Distribution by Scientific Domains
Distribution within Business, Economics, Finance and Accounting

Kinds of Bid

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  • Selected Abstracts

    Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double-blind randomized controlled trial

    A. H. Behzadi
    Objective:, The purpose of this study was to evaluate the efficacy of adding folic acid to sodium valproate in the acute phase of mania. Method:, Following a double-blind randomized controlled trial, 88 clinically manic patients with diagnosis of type I bipolar disorder (BID) were divided randomly into two groups (case and control). The case group was treated with folic acid and sodium valproate and the control group with sodium valproate and placebo. The severity of mania was assessed using the Young Mania Rating Scale (YMRS) at the beginning and end of the first, second and third weeks of the study. Results:, The case group's mean manic YMRS measurements (SD) before the initiation of therapy and in the first, second and third weeks of treatment were 34.0 ± 7.7, 26.7 ± 2.1, 18.1 ± 2.1 and 7.1 ± 0.9 respectively. The control group's measurements were 34.7 ± 3.8, 27.3 ± 2.3, 20.7 ± 2.5 and 10.1 ± 1.1. There was a statistically significant difference in YMRS scaling results between the case and control groups after 3 weeks of treatment (7.1 ± 0.9 vs. 10.1 ± 1.1, P = 0.005). Conclusion:, Based on our findings, folic acid seems to be an effective adjuvant to sodium valproate in the treatment of the acute phase of mania in patients with bipolar disorder. [source]

    Developmental cell death during Xenopus metamorphosis involves BID cleavage and caspase 2 and 8 activation

    D. Du Pasquier
    Abstract Elimination of tadpole organs during Xenopus metamorphosis is largely achieved through apoptosis, and recent evidence suggest involvement of the mitochondrial death route and bax-initiated caspase-3 and -9 deployment. However, events upstream of the activation of Bax are unknown. In other models, proteins of the BH3-only group such as BID are known to assure this function. We show that Xenopus bid transcript levels increase at metamorphosis in larval cells destined to disappear. This increase correlates with an abrupt rise in Caspase-2 and -8 mRNA levels and an enhanced activity of Caspase-2 and -8. In BIDGFP transgenic animal's tail regression is accelerated. The cleavage of BIDGFP fusion protein during natural or T3 -induced metamorphosis was specifically inhibited by caspase-8 inhibitors. Our results show that tail regression at metamorphosis implicates an apoptotic pathway inducible by T3 hormone in an organ autonomous manner and involving the cell death executioners BID and Caspases-2 and -8. Developmental Dynamics 235:2083,2094, 2006. © 2006 Wiley-Liss, Inc. [source]

    Eslicarbazepine Acetate: A Double-blind, Add-on, Placebo-controlled Exploratory Trial in Adult Patients with Partial-onset Seizures

    EPILEPSIA, Issue 3 2007
    Christian Elger
    Summary:,Objective: To explore the efficacy and safety of eslicarbazepine acetate (BIA 2-093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy. Methods: A multicenter, double-blind, randomized, placebo-controlled study was conducted in 143 refractory patients aged 18,65 years with ,4 partial-onset seizures/month. The study consisted of a 12-week treatment period followed by a 1-week tapering off. Patients were randomly assigned to one of three groups: treatment with eslicarbazepine acetate once daily (QD, n = 50), twice daily (BID, n = 46), or placebo (PL, n = 47). The daily dose was titrated from 400 mg to 800 mg and to 1,200 mg at 4-week intervals. The proportion of responders (patients with a ,50% seizure reduction) was the primary end point. Results: The percentage of responders versus baseline showed a statistically significant difference between QD and PL groups (54% vs. 28%; 90% CI =,,, ,14; p = 0.008). The difference between the BID (41%) and PL did not reach statistical significance (90% CI =,,, ,1; p = 0.12). A significantly higher proportion of responders in weeks 5,8 was found in the QD group than in the BID group (58% vs. 33%, respectively, p = 0.022). At the end of the 12-week treatment, the number of seizure-free patients in the QD and BID groups was 24%, which was significantly different from the PL group. The incidence of adverse events was similar between the treatment groups and no drug-related serious adverse events occurred. Conclusion: Eslicarbazepine acetate was efficacious and well tolerated as an adjunctive therapy of refractory epileptic patients. [source]

