bluuebunny/crossref_metadata_2025 huggingface dataset:
Cervicothoracic Intradural Arachnoid Cyst Misdiagnosed as Motor Neuron Disease
Authors: Sämann P. G. , Himmerich H. , Merl T. , Erös C. , Müller M. B. , Tonn J. C. , Buchwald B.
Published: June 2010

Recognizing syndromes which mimic ALS is crucial both to avoid giving this diagnosis erroneously and since there may be appropriate treatments. We report a 63-year-old woman diagnosed with possible ALS five years ago based on upper and lower motor neuron signs with typical electrophysiology and normal cranial MRI. At reassessment, spinal MRI revealed a cervicothoracic cyst with cord compression that was successfully treated neurosurgically. Histopathology confirmed an arachnoid origin as suspected from MRI. Spinal cysts may mimic ALS and need to be thoroughly excluded by appropriate imaging.
Foaming Behaviour, Structure, and Properties of Polypropylene Nanocomposites Foams
Authors: Antunes M. , Realinho V. , Velasco J. I.
Published: June 2010

This work presents the preparation and characterization of compression‐moulded montmorillonite and carbon nanofibre‐polypropylene foams. The influence of these nanofillers on the foaming behaviour was analyzed in terms of the foaming parameters and final cellular structure and morphology of the foams. Both nanofillers induced the formation of a more isometric‐like cellular structure in the foams, mainly observed for the MMT‐filled nanocomposite foams. Alongside their crystalline characteristics, the nanocomposite foams were also characterized and compared with the unfilled ones regarding their dynamic‐mechanical thermal behaviour. The nanocomposite foams showed higher specific storage moduli due to the reinforcement effect of the nanofillers and higher cell density isometric cellular structure. Particularly, the carbon nanofibre foams showed an increasingly higher electrical conductivity with increasing the amount of nanofibres, thus showing promising results as to produce electrically improved lightweight materials for applications such as electrostatic painting.
Design and Preparation of Cross‐Linked Polystyrene Nanoparticles for Elastomer Reinforcement
Authors: Lu Ming , Zhou Jianjun , Wang Liansheng , Zhao Wei , Lu Yonglai , Zhang Liqun , Liu Yakang
Published: June 2010

Cross‐linked polystyrene (PS) particles in a latex form were synthesized by free radical emulsion polymerization. The nano‐PS‐filled elastomer composites were prepared by the energy‐saving latex compounding method. Results showed that the PS particles took a spherical shape in the size of 40–60 nm with a narrow size distribution, and the glass‐transition temperature of the PS nanoparticles increased with the cross‐linking density. The outcomes from the mechanical properties demonstrated that when filled into styrene‐butadiene rubber (SBR), nitrile‐butadiene rubber (NBR), and natural rubber (NR), the cross‐linked PS nano‐particles exhibited excellent reinforcing capabilities in all the three matrices, and the best in the SBR matrix. In comparison with that of the carbon black filled composites, another distinguished advantage of the cross‐linked PS particles filled elastomer composites was found to be light weight in density, which could help to save tremendous amount of energy when put into end products.
Recurrent Endometrial Stromal Sarcoma: Treatment with a Progestin and Gonadotropin Releasing Hormone Agonist
Authors: duPont Nefertiti Chianti , DiSaia Philip John
Published: June 2010

Endometrial stromal sarcoma (ESS) formerly classified as low-grade endometrial stromal sarcoma is a rare uterine malignancy with a good prognosis despite a tendency to recur. Primary surgical management for ESS includes total abdominal hysterectomy and bilateral salpingo-oophorectomy. Patients with ESS have long disease-free survival rates when treated with primary surgical therapy, but nearly fifty percent of these patients will recur. We present the case of a patient with recurrent ESS who had an excellent response to combined therapy with megestrol and leuprolide.
Electrical Characteristics and Nanocrystalline Formation of Sprayed Iridium Oxide Thin Films
Authors: Mahmoud S. A. , Al-Shomar S. M. , Akl A. A.
Published: June 2010

Nanostructure and electrical properties of iridium oxide () thin films prepared by spray pyrolysis technique (SPT) have been experimentally characterized. The effect of solution molarity (SM) and substrate temperature () on the nanostructure features and electrical conductivity of these films has been investigated. The results of X-ray diffraction (XRD) showed that all samples prepared at with different SM, appear almost in amorphous form. XRD revealed that the films deposited at were tetragonal structures with a preferential orientation along direction. Moreover, the degree of crystallinity was improved by solution molarity. Single order Voigt profile method has been used to determine the nanostructure parameters at different SM and . The dark conductivity measurements at room temperature as a function of SM were observed and the value of conductivity were slightly increases at higher SM, reaching the bulk value of 20 . The values of activation energy of and of were found to be 0.21 eV and ·, respectively.
Cleavage of E-Cadherin by Matrix Metalloproteinase-7 Promotes Cellular Proliferation in Nontransformed Cell Lines via Activation of RhoA
Authors: Lynch Conor C. , Vargo-Gogola Tracy , Matrisian Lynn M. , Fingleton Barbara
Published: June 2010

