bluuebunny/crossref_metadata_2025 huggingface dataset:
CEO Commitment to the Status Quo: Replication and Extension Using Content Analysis
Authors: McClelland Patrick L. , Xin Liang  , Barker Vincent L.
Published: October 2009

A limited number of studies have identified multilevel determinants of chief executive officer (CEO) commitment to the status quo (CSQ). Using an unintrusive measure of CEO CSQ developed through computer-aided content analyses of CEO letters to shareholders, this study confirmed that determinants of CEO CSQ are multilevel, including factors at the individual (CEO age and tenure), organizational (size and financial slack), and industry (extent of industry discretion) levels of analysis. In addition, as an important extension to prior research, the authors find that CEO CSQ is associated with future performance changes depending on a firm’s industry environment. They find that in high-discretion industries, firms whose CEOs are committed to the status quo suffer future financial and market performance declines as compared with their competitors, whereas such performance deterioration does not occur in low-discretion environments. Indeed, when future performance is market based and measured as Tobin’s Q, the authors find that compared with competitors, a firm’s performance actually improves in low-discretion industries if its CEO is committed to the status quo.
Unintended Effects of Cranial Irradiation on Cognitive Function
Authors: Raber Jacob
Published: October 2009

This review summarizes some of the topics discussed at the 28th Annual Symposium of the Society of Toxicologic Pathology. The symposium was held in Washington, DC, in 2009 and dealt with unintended adverse events associated with cranial irradiation as part of cancer therapy. We will discuss the importance of considering genetic susceptibility and sex differences in susceptibility to develop these adverse events. Further, we will discuss potential mechanisms contributing to these events, including alterations in neurogenesis and increased oxidative stress following irradiation and potential alterations in synaptic and dendritic markers.
Oxidative stress in liver and red blood cells in acute lindane toxicity in rats
Authors: RadosavljeviĆ T. , MladenoviĆ D. , JakovljeviĆ V. , Vučvić D. , Rašć-Marković A. , Hrnčić D. , Djuric D. , StanojloviĆ O.
Published: October 2009

The aim of our study was to determine the role and dynamics of oxidative and nitrosative stress, as well as superoxide dismutase (SOD) and catalase activity in the hepatocytes and erythrocytes in early phase of acute lindane intoxication. Male Wistar rats were divided into groups: control, dimethylsulfoxide and lindane-treated groups (L, 8 mg/kg, intraperitoneally). Animals were sacrificed 0.5 and 4 hours after treatment (L0.5 and L4 groups, respectively). Oxidative and nitrosative stress parameters and antioxidant enzymes were determined spectrophotometrically. Liver and plasma thiobarbituric acid reactive substances (TBARS) concentration were significantly increased 0.5 after lindane administration (p < .01), with subsequent additional rise within 4 hours (p < .01), while plasma nitrite + nitrate level was significantly higher only 4 hours after lindane treatment. Total liver SOD activity was significantly increased in L4 group in comparison with control group (p < .01). In conclusion, oxidative and nitrosative stress play an important role in early phase of acute lindane hepatotoxicity. Antioxidant capacity of hepatocytes is partly increased, due to an adaptive increase in SOD activity.
Aconite poisoning presenting as hypotension and bradycardia
Authors: Chan Thomas YK
Published: October 2009

The principal toxic ingredients of aconite roots include aconitine, mesaconitine and hypaconitine, which are known cardiotoxins and neurotoxins. A 58-year-old man took a decoction of 11 g each of processed ‘chuanwu’ (the main root of Aconitum carmichaeli) and processed ‘caowu’ (the root of A. kusnezoffii) as treatment for his neck pain. One hour later, he experienced numbness of tongue and the four limbs, generalized weakness, nausea, vomiting, diarrhoea and dizziness. Three hours after ingestion, he was admitted to hospital. His blood pressure was 106/53 mmHg and heart rate 65 beats/min. Six hours after ingestion, he became hypotensive (systolic blood pressure <100 mmHg) with bradycardia (heart rate <60 beats/min). As treatments for the hypotension, he was given intravenous infusions of 0.9% saline (125 mL/hour) for 15 hours (7-21 hours after ingestion) and dopamine (3 μg/kg/min) for 36 hours (10-45 hours after ingestion). He was given atropine 0.6 mg intravenously 7 and 24 hours after ingestion. He was hypotensive for 31 hours (6-36 hours after ingestion), with a systolic blood pressure of 84-106 mmHg (mean 93.5) and a diastolic blood pressure of 40-59 mmHg (mean 51.8). He had bradycardia for 36 hours (6-41 hours after ingestion), with a heart rate of 45-68 beats/min (mean 56.5). On discharge (48 hours after ingestion), his blood pressure was 117/82 mmHg and heart rate 70 beats/min. In patients with aconite poisoning, prolonged hypotension and sinus bradycardia may occur and supportive therapy with close monitoring of blood pressure and cardiac rhythm are essential.
Discordant assessment of lupus activity between patients and their physicians: the Singapore experience
Authors: Leong KP , Chong EYY , Kong KO , Chan SP , Thong BYH , Lian TY , Chng HH , Koh ET , Teh CL , Lau TC , Law WG , Cheng YK , Badsha H. , Chew LC , Yong WH , Howe HS
Published: October 2009