    TBid mediated activation of the mitochondrial death pathway leads to genetic ablation of the lens in Xenopus laevis

    D. Du Pasquier
    Abstract Xenopus is a well proven model for a wide variety of developmental studies, including cell lineage. Cell lineage in Xenopus has largely been addressed by injection of tracer molecules or by micro-dissection elimination of blastomeres. Here we describe a genetic method for cell ablation based on the use of tBid, a direct activator of the mitochondrial apoptotic pathway. In mammalian cells, cross-talk between the main apoptotic pathways (the mitochondrial and the death domain protein pathways) involve the pro-death protein BID, the active form of which, tBID, results from protease truncation and translocation to mitochondria. In transgenic Xenopus, restricting tBID expression to the lens-forming cells enables the specific ablation of the lens without affecting the development of other eye structures. Thus, overexpression of tBid can be used in vivo as a tool to eliminate a defined cell population by apoptosis in a developing organism and to evaluate the degree of autonomy or the inductive effects of a specific tissue during embryonic development. genesis 45:1,10, 2007. © 2006 Wiley-Liss, Inc. [source]

    Efficacy and safety of mesalamine 1 g HS versus 500 mg BID suppositories in mild to moderate ulcerative proctitis: A multicenter randomized study

    Mark Lamet MD
    Abstract Background: Ulcerative proctitis (UP) usually presents as fresh rectal bleeding. Successful treatment using topical mesalamine 5-aminosalicyclic acid (5-ASA) 500 mg BID suppository led to developing a once-a-day formulation that could contribute to better acceptability and ease of use by patients. The objective of this randomized trial, conducted in 18 centers, was to compare efficacy of 2 modes of treatment with 5-ASA suppositories. Methods: Ninety-nine patients with mild or moderate UP limited to 15 cm of the anal margin, evidenced by a disease activity index (DAI) between 4 and 11, were randomized to 5-ASA 500 mg suppository (Canasa; Axcan Pharma) BID or 1 g at bedtime (HS) for 6 weeks. The study used a noninferiority hypothesis based on the mean difference in DAI values after 6 weeks of treatment on an intent-to-treat basis using analysis of covariance. DAI was derived from a composite of the measures of stool frequency, rectal bleeding, mucosal visualization at endoscopy, and general well being. Results: There was no difference between groups at baseline for demographic and clinical parameters. Mean DAIs fell from 6.6 ± 1.5 (SD) to 1.6 ± 2.3 in the 500 mg BID group (n = 48) and from 6.1 ± 1.5 to 1.3 ± 2.2 in the 1 g HS group (n = 39). There was no significant difference (P = 0.74) in mean DAI at week 6 between the 2 groups. Both groups showed a significant reduction (P < 0.0001) in DAI over the course of the 6 weeks. Both formulations showed effectiveness in reducing each individual component of the DAI. There was no significant difference between treatments in adverse events, and both groups had an overall drug compliance of greater than 95%. Conclusion: This study showed that 1 g HS and 500 mg BID mesalamine suppository treatments of UP patients were equivalent in all facets of efficacy, safety, and compliance in a 6-week trial. [source]

    Overexpression of BAD preferentially augments anoikis

    Masashi Idogawa
    Abstract BAD is a BH3-only protein, and its proapoptotic activity is negatively regulated by serine phosphorylation. Here, we show that overexpression of BAD preferentially augments anchorage loss,induced apoptosis (anoikis). Gene transfer,mediated BAD overexpression alone did not induce apoptosis in attached MDCK cells but strongly augmented apoptosis when cells were cultured in suspension. In contrast, overexpression of another BH3-only protein, BID, displayed much lower augmentation of anoikis, suggesting a preferential contribution of BAD to anoikis. During suspension culture, unphosphorylated BAD was gradually increased and targeted to the mitochondria. Cotransfection of BAD with constitutively active Akt cDNA strongly inhibited this change. In contrast, the increase of unphosphorylated BAD was not significantly inhibited by several phosphatase inhibitors or cotransfection with a dominant negative calcineurin cDNA, implying that the increase may be mainly due to a decrease of serine kinase activity, such as that of Akt. Similar results were observed in COS-7 cells, suggesting that BAD overexpression can increase sensitivity of anchorage-dependent cancer cells to anoikis. Thus, we propose that BAD can serve as a valuable gene therapeutic molecule to inhibit carcinoma progression. © 2003 Wiley-Liss, Inc. [source]