Perturbations in cell-cell contact machinery occur frequently in epithelial cancers and result in increased cancer cell migration and invasion. Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin. This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG). Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium. Here, we show that MMP-7 processing of E-cadherin mediates, (1) loss of cell-cell contact, (2) increased cell migration, (3) a loss of epithelial cell polarization and (4) increased cell proliferation via RhoA activation. These data demonstrate that MMP-7 promotes epithelial cell proliferation via the processing of E-cadherin and provide insights into the molecular mechanisms that govern epithelial cell growth.
Using Estimated On-Site Ambient Temperature Has Uncertain Benefit When Estimating Postmortem Interval
Authors: Dourel Laurent , Pasquerault Thierry , Gaudry Emmanuel , Vincent Benoît
Published: June 2010

The forensic entomologist uses weather station data as part of the calculation when estimating the postmortem interval (PMI). To reduce the potential inaccuracies of this method caused by the distance between the crime scene and the meteorological station, temperature correlation data from the site of the corpse may be used. This experiment simulated the impact of retrospective weather data correction using linear regression between seven stations and sites in three climatic exposure groups during three different seasons as part of the accumulated degree days calculation for three necrophagous species (Diptera: Calliphoridae). No consistent benefit in the use of correlation or the original data from the meteorological stations was observed. In nine cases out of 12, the data from the weather station network limited the risk of a deviation from reality. The forensic entomologist should be cautious when using this correlation model.
The Diagrammatic Soergel Category and sl(2) and sl(3) Foams
Authors: Vaz Pedro
Published: June 2010

We define two functors from Elias and Khovanov′s diagrammatic Soergel category,
one targeting Clark‐Morrison‐Walker′s category of disoriented sl(2) cobordisms and the other targeting the category of (universal) sl(3) foams.
On Symmetric Transversal Designs STD8[24; 3]′s
Authors: Hatono Teppei , Suetake Chihiro
Published: June 2010

The existence of a class regular symmetric transversal design STDλ[3λ; 3] is equivalent to a generalized Hadamard matrix of order 3u over GF(3). Let nλ be the number of nonisomorphic STDλ[3λ; 3]′s. It is known that n1 = 1, n2 = 1, n3 = 4, n4 = 1, n5 = 0, n6 ≥ 20, and n7 ≥ 5. In this paper, it is shown that n8 ≥ 24.
Assembly and Dynamics of Myofibrils
Authors: Sanger Joseph W. , Wang Jushuo , Fan Yingli , White Jennifer , Sanger Jean M.
Published: June 2010

We review some of the problems in determining how myofibrils may be assembled and just as importantly how this contractile structure may be renewed by sarcomeric proteins moving between the sarcomere and the cytoplasm. We also address in this personal review the recent evidence that indicates that the assembly and dynamics of myofibrils are conserved whether the cells are analyzed in situ or in tissue culture conditions. We suggest that myofibrillogenesis is a fundamentally conserved process, comparable to protein synthesis, mitosis, or cytokinesis, whether examinedin situorin vitro.
Significance Test and Genome Selection in Bayesian Shrinkage Analysis
Authors: Che Xiaohong , Xu Shizhong
Published: June 2010

Bayesian shrinkage analysis is the state-of-the-art method for whole genome analysis of quantitative traits. It can estimate the genetic effects for the entire genome using a dense marker map. The technique is now called genome selection. A nice property of the shrinkage analysis is that it can estimate effects of QTL as small as explaining 2% of the phenotypic variance in a typical sample size of 300–500 individuals. In most cases, QTL can be detected with simple visual inspection of the entire genome for the effect because the false positive rate is low. As a Bayesian method, no significance test is needed. However, it is still desirable to put some confidences on the estimated QTL effects. We proposed to use the permutation test to draw empirical thresholds to declare significance of QTL under a predetermined genome wide type I error. With the permutation test, Bayesian shrinkage analysis can be routinely used for QTL detection.
Shells and Spheres: An n‐Dimensional Framework for Medial‐Based Image Segmentation
Authors: Cois Aaron , Galeotti John , Tamburo Robert , Sacks Michael , Stetten George
Published: June 2010

We have developed a method for extracting anatomical shape models fromn‐dimensional images using an image analysis framework we callShells and Spheres. This framework utilizes a set of spherical operators centered at each image pixel, grown to reach, but not cross, the nearest object boundary by incorporating “shells” of pixel intensity values while analyzing intensity mean, variance, and first‐order moment. Pairs of spheres on opposite sides of putative boundaries are then analyzed to determine boundaryreflectancewhich is used to further constrain sphere size, establishing a consensus as to boundary location. The centers of a subset of spheres identified asmedial(touching at least two boundaries) are connected to identify the interior of a particular anatomical structure. For the automated 3D algorithm, the only manual interaction consists of tracing a single contour on a 2D slice to optimize parameters, and identifying an initial point within the target structure.
Development of an Orthotopic Model of Invasive Pancreatic Cancer in an Immunocompetent Murine Host
Authors: Tseng William W. , Winer Daniel , Kenkel Justin A. , Choi Okmi , Shain Alan H. , Pollack Jonathan R. , French Randy , Lowy Andrew M. , Engleman Edgar G.
Published: June 2010

Purpose: The most common preclinical models of pancreatic adenocarcinoma utilize human cells or tissues that are xenografted into immunodeficient hosts. Several immunocompetent, genetically engineered mouse models of pancreatic cancer exist; however, tumor latency and disease progression in these models are highly variable. We sought to develop an immunocompetent, orthotopic mouse model of pancreatic cancer with rapid and predictable growth kinetics.

