Sample records for previous failed pk

  1. Survival of dental implants placed in sites of previously failed implants. (United States)

    Chrcanovic, Bruno R; Kisch, Jenö; Albrektsson, Tomas; Wennerberg, Ann


    To assess the survival of dental implants placed in sites of previously failed implants and to explore the possible factors that might affect the outcome of this reimplantation procedure. Patients that had failed dental implants, which were replaced with the same implant type at the same site, were included. Descriptive statistics were used to describe the patients and implants; survival analysis was also performed. The effect of systemic, environmental, and local factors on the survival of the reoperated implants was evaluated. 175 of 10,096 implants in 98 patients were replaced by another implant at the same location (159, 14, and 2 implants at second, third, and fourth surgeries, respectively). Newly replaced implants were generally of similar diameter but of shorter length compared to the previously placed fixtures. A statistically significant greater percentage of lost implants were placed in sites with low bone quantity. There was a statistically significant difference (P = 0.032) in the survival rates between implants that were inserted for the first time (94%) and implants that replaced the ones lost (73%). There was a statistically higher failure rate of the reoperated implants for patients taking antidepressants and antithrombotic agents. Dental implants replacing failed implants had lower survival rates than the rates reported for the previous attempts of implant placement. It is suggested that a site-specific negative effect may possibly be associated with this phenomenon, as well as the intake of antidepressants and antithrombotic agents. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Modified Latarjet Procedure Without Capsulolabral Repair for the Treatment of Failed Previous Operative Stabilizations in Athletes. (United States)

    Ranalletta, Maximiliano; Rossi, Luciano A; Bertona, Agustin; Tanoira, Ignacio; Maignon, Gastón D; Bongiovanni, Santiago L


    To analyze time to return to sport, functional outcomes, and recurrences of the modified Latarjet procedure without capsulolabral repair in athletes with recurrent anterior shoulder instability after a failed previous operative stabilization. We included athletes with recurrent anterior shoulder instability with a previous failed operative stabilization treated with the modified Latarjet procedure without capsulolabral repair with a minimum of 2-year follow-up. Return to sports, range of motion, the Rowe score, a visual analog scale for pain in sport activity, and the Athletic Shoulder Outcome Scoring System were used to assess functional outcomes. Recurrences were also evaluated. The postoperative bone block position and consolidation were assessed with computed tomography. Between June 2008 and June 2015, 68 athletes were treated with the modified Latarjet procedure without capsulolabral reconstruction for recurrent shoulder instability after a previous failed stabilization surgery. The mean follow-up was 44 months (range, 24-108 months), and the mean age at the time of operation was 26.8 years (range, 17-35 years). All the patients returned to sports, and 95% returned to the same sport they practiced before the surgery, all to the same level. No significant difference in shoulder range of motion was found between preoperative and postoperative results. The Rowe score, visual analog scale, and Athletic Shoulder Outcome Scoring System showed statistical improvement after operation (P Latarjet without capsulolabral repair produced excellent functional outcomes with most athletes returning to sport at the same level they had before the surgery without recurrences. Level IV, therapeutic, case series study. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

  3. Clinical outcomes of the addition of eccentrics for rehabilitation of previously failed treatments of golfers elbow. (United States)

    Tyler, Timothy F; Nicholas, Stephen J; Schmitt, Brandon M; Mullaney, Michael; Hogan, Daniel E