    Interior Design at a Crossroads: Embracing Specificity through Process, Research, and Knowledge,

    Tiiu Poldma Ph.D.
    Tiiu Poldma is Vice Dean of Graduate Studies and Research in the Faculty of Environmental Design, and associate professor at the School of Industrial Design at the University of Montreal. Tiiu Poldma received a BID at Ryerson in 1982 (Toronto), MA in Culture and Values in Education in 1999 and Doctor of Philosophy in 2003, both from McGill University in Montreal, Canada. She teaches interior design studio and theory within the Bachelor of Interior Design program at the University of Montreal, and advanced research methodologies in the Masters of Science and Ph.D. programs at the Faculty of Environmental Design. She is currently the Director of the Research Group GRID(Group for Research in Illumination and Design) and heads up the Colour, Light and Form Lab (Laboratoire Forme*couleur*lumiere) at the faculty. She accredits design programs as a site evaluator for CIDAboth in Canada and the United States, and is also a member of the Editorial Board of Inderscience where she is the Regional Editor of the Journal of Design Research (JDR), and serves on the Editorial Board of Design/Science/Planning (Techne Press, Amsterdam). [source]

    Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone

    J. L. Goldstein
    Aliment Pharmacol Ther 2010; 32: 401,413 Summary Background, Gastroprotective co-therapy may reduce the risk of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers, but adherence is suboptimal. Aim, To compare the incidence of gastric ulcers with PN 400 [enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg], or EC naproxen. Methods, Two randomized, double-blind, multicentre studies (PN400-301, PN400-302). Patients [stratified by low-dose aspirin (,325 mg) use] aged ,50 years or 18,49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. Results, The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low-dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non-users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). Conclusions, PN 400 significantly reduces the incidence of gastric ulcers, regardless of low-dose aspirin use, in at-risk patients, and is associated with improved UGI tolerability relative to EC naproxen (, NCT00527782). [source]


    ABSTRACT:,The Olympic Park being developed in east London for the 2012 Games is one large urban renewal project among many in the city. The impact of the Games on urban development may be of less significance than the impact on city politics. Bidding for and delivering the Games has contributed to a reassessment of the recent experiment with mayoral government. The article examines these changing representations of the structures of London government that are now seen as a success. Much of the literature on Olympic cities is highly critical of the impact of the games, but the (current) substantial support for London 2012 also needs to be explained. We examine how London has created opportunities for support, and moments and spaces for celebration when political leaders and Londoners can come together around particular representations of themselves and the city. [source]


    AJ Alwood
    Objectives: 1) Validate a chromogenic assay to measure Factor Xa inhibitory activity (anti-Xa activity) in normal feline plasma and following administration of low molecular weight heparins and unfractionated heparin. 2) Compare the effects of two commercially available low molecular weight heparins (LMWH), unfractionated heparin (UFH), and placebo on TEG, anti-Xa activity, PT/aPTT, PCV/TS and platelet count in healthy cats. Methods: Our study consisted of two phases: 1) the evaluation of a commercially available chromogenic anti-Xa assay (Rotachrom Heparin, Diagnostic Stago) for use in cats, and 2) the evaluation of hemostatic effects of LMWH in healthy cats. Phase 1: The anti-Xa assay was validated for use in cats using feline plasma and serial dilutions of the plasma spiked with UFH, enoxaparin, and dalteparin. Phase 2: Five healthy cats were included in a randomized Latin Squares model crossover-design to compare the effects of UFH and LMWH in cats. The cats then received one of the following subcutaneously: 1) 250 IU/kg UFH QID, 2) 100 IU/kg dalteparin BID, 3) 1 mg/kg enoxaparin BID, 4) 0.25 mL/kg 0.9% saline (placebo) QID. A minimum of a two-week washout period separated each treatment period. Each drug was administered for 5 days. Blood samples were obtained to measure anti-Xa, TEG, PT/aPTT, platelet count, and PCV/TS on Days 1, 3, 5, and 6 of each treatment cycle. Samples were collected at time 0 on each sample day for all parameters and on select days at hours 4, 8, and 12 for anti-Xa and TEG. Results: Preliminary results using the validated anti-Xa assay (from the first part of this study) demonstrate that LMWH treatment results in peak anti-Xa activity at the 4-hour sampling time that returned toward baseline by 8 hours (in 5/6 cats treated with LMWH thus far). Similar anticoagulant effects were noted in the TEG parameters of cats receiving LMWH (i.e., peak effects were noted at 4 hours). Analysis of current data by linear regression identifies a relationship between anti-Xa measurements and TEG parameters for cats treated with all heparin therapies (p<0.001). A similar relationship exists between anti-Xa and aPTT. Conclusions: Preliminary results suggest an anticoagulant effect of LMWH in cats that may not be uniform across individuals. Anti-Xa activity or TEG may provide useful tools for monitoring LMWH. [source]

    Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosing

    Masahide Fukudo
    We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once- and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n = 5) or once daily in the morning (QD, n = 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C2) and area under the concentration-time curve (AUC) for 4 hours (AUC0,4), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA0,12) and 24 hours (AUA0,24) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C2 level was significantly correlated with the AUC0,4 (r2 = 0.95), which was negatively related to the AUA0,12 with a large interindividual variability (r2 = 0.59). However, a significant correlation was found between the AUA0,12 or AUA0,24 and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (Emax) model, the mean estimates of Emax and the Cb value that gives a half-maximal effect (EC50) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration. Liver Transpl 12:292,300, 2006. © 2006 AASLD. [source]

    Duloxetine for the Management of Diabetic Peripheral Neuropathic Pain: Response Profile

    PAIN MEDICINE, Issue 5 2007
    Yili L. Pritchett PhD
    ABSTRACT Objective., The current analysis examines the response profile in patients receiving duloxetine for the management of diabetic peripheral neuropathic pain (DPNP). Patients/Design., Data were pooled from three double-blind, randomized, placebo-controlled 12-week acute therapy trials of patients with DPNP of at least 6 months' duration. Study 1 (N = 457) had treatment groups of duloxetine 20 mg once daily (QD), 60 mg QD, 60 mg twice daily (BID), and placebo; Studies 2 (N = 334) and 3 (N = 348) compared duloxetine 60 mg QD and 60 mg BID with placebo. The primary efficacy measure in each study was the weekly mean score of the 24-hour average pain severity. Treatment response was defined as a 30% reduction in pain severity, although some analyses were repeated using alternative response criteria (50% reduction, or 2-point reduction, in pain severity). Results., Consistently across the three studies, response rates at endpoint were significantly higher among patients receiving duloxetine (60 mg QD or 60 mg BID) than among those receiving placebo, regardless of the chosen response criterion (30% reduction, 50% reduction, or 2-point reduction in weekly mean of 24-hour average pain severity). The proportion of patients achieving pain relief in the duloxetine treatment groups was significantly greater than that in the placebo group at Week 1 and at all subsequent study visits to the end of acute phase therapy. Using diary data (24-hour average pain severity) from the first 7 days of treatment, the first significant separation from placebo in pain severity reduction for duloxetine 60 mg QD occurred at Day 1 (Study 1), Day 2 (Study 2), and Day 4 (Study 3), while significant separation in response rates first occurred at Day 3 when using pooled data. Conclusions., Patients with DPNP receiving duloxetine 60 mg QD or 60 mg BID had significantly higher rates of treatment response, when compared with patients receiving placebo, regardless of the chosen response criterion. Response to duloxetine treatment tended to occur early in therapy. [source]


    Bart Frijns
    Abstract In this article we investigate the relation between insider trading regulations and the bid,ask spread. We decompose the spread into its components before and after the enactment of strict new insider trading rules in New Zealand. We find that the enactment led to a significant decrease in the information asymmetry component of the spread, which is observed mainly in illiquid and high prechange information asymmetry companies. These findings are robust to model specification. In addition, we find a decrease in the contribution of information asymmetry to price volatility. [source]

    Once-Daily Prolonged-Release Tacrolimus (ADVAGRAF) Versus Twice-Daily Tacrolimus (PROGRAF) in Liver Transplantation

    P. Trune
    The efficacy and safety of dual-therapy regimens of twice-daily tacrolimus (BID; Prograf) and once-daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were compared in a multicenter, 1:1-randomized, two-arm, parallel-group study in 475 primary liver transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy-proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per-protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval ,7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelve-month patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID. [source]