Experimental Design: Cell lines with epithelial morphology were derived from liver metastases obtained from KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice. Tumor cells were implanted in the pancreas of immunocompetent, histocompatible B6/129 mice, and the mice were monitored for disease progression. Relevant tissues were harvested for histologic, genomic, and immunophenotypic analysis.

Results: All mice developed pancreatic tumors by two weeks. Invasive disease and liver metastases were noted by six to eight weeks. Histologic examination of tumors showed cytokeratin-19–positive adenocarcinoma with regions of desmoplasia. Genomic analysis revealed broad chromosomal changes along with focal gains and losses. Pancreatic tumors were infiltrated with dendritic cells, myeloid-derived suppressor cells, macrophages, and T lymphocytes. Survival was decreased in RAG−/− mice, which are deficient in T cells, suggesting that an adaptive immune response alters the course of disease in wild-type mice.

Conclusions: We have developed a rapid, predictable orthotopic model of pancreatic adenocarcinoma in immunocompetent mice that mimics human pancreatic cancer with regard to genetic mutations, histologic appearance, and pattern of disease progression. This model highlights both the complexity and relevance of the immune response to invasive pancreatic cancer and may be useful for the preclinical evaluation of new therapeutic agents. Clin Cancer Res; 16(14); 3684–95. ©2010 AACR.
GDF-15 Contributes to Proliferation and Immune Escape of Malignant Gliomas
Authors: Roth Patrick , Junker Markus , Tritschler Isabel , Mittelbronn Michel , Dombrowski Yvonne , Breit Samuel N. , Tabatabai Ghazaleh , Wick Wolfgang , Weller Michael , Wischhusen Jörg
Published: June 2010

Purpose: Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-β family. GDF-15 is necessary for the maintenance of pregnancy but has also been linked to other physiologic and pathologic conditions.

Experimental Design: The expression of GDF-15 in glioma cell lines was assessed by quantitative reverse transcriptase-PCR and immunoblot. GDF-15 levels in situ and in the peripheral blood of glioma patients were examined by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The effects of short hairpin RNA-mediated GDF-15 inhibition on proliferation and immunogenicity of SMA-560 glioma cells were investigated by [methyl-3H]thymidine incorporation and immune-mediated target cell lysis. The impact of GDF-15 on glioma growth in vivo was assessed in syngeneic mice.

Results: GDF-15 is expressed by gliomas of different WHO grades as assessed by immunohistochemistry. The high expression of GDF-15 in tumor tissue translates into elevated GDF-15 serum levels in glioblastoma patients compared with healthy controls. GDF-15 mRNA and protein are also detectable in human and mouse glioma cells in vitro. Silencing of GDF-15 by RNA interference reduces the proliferation of malignant glioma cells. Immunologically, the depletion of glioma-derived GDF-15 enhances the susceptibility of mouse glioma cells towards syngeneic natural killer cells and splenocytes. This results in a reduced in vivo tumorigenicity and increased T-cell infiltration of GDF-15–deficient glioma cells in syngeneic mice.

Conclusions: Although previous studies focusing on ectopic overexpression of GDF-15 have proposed unclear or antitumorigenic effects of GDF-15 in glioma cells, we here show that GDF-15 at endogenous levels contributes to proliferation and immune escape of malignant gliomas in an immunocompetent host. Clin Cancer Res; 16(15); 3851–9. ©2010 AACR.
Pancreatobiliary Disorders Associated with Pancreaticobiliary Maljunction
Authors: Kamisawa Terumi , Honda Goro , Kurata Masanao , Tokura Michiyo , Tsuruta Koji
Published: June 2010

Aim: To clarify the features of biliary carcinomas and pancreatic disorders associated with pancreaticobiliary maljunction (PBM). Method: A total of 107 PBM patients with biliary dilatation were reviewed (52 with and 55 without PBM). Clinicopathological findings of biliary carcinomas, and acute or chronic pancreatitis were examined in association with PBM. We also investigated pancreatographic findings in PBM patients and the relationship to their clinical findings in view of pancreatic juice flow. Results:Gallbladder and bile duct carcinomas were seen in 11 (21%) and 8 (15%) of the 52 patients with PBM and biliary dilatation, respectively. In patients with PBM without biliary dilatation (n = 55), only gallbladder carcinoma was detected in 36 (65%) patients. At diagnosis, patients with gallbladder or bile duct carcinoma associated with PBM were younger than those without PBM (p < 0.01). Gallstones were detected only in 6% of the patients with PBM-associated gallbladder carcinoma. Multiple biliary carcinomas were detected in 3 patients (38%) with PBM-associated bile duct carcinoma. While 48 patients (60%) with biliary carcinoma and PBM had a normal pancreatic duct system, only 2 gallbladder carcinomas occurred in 11 dorsal pancreatic duct (DPD)-dominant patients (p < 0.05). Amylase concentration in the bile of DPD-dominant patients was significantly lower than that of patients with a normal pancreatic duct system (p < 0.05). Ten PBM patients had pancreatic disorders: acute pancreatitis (n = 3), chronic pancreatitis (n = 5), and pancreatic carcinoma (n = 2). Conclusions: In PBM patients, pancreatobiliary reflux frequently leads to biliary cancer, and biliopancreatic reflux often leads to acute or chronic pancreatitis. The biliary tract of PBM patients can be considered premalignant.
Juxtapapillary Duodenal Diverticula and Pancreatobiliary Disease
Authors: Egawa Naoto , Anjiki Hajime , Takuma Kensuke , Kamisawa Terumi
Published: June 2010