    Eccentric training of the wrist extensors has been shown to be effective in treating chronic lateral epicondylosis. However, its efficacy in the treatment of medial epicondylosis has yet to be demonstrated. The objective of this study was to assess the effectiveness of a novel eccentric wrist flexor exercise added to standard treatment for chronic medial epicondylosis in patients who did not respond to previous therapeutic interventions for this disorder. 20. Patients (13 men, 7 women; age 49±12 yr) with chronic medial epicondylosis who had failed previous treatment for this disorder (physical therapy 7, cortisone injection 7, PRP 1, NSAIDS 15) were prescribed isolated eccentrics in addition to wrist stretching, ultrasound, cross-friction massage, heat and ice. The specific isolated eccentric wrist flexor strengthening exercise performed by the patients involved twisting a rubber bar (Flexbar, Hygenic Corportation, Akron OH) with concentric wrist flexion of the noninvolved arm and releasing the twist by eccentrically contracting the wrist flexors of the involved arm (3 × 15 twice daily). A DASH questionnaire was recorded at baseline and again after the treatment period. Treating clinicians were blinded to baseline DASH scores. Treatment effect was assessed using paired t-test. Based on previous work it was estimated that with a sample of 20 patients there would be 80% power to detect a 13 point improvement in DASH scores (ptennis (2), basketball (1), weight lifting (1), and general activities of daily living (2). There was a significant improvement in outcomes following the addition of isolated eccentrics (Pre DASH 34.7±16.2 vs. Post DASH 7.9±11.1, p<.001). For the 18 patients involved in sports, the sports module of the DASH score improved from 73.9±28.9 to 13.2±25.0, p<.001). Physical therapy visits ranged from 1-22 with an average of 12±6 and, average treatment duration of 6.1±2.5 wks (range 1-10). Home exercise program compliance was recorded for each

  4. Bessong, PK

    African Journals Online (AJOL)

    Bessong, PK. Vol 11, No 2 (2012) - Articles The Accounting Implication of Cultural Dimensions on Financial Reporting: A Study of Selected Manufacturing Companies in Nigeria Abstract PDF · Vol 11, No 2 (2012) - Articles Human Resource Valuation and the Performance of Selected Banks in Nigeria Abstract PDF.

  5. Treatment of osteochondral defects of the talus with a metal resurfacing inlay implant after failed previous surgery: a prospective study

    NARCIS (Netherlands)

    van Bergen, C. J. A.; van Eekeren, I. C. M.; Reilingh, M. L.; Sierevelt, I. N.; van Dijk, C. N.


    We have evaluated the clinical effectiveness of a metal resurfacing inlay implant for osteochondral defects of the medial talar dome after failed previous surgical treatment. We prospectively studied 20 consecutive patients with a mean age of 38 years (20 to 60), for a mean of three years (2 to 5)

  6. Correction of Large Oro-antral Communications From Previously Failed Implant Treatment: Reconstruction of Hard and Soft Tissues. (United States)

    Petrungaro, Paul S; Gonzalez, Santiago; Villegas, Carlos


    As dental implants become more popular for the treatment of partial and total edentulism and treatment of "terminal dentitions," techniques for the management of the atrophic posterior maxillae continue to evolve. Although dental implants carry a high success rate long term, attention must be given to the growing numbers of revisions or retreatment of cases that have had previous dental implant treatment and/or advanced bone replacement procedures that, due to either poor patient compliance, iatrogenic error, or poor quality of the pre-existing alveolar and/or soft tissues, have led to large osseous defects, possibly with deficient soft-tissue volume. In the posterior maxillae, where the poorest quality of bone in the oral cavity exists, achieving regeneration of the alveolar bone and adequate volume of soft tissue remains a complex procedure. This is made even more difficult when dealing with loss of dental implants previously placed, aggressive bone reduction required in various implant procedures, and/or residual sinus infections precluding proper closure of the oral wound margins. The purpose of this article is to outline a technique for the total closure of large oro-antral communications, with underlying osseous defects greater than 15 mm in width and 30 mm in length, for which multiple previous attempts at closure had failed, to achieve not only the reconstruction of adequate volume and quality of soft tissues in the area of the previous fistula, but also total regeneration of the osseous structures in the area of the large void.