Patients with systemic lupus erythematosus often assess their disease activity differently from their physicians. We studied the factors associated with this discordance. The data provided by 534 systemic lupus erythematosus patients were analyzed. We compared the physician and patient assessments of lupus activity on a visual-assessment scale from the same visit. We collected clinical data and scores from MOS 36-Item Short-Form Health Survey, Systemic Lupus Erythematosus Quality-of-Life Questionnaire, Rheumatology Attitudes Index, Systemic Lupus Erythematosus Disease Activity Index, and revised Systemic Lupus Activity Measure. Patients tended to score their disease activity higher than do their physicians, when these factors were present: poorer general health assessment, presence of thrombocytopenia, hypertension and urinary sediments, and difficulty in carrying groceries. Physicians tended to score the disease activity higher than do the patients in these circumstances proteinuria, hemolysis, use of azathioprine or cyclophosphamide, tiredness, photosensitivity, higher revised Systemic Lupus Activity Measure score, casturia, and patient report of being more easily ill than are other patients. There was only moderate correlation between the discordance in the baseline and the subsequent visits. The physician assessment of disease activity at baseline correlated better with an objective measure of disease activity (revised Systemic Lupus Activity Measure) in the subsequent visit than the patient assessment. In conclusion, discordance in the perception of disease activity between patients and physicians may be amenable to intervention.
Combined central retinal artery and vein occlusion in a patient with systemic lupus erythematosus and anti-phospholipid syndrome
Authors: Chang P-C. , Chen W-S. , Lin H-Y. , Lee H-M. , Chen S-J.
Published: October 2009

Combined central retinal artery occlusion and central retinal venous occlusion have been rarely reported in patients with systemic lupus erythematosus and anti-phospholipid syndrome. The impact of this severe vaso-occlusive disease on vision is usually devastating and permanent in spite of vigorous treatment. We report herein a 35-year-old female patient displaying a transient and reversible process. Her best-corrected visual acuity improved from 6/60 to 6/8.6 1 day later, before the initiation of systemic corticosteroid and anticoagulant treatment. The retina regained a normal appearance with her vision recovering to 6/6 2 weeks after the episode of temporary vision loss. Her rapid recovery suggests that continued anti-coagulation therapy and close follow-up to prevent severe complications and recurrent thrombosis is warranted. Lupus (2010) 19, 206—209.
Polymorphisms in the DNA repair gene XRCC1 and associations with systemic lupus erythematosus risk in the Taiwanese Han Chinese population
Authors: Lin Y-J. , Wan L. , Huang C-M. , Chen S-Y. , Huang Y-C. , Lai C-H. , Lin W-Y. , Liu H-P. , Wu Y-S. , Chen C-M. , Tsai Y-H. , Tsai C-H. , Sheu JJ-C , Tsai F-J.
Published: October 2009

XRCC1 plays a central role in mammalian DNA repair processes. Two polymorphisms of XRCC1, rs1799782 (Arg > Trp at codon 194) and rs25487 (Arg > Gln at codon 399), are common in the Han Chinese population. Our objective was to analyze the relationship between these two functional single-nucleotide polymorphisms (SNPs) and systemic lupus erythematosus (SLE) in the Taiwanese Han Chinese population. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) on 172 SLE patients and 160 normal controls. Our data indicate that the frequency of A/G at codon 399 differed between patients and controls (p = 0.01; odds ratio: 1.80; 95% confidence interval: 1.17—2.75), but the allelic frequency analysis did not reveal significant differences. For the SNP at codon 194, there were no differences in either allelic or genotype frequencies between SLE patients and normal subjects. Clinical association studies of SLE symptoms revealed the involvement of the A/G polymorphism at codon 399 in SLE pathogenesis. Our results indicate that a functional SNP at codon 399 of XRCC1 is associated with the development of SLE. Lupus (2009) 18, 1246—1251.
“What a Long, Strange Trip It’s Been…”: Twenty-Five Years of Qualitative and New Paradigm Research
Authors: Lincoln Yvonna S.
Published: October 2009

Tracking the history of qualitative research is to some extent a personal journey, reflective of the individual's own experience in the field. Many scholars participated in the ongoing dialogue around the shift from a solely positivist model of research to a multiple-models context. There still remain some philosophical and practical problems, around which the field will be in dialogue for some time to come. Those problems include the issue of rapport, especially in the face of an increasingly critical turn in the social sciences, and the stances adopted for mixed-methods models. Conversations around these and other issues have never been more urgent, in light of the National Research Council's press for a return to conventional scientific inquiry.
Disease progression among multiple sclerosis patients before and during a disease-modifying drug program: a longitudinal population-based evaluation
Authors: Veugelers PJ , Fisk JD , Brown MG , Stadnyk K. , Sketris IS , Murray TJ , Bhan V.
Published: October 2009