    Pharmacokinetics for Once- Versus Twice-Daily Tacrolimus Formulations in De Novo Kidney Transplantation: A Randomized, Open-Label Trial

    Z. Wlodarczyk
    Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC0,24 of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC0,24 and Cmin for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID. [source]

    Calcineurin-Inhibitor-Free Immunosuppression Based on the JAK Inhibitor CP-690,550: A Pilot Study in De Novo Kidney Allograft Recipients

    S. Busque
    This randomized, pilot study compared the Janus kinase inhibitor CP-690,550 (15 mg BID [CP15] and 30 mg BID [CP30], n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients received an IL-2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP-690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6-month biopsy-proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6-month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by ,77% in CP-690,550-treated patients. In the CP-690,550 arms, there were modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months. These data suggest that coadministration of CP-690,550 30 mg BID with MMF is associated with overimmunosuppression. At 15 mg BID, the efficacy/safety profile was comparable to the tacrolimus control group, excepting a higher rate of viral infection. Further dose-ranging evaluation of CP-690,550 is warranted. [source]

    Safety and Efficacy of Raltegravir in HIV-Infected Transplant Patients Cotreated with Immunosuppressive Drugs

    L. Tricot
    Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug,drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176,890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6,14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT. [source]

    Phase 1 Dose-Escalation Study of CP-690 550 in Stable Renal Allograft Recipients: Preliminary Findings of Safety, Tolerability, Effects on Lymphocyte Subsets and Pharmacokinetics

    E. Van Gurp
    CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19+ B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4+ or CD8+ T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration. [source]


    Andrea Benvenuti
    Australia; European Union; international trade; trade policy; United Kingdom This article examines the problems and challenges which confronted the Australian government in its response to Britain's second attempt to join the European Economic Community (EEC) in 1967. While an adequate body of literature exists on Australia's policy towards Britain's first application to the EEC (1961,63), the Australian government's response to the 1967 bid has been completely ignored by historians. This article, therefore, aims to make a historical contribution to the understanding of Australia's policy towards Britain's ,turn to Europe'. [source]

    Gene expression of anti- and pro-apoptotic proteins in malignant and normal plasma cells

    Michel Jourdan
    Summary The survival of malignant plasma cells is a key event in disease occurrence, progression and chemoresistance. Using DNA-microarrays, we analysed the expression of genes coding for 58 proteins linked with extrinsic and intrinsic apoptotic pathways, caspases and inhibitor of apoptosis proteins. We considered six memory B cells (MBC), seven plasmablasts (PPC), seven bone marrow plasma cells (BMPC) and purified myeloma cells (MMC) from 92 newly-diagnosed patients. Forty out of the 58 probe sets enabled the separation of MBC, PPC and BMPC in three homogeneous clusters, characterized by an elevated expression of TNFRSF10A, TNFRSF10B, BCL2A1, CASP8, CASP9 and PMAIP1 genes for MBC, of FAS, FADD, AIFM1, BIRC5, CASP CASP2, CASP3 and CASP6 for PPC and of BCL2, MCL1, BID, BIRC3 and XIAP for BMPC. Thus, B cell differentiation was associated with change of expression of pro-apoptotic and anti-apoptotic genes. Regarding MMC, the major finding was TRAIL upregulation that might be counteracted by a high osteoprotegerin production by BM stromal cells and a decreased expression of FAS, APAF1 and BNIP3 compared to normal BMPC. Out of the 40 genes, CASP2 and BIRC5 expression in MMC had adverse prognosis in two independent series of previously-untreated patients. [source]

    Synthesis and properties of organic/inorganic hybrid nanoparticles prepared using atom transfer radical polymerization

