bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of Prolonged Cholestatic Hepatitis Induced by Azithromycin in a Young Woman
Authors: Maggioli Caterina , Santi Luca , Zaccherini Giacomo , Bevilacqua Vittoria , Giunchi Francesca , Caraceni Paolo
Published: January 2012

Azithromycin, a semisynthetic macrolides, is frequently prescribed for the treatment of middle ear and upper respiratory tract infections, bronchitis, and community-acquired pneumonia. This antibiotic is usually well tolerated, and a rapid resolving cholestatic hepatitis has been described up to now only in six patients all, except one, over 65 years of age. We here report the case of a prolonged cholestatic hepatitis after administration of azithromycin in a young woman with no history of liver disease.
Asymmetry of Polarization Reversal and Current-Voltage Characteristics of Pt/PZT-Film/Pt:Ti/SiO2/Si-Substrate Structures
Authors: Bravina S. L. , Morozovsky N. V. , Costecalde J. , Soyer C. , Remiens D. , Deresmes D.
Published: January 2012

The characterization of the asymmetries of bipolar charge-voltage and current-voltage loops of polarization reversal and unipolar current-voltage curves for Pt/PZT-film/Pt:Ti/SiO2/Si-substrate systems was performed in the dynamic mode. The asymmetry of local deformation-voltage loops was observed by piezoresponse force microscopy. The comparison of the dependences of introduced asymmetry factors for the bipolar charge-voltage and current-voltage loops and unipolar current-voltage curves on drive voltage indicates the interconnection of ferroelectric and electrical space charge transfer asymmetries.
Creating Values for Sustainability: Stakeholders Engagement, Incentive Alignment, and Value Currency
Authors: Lorne Frank T. , Dilling Petra
Published: January 2012

A shareholder theory of firm and a stakeholder theory of firm may differ in their respective evaluation method of firm performance. Both theories however recognize the importance of value creation as the economic role of firms as institutions. The New Institutional Economics (NIE) emphasizes incentives alignment, while also viewing stakeholder engagements as methods to expand the boundaries of firms. The difference in performance evaluation between the two approaches can be reduced if stakeholders, while formulating incentive alignment, also evaluate the mechanisms of establishing a common currency value. The concomitant development of stakeholder engagement, incentive alignment, and value currency creation is argued to be an evolutionary process with the efficiency implications of the two theories tending to converge.
Recurrent Focal Segmental Glomerulosclerosis: A Discrete Clinical Entity
Authors: Torban Elena , Bitzan Martin , Goodyer Paul
Published: January 2012

Focal segmental glomerulosclerosis refers to a set of particular histopathologic lesions in which steroid-resistant podocyte injury leads to patchy adhesions between the glomerular tuft and Bowman's capsule, followed by progressive glomerulosclerosis and proteinuric renal failure. Because of the nonspecific nature of this lesion, it has been difficult to classify the various forms of primary nephrotic syndrome in children. However, with the recognition of hereditary FSGS caused by mutations podocyte slit diaphragm genes, it is increasingly clear that the steroid-resistant form of FSGS that recurs in the renal allografts (R-FSGS) constitutes a distinct clinical entity. Capitalizing on recent studies in which patients have been screened for slit diaphragm gene mutations, this review focuses on the natural history and pathogenesis of R-FSGS.
The Utilization of Waste Date Seed as Bio-Oil and Activated Carbon by Pyrolysis Process
Authors: Joardder Mohammad Uzzal Hossain , Uddin Md. Shazib , Islam Mohammad Nurul
Published: January 2012

The renovation of biomass waste in the form of date seed waste into activated carbon and biofuel by fixed bed pyrolysis reactor has been focused in this study to obtain gaseous, liquid, and solid products. The date seed in particle form is pyrolysed in an externally heated fixed bed reactor with nitrogen as the carrier gas. The reactor is heated from 400°C to 600°C. A maximum liquid yield of 50 wt.% and char of 30 wt.% are obtained at a reactor bed temperature of 500°C with a running time of 120 minutes. The oil is found to possess favorable flash point and reasonable density and viscosity. The higher calorific value is found to be 28.636 MJ/kg which is significantly higher than other biomass derived. Decolonization of 85–97% is recorded for the textile effluent and 75–90% for the tannery effluent, in all cases decreasing with temperature increase. Good adsorption capacity of the prepared activated carbon in case of diluted textile and tannery effluent was found.
Nucleic Acid-Based Therapy Approaches for Huntington's Disease
Authors: Vagner Tatyana , Young Deborah , Mouravlev Alexandre
Published: January 2012

Huntington's disease (HD) is caused by a dominant mutation that results in an unstable expansion of a CAG repeat in the huntingtin gene leading to a toxic gain of function in huntingtin protein which causes massive neurodegeneration mainly in the striatum and clinical symptoms associated with the disease. Since the mutation has multiple effects in the cell and the precise mechanism of the disease remains to be elucidated, gene therapy approaches have been developed that intervene in different aspects of the condition. These approaches include increasing expression of growth factors, decreasing levels of mutant huntingtin, and restoring cell metabolism and transcriptional balance. The aim of this paper is to outline the nucleic acid-based therapeutic strategies that have been tested to date.
Variability in the Responsiveness to Low-Dose Aspirin: Pharmacological and Disease-Related Mechanisms
Authors: Rocca Bianca , Petrucci Giovanna
Published: January 2012