Juxtapapillary duodenal diverticula (JPD) are observed in around 10–20% of patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). They are acquired extraluminal outpouchings of the duodenal wall through ‘locus minoris resistance’ and their incidence increases with age. They have been studied mainly with regard to their association with pancreatobiliary disease. Choledocholithiasis is considered to be strongly associated with JPD, but the role of JPD in the development of cholecystolithiasis and pancreatitis is still disputable. Since JPD are located in the vicinity of the papilla of Vater, they not only cause mechanical compression of the bile duct but also induce dysfunction of the sphincter of Oddi. They are considered to lead to bile stasis and to allow reflux from the duodenum into the bile duct, which results in an ascending infection of β-glucuronidase-producing bacteria. The ERCP procedure can be hampered by JPD, although recent papers have reported no difference in the successful cannulation rate or complications between patients with JPD and those without JPD. Disorders caused by JPD are amenable to appropriate therapy, e.g. endoscopic sphincterotomy and surgical intervention.
Diagnosis of Ampullary Cancer
Authors: Ito Kei , Fujita Naotaka , Noda Yutaka , Kobayashi Go , Horaguchi Jun
Published: June 2010

Endoscopic papillectomy has been reported to be the treatment of choice in patients with ampullary adenoma. For ampullary cancer, pancreaticoduodenectomy is the standard treatment. Since neither lymphatic permeation, vascular invasion, nor lymph node metastasis is observed in patients with ampullary cancer limited to the mucosa, endoscopic resection of such tumors can be justified if no ductal infiltration into the bile or pancreatic duct is documented. For its application, accurate preoperative staging is mandatory. Transpapillary intraductal ultrasonography can provide useful information for making therapeutic decisions, especially in the selection of patients for endoscopic papillectomy.
Endoscopic Snare Excision of a Major Duodenal Papillary Tumor
Authors: Igarashi Yoshinori , Okano Naoki , Ito Ken , Mimura Takahiko , Nakano Shigeru
Published: June 2010

Background/Aims: Tumors of the duodenal papilla include hyperplasia, adenoma, carcinoma in adenoma, and carcinoma. Since the duodenal papilla has special anatomical characteristics and treatment involves major intervention, a correct preoperative diagnosis is essential for successful treatment. Methods: In patients with adenoma or early carcinoma of the papilla, endoscopic snare excision is indicated for complete removal of the tumor. Postoperative pancreatitis and cholangitis are major complications of endoscopic techniques, and we describe here in detail our procedure aiming to reduce the incidence of such complications. Results: Endoscopic snare excision of a tumor of the major duodenal papilla was carried out in 36 patients. Bleeding after endoscopic excision occurred in 6 cases (17%), postoperative pancreatitis in 11 cases (30%), and postoperative cholecystitis in 1 case (3%). All patients recovered from the complications within 1 week. Conclusion: Our results suggest that the procedure for endoscopic snare excision used to resect major papillary tumors is safe and helps to prevent serious complications.
A Patent Accessory Pancreatic Duct Prevents Pancreatitis following Endoscopic Retrograde Cholangiopancreatography
Authors: Tabata Taku , Kamisawa Terumi , Takuma Kensuke , Anjiki Hajime , Egawa Naoto
Published: June 2010

Background/Aim: Pancreatitis is the most common and feared complication of endoscopic retrograde cholangiopancreatography (ERCP). We previously examined patency of the accessory pancreatic duct (APD) by dye injection endoscopic retrograde pancreatography (ERP). APD patency was found in 43% of 291 control cases who had no particular changes in the head of the pancreas compared to only 6% in patients with acute pancreatitis. APD patency was closely related with the shape of the terminal portion of the APD. This study aimed to clarify whether patency of the APD prevents post-ERCP pancreatitis. Methods:We examined retrospectively the terminal shape of the APD by ERP in 34 patients with post-ERCP pancreatitis. Based on these data, patency of the APD was estimated from its terminal shape in patients with post-ERCP pancreatitis. Results: The stick-type APD (p < 0.01), which indicated high patency, was less frequent, and the branch-type APD (p < 0.01) and halfway-type APD, or no APD (p < 0.01), which showed quite low patency, were more frequent in patients with post-ERCP pancreatitis compared with controls. Accordingly, the estimated patency of the APD in post-ERCP pancreatitis patients was only 16%, which was significantly lower than the 43% in controls. There was no significant relationship between the estimated APD patency and the severity of post-ERCP pancreatitis. Conclusions: The estimated APD patency was significantly lower in patients with post-ERCP pancreatitis. A patent APD may function as a second drainage system to reduce the pressure in the main pancreatic duct and prevent post-ERCP pancreatitis.
Endoscopic Approach via the Minor Duodenal Papilla
Authors: Inui Kazuo , Yoshino Junji , Miyoshi Hironao
Published: June 2010