Randomized controlled trials have demonstrated the efficacy of disease-modifying drugs (DMDs) in persons with relapsing—remitting multiple sclerosis (MS) and secondary progressive MS with superimposed relapses. However, these brief studies of selected patients have focused mainly on reducing attacks and must be complemented by evaluations in ‘realworld’ clinical settings to establish the effectiveness of DMD programs in slowing disease progression and to inform health policy and program decision-making. We assessed the effectiveness of DMDs as administered in a comprehensive publicly funded drug insurance program that provides DMDs to a geographically defined population of MS patients who meet specific eligibility criteria. Data from 1752 MS patients (10,312 assessments) seen between 1980 and 2004 at a regional MS Clinic serving the entire population of Nova Scotia, Canada were analysed. Using survival methods we observed a statistically significant reduction in disease progression to specific Expanded Disability Status Scale endpoints following the introduction of this program. Subgroup analyses of patients eligible for treatment using hierarchical linear regression methods also suggested that disease progression was slowed in patients treated with the first DMD prescribed. These findings provide evidence supporting DMD program effectiveness that can be used to inform the broader implementation of such programs.
The epidemiology of injury in the Republic of Lithuania
Authors: Lunevicius Raimundas , Stevens Kent A. , Puvanachandra Prasanthi , Hyder Adnan A.
Published: October 2009

Aims: The overall goal of this paper is to highlight the epidemiology of injury in Lithuania between 1998 and 2006. Such a situation analysis will inform the important dialogue happening in Lithuania with respect to renewal of the trauma programme and help to profile the burden of injury in the country. Methods: Review of the literature, and secondary analysis of data from the Lithuanian Health Information Center and the European Detailed Mortality database. Results: Sixteen articles were identified as population-based studies; only incidence of burn injuries was reported as 240 per 100,000 per year. According to our analysis, the overall incidence of injury increased from 76 cases per 1,000 individuals in 1998 to 121 cases per 1,000 individuals in 2006. The total number of deaths from external causes remained similar with an average of 5,301 per year, as did the age-standardized mortality rates of 152 in 1998 and 150 per 100,000 in 2006. The mortality rate in men was four times higher than in women. Suicide was the most frequent cause of death (34% in 2006); while road traffic injuries were the second most frequent accounting for 17—19% of deaths. There were 429 deaths due to exposure to natural cold in 2006, which constituted 8% of all deaths due to injury. Conclusions: Injury incidence and mortality from external causes in Lithuania has not declined over an eight year time frame. New efforts should be launched in the health sector to address this major cause of deaths.
Greenlandic adoptees’ psychiatric inpatient contact. A comparative register-based study
Authors: Laubjerg Merete , Petersson Birgit
Published: October 2009

Aims: The aim is to highlight adoptees’ and stepchildren’s psychiatric contact and diagnoses compared with non-adoptees. Methods: The setting is Greenland and the methodology is a comparative in-ward patient register-based study. The background is the Greenlandic tradition for adoption and community child care and international research stressing that adoptees demonstrate adverse health outcomes. The cohort is in-ward patients (>24 hours), born between 1973 and 2005. Correlation between various dependent and independent variables are analyzed. The research makes different comparative statements of psychiatric admissions and diagnoses related to adoptees and stepchildren compared to non-adoptees with respect to demographic and socioeconomic indicators. The psychiatric data material is collected from 1992 to 2008 and the socioeconomic indicators are included from 1996. Results: The findings show, contrary to findings related to adoptees in Western societies, that being an adoptee in Greenland does not increase the risk for psychiatric admission, but being a ‘‘female stepchild’’ does. The adjusted risk for adoptees is ‘‘non-significant’’ at 1.1 (95% confidence interval (95% CI) 0.6— 1.9) but the adjusted risk for female stepchildren is ‘‘significant’’ at 3.4 (95% CI 1.8—6.6). The most frequent diagnosis is ‘‘Inherent or acquired brain suffering’’. The findings open up possibilities for new hypotheses as to reasons for adoptees’ adverse health outcomes in the Western world. Conclusions: Epidemiological and medical contact recording do not exist outside central hospital level in Greenland, therefore, in order to put psychiatric contact patterns into perspective, in-depth field studies are required in close collaboration with the local Greenlandic population.
Development of selective non-peptide angiotensin II type 2 receptor agonsists
Authors: Alterman Mathias
Published: October 2009

The development of the first drug-like selective angiotensin II type 2 (AT2) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT1) receptor/AT2receptor agonist L-162,313 is presented. Compound 22 with a Kivalue of 0.4 nM for the AT2receptor and a Ki> 10 μM for the AT1receptor induces outgrowth of neurite cells, stimulates p42/p44mapk, enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats and lowers the mean arterial blood pressure in anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT2receptor. In addition, Compound 22 has a bioavailability of 20—30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT2receptor in more detail.
Reflections on Leadership from the Perspective of an African American Woman of Faith
Authors: Walker Shirley A.
Published: October 2009