The main pharmacological aspects of pharmacodynamics (PD) and pharmacokinetics (PK) of aspirin as antiplatelet agent were unravelled between the late sixties and the eighties, and low-dose aspirin given once daily has been shown to be a mainstay in the current treatment and prevention of cardiovascular disorders. Nevertheless, several PD and PK aspects of aspirin in selected clinical conditions have recently emerged and deserve future clinical attention. In 1994, the term “aspirin resistance” was used for the first time, but, until now, no consensus exists on definition, standardized assay, underlying mechanisms, clinical impact, and possible efficacy of alternative therapeutic interventions. At variance with an undefined aspirin-resistant status, in the last 5 years, the concept of variability in response to aspirin due to specific pathophysiological mechanisms and based on PK and/or PD of the drug has emerged. This growing evidence highlights the existence and possible clinical relevance of an interindividual variability of pharmacological aspirin response and calls for new, large studies to test new low-dose aspirin-based regimens which may ameliorate platelet acetylation, reduce variability in drug responsiveness, and improve clinical efficacy on selected populations.
On the Feasibility and Limitations of Just-in-Time Instruction Set Extension for FPGA-Based Reconfigurable Processors
Authors: Grad Mariusz , Plessl Christian
Published: January 2012

Reconfigurable instruction set processors provide the possibility of tailor the instruction set of a CPU to a particular application. While this customization process could be performed during runtime in order to adapt the CPU to the currently executed workload, this use case has been hardly investigated. In this paper, we study the feasibility of moving the customization process to runtime and evaluate the relation of the expected speedups and the associated overheads. To this end, we present a tool flow that is tailored to the requirements of this just-in-time ASIP specialization scenario. We evaluate our methods by targeting our previously introduced Woolcano reconfigurable ASIP architecture for a set of applications from the SPEC2006, SPEC2000, MiBench, and SciMark2 benchmark suites. Our results show that just-in-time ASIP specialization is promising for embedded computing applications, where average speedups of 5x can be achieved by spending 50 minutes for custom instruction identification and hardware generation. These overheads will be compensated if the applications execute for more than 2 hours. For the scientific computing benchmarks, the achievable speedup is only 1.2x, which requires significant execution times in the order of days to amortize the overheads.
An Improved Scoring Matrix for Multiple Sequence Alignment
Authors: Shu Jian-Jun , Yong Kian Yan , Chan Weng Kong
Published: January 2012

The way for performing multiple sequence alignment is based on the criterion of the maximum‐scored information content computed from a weight matrix, but it is possible to have two or more alignments to have the same highest score leading to ambiguities in selecting the best alignment. This paper addresses this issue by introducing the concept of joint weight matrix to eliminate the randomness in selecting the best multiple sequence alignment. Alignments with equal scores are iteratively rescored with the joint weight matrix of increasing level (nucleotide pairs, triplets, and so on) until one single best alignment is eventually found. This method for resolving ambiguity in multiple sequence alignment can be easily implemented by use of the improved scoring matrix.
A Method for Reviewing the Accuracy and Reliability of a Five-Level Triage Process (Canadian Triage and Acuity Scale) in a Community Emergency Department Setting: Building the Crowding Measurement Infrastructure
Authors: Howlett Michael K. , Atkinson Paul R. T.
Published: January 2012

Objectives.Triage data are widely used to evaluate patient flow, disease severity, and emergency department (ED) workload, factors used in ED crowding evaluation and management. We defined an indicator-based methodology that can be easily used to review the accuracy of Canadian Triage and Acuity Scale (CTAS) performance.Methods.A trained nurse reviewer (NR) retrospectively triaged two separate month’s ED charts relative to a set of clinical indicators based on CTAS Chief Complaints. Interobserver reliability and accuracy were compared using Kappa and comparative statistics.Results.There were 2838 patients in Trial 1 and 3091 in Trial 2. The rate of inconsistent triage was 14% and 16% (Kappa 0.596 and 0.604). Clinical Indicators “pain scale, chest pain, musculoskeletal injury, respiratory illness, and headache” captured 68% and 62% of visits.Conclusions.We have demonstrated a system to measure the levels of process accuracy and reliability for triage over time. We identified five key clinical indicators which captured over 60% of visits. A simple method for quality review uses a small set of indicators, capturing a majority of cases. Performance consistency and data collection using indicators may be important areas to direct training efforts.
Peroxisome Proliferator-Activator Receptorγ: A Link between Macrophage CD36 and Inflammation in Malaria Infection
Authors: Ren Yi
Published: January 2012

Severe malaria infection caused byPlasmodium falciparumis a global life-threatening disease and a leading cause of death worldwide. Intensive investigations have demonstrated that macrophages play crucial roles in control of inflammatory and immune responses and clearance ofPlasmodium-falciparum-parasitized erythrocytes (PE). This paper focuses on how macrophage CD36 recognizes and internalizes PE and participates the inflammatory signaling in response toPlasmodium falciparum. In addition, recent advances in our current understanding of the biological actions of PPARγ on CD36 and malaria clearance from the hosts are highlighted.
Root Canal Morphology of Mandibular First Permanent Molars in an Indian Population
Authors: Chourasia Hemant Ramesh , Meshram Ganesh K. , Warhadpande Manjusha , Dakshindas Darshan
Published: January 2012