  7. Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial. (United States)

    Coppens, Michiel; Synhorst, David; Eikelboom, John W; Yusuf, Salim; Shestakovska, Olga; Connolly, Stuart J


    The AVERROES double-blinded, randomized trial demonstrated that apixaban reduces the risk of stroke or systemic embolism (SSE) by 55% compared with aspirin without an increase in major bleeding in patients with atrial fibrillation either who previously tried but failed vitamin K antagonists (VKA) therapy or who were expected to be unsuitable for VKA therapy. In this pre-specified analysis, we explored the consistency of the results in the subgroup of patients who tried but failed VKA therapy. Of 5599 patients, 2216 (40%) had previously failed VKA treatment [main reasons: poor international normalized ratio (INR) control 42%, refusal 37%, bleeding on VKA 8%]. Compared with those expected to be unsuitable for VKA therapy, those who had previously failed were older, more often male, had higher body mass index, more likely to have moderate renal impairment and a history of stroke and less likely to have heart failure or to be medically undertreated. The effects of apixaban compared with aspirin were consistent in those who previously failed and those who were expected to be unsuitable, for both SSE (P interaction 0.13) and major bleeding (P interaction 0.74) and were also consistent among different subgroups of patients who had previously failed VKA therapy defined by reasons for unsuitability, age, sex, renal function, CHADS2 score, aspirin dose, duration, indication, and quality of INR control of prior VKA use. The efficacy and safety of apixaban compared with aspirin is consistent in subgroups of patients who have previously attempted but failed VKA therapy, irrespective of the reason for discontinuation. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email:

  8. Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial

    NARCIS (Netherlands)

    Coppens, Michiel; Synhorst, David; Eikelboom, John W.; Yusuf, Salim; Shestakovska, Olga; Connolly, Stuart J.


    The AVERROES double-blinded, randomized trial demonstrated that apixaban reduces the risk of stroke or systemic embolism (SSE) by 55% compared with aspirin without an increase in major bleeding in patients with atrial fibrillation either who previously tried but failed vitamin K antagonists (VKA)

  9. DNA-PK assay

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, Carl W.; Connelly, Margery A.


    The present invention provides a method for detecting DNA-activated protein kinase (DNA-PK) activity in a biological sample. The method includes contacting a biological sample with a detectably-labeled phosphate donor and a synthetic peptide substrate defined by the following features to provide specific recognition and phosphorylation by DNA-PK: (1) a phosphate-accepting amino acid pair which may include serine-glutamine (Ser-Gln) (SQ), threonine-glutamine (Thr-Gln) (TQ), glutamine-serine (Gln-Ser) (QS), or glutamine-threonine (Gln-Thr) (QT); (2) enhancer amino acids which may include glutamic acid or glutamine immediately adjacent at the amino- or carboxyl- side of the amino acid pair and forming an amino acid pair-enhancer unit; (3) a first spacer sequence at the amino terminus of the amino acid pair-enhancer unit; (4) a second spacer sequence at the carboxyl terminus of the amino acid pair-enhancer unit, which spacer sequences may include any combination of amino acids that does not provide a phosphorylation site consensus sequence motif; and, (5) a tag moiety, which may be an amino acid sequence or another chemical entity that permits separating the synthetic peptide from the phosphate donor. A compostion and a kit for the detection of DNA-PK activity are also provided. Methods for detecting DNA, protein phosphatases and substances that alter the activity of DNA-PK are also provided. The present invention also provides a method of monitoring protein kinase and DNA-PK activity in living cells. -A composition and a kit for monitoring protein kinase activity in vitro and a composition and a kit for monitoring DNA-PK activities in living cells are also provided. A method for identifying agents that alter protein kinase activity in vitro and a method for identifying agents that alter DNA-PK activity in living cells are also provided.

  10. Influence of Previous Failed Antispasticity Therapy on the Efficacy and Tolerability of THC:CBD Oromucosal Spray for Multiple Sclerosis Spasticity. (United States)

    Haupts, Michael; Vila, Carlos; Jonas, Anna; Witte, Kerstin; Álvarez-Ossorio, Lourdes