    Tzong-Liu Wang
    Abstract The synthesis of organic/inorganic hybrid materials was conducted by atom transfer radical polymerization (ATRP) of styrene and methyl methacrylate (MMA) from the surface of silica colloids. Colloidal initiators were prepared by the functionalization of silica nanoparticles with (3-(2-bromoisobutyryl)propyl) dimethylethoxysilane (BIDS). Well-defined polymer chains were grown from the nanoparticle surfaces to yield individual particles composed of a silica core and a well-defined outer polystyrene (PS) or poly(methyl methacrylate) (PMMA) layer. Fourier transform infrared (FTIR) and solid state 13C and 29Si-NMR spectroscopy confirmed the successful modification of nanosilica surfaces. Subsequent grafting of polymers on silica surfaces by ATRP was also performed with success based on FTIR and NMR data. Scanning electron microscopy (SEM) and silicon mapping showed both hybrid materials were homogeneous dispersion systems. Energy dispersive X-ray spectrometer (EDS) analysis indicated that the BIDS initiator was covalently attached on surfaces of silica nanoparticles and ATRP of styrene and MMA were accomplished. Thermogravimetric analysis (TGA) results displayed higher thermal stabilities for both nanohybrids in comparison with the linear-type vinyl polymers. Contact angle measurements revealed the nanomaterials character for both silica-based hybrid materials. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008 [source]

    The use of tinted lenses to alleviate reading difficulties

    Helen Whiteley
    An increasing number of optometrists are offering assessments using the Intuitive Colorimeter (Wilkins, Nimmo-Smith and Jansons, 1992) to determine whether children who have reading difficulties might benefit from the use of tinted lenses. Suggestions have been made in the media that tinted lenses may provide a ,cure' for developmental dyslexia, and there have been many anecdotal accounts of improvements in reading following their use (e.g. Brace, 1993). However, such extreme claims are not typical of the scientific literature supporting the use of tinted lenses. This article provides an overview of the research into the use of tinted lenses for the amelioration of reading difficulties. The electronic databases searched for this review were BIDS, MEDLINE, PsychInfo, PsychLit and Science Direct. Key search terms used were coloured (colored) lenses, Irlen lenses, scotopic sensitivity and visual deficits in combination with the term ,reading difficulties'. [source]

    A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer

    BJU INTERNATIONAL, Issue 3 2001
    M.D. Shelley
    Objective,To assess, in a systematic review, the effectiveness of intravesical bacillus Calmette-Guérin (BCG) in preventing tumour recurrence in patients with medium/high risk Ta and T1 bladder cancer. Patients and methods,An electronic database search of Medline, Embase, DARE, the Cochrane Library, Cancerlit, Healthstar and BIDS was undertaken, plus hand searching of the Proceedings of ASCO, for randomized controlled trials, in any language, comparing transurethral resection (TUR) alone with TUR followed by intravesical BCG in patients with Ta and T1 bladder cancer. Results,The search identified 26 publications comparing TUR with TUR + BCG. Six trials were considered acceptable, representing 585 eligible patients, 281 in the TUR-alone group and 304 in the TUR + BCG group. The major clinical outcome chosen was tumour recurrence. The weighted mean log hazard ratio for the first recurrence, taken across all six trials, was ,0.83 (95% confidence interval ,0.57 to ,1.08, P < 0.001), which is equivalent to a 56% reduction in the hazard, attributable to BCG. The Peto odds ratio for patients recurring at 12 months was 0.3 (95% confidence interval of 0.21,0.43, P < 0.001), significantly favouring BCG therapy. Manageable toxicities associated with intravesical BCG were cystitis (67%), haematuria (23%), fever (25%) and urinary frequency (71%). No BCG-induced deaths were reported. Conclusion,TUR with intravesical BCG provides a significantly better prophylaxis of tumour recurrence in Ta and T1 bladder cancer than TUR alone. Randomized trials are still needed to address the issues of BCG strain, dose and schedule, and to better quantify the effect on progression to invasive disease. [source]

    Bifocals in children with Down syndrome (BiDS) , visual acuity, accommodation and early literacy skills