Anin vitrostudy was performed to determine the number of roots, root canals per tooth, root canal configurations, and frequency of isthmi and apical deltas in mandibular first permanent molars in an Indian population. Hundred and fifty mandibular first permanent molars were collected and subjected to clearing technique. The cleared teeth were examined in a stereomicroscope under 7.5x magnifications. The canal configurations were categorized using Vertucci's classification. Overall 94.6% of the mandibular first molars had two roots, and 5.3% had extradistal roots (distolingual root). In addition, 64% of the specimens had three root canals, and 36% had four root canals. The most common canal configurations of mesial and distal roots were Vertucci type IV (54%) and type I (65.3%), respectively. Clinician should be aware of the complex root canal morphology of mandibular first molars among the Indian population before and during the root canal treatment.
Arthroscopic Bony Bankart Repair Using Double-Threaded Headless Screw: A Case Report
Authors: Kokubu Takeshi , Nagura Issei , Mifune Yutaka , Kurosaka Masahiro
Published: January 2012

We present a case of arthroscopic fixation for bony Bankart lesion using a double-threaded cannulated screw. A 39-year-old man sustained a left shoulder injury from a motorcycle accident. Radiographs showed bony Bankart lesion and CT revealed 40% defect of glenoid articular surface. Arthroscopic fixation was performed using double-threaded cannulated screw after the bony fragment was reduced by suturing the labrum at the edge with a suture anchor. Arthroscopic bony Bankart repair using double-threaded cannulated screw fixation is effective because compression force could be applied between bony fragments and the screw head is not exposed in the glenohumeral joint.
The Analytical and a Higher‐Accuracy Numerical Solution of a Free Boundary Problem in a Class of Discontinuous Functions
Authors: Sinsoysal Bahaddin
Published: January 2012

A new method is suggested for obtaining the exact and
numerical solutions of the initial‐boundary value problem for a nonlinear
parabolic type equation in the domain with the free boundary.
With this aim, a special auxiliary problem having some advantages
over the main problem and being equivalent to the main problem in
a definite sense is introduced. The auxiliary problem allows us to
obtain the weak solution in a class of discontinuous functions. Moreover,
on the basis of the auxiliary problem a higher‐resolution numerical
method is developed so that the solution accurately describes all
physical properties of the problem. In order to extract the significance
of the numerical solutions obtained by using the suggested auxiliary
problem, some computer experiments are carried out.
Plasmonic Properties of Vertically Aligned Nanowire Arrays
Authors: Qi Hua , Glembocki O. J. , Prokes S. M.
Published: January 2012

Nanowires (NWs)/Ag sheath composites were produced to investigate plasmonic coupling between vertically aligned NWs for surface‐enhanced Raman scattering (SERS) applications. In this investigation, two types of vertical NW arrays were studied; those of ZnO NWs grown on nanosphere lithography patterned sapphire substrate via vapor‐liquid‐solid (VLS) mechanism and Si NW arrays produced by wet chemical etching. Both types of vertical NW arrays were coated with a thin layer of silver by electroless silver plating for SERS enhancement studies. The experimental results show extremely strong SERS signals due to plasmonic coupling between the NWs, which was verified by COMSOL electric field simulations. We also compared the SERS enhancement intensity of aligned and random ZnO NWs, indicating that the aligned NWs show much stronger and repeatable SERS signal than those grown in nonaligned geometries.
Helicopter EMS Transport Outcomes Literature: Annotated Review of Articles Published 2007–2011
Authors: Brown Brandon S. , Pogue Korby A. , Williams Emily , Hatfield Jesse , Thomas Matthew , Arthur Annette , Thomas Stephen H.
Published: January 2012

Helicopter EMS (HEMS) and its possible association with outcomes improvement continues to be a subject of discussion. As is the case with other scientific discourse, debate over HEMS usefulness should be framed around an evidence-based assessment of the relevant literature. In an effort to facilitate the academic pursuit of assessment of HEMS utility, in late 2000 the National Association of EMS Physicians' (NAEMSP) Air Medical Task Force prepared annotated bibliographies of the HEMS-related outcomes literature. As a result of that work, two review articles, one covering HEMS use in nontrauma and the other in trauma, published in 2002 inPrehospital Emergency Caresurveyed HEMS outcomes-related literature published between 1980 and mid-2000. The project was extended with two subsequent reviews covering the literature through 2006. This review continues the series, outlining outcomes-associated HEMS literature for the three-year period 2007 through the first half of 2011.
In Vivo Computed Tomography as a Research Tool to Investigate Asthma and COPD: Where Do We Stand?
Authors: Dournes Gaël , Montaudon Michel , Berger Patrick , Laurent François
Published: January 2012

Computed tomography (CT) is a clinical tool widely used to assess and followup asthma and chonic obstructive pulmonary disease (COPD) in humans. Strong efforts have been made the last decade to improve this technique as a quantitative research tool. Using semiautomatic softwares, quantification of airway wall thickness, lumen area, and bronchial wall density are available from large to intermediate conductive airways. Skeletonization of the bronchial tree can be built to assess its three-dimensional geometry. Lung parenchyma density can be analysed as a surrogate of small airway disease and emphysema. Since resident cells involve airway wall and lung parenchyma abnormalities, CT provides an accurate and reliable research tool to assess their role in vivo. This litterature review highlights the most recent advances made to assess asthma and COPD with CT, and also their drawbacks and the place of CT in clarifying the complex physiopathology of both diseases.
Characterization and Clinical Evaluation of CD10+ Stroma Cells in the Breast Cancer Microenvironment
Authors: Desmedt Christine , Majjaj Samira , Kheddoumi Naima , Singhal Sandeep K. , Haibe-Kains Benjamin , El Ouriaghli Frank , Chaboteaux Carole , Michiels Stefan , Lallemand Françoise , Journe Fabrice , Duvillier Hughes , Loi Sherene , Quackenbush John , Dekoninck Sophie , Blanpain Cédric , Lagneaux Laurence , Houhou Nawal , Delorenzi Mauro , Larsimont Denis , Piccart Martine , Sotiriou Christos
Published: January 2012

Purpose: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10+ stromal cells, we aimed to better characterize this cell population and its clinical relevance.