This article centers on faith and spirituality in the lived experiences of African American women in predominantly White organizations. Faith and spirituality are discussed as sources for coping and surviving adverse situations that emerge from intersectionality in these types of environments. The author gives personal reflections on how faith and spirituality have informed her experiences in various leadership roles. In this article, a historical and cultural background of faith and spirituality in the leadership experiences of African American women leaders will be emphasized. The discussion will include ways that faith and spirituality have provided a safe haven for African American women leaders when facing adversities in predominantly White organizations.
The lipid A of Burkholderia multivorans C1576 smooth-type lipopolysaccharide and its pro-inflammatory activity in a cystic fibrosis airways model
Authors: Ieranò Teresa , Cescutti Paola , Leone Maria Rosaria , Luciani Alessandro , Rizzo Roberto , Raia Valeria , Lanzetta Rosa , Parrilli Michelangelo , Maiuri Luigi , Silipo Alba , Molinaro Antonio
Published: October 2009

Cystic fibrosis is an autosomal recessive disorder and it is characterised by chronic bacterial airway infection which leads to progressive lung deterioration, sometimes with fatal outcome. Burkholderia multivorans and Burkholderia cenocepacia are the species responsible for most of the infections of cystic fibrosis patients. Lipopolysaccharide endotoxins (LPSs) are among the foremost factors of pathogenesis of Gram-negative infection and, in particular, lipid A is the endotoxic portion of LPS responsible for eliciting host innate immune response. In this work, the complete primary structure of the lipid A from B. multivorans C1576 has been defined and, further, its pro-inflammatory activity in a cystic fibrosis airways model is shown. The structure of B. multivorans lipid A was attained by chemical, mass spectrometry and nuclear magnetic resonance analyses whereas its biological activity was assessed on the intestinal epithelial cell line CACO-2 cells, on the airway epithelial IB3-1 cells, carrying the ΔF508/W1282X CFTR mutation and on an ex vivo model of culture explants of nasal polyps.
Expression of NOD2 is increased in inflamed human dental pulps and lipoteichoic acid-stimulated odontoblast-like cells
Authors: Keller Jean-François , Carrouel Florence , Staquet Marie-Jeanne , Kufer Thomas A. , Baudouin Caroline , Msika Philippe , Bleicher Françoise , Farges Jean-Christophe
Published: October 2009

Human odontoblasts trigger immune response s to oral bacteria that invade dental tissues during the caries process. To date, their ability to regulate the expression of the nucleotide-binding domain leucine-rich repeat containing receptor NOD2 when challenged by Gram-positive bacteria is unknown. In this study, we investigated NOD2 expression in healthy and inflamed human dental pulps challenged by bacteria, and in cultured odontoblast-like cells stimulated with lipoteichoic acid (LTA), a Toll-like receptor (TLR) 2 agonist which is specific for Gram-positive bacteria. We found that NOD2 gene expression was significantly up-regulated in pulps with acute inflammation compared to healthy ones. In vitro, LTA augmented NOD2 gene expression and protein level in odontoblast-like cells. The increase was more pronounced in odontoblast-like cells compared to dental pulp fibroblasts. Blocking experiments in odontoblast-like cells with anti-TLR2 antibody strongly reduced the NOD2 gene expression increase, whereas stimulation with the synthetic TLR2 ligand Pam2CSK4 confirmed NOD2 gene up-regulation following TLR2 engagement. These data suggest that NOD2 up-regulation is part of the odontoblast immune response to Gram-positive bacteria and might be important in protecting human dental pulp from the deleterious effects of cariogenic pathogens.
Sleep disorders and their management in patients with COPD
Authors: Sharafkhaneh Amir , Jayaraman Gnananandh , Kaleekal Thomas , Sharafkhaneh Hossein , Hirshkowitz Max
Published: October 2009

Chronic obstructive pulmonary disease (COPD) is a prevalent progressive condition that adversely affects quality of life and sleep. Patients with COPD suffer from variety of sleep disorders including insomnia, sleep disordered breathing and restless leg syndrome. The sleep disorders in COPD patients may stem from poor control of primary disease or due to side effects of pharmacotherapy. Thus, optimization of COPD therapy is the main step in treating insomnia in these patients. Further, pharmacotherapy of sleep disorders may result in respiratory depression and related complications. Therefore, clear understanding of respiratory physiology during transition from wakefulness to sleep and during various stages of sleep plays an important role in therapies that are recommended in patients with significant airway obstruction. In this publication, we review respiratory physiology as it relates to sleep and discuss sleep disorders and their management in patients with COPD.
Characterisation of exacerbations of chronic bronchitis and COPD in Europe: the GIANT study
Authors: Miravitlles Marc , Anzueto Antonio , Ewig Santiago , Legnani Delfino , Stauch Kathrin
Published: October 2009

Objective: The GIANT study collected information on patients with acute exacerbations of chronic bronchitis (AECB) and chronic obstructive pulmonary disease (COPD) and the effect of treatment with moxifloxacin.

Methods: AECB history, concomitant diseases, moxifloxacin treatment, concomitant medication, clinical symptoms and adverse events were recorded. A questionnaire at the end of treatment recorded the impact on patients’ daily lives.

Results: Among 9225 patients from eight European countries, marked variation was seen in characteristics including age, smoking history and type of exacerbation. Spirometry use was more common among chest physicians (66.7%) than GPs (15.5%). Patients with Anthonisen type 1 and 2 exacerbations had more frequent exacerbations and these patients experienced a greater impact on daily activities compared with patients with type 3 episodes. Patient symptoms improved with moxifloxacin treatment after a mean (SD) of 3.4 (1.8) days, allowing return to normal daily activities after 5.4 (4.4) days and with full recovery taking 6.5 (3.1) days.