    Krithika Nandakumar
    Acta Ophthalmol. 2010: 88: e196,e204 Abstract. Purpose:, Reduced accommodation is seen in children and young adults with Down syndrome (DS), yet providing bifocals has not become a routine clinical management. This study investigates the impact of bifocals on visual function, visual perceptual and early literacy skills in a group of school children with DS. Methods:, In this longitudinal study, each child was followed for 5 months with single-vision (SV) lenses after which bifocals were prescribed if required, based on their accommodative response. Visual acuity (VA), accommodation, perceptual and literacy skills were measured after adaptation to bifocals and 5 months later. Educational progress and compliance with spectacle wear were assessed through school and parental reports. Results:, Fourteen children and young adults with DS participated in the study. Eighty-five percent required bifocals with additions ranging from +1.00 D to +3.50 D. The mean near logMAR VA improved with bifocals (p = 0.007) compared to SV lenses. Repeated measures anova showed that there was more accurate focus (less accommodative lag) through the bifocals (p = 0.002), but no change in the accommodation exerted through the distance portion compared to SV lenses (p = 0.423). There was a main effect of time on sight words (p = 0.013), Word Identification (p = 0.047), Visual Closure (p = 0.006) and Visual Form Constancy (p = 0.001). Conclusion:, Bifocals provide clearer near vision in DS children with reduced accommodation. This is shown by improved VA and decreased lag of accommodation. The results indicate that the improvement in VA results in improved scores in early literacy skills. Better compliance with bifocals over SV lenses was seen. [source]

    Over-the-Counter Markets

    ECONOMETRICA, Issue 6 2005
    Darrell Duffie
    We study how intermediation and asset prices in over-the-counter markets are affected by illiquidity associated with search and bargaining. We compute explicitly the prices at which investors trade with each other, as well as marketmakers' bid and ask prices, in a dynamic model with strategic agents. Bid,ask spreads are lower if investors can more easily find other investors or have easier access to multiple marketmakers. With a monopolistic marketmaker, bid,ask spreads are higher if investors have easier access to the marketmaker. We characterize endogenous search and welfare, and discuss empirical implications. [source]

    Involvement of mitochondrial signaling pathways in the mechanism of Fas-mediated apoptosis after spinal cord injury

    Wen Ru Yu
    Abstract Activation of the Fas receptor has been recently linked to apoptotic cell death after spinal cord injury (SCI). Although it is generally considered that Fas activation mediates apoptosis predominantly through the extrinsic pathway, we hypothesized that intrinsic mitochondrial signaling could be involved in the underlying mechanism of Fas-induced apoptosis after SCI. In the present study, we utilized the FejotaTM clip compression model of SCI at T5,6 in C57BL/6 Fas-deficient (lpr) and wild-type mice. Complementary studies were conducted using an in vitro model of trauma or a Fas-activating antibody to induce apoptosis in primary neuronal,glial mixed spinal cord cultures. After in vivo SCI, lpr mice, in comparison with wild-type mice, exhibited reduced numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells at the lesion, reduced expression of truncation of Bid (tBid), apoptosis-inducing factor, activated caspase-9 and activated caspase-3, and increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. After in vitro neurotrauma or the induction of Fas signaling by the Jo2 activating antibody, lpr spinal cord cultures showed an increased proportion of cells retaining mitochondrial membrane integrity and a reduction of tBid expression, caspase-9 and caspase-3 activation, and TUNEL-positive cells as compared to wild-type spinal cord cultures. The neutralization of Fas ligand (FasL) protected against traumatically induced or Fas-mediated caspase-3 activation and the loss of mitochondrial membrane potential and tBid expression in wild-type spinal cord cultures. However, in lpr spinal cord cultures, FasL neutralization had no protective effects. In summary, these data provide direct evidence for the induction of intrinsic mitochondrial signaling pathways following Fas activation after SCI. [source]

    Interaction of the alpha-helical H6 peptide from the pro-apoptotic protein tBid with cardiolipin

    FEBS JOURNAL, Issue 21 2009
    Patrice X. Petit
    BH3 interacting domain death agonist (Bid), a pro-apoptotic member of the Bcl-2 family of proteins, is activated through cleavage by caspase-8. The active C-terminal fragment of Bid (tBid) translocates to the mitochondria where it interacts with cardiolipins at contact sites and induces the release of cytochrome c by a mechanism that is not yet fully understood. It has been shown that the alpha-helices ,H6 and ,H7 (which create the hairpin-forming domain of tBid) mediate the insertion of Bid into mitochondrial membranes and are essential for the cytochrome c -releasing activity. In the present study, we focused on the interaction between the ,H6 and the mitochondrial membrane. By the use of single-cell electropermeabilization associated with flow cytometric analysis of intact cells, we demonstrated that H6 is able to induce cell death when used in the micromolar range. We also studied the interactions of the ,H6 with artificial monolayers. We showed that the presence of negatively charged cardiolipins greatly enhances the insertion of ,H6 into the phospholipid monolayer. The modification of two charged amino acid residues in ,H6 abolished its insertion and also its in vivo effects. Furthermore, the negative values of the excess areas of mixing indicate that attractive interactions between cardiolipins and ,H6 occur in the mixed monolayers. Fluorescence microscopy observations revealed that ,H6 significantly disrupts cardiolipin packing and stabilizes the fluid lipid phase. These results suggest that cardiolipins at the contact sites between the two mitochondrial membranes could mediate the binding of tBid via ,H6. [source]