Experimental Design: We developed a CD10+ stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10+ cells by coculture experiments of representative breast cancer cell lines with the different CD10+ stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets.

Results: This 12-gene CD10+ stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10+ cell types contribute to the CD10+ stroma signature, although mesenchymal stem cells have the highest CD10+ stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2+ subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients.

Conclusions: Our results highlight the importance of CD10+ cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2+ breast cancer disease. Clin Cancer Res; 18(4); 1004–14. ©2012 AACR.
Association of Hypothalamic-Pituitary-Adrenal Axis-Related Polymorphisms with Stress in Asthmatic Children on Inhaled Corticosteroids
Authors: Tsartsali Lemonia , Papadopoulos Marios , Lagona Evagelia , Papadimitriou Anastasios , Kanaka-Gantenbein Christina , Louizou Eirini , Kastania Anastasia , Priftis Kostas N. , Chrousos George
Published: January 2012

Objective: Long-term treatment of asthmatic children with low and moderate doses of inhaled corticosteroids (ICS) may result in mild adrenal suppression. Various associations have been shown between adrenal reactivity and single nucleotide polymorphisms (SNPs) related to the hypothalamic-pituitary-adrenal (HPA) axis. We aimed to investigate the genetic contribution of four HPA axis-related SNPs to the individual stress response when on ICS. Methods: The low dose Synacthen test was performed in 62 asthmatic children (43 males, median age 7.9 years) before and after 3 months of treatment with inhaled fluticasone (200 µg/day) or budesonide (400 µg/day). The SNPs determined were: rs1876828 and rs242941 in the corticotropin-releasing hormone receptor 1 (CRHR1) gene, T(-2C) in the promoter region of the melanocortin receptor 2 (MC2R) gene and BclI restriction fragment length polymorphsism in the glucocorticoid receptor (GR) gene. Results: Homozygotes for the variant rs242941 (TT) demonstrated a delayed cortisol response after treatment with ICS compared to heterozygotes (GT) (p = 0.033) and those with the wild-type (GG) genotype (p = 0.018). Homozygotes for the variant rs1876828 (AA) manifested lower baseline cortisol levels before treatment (p = 0.009) compared to the GG genotype and delayed cortisol response after treatment compared to the GA genotype (p = 0.05). BclI heterozygotes for the G allele (GC) demonstrated higher basal cortisol levels before and after treatment with ICS compared to homozygotes (CC) (p = 0.024, p = 0.018). Three SNP interactions were associated with serum cortisol levels. Conclusion: There is evidence of a contribution of HPA axis-related genetic variation to the stress response of asthmatic children on ICS. The clinical importance of this finding needs further elucidation.
Aquaporin 4 Antibodies in the Cerebrospinal Fluid Are Helpful in Diagnosing Chinese Patients with Neuromyelitis Optica
Authors: Long Youming , Qiu Wei , Lu Zhengqi , Bao Jian , Wu Aimin , Wang Yuge , Wang Honghao , Hu Xueqiang
Published: January 2012

Objective: It was the aim of this study to compare the diagnostic efficiency of anti-aquaporin 4 (AQP4) antibody detection between serum and cerebrospinal fluid (CSF) samples in Chinese patients with central nervous system demyelinating diseases. Methods: Anti-AQP4 antibodies were detected by a cell-based assay. We calculated the sensitivity, specificity and coherence in 118 patients with neuromyelitis optica (NMO, n = 39), multiple sclerosis (n = 34), longitudinally extensive transverse myelitis (LETM, n = 22), optic neuritis (ON, n = 6), opticospinal multiple sclerosis (n = 8) and acute partial transverse myelitis (n = 9). Results: Forty-four serum samples (33.8%) were positive for anti-AQP4 antibodies. Anti-AQP4 antibody seropositivity was 76.9, 59.1 and 16.7% in patients with NMO, LETM and ON, respectively. Sixty-five CSF samples (50%) were positive for anti-AQP4 antibodies. Anti-AQP4 antibody positivity was 87.1, 81.8, 83.3, 62.5 and 11.8% in patients with NMO, LETM, ON, opticospinal multiple sclerosis and multiple sclerosis, respectively. The ĸ value of the coherence test was 0.585 (p < 0.0001) between the two types of samples. The antibody positivity rate was significantly different between the two body fluids (p = 0.0008, McNemar test). The sensitivity and specificity were 74.3 and 100% in serum, 85.7 and 88.2% in CSF, and 94.3 and 88.2% for serum and CSF combined, respectively. Conclusion: The sensitivity of anti-AQP4 antibodies in the CSF was higher than that in the serum, and their combined use is helpful in diagnosing Chinese patients with NMO.
Interferon (Alpha, Beta and Omega) Receptor 2 Is a Prognostic Biomarker for Lung Cancer
Authors: Tanaka Sonosuke , Hattori Noboru , Ishikawa Nobuhisa , Horimasu Yasushi , Deguchi Naoko , Takano Atsushi , Tomoda Yoshitaka , Yoshioka Koji , Fujitaka Kazunori , Arihiro Koji , Okada Morihito , Yokoyama Akihito , Kohno Nobuoki
Published: January 2012

