletal muscle fatty acid β-oxidation rate in vitro and in vivo, even after glucose ingestion in FPLD patients. However, fatty acid oxidation was largely incomplete and accompanied by increased ketogenesis. The lipid oxidation abnormality was associated with impaired glucose disposition through reduction in glucose oxidation, rather than decreased cellular glucose uptake. A microarray showed down-regulation of complex I respiratory chain, glycolysis, and nuclear transport genes. Although not overtly insulin resistant, the LGMD1B patient showed similar metabolic derangements as the FPLD patients.
Conclusions: Our study suggests imbalance between lipid oxidation and oxidative glucose metabolism in FPLD and LGMD1B patients. The observation suggests an intrinsic defect in skeletal muscle metabolism due to lamin A/C dysfunction. The metabolic FPLD phenotype likely results from this intrinsic defect combined with lipodystrophic “lipid pressure” due to decreased adipose tissue lipid storage capacity.
Fractures of the acetabulum in patients aged 60 years and older
Authors: Ferguson T. A. , Patel R. , Bhandari M. , Matta J. M. 
Published: February 2010

Using a prospective database of 1309 displaced acetabular fractures gathered between 1980 and 2007, we calculated the annual mean age and annual incidence of elderly patients > 60 years of age presenting with these injuries. We compared the clinical details and patterns of fracture between patients > 60 years of age (study group) with those < 60 years (control group). We performed a detailed evaluation of the radiographs of the older group to determine the incidence of radiological characteristics which have been previously described as being associated with a poor patient outcome. In all, 235 patients were > 60 years of age and the remaining 1074 were < 60 years. The incidence of elderly patients with acetabular fractures increased by 2.4-fold between the first half of the study period and the second half (10% (62) vs 24% (174), p < 0.001). Fractures characterised by displacement of the anterior column were significantly more common in the elderly compared with the younger patients (64% (150) vs 43% (462), respectively, p < 0.001). Common radiological features of the fractures in the study group included a separate quadrilateral-plate component (50.8% (58)) and roof impaction (40% (46)) in the anterior fractures, and comminution (44% (30)) and marginal impaction (38% (26)) in posterior-wall fractures. The proportion of elderly patients presenting with acetabular fractures increased during the 27-year period. The older patients had a different distribution of fracture pattern than the younger patients, and often had radiological features which have been shown in other studies to be predictive of a poor outcome.
Orthopaedic aspects of paediatric non-accidental injury
Authors: Jayakumar P. , Barry M. , Ramachandran M. 
Published: February 2010

Non-accidental injury (NAI) in children includes orthopaedic trauma throughout the skeleton. Fractures with soft-tissue injuries constitute the majority of manifestations of physical abuse in children. Fracture and injury patterns vary with age and development, and NAI is intrinsically related to the mobility of the child. No fracture in isolation is pathognomonic of NAI, but specific abuse-related injuries include multiple fractures, particularly at various stages of healing, metaphyseal corner and bucket-handle fractures and fractures of ribs. Isolated or multiple rib fractures, irrespective of location, have the highest specificity for NAI. Other fractures with a high specificity for abuse include those of the scapula, lateral end of the clavicle, vertebrae and complex skull fractures.Injuries caused by NAI constitute a relatively small proportion of childhood fractures. They may be associated with significant physical and psychological morbidity, with wide- ranging effects from deviations in normal developmental progression to death.Orthopaedic surgeons must systematically assess, recognise and act on the indicators for NAI in conjunction with the paediatric multidisciplinary team.
Perioperative Gene Expression Analysis for Prediction of Postoperative Sepsis
Authors: Hinrichs Carl , Kotsch Katja , Buchwald Sandra , Habicher Marit , Saak Nicole , Gerlach Herwig , Volk Hans-Dieter , Keh Didier 
Published: February 2010

Abstract
Background: Postoperative sepsis is one of the main causes of death after major abdominal surgery; however, the immunologic factors contributing to the development of sepsis are not completely understood. In this study, we evaluated gene expression in patients who developed postoperative sepsis and in patients with an uncomplicated postoperative course.
Methods: We enrolled 220 patients in a retrospective matched-pair, case–control pilot study to investigate the perioperative expression of 23 inflammation-related genes regarding their properties for predicting postoperative sepsis. Twenty patients exhibiting symptoms of sepsis in the first 14 days after surgery (case group) were matched with 20 control patients with an uncomplicated postoperative course. Matching criteria were sex, age, main diagnosis, type of surgery, and concomitant diseases. Blood samples were drawn before surgery and on the first and second postoperative days. Relative gene expression was analyzed with real-time reverse-transcription PCR.
Results: Significant differences (P &lt; 0.005) in gene expression between the 2 groups were observed for IL1B (interleukin 1, beta), TNF [tumor necrosis factor (TNF superfamily, member 2)], CD3D [CD3d molecule, delta (CD3-TCR complex)], and PRF1 [perforin 1 (pore forming protein)]. Logistic regression analysis and a subsequent ROC curve analysis revealed that the combination of TNF, IL1B, and CD3D expression had a specificity and specificity of 90% and 85%, respectively, and predicted exclusion of postoperative sepsis with an estimated negative predictive value of 98.1%.
Conclusions: These data suggest that gene expression analysis may be an effective tool for differentiating patients at high and low risk for sepsis after abdominal surgery.