    An Intraday Examination of the Components of the Bid,Ask Spread

    FINANCIAL REVIEW, Issue 4 2002
    Thomas H. McInish
    Using transactions data for a sample of NYSE stocks, we decompose the bid,ask spread (BAS) into order,processing (OP) and asymmetric information (AI) components using the techniques of George, Kaul, and Nimalendran (1991) and Madhavan, Richardson, and Roomans (1997). McInish and Wood (1992) demonstrate that the intraday behavior of BASs can be explained by variables measuring activity, competition, risk, and information. We investigate whether these variables explain the behavior of the OP and AI components of the spread over the trading day. We conclude that, on balance, the variables that determine the aggregate BAS also determine its intraday components. [source]

    The initiator caspase, caspase-10,, and the BH-3-only molecule, Bid, demonstrate evolutionary conservation in Xenopus of their pro-apoptotic activities in the extrinsic and intrinsic pathways

    GENES TO CELLS, Issue 7 2006
    Katsuya Kominami
    Two major apoptotic signaling pathways have been defined in mammals, the extrinsic pathway, initiated by ligation of death receptors, and the intrinsic pathway, triggered by cytochrome c release from mitochondria. Here, we identified and characterized the Xenopus homologs of caspase-10 (xCaspase-10,), a novel initiator caspase, and Bid (xBid), a BH3-only molecule of the Bcl-2 family involved in both the extrinsic and intrinsic pathways. Exogenous expression of these molecules induced apoptosis of mammalian cells. By biochemical and cytological analyses, we clarified that xCaspase-10, and xBid exhibit structural and functional similarities to their mammalian orthologues. We also detected xCaspase-10, and xBid transcripts during embryogenesis by whole-mount in situ hybridization and RT-PCR analysis. Microinjection of mRNA encoding a protease-defect xCaspase-10, mutant into embryos resulted in irregular development. Enforced expression of active xBid induced cell death in developing embryos. Using transgenic frogs established to allow monitoring of caspase activation in vivo, we confirmed that this form of cell death is caspase-dependent apoptosis. Thus, we demonstrated that the machinery governing the extrinsic and intrinsic apoptotic pathways are already established in Xenopus embryos. Additionally, we propose that the functions of the initiator caspase and BH3-only molecule are evolutionarily conserved in vertebrates, functioning during embryonic development. [source]

    Bid-dependent generation of oxygen radicals promotes death receptor activation,induced apoptosis in murine hepatocytes

    HEPATOLOGY, Issue 2 2004
    Wen-Xing Ding
    Activation of tumor necrosis factor receptor 1 or Fas leads to the generation of reactive oxygen species, which are important to the cytotoxic effects of tumor necrosis factor , (TNF-,) or Fas ligand. However, how these radicals are generated following receptor ligation is not clear. Using primary hepatocytes, we found that TNF-, or anti,Fas antibody,induced burst of oxygen radicals was mainly derived from the mitochondria. We discovered that Bid,a pro-death Bcl-2 family protein activated by ligated death receptors,was the main intracellular molecule signaling the generation of the radicals by targeting to the mitochondria and that the majority of oxygen radical production was dependent on Bid. Reactive oxygen species contributed to cell death and caspase activation by promoting FLICE-inhibitory protein degradation and mitochondrial release of cytochrome c. For the latter part, the oxygen radicals did not affect Bak oligomerization but instead promoted mitochondrial cristae reorganization and membrane lipid peroxidation. Antioxidants could reverse these changes and therefore protect against TNF-, or anti,Fas-induced apoptosis. In conclusion, our studies established the signaling pathway from death receptor engagement to oxygen radical generation and determined the mechanism by which reactive oxygen species contributed to hepatocyte apoptosis following death receptor activation. (HEPATOLOGY 2004;40:403,413.) [source]