Objectives: It has been reported that the type I interferon receptor subunit, interferon (alpha, beta and omega) receptor 2 (IFNAR2), is overexpressed in several malignancies, primarily adenocarcinomas (ADCs); however, the biological significance of IFNAR2 in human lung cancer has not yet been studied. Methods: Immunohistochemical analysis of 113 surgically resected lung specimens was performed, and the results were evaluated in association with clinical variables, including survival. Serum concentrations of IFNAR2 were also determined by an enzyme-linked immunosorbent assay in 157 lung cancer patients and 164 healthy volunteers. Results: IFNAR2 overexpression was observed in all histological types of lung cancer examined. Furthermore, strong IFNAR2 expression was associated with shorter progression-free survival (PFS) and overall survival (OS) (p < 0.0001 and p = 0.0110, respectively) in non-small cell lung cancer patients. Multivariate analyses confirmed its independent prognostic value for PFS and OS (p < 0.0001 and p = 0.0222, respectively). IFNAR2 serum levels were also significantly higher in lung cancer patients than in healthy volunteers (p < 0.0001). Conclusions: IFNAR2 overexpression was observed in various histological types of lung cancer, and appears to be associated with lung cancers that behave aggressively. The results of this study strongly support the potential of IFNAR2 to be a prognostic biomarker for lung cancer.
Relationship between Urinary Tract Infection Categorization and Pathogens’ Antimicrobial Susceptibilities
Authors: Yamamichi Fukashi , Shigemura Katsumi , Matsumoto Minori , Nakano Yuzo , Tanaka Kazushi , Arakawa Soichi , Fujisawa Masato
Published: January 2012

Background: Urinary tract infections (UTIs) can be hard to treat and treatment plans need to include accurate categorization such as uncomplicated or complicated UTI, or catheterized or uncatheterized UTI. We investigated the antibiotic susceptibilities of representative uropathogens in UTI categories. Methods: We isolated uropathogens and analyzed their antimicrobial susceptibilities according to UTI categorization such as: (1) urology outpatients, urology inpatients, or other department inpatients; (2) uncomplicated or complicated UTIs; (3) upper or lower UTIs, and (4) non-catheterized or catheterized UTIs. Results:Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa were representative uropathogens. Susceptibilities to levofloxacin (LVFX) in E. coli in urology outpatients (p = 0.0179), those to ceftadizime in E. coli in other department inpatients (p = 0.0327), and those to LVFX in E. faecalis in complicated UTI (p = 0.0137) significantly decreased in these 3 years compared with the previous 3 years. Susceptibilities of upper UTI to LVFX in E. coli were significantly lower in the recent 4 years compared to lower UTI (p = 0.0452) and those of catheterized UTI to LVFX in E. faecalis were significantly lower than in non-catheterized UTI (p = 0.0153). Conclusions: Data demonstrated different tendencies of uropathogens’ antibiotic susceptibilities according to UTI categorizations and they could be useful for planning UTI treatments.
Prognostic Value of Arterial Pulse Wave Velocity in Peritoneal Dialysis Patients
Authors: Szeto Cheuk-Chun , Kwan Bonnie Ching-Ha , Chow Kai-Ming , Leung Chi-Bon , Law Man-Ching , Li Philip Kam-Tao
Published: January 2012

Background: Cardiovascular disease is the most common cause of mortality in chronic peritoneal dialysis (PD) patients. Increased arterial stiffness may be related to a high peritoneal permeability, resulting in fluid overload of PD patients. We examined the prognostic value and factors that govern the longitudinal change of arterial pulse wave velocity (PWV) in Chinese PD patients. Method: We enrolled 155 new PD patients. PWV was measured at baseline and then repeated after 2 years of follow-up. Results: At 24 months, the survival of patients with baseline carotid-femoral (CF)-PWV above 10 m/s was significantly worse than that of those with CF-PWV below 10 m/s (76.1 vs. 88.6%, p = 0.006). However, after adjusting for confounding factors, CF-PWV was not an independent predictor of survival. Amongst the 100 patients who had repeated PWV measurement after 2 years, the average CF-PWV increased from 9.92 ± 2.04 to 11.00 ± 2.30 m/s (p < 0.0001). The change in CF-PWV over 2 years significantly correlated with systolic blood pressure (r = 0.241, p = 0.036), serum calcium level (r = 0.231, p = 0.044), and normalized protein nitrogen appearance (NPNA) (r = –0.337, p = 0.001). Conclusions: A high baseline CF-PWV was associated with a lower overall survival of Chinese PD patients, but the prognostic value of CF-PWV disappeared after adjusting for confounding factors. After 2 years of PD, most patients had progressive increase in CF-PWV; the magnitude of increase is related to systolic blood pressure, serum calcium level, and baseline NPNA. Further study is needed to determine whether serial measurement of CF-PWV provides additional prognostic information.
A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired haemophilia A patients with anti-C2 autoantibodies
Authors: Matsumoto Tomoko , Ogiwara Kenichi , Shima Midori , Nogami Keiji
Published: January 2012