Conclusions: Characteristics of patients with AECB and acute exacerbations of COPD differ among European countries. Spirometry is under-used, particularly in primary care and antibiotic treatment does not always follow current guidelines. Results confirm the efficacy of moxifloxacin in the treatment of AECB in real-life conditions.
Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway
Authors: Yang Jun , Liu Xin , Nyland Susan B. , Zhang Ranran , Ryland Lindsay K. , Broeg Kathleen , Baab Kendall Thomas , Jarbadan Nancy Ruth , Irby Rosalyn , Loughran Thomas P.
Published: October 2009

Large granular lymphocyte (LGL) leukemia results from chronic expansion of cytotoxic T cells or natural killer (NK) cells. Apoptotic resistance resulting from constitutive activation of survival signaling pathways is a fundamental pathogenic mechanism. Recent network modeling analyses identified platelet-derived growth factor (PDGF) as a key master switch in controlling these survival pathways in T-cell LGL leukemia. Here we show that an autocrine PDGF regulatory loop mediates survival of leukemic LGLs of both T- and NK-cell origin. We found high levels of circulating PDGF-BB in platelet-poor plasma samples from LGL leukemia patients. Production of PDGF-BB by leukemic LGLs was demonstrated by immunocytochemical staining. Leukemic cells expressed much higher levels of PDGFR-β transcripts than purified normal CD8+ T cells or NK cells. We observed that phosphatidylinositol-3-kinase (PI3 kinase), Src family kinase (SFK), and downstream protein kinase B (PKB)/AKT pathways were constitutively activated in both T- and NK-LGL leukemia. Pharmacologic blockade of these pathways led to apoptosis of leukemic LGLs. Neutralizing antibody to PDGF-BB inhibited PKB/AKT phosphorylation induced by LGL leukemia sera. These results suggest that targeting of PDGF-BB, a pivotal regulator for the long-term survival of leukemic LGLs, may be an important therapeutic strategy.
Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice
Authors: James Scott E. , Orgun Nural N. , Tedder Thomas F. , Shlomchik Mark J. , Jensen Michael C. , Lin Yukang , Greenberg Philip D. , Press Oliver W.
Published: October 2009

We have established a model of leukemia immunotherapy using T cells expressing chimeric T-cell receptors (cTCRs) targeting the CD20 molecule expressed on normal and neoplastic B cells. After transfer into human CD20 (hCD20) transgenic mice, cTCR+ T cells showed antigen-specific delayed egress from the lungs, concomitant with T-cell deletion. Few cTCR+ T cells reached the bone marrow (BM) in hCD20 transgenic mice, precluding effectiveness against leukemia. Anti-hCD20 antibody-mediated B-cell depletion before adoptive T-cell therapy permitted egress of mouse CD20-specific cTCR+ T cells from the lungs, enhanced T-cell survival, and promoted cTCR+ T cell–dependent elimination of established mouse CD20+ leukemia. Furthermore, CD20-specific cTCR+ T cells eliminated residual B cells refractory to depletion with monoclonal antibodies. These findings suggest that combination of antibody therapy that depletes antigen-expressing normal tissues with adoptive T-cell immunotherapy enhances the ability of cTCR+ T cells to survive and control tumors.
Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion
Authors: Varin Audrey , Mukhopadhyay Subhankar , Herbein Georges , Gordon Siamon
Published: October 2009

Alternatively activated macrophages play an important role in host defense in the context of a T helper type 2 (Th2) microenvironment such as parasitic infection. However, the role of these macrophages during secondary challenge with Th1 pathogens is poorly defined. In this study, thioglycollate-elicited mouse peritoneal macrophages were treated with interleukin-4 (IL-4) or IL-13 in vitro and challenged with Neisseria meningitidis. After 8 to 12 hours of IL-4 pretreatment, the nonopsonic phagocytic uptake of N meningitidis was markedly reduced, depending on the common IL-4Rα chain, but independent of Scavenger receptor A and macrophage receptor with collagenous structure (MARCO), 2 known receptors for N meningitidis. Inhibition of phagocytosis extended to several other microbial particles, zymosan, and other bacteria. Concomitantly, IL-4 potentiated the secretion of proinflammatory cytokines, after additional bacterial stimulation, which depended on the MyD88 signaling pathway. Similar results were obtained after intraperitoneal stimulation of IL-4 and N meningitidis in vivo. Further in vitro studies showed a striking correlation with inhibition of Akt phosphorylation and stimulation of the mitogen-activated protein kinase pathway; inhibition of phagocytosis was associated with inhibition of phagosome formation. These findings are relevant to host defense in mixed infections within a Th2 microenvironment and shed light on immunologic functions associated with alternative priming and full activation of macrophages.
Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients
Authors: Heslop Helen E. , Slobod Karen S. , Pule Martin A. , Hale Gregory A. , Rousseau Alexandra , Smith Colton A. , Bollard Catherine M. , Liu Hao , Wu Meng-Fen , Rochester Richard J. , Amrolia Persis J. , Hurwitz Julia L. , Brenner Malcolm K. , Rooney Cliona M.
Published: October 2009