    Sativex® (THC:CBD oromucosal spray) is indicated as add-on treatment for patients with moderate to severe multiple sclerosis (MS) spasticity. We aimed to determine whether antispasticity treatment history influenced the efficacy and safety of add-on THC:CBD oromucosal spray in MS spasticity patients. Post hoc analysis of an enriched-design clinical trial of THC:CBD oromucosal spray versus placebo, using records of patients under previous and current ineffective antispasticity therapies. Subgroups were patients with at least 1 failed therapy attempt with either baclofen or tizanidine (Group 1) or at least 2 failed therapy attempts with both baclofen and tizanidine (Group 2). Of 241 patients in the intent-to-treat population, 162 and 57 patients met the criteria for Groups 1 and 2, respectively. In all groups, response on the spasticity 0-10 Numerical Rating Scale was significantly greater with THC:CBD oromucosal spray versus placebo, for minimal clinically important difference (MCID ≥18% improvement vs. baseline) and clinically important difference (CID, ≥30% improvement vs. baseline). THC:CBD oromucosal spray improved spasticity-related symptoms such as sleep quality and timed 10-meter walk independent of the number of prior failed therapy attempts. Tolerability was not influenced by pre-treatment history. THC:CBD oromucosal spray provided consistent relief with good tolerability in MS spasticity patients irrespective of their antispasticity pre-treatment history. © 2016 S. Karger AG, Basel.

  11. Failing Failed States

    DEFF Research Database (Denmark)

    Holm, Hans-Henrik


    from inaction. Often, the media are blamed. Politicians complain about the media when they interfere (the CNN effect), and when they do not. This article looks at how the media do cover failing states. Sierra Leone and Congo are used as examples. The analysis shows that there is little independent...

  12. A physiologically-based pharmacokinetic(PB-PK) model for ethylene dibromide : relevance of extrahepatic metabolism

    NARCIS (Netherlands)

    Hissink, A M; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, D.J.; Commandeur, J N; Vermeulen, N P; van Bladeren, P.J.

    A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

  13. A physiologically-based pharmacokinetic (PB-PK) model for ethylene dibromide : relevance of extrahepatic metabolism

    NARCIS (Netherlands)

    Hissink, A.M.; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, J.D.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, P.J. van


    A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

  14. Descemet's stripping endothelial keratoplasty under failed penetrating keratoplasty: visual rehabilitation and graft survival rate. (United States)

    Anshu, Arundhati; Price, Marianne O; Price, Francis W


    To evaluate graft survival, risk factors for failure, complications, and visual rehabilitation in patients who underwent Descemet's stripping endothelial keratoplasty (DSEK) under a failed penetrating keratoplasty (PK). Retrospective interventional case series. Sixty eyes (60 patients) treated at Price Vision Group, Indianapolis, Indiana. Graft diameters ranged from 8 to 9 mm and were ∼1 mm larger than the previous PK. The Descemet's membrane was not stripped in the majority (54, 84%). The graft was inserted using forceps or a Busin funnel glide (Moria, Anthony, France). The probability of graft survival was calculated by Kaplan-Meier survival analysis. Graft survival, best-corrected visual acuity (BCVA), and complications. The mean recipient age was 68 years (range, 17-95 years). Forty eyes had 1 previous failed PK, 14 eyes had 2 previous failed PKs, and 6 eyes had 3 previous failed PKs. Thirty-one eyes (52%) had preexisting glaucoma, and 16 eyes (27%) had prior glaucoma surgery (trabeculectomy in 4, shunt procedure in 12). Fifty-five grafts were performed for visual rehabilitation, and 5 grafts were performed for pain relief. Median follow-up was 2.3 years (range, 2 months to 6 years). Median preoperative BCVA was 1.23 logarithm of the minimum angle of resolution (logMAR) (range, 0.2-3, Snellen 20/340), and median postoperative visual improvement was 0.6 logMAR (6 lines), range -0.3 to +2.7. Four eyes had graft detachment (6.6%), 7 eyes (10.5%) had endothelial rejection, and 10 eyes (16.6%) had graft failure (primary failure in 2, secondary failure in 8). The overall secondary graft survival rates were 98%, 90%, 81%, and 74% at 1, 2, 3, and 4 years, respectively. Prior glaucoma shunt was the principal risk factor for graft failure. The graft survival rates were 100%, 96%, 96%, and 96% in eyes without a prior shunt versus 93%, 74%, 44%, and 22% with a prior shunt at 1, 2, 3, and 4 years, respectively (P=0.0005; relative risk = 20). Peripheral anterior synechiae