Acquired haemophilia A (AHA) is caused by the development of factor (F)VIII autoantibodies, demonstrating type 1 or type 2 inhibitory behaviour, and results in more serious haemorrhagic symptoms than in congenital severe HA. The reason(s) for this remains unknown, however. The global coagulation assays, thrombin generation tests and clot waveform analysis, demonstrated that coagulation parameters in patients with AHA-type 2 inhibitor were more significantly depressed than those in patients with moderate HA with similar FVIII activities. Thrombin and intrinsic FXa generation tests were significantly depressed in AHA-type 1 and AHA-type 2 compared to severe HA, and more defective in AHA-type 1 than in AHA-type 2. To investigate these inhibitory mechanism(s), anti-FVIII autoantibodies were purified from AHA plasmas. AHA-type 1 autoantibodies, containing an anti-C2 ESH4-epitope, blocked FVIII(a)-phospholipid binding, whilst AHA-type 2, containing an anti-C2 ESH8-epitope, inhibited thrombin-catalysed FVIII activation. The coagulation function in a reconstituted AHA-model containing exogenous ESH4 or ESH8 was more abnormal than in severe HA. The addition of anti-FIX antibody to FVIII-deficient plasma resulted in lower coagulation function than its absence. These results support the concept that global coagulation might be more suppressed in AHA than in severe HA due to the inhibition of FIXa-dependent FX activation by steric hindrance in the presence of FVIII-anti-C2 autoantibodies. Additionally, AHA-type 1 inhibitors prevented FVIIIa-phospholipid binding, essential for the tenase complex, whilst AHA-type 2 antibodies decreased FXa generation by inhibiting thrombin-catalysed FVIII activation. These two distinct mechanisms might, in part, contribute to and exacerbate the serious haemorrhagic symptoms in AHA.

Presented in abstract form at the 52nd annual meeting of the American Society of Hematology, Orlando, Florida, USA, December 6, 2010.
Upregulation of CD40 ligand and enhanced monocyte-platelet aggregate formation are associated with worse clinical outcome after ischaemic stroke
Authors: Dworacki Grzegorz , Kufel-Grabowska Joanna , Watala Cezary , Kozubski Wojciech , Lukasik Maria
Published: January 2012

The white blood cell count and mean platelet volume determined shortly after the symptom onset are known as independent predictors for clinical outcome after stroke. In the present study we sought to evaluate the prognostic value of platelet-derived inflammatory biomarkers measured prospectively after an ischaemic event. Using five-colour flow cytometry, the platelet surface expression of CD40L, CD62P and subpopulations of leukocyte-platelet aggregates were assessed in 93 stroke patients on the first (V0), 10th (V1) and 90th (V2) day after stroke, and once in 65 disease controls. The clinical outcome was evaluated using the Scandinavian Stroke Scale (SSS) and modified Rankin Scale (mRS) at the same time points as blood sampling and 24 months after the event. Patients with either CD40L surface expression or the percentage of monocyte-platelet aggregates (M-plt) in the third tertile (T3) at V0 had a significantly lower score on the SSS at V1. Patients with the percentage M-plt at V0 higher than the median value of M-plt in controls were at increased risk of SSS < 40 at V1 (odds ratio: 2.6; 95% confidence interval [CI]: 1.4 – 8.7; p=0.006). Patients with the percentage of M-plt in T3 at V0 showed progressive decline in survival (hazard ratio [HR]: 1.6; 95% CI: 1.1–1.9; p=0.02) and a significantly higher number of recurrent vascular events (HR: 2.64; 95% CI: 1.3–3.2; p=0.02) when compared to the first tertile. In conclusion, increased levels of M-plt could be a predictive marker for both early outcome and long-term prognosis while increased CD40L was correlated with worse clinical outcome.

The preliminary results of this study were presented in part during a poster session at the 62nd Annual Meeting of the American Academy of Neurology in Toronto, 7–17 April 2010.
A review of the two major regulatory pathways for non-proprietary low-molecular-weight heparins
Authors: Ofosu Frederick
Published: January 2012

With the expiry or pending expiry of originator low-molecular-weight heparin (LMWH) patents, pharmaceutical companies have invested in developing non-proprietary versions of LMWHs. LMWHs are manufactured by depolymerising highly purified unfractionated heparin. In contrast to traditional synthetic drugs with well-defined chemical structures, LMWHs contain complex oligosaccharide mixtures and the different manufacturing processes for LMWHs add to the heterogeneity in their physicochemical properties such that the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) consider existing originator LMWHs to be distinct medicinal entities that are not clinically interchangeable. The FDA views LMWHs as drugs and has approved two non-proprietary (generic) LMWHs, using the Abbreviated New Drug Application pathway. In contrast, the World Health Organization and the EMA view LMWHs as biological medicines. Therefore, the EMA and also the Scientific and Standardization Subcommittee on Anticoagulation of the International Society on Thrombosis and Haemostasis and the South Asian Society of Atherosclerosis and Thrombosis have all published specific guidelines for assessing non-proprietary (biosimilar) LMWHs. This manuscript reviews why there are two distinct pathways for approving non-proprietary LMWHs. Available literature on non-proprietary LMWHs approved in some jurisdictions is also reviewed in order to assess whether they satisfy the requirements for LMWHs in the three guidance documents. The review also highlights some of the significant difficulties the two pathways pose for manufacturers and an urgent need to develop a consensus governing the manufacture and regulation of non-proprietary LMWHs to make them more widely available.
The thrombin inhibitors hirudin and Refludan® activate the soluble guanylyl cyclase and the cGMP pathway in washed human platelets
Authors: Koessler Juergen , Kehrer Linda , Gambaryan Stepan , Walter Ulrich , Kobsar Anna
Published: January 2012