Background/Aims: We describe procedures for endoscopic approach via the minor papilla in symptomatic patients with pancreas divisum, pancreatic stones, and stricture of the Santorini’s duct, and neoplasms of the minor papilla: endoscopic minor papilla sphincterotomy, endoscopic pancreatic stone removal, endoscopic stent placement in Santorini’s duct, and resection of minor papilla neoplasms. Methods: The most important procedural detail was insertion of a guide wire into Santorini’s duct via the minor papilla, requiring gentle manipulation of both the cannula and guide wire to avoid subsequent complications such as pancreatitis. Results: Minor papilla sphincterotomy was most effective in the treatment of patients with pancreas divisum and associated with acute recurrent pancreatitis; these patients are the best candidates for endoscopic dorsal duct decompression including minor papilla sphincterotomy and stenting. Endoscopic treatment via the minor duodenal papilla was the only useful method for patients whose lesions could not be approached via the major papilla. It is a safe procedure to relieve pain. Long-term results of dorsal ductal stenting were satisfactory in 76 and 90% of patients (19/25 and 9/10, respectively). Conclusion: The high level of endoscopic skills necessary and the small number of patients who need these procedures should limit this approach to select institutions with appropriate endoscopic expertise.
Enhancing Functional Maturity before Preterm Birth
Authors: Hallman Mikko , Peltoniemi Outi , Kari M. Anneli
Published: June 2010

Enhancing functional maturity of the high-risk preterm fetus is aimed at decreasing the life-threatening neonatal disorders that increase the burden of chronic disease. A course of antenatal glucocorticoids before 35 weeks of pregnancy substitutes endogenous activation of the hypothalamic-adrenal axis that spontaneously enhances functional maturity and augments cytokine-induced preterm lung maturity. It is the main fetal therapy that decreases the functional prematurity-related neonatal morbidity in the era of surfactant therapy. Tocolytic agents potentiate the effect of glucocorticoids on the fetus. Repeating an antenatal glucocorticoid course may be recommended if the preterm fetus remains undelivered for more than 7 days and very preterm birth is imminent. However, the follow-up results are still incomplete, and available preliminary studies warn against adverse neurological and metabolic consequences following several antenatal repeat courses of glucocorticoids. Administration of glucocorticoids after 34 weeks of pregnancy may be considered in selected high-risk cases, preferably with documented lung immaturity. We recommend delaying elective delivery in low-risk pregnancies without established lung maturity until 40 weeks, unless labor starts earlier. In a selected high-risk population 17α-hydroxyprogesterone acetate decreases the prematurity rate. However, this drug has a limited impact on functional maturity of the preterm fetus and its effects on the development of the child remain to be studied further.
Cardiovascular and Thromboembolic Risk Factors in Idiopathic Sudden Sensorineural Hearing Loss: A Case-Control Study
Authors: Mosnier Isabelle , Stepanian Alain , Baron Gabriel , Bodenez Camille , Robier Alain , Meyer Bernard , Fraysse Bernard , Bertholon Pierre , Defay Fannie , Ameziane Nejma , Ferrary Evelyne , Sterkers Olivier , de Prost Dominique
Published: June 2010

Objective: The pathogenesis of idiopathic sudden sensorineural hearing loss (ISSHL) remains unknown, but vascular involvement is one of the main hypotheses. The main objective of this study was to investigate the association between ISSHL and cardiovascular and thromboembolic risk factors. Study Design: Multicentric case-control study. Methods: Ninety-six Caucasian patients with ISSHL and 179 sex- and age-matched controls were included. Patients were evaluated on the day of the inclusion and 1 week, 3 weeks and 3 months later. Clinical information concerning personal and familial cardiovascular and thromboembolic risk factors and concerning the ISSHL was collected. Blood samples were collected for genetic analysis of factor V Leiden and G20210A polymorphism in the factor II gene. The severity of the hearing loss was classified as mild (21–40 dB), moderate (41–70 dB), severe (71–90 dB) and profound or total (>90 dB). Hearing improvement was calculated as a relative improvement of hearing thresholds using the contralateral ear as baseline. Results: Systolic blood pressure was higher in patients (130 ± 1.7 mm Hg) than in controls (124 ± 1.1 mm Hg, p = 0.003). The personal/familial history of cardiovascular events was also more prevalent in patients (p = 0.023 and p = 0.014, respectively), whereas no difference was found in the prevalence of personal cardiovascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, smoking habits). There was no correlation between the audiogram type, the hearing outcome and the presence of cardiovascular risk factors. No significant difference was observed in the personal/familial history or in the presence of thromboembolic risk factors. The prothrombin and factor V mutations were uncommon in both patients and controls. The final hearing threshold was only correlated with the severity of the initial hearing loss (p < 0.001), but not influenced by the presence of vertigo, audiogram type, time elapsed from onset of ISSHL to hospitalization or failure of a previous oral therapy. Hearing stabilization was obtained at 21 days in 92% of patients. Conclusion: These results support the theory of vascular involvement as the etiology of some cases of ISSHL. The sole predictive factor of poor final hearing is the severity of the initial hearing loss.
Validation of the Jugular Venous Reflux Animal Model by Three-Dimensional Time-of-Flight MRA with a Clinical Scanner
Authors: Shieh Charng-Chyi , Hu Han-Hwa , Yang Shun-Tai , Lee Tsong-Hai , Hsu Jee-Ching , Wai Yau-Yau , Wong Ho-Fai , Chung Chih-Ping
Published: June 2010