  15. Effect of a supplementation with myo-inositol plus melatonin on oocyte quality in women who failed to conceive in previous in vitro fertilization cycles for poor oocyte quality: a prospective, longitudinal, cohort study. (United States)

    Unfer, Vittorio; Raffone, Emanuela; Rizzo, Piero; Buffo, Silvia


    Several factors can affect oocyte quality and therefore pregnancy outcome in assisted reproductive technology (ART) cycles. Recently, a number of studies have shown that the presence of several compounds in the follicular fluid positively correlates with oocyte quality and maturation (i.e., myo-inositol and melatonin). In the present study, we aim to evaluate the pregnancy outcomes after the administration of myo-inositol combined with melatonin in women who failed to conceive in previous in vitro fertilization (IVF) cycles due to poor oocyte quality. Forty-six women were treated with 4 g/day myo-inositol and 3 mg/day melatonin (inofolic® and inofolic® Plus, Lo.Lipharma, Rome) for 3 months and then underwent a new IVF cycle. After treatment, the number of mature oocytes, the fertilization rate, the number of both, total and top-quality embryos transferred were statistically higher compared to the previous IVF cycle, while there was no difference in the number of retrieved oocyte. After treatment, a total of 13 pregnancies occurred, 9 of them were confirmed echographically; four evolved in spontaneous abortion. The treatment with myo-inositol and melatonin improves ovarian stimulation protocols and pregnancy outcomes in infertile women with poor oocyte quality.

  16. Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs. (United States)

    Kristoffersson, Anders N; David-Pierson, Pascale; Parrott, Neil J; Kuhlmann, Olaf; Lave, Thierry; Friberg, Lena E; Nielsen, Elisabet I


    Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa. A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated. The previous murine study data were well replicated with fT > MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT > MIC and fAUC/MIC had similar predictive capacities with preference for fT > MIC when short t1/2 and fAUC/MIC when long t1/2. A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.

  17. Synthesis and characterization of [{sup 11}C]PK11195 as a PET radiopharmaceutical

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Fernanda A. F.; Silveira, Marina B.; Oliveira, Amanda P.; Nascimento, Leonardo T.C.; Silva, Juliana B.; Mamede, Marcelo, E-mail:, E-mail: [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizontge, MG (Brazil). Unidade de Pesquisa e Produção de Radiofármacos


    The radiopharmaceutical [{sup 11}C]PK11195 has been used for Positron Emission Tomography (PET) imaging of neuroinflammatory diseases. PK11195 is a tracer that binds to the benzodiazepine peripheral receptor (PBR) currently known as membrane translocator protein (TSPO). [{sup 11}C]PK11195 is differentially accumulated in tissues which have high TSPO expression, typically microglia activation in brain tissue, which has normally low TSPO expression. The aim of this work was to synthesize and characterize [{sup 11}C]PK11195 at the Radiopharmaceutical Production Unit of CDTN to make it available for future studies and applications in major brain inflammatory diseases. The [{sup 11}C]PK11195 syntheses were performed using Tracerlab™ FXC PRO (GE) by [{sup 11}C]methylation of the precursor (R)-[N-desmethyl] PK11195. Optimizations of the reaction conditions for the synthesis of [{sup 11}C]PK11195 were: Anhydrous dimethylsulfoxide (DMSO) volume, mass of precursor, and potassium hydroxide (KOH), labelling reaction temperature and time. After comparison of the results obtained for each condition evaluated, the standard best reaction parameters were defined as: 1mg of the precursor dissolved in 300 μL of DMSO (anhydrous); 10-15mg of KOH; and labeling reaction temperature of 40°C during 2 minutes. The total synthesis time was 40 minutes and the mean non-decay-corrected radiochemical yield was 10.93 ± 3.44%. All quality control criteria were met according to previous specifications. (author)

  18. Synthesis and characterization of [11C]PK11195 as a PET radiopharmaceutical

    International Nuclear Information System (INIS)

    Almeida, Fernanda A. F.; Silveira, Marina B.; Oliveira, Amanda P.; Nascimento, Leonardo T.C.; Silva, Juliana B.; Mamede, Marcelo