A number of direct thrombin inhibitors are successfully used clinically and experimentally as novel antithrombotics and specific anticoagulants. They are also used as anticoagulants in certain blood collection tubes for the analysis of platelet function. A series of platelet function tests have emerged to measure adequate responses to antiplatelet therapy. For comparative and practical reasons, it would be of advantage to use the same anticoagulant in blood collection tubes for different methods, e.g. thrombin inhibitors. However, there are little data on the effects of thrombin inhibitors on platelet signalling pathways that could influence results. We examined the applicability of thrombin inhibitor containing blood for platelet reactivity index (PRI) measurements of the VASP assay and investigated the effects of two thrombin inhibitors (hirudin and lepirudin) on cAMP- and cGMP-mediated signalling pathways in washed human platelets. We show that induction of VASP phosphorylation by PGE1 is markedly reduced in lepirudin containing blood samples. In consequence, PRI levels were highly variable compared to routinely used citrated blood. Surprisingly, in vitro incubation of platelets with thrombin inhibitors increases platelet cGMP levels and induces NOS independent sGC/PKG-mediated VASP phosphorylation. We conclude that thrombin inhibitors activate sGC/PKG-dependent pathways resulting in an increase of VASP phosphorylation which contributes to deviations in PRI measurements. These effects of thrombin inhibitors on sGC- and cGMP-mediated pathways including increased VASP phosphorylation may indicate the presence of an important additional platelet-based mechanism for the reduction of thrombus formation and thromboembolism by thrombin inhibitors.
Performance of five D-dimer assays for the exclusion of symptomatic distal leg vein thrombosis
Authors: Schwonberg Jan , Hecking Carola , Schindewolf Marc , Zgouras Dimitrios , Lehmeyer Susanne , Lindhoff-Last Edelgard , Luxembourg Beate
Published: January 2012

The diagnostic value of D-dimer (DD) in the exclusion of proximal deep-vein thrombosis (DVT) is well-established but is less well-known in the exclusion of distal (infrapopliteal) DVT. Therefore, we evaluated the diagnostic abilities of five DD assays (Vidas-DD, Liatest-DD, HemosIL-DD, HemosIL-DDHS, Innovance-DD) for excluding symptomatic proximal and distal leg DVT. A total of 243 outpatients whose symptoms were suggestive of DVT received complete compression ultrasonography (cCUS) of the symptomatic leg(s). The clinical probability of DVT (PTP) was assessed by Wells score. Thirty-eight proximal and 31 distal DVTs (17 tibial/fibular DVTs, 14 muscle DVTs) were diagnosed by cCUS. Although all assays showed high sensitivity for proximal DVT (range 97–100%), the sensitivity was poor for distal DVT (range 78–93%). None of the assays were individually able to rule out all DVTs as a stand-alone test (negative predictive value [NPV] 91–96%). However, a negative DD test result combined with a low PTP exhibited a NPV of 100% for all DVTs (including proximal, tibial/fibular, and muscle DVTs) with the HemosIL-DDHS and Innovance-DD. All proximal and tibial/fibular DVTs, but not all muscle DVTs, could be ruled out with this strategy using the Liatest-DD and Vidas-DD. The HemosIL-DD could not exclude distal leg DVT, even in combination with a low PTP. The combination of a negative DD with a low PTP showed a specificity of 32–35% for all DVTs. In conclusion, our study shows that when used in conjunction with a low PTP some DD assays are useful tools for the exclusion of distal leg DVT.
Sphingosine kinase inhibition exerts both pro- and anti-atherogenic effects in low-density lipoprotein receptor-deficient (LDL-R−/−) mice
Authors: Potì Francesco , Bot Martine , Costa Sara , Bergonzini Valeria , Maines Lynn , Varga Georg , Freise Hendrik , Robenek Horst , Simoni Manuela , Nofer Jerzy-Roch
Published: January 2012

Sphingosine 1-phosphate (S1P), a lysosphingolipid associated with high-density lipoprotein (HDL), contributes to the anti-atherogenic potential attributed to this lipoprotein. This study examined whether a reduction of S1P plasma levels affects atherosclerosis in a murine model of disease. LDL-R−/−mice on Western diet were given ABC294640, an inhibitor of sphingosine kinase (SphK) for 16 weeks. ABC294640 decreased plasma S1P by approximately 30%. However, ABC294640 failed to affect atherosclerotic lesion formation. Plasma triglycerides were reduced whereas total and HDL-cholesterol remained unchanged in course of ABC294640 treatment. ABC294640 increased plasma interleukin (IL)-12p70 and RANTES concentration as well as IL-12p70, RANTES and interferon (IFN)-γ production by peritoneal cells and this was paralleled by enhanced activity of peritoneal and spleen dendritic cells as evidenced by up-regulation of CD86 and MHC-II on CD11c+ cells. As a consequence, increased T-cell activation was noted in ABC294640-treated mice as indicated by enhanced CD4+ splenocyte proliferation, IFN-γ and IL-2 production, and CD69 expression. Con-comitantly, however, ABC294640 treatment redistributed CD4+ and CD8+ cells from blood to lymphatic organs and reduced T-cell number within atherosclerotic lesions. In addition, plasma sVCAM-1, sICAM-1, and MCP-1 levels as well as in vivo leukocyte adhesion and CCL19-induced T-cell penetration into peritoneum were lower in ABC294640-treated animals. In vitro experiments demonstrated reduced VCAM-1 and ICAM-1 expression and lymphocyte adhesion to endothelial cells exposed to ABC294640. In conclusion, treatment with SphK inhibitor leads to both pro- and anti-atherogenic effects in LDL-R−/− mice. As a consequence, SphK inhibition fails to affect atherosclerosis despite significant S1P reduction in plasma.
Abnormal inflammation leads to maternal coagulopathies associated with placental haemostatic alterations in a rat model of foetal loss
Authors: Falcón Bani J. , Cotechini Tiziana , Macdonald-Goodfellow Shannyn K. , Othman Maha , Graham Charles H.
Published: January 2012