Background and Purpose: A rat model of jugular venous reflux (JVR) is widely used in studies of cerebral arteriovenous fistula, cerebral venous hypertension and chronic cerebral hypoperfusion. However, methods to validate the effectiveness of the operation are needed. Methods: We performed neck 3-dimensional time-of-flight magnetic resonance angiography (MRA) with a clinical scanner in a rat model of JVR before and after the operation. High-resolution arterial angiography of the rat neck was acquired with maximum intensity projection. Results: In the JVR model, the success of the operation was validated by enhanced venous structures on MRA. The angiogram also provided information on the height of JVR and the status of other neck vessels. Conclusions: In conclusion, neck 3-dimensional time-of-flight MRA is a useful noninvasive method for monitoring the blood flow in multiple cerebral vessels in this animal model. It also revealed the height of JVR, collateral development and changes in vessels over time in longitudinal studies. This information should be considered in the evaluation of the animal model.
Risk of recurrent venous thromboembolism after a first oestrogen-associated episode
Authors: Gal Grégoire Le , Kovacs Michael , Carrier Marc , Do Kimberley , Kahn Susan , Wells Philip , Anderson David , Chagnon Isabelle , Solymoss Susan , Crowther Mark , Righini Marc , Lacut Karine , White Richard , Vickars Linda , Rodger Marc
Published: June 2010

The use of exogenous oestrogen in women with otherwise unprovoked venous thromboembolism (VTE) could be considered sufficient explanation to classify VTE as provoked if the risk of recurrent VTE after 3–6 months of anticoagulant treatment is similar to the risk of recurrent VTE observed after a surgery or prolonged immobilisation. Our objective was to assess the risk of recurrent VTE in women after a first unprovoked episode on oestrogen. The REVERSE study is a cohort study of patients with a first unprovoked VTE treated with anticoagulant treatment for 5–7 months. The risk of recurrent VTE during follow-up was compared between women users and non users of oestrogen at the time of index VTE. Among the 646 patients included, 314 were women, of them 67 were current users of oestrogen at the time of their VTE: 49 were on oral contraceptives and 18 on post-menopausal hormone replacement therapy (HRT). No significant association was found between oestrogen exposure, either oral contraceptives or HRT, and a lower risk of recurrent VTE after adjustment for age, or analysis restricted to women in the same age range as oestrogen contraceptives and HRT users, respectively. The risk of recurrent VTE is low in women after a first otherwise unprovoked oestrogen-associated VTE. However, this risk is not significantly lower than in women whose VTE was not related to oestrogen use.
Tissue factor and thrombosis: The clot starts here
Authors: Owens A. Phillip , Mackman Nigel
Published: June 2010

Thrombosis, or complications from thrombosis, currently occupies the top three positions in the cardiovascular causes of morbidity and mortality in the developed world. There are a limited number of safe and effective drugs to prevent and treat thrombosis. Animal models of thrombosis are necessary to better understand the complex components and interactions involved in the formation of a clot. Tissue factor (TF) is required for the initiation of blood coagulation and likely plays a key role in both arterial and venous thrombosis. Understanding the role of TF in thrombosis may permit the development of new antithrombotic drugs. This review will focus on the role of TF in in vivo models of thrombosis.
Regulation of von Willebrand factor-platelet interactions
Authors: Pegon Julie , Groot Evelyn , de Groot Philip , Lenting Peter
Published: June 2010

The formation of thrombi is a multistep process involving several components, including von Willebrand factor (VWF). VWF is an adhesive multimeric protein, which acts as a molecular bridge between the subendothelial matrix and the glycoprotein Ib/IX/V receptor complex. Furthermore, VWF promotes the expansion of the platelet plug by cross-linking platelets via binding to integrin αIIbβ3. In terms of thrombus formation, it is essential that VWF-platelet interactions occur timely, that is: it should happen not too early or too late. Given the co-existence of VWF and platelets in the circulation, this implies that there must be regulatory mechanisms that prevent premature formation of VWF-rich platelet aggregates that could occlude the vasculature. Indeed, several mechanisms have been identified at the level of VWF, which are dedicated to the prevention of excessive VWF-platelet interactions following endothelial release of VWF (which may include limited exposure to shear stress, the presence of Mg2+ ions, inhibition of VWF-platelet interactions by endothelial proteins, ADAMTS13-mediated proteolysis) and of circulating VWF-platelet aggregates during normal circulation (shielding of the platelet-binding A1 domain by other regions of the VWF molecule, inhibition of VWF-platelet interactions by β2-glycoprotein I). In the present review an overview of these mechanisms will be discussed.
FIX-Triple, a gain-of-function factor IX variant, improves haemostasis in mouse models without increased risk of thrombosis
Authors: Kao Chung-Yang , Lin Chia-Ni , Yu I-Shing , Tao Mi-Hua , Wu Hua-Lin , Shi Guey-Yueh , Yang Yung-Li , Kao Jau-Tsuen , Lin Shu-Wha
Published: June 2010