T-cell immunotherapy that takes advantage of Epstein-Barr virus (EBV)–stimulated immunity has the potential to fill an important niche in targeted therapy for EBV-related cancers. To address questions of long-term efficacy, safety, and practicality, we studied 114 patients who had received infusions of EBV-specific cytotoxic T lymphocytes (CTLs) at 3 different centers to prevent or treat EBV+ lymphoproliferative disease (LPD) arising after hematopoietic stem cell transplantation. Toxicity was minimal, consisting mainly of localized swelling at sites of responsive disease. None of the 101 patients who received CTL prophylaxis developed EBV+ LPD, whereas 11 of 13 patients treated with CTLs for biopsy-proven or probable LPD achieved sustained complete remissions. The gene-marking component of this study enabled us to demonstrate the persistence of functional CTLs for up to 9 years. A preliminary analysis indicated that a patient-specific CTL line can be manufactured, tested, and infused for $6095, a cost that compares favorably with other modalities used in the treatment of LPD. We conclude that the CTL lines described here provide safe and effective prophylaxis or treatment for lymphoproliferative disease in transplantation recipients, and the manufacturing methodology is robust and can be transferred readily from one institution to another without loss of reproducibility. The current trial was registered at www.clinicaltrials.gov as #NCT00058812.
The new oral anticoagulants
Authors: Garcia David , Libby Edward , Crowther Mark A.
Published: October 2009

Although their first application in clinical practice occurred in the 1940s, vitamin K antagonists remain the only form of oral anticoagulant medication approved for long-term use. Although the available vitamin K antagonists are highly effective for the prevention and/or treatment of most thrombotic disease, the significant interpatient and intrapatient variability in dose-response, the narrow therapeutic index, and the numerous drug and dietary interactions associated with these agents have led clinicians, patients, and investigators to search for alternative agents. Three new orally administered anticoagulants (apixaban, dabigatran, and rivaroxaban) are in the late stages of development and several others are just entering (or moving through) earlier phases of investigation. These novel anticoagulant medications are being studied for the prevention and treatment of venous thromboembolism, the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation. This review summarizes published clinical trial data pertinent to apixaban, dabigatran, and rivaroxaban.
The bioavailability and airway clearance of the steroid component of budesonide/formoterol and salmeterol/fluticasone after inhaled administration in patients with COPD and healthy subjects: a randomized controlled trial
Authors: Dalby Chris , Polanowski Tomasz , Larsson Thomas , Borgström Lars , Edsbäcker Staffan , Harrison Tim W
Published: October 2009

Background

Airway absorption and bioavailability of inhaled corticosteroids (ICSs) may0020be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in patients with severe chronic obstructive pulmonary disease (COPD) by measuring the systemic availability and sputum concentration of budesonide and fluticasone, administered via combination inhalers with the respective long-acting β2-agonists, formoterol and salmeterol.

Methods

This was a randomized, double-blind, double-dummy, two-way crossover, multicenter study. Following a run-in period, 28 patients with severe COPD (mean age 65 years, mean forced expiratory volume in 1 second [FEV1] 37.5% predicted normal) and 27 healthy subjects (mean age 31 years, FEV1 103.3% predicted normal) received two single-dose treatments of budesonide/formoterol (400/12 μg) and salmeterol/fluticasone (50/500 μg), separated by a 4–14-day washout period. ICS concentrations were measured over 10 hours post-inhalation in plasma in all subjects, and over 6 hours in spontaneously expectorated sputum in COPD patients. The primary end point was the area under the curve (AUC) of budesonide and fluticasone plasma concentrations in COPD patients relative to healthy subjects.

Results

Mean plasma AUC values were lower in COPD patients versus healthy subjects for budesonide (3.07 μM·hr versus 6.21 μM·hr) and fluticasone (0.84 μM·hr versus 1.50 μM·hr), and the dose-adjusted AUC (geometric mean) ratios in healthy subjects and patients with severe COPD for plasma budesonide and fluticasone were similar (2.02 versus 1.80; primary end point). In COPD patients, the Tmax and the mean residence time in the systemic circulation were shorter for budesonide versus fluticasone (15.5 min versus 50.8 min and 4.41 hrs versus 12.78 hrs, respectively) and Cmax was higher (1.08 μM versus 0.09 μM). The amount of expectorated fluticasone (percentage of estimated lung-deposited dose) in sputum over 6 hours was significantly higher versus budesonide (ratio 5.21; p = 0.006). Both treatments were well tolerated.

Conclusion

The relative systemic availabilities of budesonide and fluticasone between patients with severe COPD and healthy subjects were similar. In patients with COPD, a larger fraction of fluticasone was expectorated in the sputum as compared with budesonide.