Spontaneous pregnancy loss is often associated with aberrant maternal inflammation and systemic coagulopathies. However, the role of inflammation in the development of obstetric coagulopathies is poorly understood. Further, questions remain as to whether systemic coagulo-pathies are linked to placental haemostatic alterations, and whether these local alterations contribute to a negative foetal outcome. Using a model of spontaneous foetal loss in which pregnant rats are given a single injection of bacterial lipopolysaccharide (LPS), we characterised the systemic maternal coagulation status following LPS administration using thromboelastography (TEG), a global haemostatic assay that measures the kinetics of clot formation. Systemic maternal coagulopathy was evident in 82% of LPS-treated rats. Specifically, we observed stage-I, -II, and -III disseminated intravascular coagulation (DIC) and hypercoagulability. Modulation of inflammation through inhibition of tumour necrosis factor α with etanercept resulted in a 62% reduction in the proportion of rats exhibiting coagulopathy. Moreover, inflammation-induced systemic coagulopathies were associated with placental haemostatic alterations, which included increased intravascular, decidual, and labyrinth fibrin deposition in cases of DIC-I and hypercoagulability, and an almost complete absence of fibrin deposition in cases of DIC-III. Furthermore, systemic and placental haemostatic alterations were associated with impaired utero-placental haemodynamics, and inhibition of these haemostatic alterations by etanercept was associated with maintenance of utero-placental haemodynamics. These findings indicate that modulation of maternal inflammation may be useful in the prevention of coagulopathies associated with complications of pregnancy.
Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT
Authors: Tan Chee , Brighton Timothy A , McRae Simon , Baker Ross , Tran Huyen , Mollee Peter , Kershaw Geoffrey , Joseph Joanne , Ward Christopher , Morel-Kopp Marie-Christine ,   the ASTH Clinical Trials Group
Published: January 2012

Heparin-induced thrombocytopenia (HIT) remains a challenge, with diagnosis confirmed only by functional assays. The gold standard 14C-se-rotonin release assay (SRA) is highly sensitive but technically challenging and unsuitable for routine use. We conducted a large study to validate whole blood impedance aggregometry (WBIA) as a suitable diagnostic tool for HIT. WBIA and SRA were used to test 181 samples positive for H-PF4 antibodies by PaGIA or ELISA. Using the same high responder donor, 77 samples were positive by WBIA (aggregation with low-dose but not high-dose heparin). Using the strict definition for SRA positivity, 72 samples were true HIT. In nine samples, serotonin release with high-dose heparin dropped by > 50% but was still >20%; these were retested after a one-half dilution and 8/9 became positive. Ten other samples were discrepant between the two assays: one strongly positive (89% release) and six weakly positive samples by SRA (average release 56%) were WBIA negative. When these samples were retested using a random donor, only two remained SRA positive. Three samples were strongly WBIA positive but SRA negative; two were retested by SRA with 0.5IU/ml heparin and one became positive. Under controlled conditions, using the same selected high-responder donor, WBIA and SRA performed similarly with slightly increased sensitivity of the WBIA when using the strict definition of SRA positivity. WBIA is easy to perform with rapid turn-around time and warrants a multi-laboratory trial to complete its validation as a confirmatory assay for platelet-activating HIT antibodies.
Structure and haemostatic effects of generic versions of enoxaparin available for clinical use in Brazil: Similarity to the original drug
Authors: Glauser Bianca , Vairo Bruno , Oliveira Stephan-Nicollas , Cinelli Leonardo , Pereira Mariana , Mourão Paulo
Published: January 2012

Patent protection for enoxaparin has expired. Generic preparations are developed and approved for clinical use in different countries. However, there is still skepticism about the possibility of making an exact copy of the original drug due to the complex processes involved in generating low-molecular-weight heparins. We have undertaken a careful analysis of generic versions of enoxaparin available for clinical use in Brazil. Thirty-three batches of active ingredient and 70 of the final pharmaceutical product were obtained from six different suppliers. They were analysed for their chemical composition, molecular size distribution, in vitro anticoagulant activity and pharmacological effects on animal models of experimental thrombosis and bleeding. Clearly, the generic versions of enoxaparin available for clinical use in Brazil are similar to the original drug. Only three out of 33 batches of active ingredient from one supplier showed differences in molecular size distribution, resulting from a low percentage of tetrasaccharide or the presence of a minor component eluted as monosaccharide. Three out of 70 batches of the final pharmaceutical products contained lower amounts of the active ingredient than that declared by the suppliers. Our results suggest that the generic versions of enoxaparin are a viable therapeutic option, but their use requires strict regulations to ensure accurate standards.