Engineered recombinant factor IX (FIX) with augmented clotting activity may prove useful for replacement therapy, but it has not been studied for risk of thrombosis. We used three mouse models to evaluate thrombosis risk associated with the FIX variant FIX-Triple, which has a 13-fold higher specific activity than wild-type FIX (FIX-WT). Protein infusion of FIX-Triple into haemophilia B mice was not thrombogenic, even at a dose of 13-fold higher than FIX-WT. Gene knock-in to generate mice that constitutively produce FIX-WT or FIX-Triple protein revealed that all mice expressed equal antigen levels. FIX-Triple knock-in mice that exhibited 10-fold higher FIX clotting activity did not show hypercoagulation. Adeno-associated viral (AAV) delivery of the FIX gene into mice was used to mimic gene therapy. Haemophilia B and inbred C57Bl/6 mice injected with different doses of virus particles carrying FIX-WT or FIX-Triple and expressing up to a nearly 13-fold excess (1289% of normal) of FIX clotting activity did not show increased risk of thrombosis compared with untreated wild-type mice in a normal haemostatic state. When challenged with ferric chloride (FeCl3), the mesenteric venules of AAV-treated C57Bl/6 mice that gave a nearly five-fold excess (474%) of FIX clotting activity were not thrombotic; however, thrombosis became obvious in FeCl3-challenged mice expressing extremely high FIX clotting activities (976–1289%) achieved by AAV delivery of FIX-Triple. These studies suggest that FIX-Triple is not thrombogenic at therapeutic levels and is a potential therapeutic substitute for FIX-WT.
A combined immunostimulatory and immunoinhibitory short interference RNA reduces hypercoagulability in a rat model of acute promyelocytic leukaemia
Authors: Sørensen Dag Reidar , Sioud Mouldy , Iversen Per Ole
Published: June 2010

Acute promyelocytic leukaemia (APL) confers an increased risk of thrombosis and bleeding. Current treatments are insufficient to inhibit these complications. We recently showed that a combined immunoinhibitory and immunostimulatory short interference (si) RNA effectively inhibited leukaemic growth and metastasis in rats with APL. We now asked if the reported anti-leukaemic effects of siRNA treatment could be explained by inhibition of hypercoagulability. We measured markers of coagulation and fibrinolysis in plasma collected from APL rats with overt leukaemia using conventional assays. Coagulopathy developed in untreated leukaemic rats evidenced by increase in several haemostatic markers. Treatment of leukaemic rats with the siRNA reduced (p < 0.05) the concentration of thrombin-anti-thrombin complex (a marker of coagulation) by 40% compared with rats treated with an inactive, control siRNA. Substantial reductions (p < 0.05) were also obtained for two markers of fibrinolysis: D-dimer (72%) and plasminogen activator inhibitor type 1 (51%). The activity of tissue factor, the main initiator of coagulation, was not increased (p > 0.05) in untreated leukaemic rats compared with healthy rats, and did not change (p > 0.05) upon treatment with the siRNA. The bifunctional siRNA reduces the hypercoagulable state in APL in addition to its direct anti-leukaemic properties, supporting testing of this small molecule in human APL.
Heme oxygenase-1 in neovascularisation: A diabetic perspective
Authors: Grochot-Przeczek Anna , Dulak Jozef , Jozkowicz Alicja
Published: June 2010

Neovascularisation is crucial both for physiological processes, like development, wound healing, tissue regeneration, hair growth or menstrual cycle, and for pathological states, such as tumour progression, retinopathy and psoriasis. Blood vessel formation is orchestrated by numerous pro-angiogenic and anti-angiogenic factors, acting together to keep tight rein on this complicated, desirable but also dangerous process. One of the proteins important for neovascularisation is heme oxygenase-1 (HO-1), an enzyme degrading heme. This review focuses on the role of HO-1 in angiogenesis and vasculogenesis, having a closer look at the significance of this system in diabetes.
Phagocytosis of platelet microvesicles and β2– glycoprotein I
Authors: Le Anhquyen , Prakasam Anthony , Abdel-Monem Hanan , Dasgupta Swapan , Thiagarajan Perumal
Published: June 2010

The majority of the antiphospholipid antibodies, present in patients with antiphospholipid syndrome, are directed against conformational epitopes in β2-glycoprotein I. β2-glycoprotein I is an anionic phospholipid- binding 50-kDa plasma protein whose physiological role is not clear. Here we investigate the role of β2-glycoprotein I in the phagocytosis of phosphatidylserine-expressing platelet microvesicles and the effect of autoantibodies to β2-glycoprotein I on this process. We labelled the glycans of β2-glycoprotein I with BODIPY (4,4-difluoro- 4-bora-3a,4a-diaza-s-indacene)-hydrazide without affecting its phospholipid binding capacity. BODIPY-β2-glycoprotein I bound to platelet microvesicles in a concentration-dependent manner and promoted the phagocytosis of platelet microvesicles by THP-1 derived macrophages in vitro at physiological plasma concentrations with a half maximal effect at ∼10 μg/ml. β2-glycoprotein I-stimulated phagocytosis was inhibited by annexin A5 and the phosphatidylserine-binding C1C2 fragment of lactadherin. Furthermore, immunoaffinity purified β2-glycoprotein I-dependent antiphospholipid antibodies from five patients with antiphospholipid syndrome inhibited the phagocytosis in a concentration- dependent manner. These studies suggest that the binding of β2-glycoprotein I to phosphatidylserine-expressing procoagulant platelet microvesicles may promote their clearance by phagocytosis and autoantibodies to β2-glycoprotein I may inhibit this process to induce a procoagulant state.
Evaluation of a new automated panel of assays for the detection of anti-PF4/heparin antibodies in patients suspected of having heparin-induced thrombocytopenia
Authors: Cini Michela , Pili Caterina , Boggian Ottavio , Frascaro Mirella , Palareti Gualtiero , Legnani Cristina
Published: June 2010