Trial registration

Trial registration number NCT00379028
(PS)2-v2: template-based protein structure prediction server
Authors: Chen Chih-Chieh , Hwang Jenn-Kang , Yang Jinn-Moon
Published: October 2009

Background

Template selection and target-template alignment are critical steps for template-based modeling (TBM) methods. To identify the template for the twilight zone of 15~25% sequence similarity between targets and templates is still difficulty for template-based protein structure prediction. This study presents the (PS)2-v2 server, based on our original server with numerous enhancements and modifications, to improve reliability and applicability.

Results

To detect homologous proteins with remote similarity, the (PS)2-v2 server utilizes the S2A2 matrix, which is a 60 × 60 substitution matrix using the secondary structure propensities of 20 amino acids, and the position-specific sequence profile (PSSM) generated by PSI-BLAST. In addition, our server uses multiple templates and multiple models to build and assess models. Our method was evaluated on the Lindahl benchmark for fold recognition and ProSup benchmark for sequence alignment. Evaluation results indicated that our method outperforms sequence-profile approaches, and had comparable performance to that of structure-based methods on these benchmarks. Finally, we tested our method using the 154 TBM targets of the CASP8 (Critical Assessment of Techniques for Protein Structure Prediction) dataset. Experimental results show that (PS)2-v2 is ranked 6th among 72 severs and is faster than the top-rank five serves, which utilize ab initio methods.

Conclusion

Experimental results demonstrate that (PS)2-v2 with the S2A2 matrix is useful for template selections and target-template alignments by blending the amino acid and structural propensities. The multiple-template and multiple-model strategies are able to significantly improve the accuracies for target-template alignments in the twilight zone. We believe that this server is useful in structure prediction and modeling, especially in detecting homologous templates with sequence similarity in the twilight zone.
Phylogenetic analysis of mitochondrial substitution rate variation in the angiosperm tribe Sileneae
Authors: Sloan Daniel B , Oxelman Bengt , Rautenberg Anja , Taylor Douglas R
Published: October 2009

Background

Recent phylogenetic studies have revealed that the mitochondrial genome of the angiosperm Silene noctiflora (Caryophyllaceae) has experienced a massive mutation-driven acceleration in substitution rate, placing it among the fastest evolving eukaryotic genomes ever identified. To date, it appears that other species within Silene have maintained more typical substitution rates, suggesting that the acceleration in S. noctiflora is a recent and isolated evolutionary event. This assessment, however, is based on a very limited sampling of taxa within this diverse genus.

Results

We analyzed the substitution rates in 4 mitochondrial genes (atp1, atp9, cox3 and nad9) across a broad sample of 74 species within Silene and related genera in the tribe Sileneae. We found that S. noctiflora shares its history of elevated mitochondrial substitution rate with the closely related species S. turkestanica. Another section of the genus (Conoimorpha) has experienced an acceleration of comparable magnitude. The phylogenetic data remain ambiguous as to whether the accelerations in these two clades represent independent evolutionary events or a single ancestral change. Rate variation among genes was equally dramatic. Most of the genus exhibited elevated rates for atp9 such that the average tree-wide substitution rate for this gene approached the values for the fastest evolving branches in the other three genes. In addition, some species exhibited major accelerations in atp1 and/or cox3 with no correlated change in other genes. Rates of non-synonymous substitution did not increase proportionally with synonymous rates but instead remained low and relatively invariant.

Conclusion

The patterns of phylogenetic divergence within Sileneae suggest enormous variability in plant mitochondrial mutation rates and reveal a complex interaction of gene and species effects. The variation in rates across genomic and phylogenetic scales raises questions about the mechanisms responsible for the evolution of mutation rates in plant mitochondrial genomes.
Phylogenetic relatedness and host plant growth form influence gene expression of the polyphagous comma butterfly (Polygonia c-album)
Authors: Heidel-Fischer Hanna M , Freitak Dalial , Janz Niklas , Söderlind Lina , Vogel Heiko , Nylin Sören
Published: October 2009

Background

The mechanisms that shape the host plant range of herbivorous insect are to date not well understood but knowledge of these mechanisms and the selective forces that influence them can expand our understanding of the larger ecological interaction. Nevertheless, it is well established that chemical defenses of plants influence the host range of herbivorous insects. While host plant chemistry is influenced by phylogeny, also the growth forms of plants appear to influence the plant defense strategies as first postulated by Feeny (the "plant apparency" hypothesis). In the present study we aim to investigate the molecular basis of the diverse host plant range of the comma butterfly (Polygonia c-album) by testing differential gene expression in the caterpillars on three host plants that are either closely related or share the same growth form.

Results

In total 120 genes were identified to be differentially expressed in P. c-album after feeding on different host plants, 55 of them in the midgut and 65 in the restbody of the caterpillars. Expression patterns could be confirmed with an independent method for 14 of 27 tested genes. Pairwise similarities in upregulation in the midgut of the caterpillars were higher between plants that shared either growth form or were phylogenetically related. No known detoxifying enzymes were found to be differently regulated in the midgut after feeding on different host plants.