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin treatment; the prognosis depends on early and accurate diagnosis, and prompt start of alternative anticoagulants. Because of high sensitivity, the commercially available immunologic assays are widely used, though not suited to be run on single samples and with a turnaround time of 2–3 hours. We evaluated two new, rapid, automated, semi-quantitative chemiluminescent immunoassays in HIT suspected patients: HemosIL® AcuStar HIT-IgG(PF4-H) (specific for IgG anti- PF4/heparin antibodies) and HemosIL® AcuStar HIT-Ab(PF4-H) (detecting IgG, IgM and IgA anti-PF4/heparin antibodies) (both from Instrumentation Laboratory). A total of 102 patients with suspected HIT were included; HIT was diagnosed in 17 (16.7%). No false negative cases were observed using either the HemosIL AcuStar HIT-IgG(PF4-H) or the HITAb(PF4-H) assay (sensitivity and negative predictive values = 100%; negative likelihood ratios <0.01). The specificity was higher for the He-mosIL AcuStar HIT-IgG(PF4-H) in comparison with that of the HemosIL AcuStar HIT-Ab(PF4-H) (96.5% vs. 81.2%). Higher values of the HemosIL AcuStar HIT-IgG(PF4-H) were associated with increased probability of HIT. Patients with confirmed HIT and thrombotic complications had significantly higher levels of HemosIL AcuStar HIT-IgG(PF4-H) than those without thrombotic complications. The HemosIL AcuStar HIT-IgG(PF4-H) and HIT-Ab(PF4-H) assays showed a very high sensitivity, and therefore they can reliably be used to rule out HIT in suspected patients. The diagnostic specificity was greatly increased by using the HemosIL AcuStar HITIgG(PF4-H). Both the assays are reproducible (CVs <6%), rapid (turnaround time 30 minutes), automated, and semi-quantitative, and they can be run for single sample testing.
The in vitro effects of niacin on platelet biomarkers in human volunteers
Authors: Malinin Alex , Aradi Daniel , Kuliczkowski Wiktor , Norgard Nicholas , Boden William , Serebruany Victor
Published: June 2010

Niacin is a natural pyridine derivative, proven to favorably modulate the blood lipid profile by increasing levels of high-density lipoprotein (HDL) cholesterol, and by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp (a) lipoprotein concentrations. Considering that platelet activity is important in predicting vascular outcomes, and that HDL heavily constitutes platelet cellular membranes, we sought to evaluate the effect of niacin on human platelet activity indices. The blood obtained from 30 aspirin-naïve volunteers was preincubated with escalating concentrations of niacin in vitro. Platelet tests included whole blood and plasma aggregometry, rapid cartridgebased analyser, expression of major surface receptors by flow cytometry, and plasma prostaglandins by ELISA. Preincubation of blood with niacin at 0.3, 1.0 and 3.0 mM resulted in significant inhibition of maximal adenosine diphosphate (ADP)- (p=0.03), and collagen-induced platelet aggregation (p=0.01), and reduced activity by VerifyNow™ (p=0.007) bedside analyser. Surface platelet PAR-1 (MoAb WEDE-15; p=0.04), and vitronectin (CD51/CD61; p=0.02) receptors were up-regulated. Niacin was associated with a two- to three-fold increase of thromboxane B2, prostaglandins D2, and E2. Formation of platelet-monocyte microparticles (CD14+CD151), and expression of PECAM-1 (CD31), thrombospondin (CD36), GP IIb/IIIa (CD41a) antigen, and activity with MoAb PAC-1, GPIb (CD42b), P-selectin (CD62p), LAMP-3 (CD63), LAMP-1 (CD107a), CD40-ligand (CD154), GP37 (CD165), were not affected by niacin, suggesting no effect on prostacyclin release. In conclusion, niacin in vitro affects platelet activity by mildly inhibiting aggregation, and stimulating significant prostaglandin release, with mostly intact major platelet receptor expression. The effect of niacin is unique, differs from other known antiplatelet agents, and suggests potential opportunities for therapeutic combination, particularly in patients with low levels of HDL-C. These preliminary data, while intriguing, require confirmation in subjects receiving orally dosed extended-release niacin in order to determine whether these findings are clinically relevant.
Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice
Authors: Zufferey Paul , Baylot Denis , Nguyen Philippe , Borg Jeanne-Yvonne , Fontenay Michaela , Deygas Beatrice , Mismetti Patrick , Laporte Silvy , Delavenne Xavier ,   for the GETHCAM study group and POP-A-RIX investigators
Published: June 2010

Fondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.
Future perspective of induced pluripotent stem cells for diagnosis, drug screening and treatment of human diseases
Authors: Lian Qizhou , Chow Yenyen , Esteban Miguel , Pei Duanqing , Tse Hung-Fat
Published: June 2010

Recent advances in stem cell biology have transformed the understanding of cell physiology and developmental biology such that it can now play a more prominent role in the clinical application of stem cell and regenerative medicine. Success in the generation of human induced pluripotent stem cells (iPS) as well as related emerging technology on the iPS platform provide great promise in the development of regenerative medicine. Human iPS cells show almost identical properties to human embryonic stem cells (ESC) in pluripotency, but avoid many of their limitations of use. In addition, investigations into reprogramming of somatic cells to pluripotent stem cells facilitate a deeper understanding of human stem cell biology. The iPS cell technology has offered a unique platform for studying the pathogenesis of human disease, pharmacological and toxicological testing, and cell-based therapy. Nevertheless, significant challenges remain to be overcome before the promise of human iPS cell technology can be realised.