Conclusion

Our data suggest a complex picture of gene expression in response to host plant feeding. While each plant requires a unique gene regulation in the caterpillar, both phylogenetic relatedness and host plant growth form appear to influence the expression profile of the polyphagous comma butterfly, in agreement with phylogenetic studies of host plant utilization in butterflies.
Proliferation and survival molecules implicated in the inhibition of BRAF pathway in thyroid cancer cells harbouring different genetic mutations
Authors: Preto Ana , Gonçalves Joana , Rebocho Ana P , Figueiredo Joana , Meireles Ana M , Rocha Ana S , Vasconcelos Helena M , Seca Hugo , Seruca Raquel , Soares Paula , Sobrinho-Simões Manuel
Published: October 2009

Background

Thyroid carcinomas show a high prevalence of mutations in the oncogene BRAF which are inversely associated with RAS or RET/PTC oncogenic activation. The possibility of using inhibitors on the BRAF pathway as became an interesting therapeutic approach. In thyroid cancer cells the target molecules, implicated on the cellular effects, mediated by inhibition of BRAF are not well established. In order to fill this lack of knowledge we studied the proliferation and survival pathways and associated molecules induced by BRAF inhibition in thyroid carcinoma cell lines harbouring distinct genetic backgrounds.

Methods

Suppression of BRAF pathway in thyroid cancer cell lines (8505C, TPC1 and C643) was achieved using RNA interference (RNAi) for BRAF and the kinase inhibitor, sorafenib. Proliferation analysis was performed by BrdU incorporation and apoptosis was accessed by TUNEL assay. Levels of protein expression were analysed by western-blot.

Results

Both BRAF RNAi and sorafenib inhibited proliferation in all the cell lines independently of the genetic background, mostly in cells with BRAFV600E mutation. In BRAFV600E mutated cells inhibition of BRAF pathway lead to a decrease in ERK1/2 phosphorylation and cyclin D1 levels and an increase in p27Kip1. Specific inhibition of BRAF by RNAi in cells with BRAFV600E mutation had no effect on apoptosis. In the case of sorafenib treatment, cells harbouring BRAFV600E mutation showed increase levels of apoptosis due to a balance of the anti-apoptotic proteins Mcl-1 and Bcl-2.

Conclusion

Our results in thyroid cancer cells, namely those harbouring BRAFV600Emutation showed that BRAF signalling pathway provides important proliferation signals. We have shown that in thyroid cancer cells sorafenib induces apoptosis by affecting Mcl-1 and Bcl-2 in BRAFV600E mutated cells which was independent of BRAF. These results suggest that sorafenib may prove useful in the treatment of thyroid carcinomas, particularly those refractory to conventional treatment and harbouring BRAF mutations.
Pan-European Chikungunya surveillance: designing risk stratified surveillance zones
Authors: Tilston Natasha , Skelly Chris , Weinstein Phil
Published: October 2009

The first documented transmission of Chikungunya within Europe took place in Italy during the summer of 2007. Chikungunya, a viral infection affecting millions of people across Africa and Asia, can be debilitating and no prophylactic treatment exists. Although imported cases are reported frequently across Europe, 2007 was the first confirmed European outbreak and available evidence suggests thatAedes albopictuswas the vector responsible and the index case was a visitor from India. This paper proposed pan-European surveillance zones for Chikungunya, based on the climatic conditions necessary for vector activity and viral transmission. Pan-European surveillance provides the best hope for an early-warning of outbreaks, because national boundaries do not play a role in defining the risk of this new vector borne disease threat. A review of climates, where Chikungunya has been active, was used to inform the delineation of three pan-European surveillance zones. These vary in size each month across the June-September period of greatest risk. The zones stretch across southern Europe from Portugal to Turkey. Although the focus of this study was to define the geography of potential surveillance zones based on the climatic limits on the vector and virus, a preliminary examination of inward bound airline passengers was also undertaken. This indicated that France and Italy are likely to be at greater risk due to the number of visitors they receive from Chikungunya active regions, principally viraemic visitors from India. Therefore this study represents a first attempt at creating risk stratified surveillance zones, which we believe could be usefully refined with the use of higher resolution climate data and more complete air travel data.
C-Reactive protein is an independent surgical indication marker for appendicitis: a retrospective study
Authors: Yokoyama Shozo , Takifuji Katsunari , Hotta Tsukasa , Matsuda Kenji , Nasu Toru , Nakamori Mikihito , Hirabayashi Naoki , Kinoshita Hiroyuki , Yamaue Hiroki
Published: October 2009

Background

This study is an attempt to clarify the role of C-reactive protein (CRP) as a surgical indication marker for appendicitis.

Methods

One hundred and fifty patients who underwent appendectomies and had pathologically confirmed appendicitis were reviewed between May 1, 1999 and September 31, 2007. The correlation between preoperative clinical factors and the actual histological severity, and identify surgical indication markers were assessed by univariate and multivariate analyses.

Results

Univariate analysis showed that only the CRP level significantly differ between the surgical treatment necessary group (gangrenous appendicitis) and the possible non-surgical treatment group (catarrhalis and phlegmonous appendicitis). Multivariate analysis indicated only the CRP level to be a surgical indication marker for acute appendicitis. The receiver-operating characteristic (ROC) curve indicated that the cutoff value of CRP for surgical indication of appendicitis is 4.95 mg/dl.

Conclusion

Only the CRP level is consistent with the severity of appendicitis, and considered to be a surgical indication marker for acute appendicitis.