    The radiopharmaceutical [ 11 C]PK11195 has been used for Positron Emission Tomography (PET) imaging of neuroinflammatory diseases. PK11195 is a tracer that binds to the benzodiazepine peripheral receptor (PBR) currently known as membrane translocator protein (TSPO). [ 11 C]PK11195 is differentially accumulated in tissues which have high TSPO expression, typically microglia activation in brain tissue, which has normally low TSPO expression. The aim of this work was to synthesize and characterize [ 11 C]PK11195 at the Radiopharmaceutical Production Unit of CDTN to make it available for future studies and applications in major brain inflammatory diseases. The [ 11 C]PK11195 syntheses were performed using Tracerlab™ FXC PRO (GE) by [ 11 C]methylation of the precursor (R)-[N-desmethyl] PK11195. Optimizations of the reaction conditions for the synthesis of [ 11 C]PK11195 were: Anhydrous dimethylsulfoxide (DMSO) volume, mass of precursor, and potassium hydroxide (KOH), labelling reaction temperature and time. After comparison of the results obtained for each condition evaluated, the standard best reaction parameters were defined as: 1mg of the precursor dissolved in 300 μL of DMSO (anhydrous); 10-15mg of KOH; and labeling reaction temperature of 40°C during 2 minutes. The total synthesis time was 40 minutes and the mean non-decay-corrected radiochemical yield was 10.93 ± 3.44%. All quality control criteria were met according to previous specifications. (author)

  19. Failing Decision

    DEFF Research Database (Denmark)

    Knudsen, Morten


    Recently the Danish subway trains have begun to announce “on time” when they arrive at a station on time. This action reflects a worrying acceptance of the normality of failure. If trains were generally expected to be on time, there would be no reason to – triumphantly – announce it. This chapter...... as a controlled cost for achieving organizational goals. Decisions must fail so the organization can succeed. This chapter uses two cases to elaborate on these ideas. By way of introduction, I will reflect on the notion of ‘failing decisions’ within organization and decision theory. This chapter is also propelled...

  20. PK-tilitoimistojen paperisen kirjanpidon kilpailuvaltin katoaminen


    Valli, Kari


    Opinnäytetyön tavoitteena oli selvittää taloushallintoalan kehitystä. Painopiste oli kirjanpidon digitalisoitumisessa, koska se on paperisen kirjanpidon ainoa luonnollinen haastaja. Tutkimuksen tarkoituksena oli selvittää ja keskustella PK-tilitoimistojen kirjanpitäjien ja ITC-vastaavien kanssa paperisen kirjanpidon jäämisestä vanhanaikaiseksi täysin digitaalisen kirjanpidon edellä. Opinnäytteen tutkimuskysymyksenä oli, milloin PK-yrityksen tulisi siirtyä digitaaliseen kirjanpitoon. Tutk...

  1. Pk-rityksen riskit Kiinan markkinoilla


    Vahala, Kari


    Kiinan talous on kasvanut erittäin nopeasti viimeisten vuosikymmenien aikana. Eri mittarien mukaan Kiina on maailman suurin talous. Kiinan markkinat houkuttelevat myös suomalaisia pk-yrityksiä. Yritysten pitää kuitenkin ymmärtää Kiinan markkinoiden erityispiirteitä ja samalla ennakoida myös tulevia riskejä. Opinnäytetyössä kartoitettiin suomalaisten pk-yritysten riskejä Kiinan markkinoilla. Tämä idea lähti liikkeelle omasta mielenkiinnostani Aasian maita ja kulttuuria kohtaan. Vuonna 2016...

  2. Algebra task sheets : grades pk-2

    CERN Document Server

    Reed, Nat


    For grades PK-2, our Common Core State Standards-based resource meets the algebraic concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

  3. Geometry task sheets : grades pk-2

    CERN Document Server

    Rosenberg, Mary


    For grades PK-2, our Common Core State Standards-based resource meets the geometry concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

  4. Beyond DNA repair: DNA-PK function in cancer


    Goodwin, Jonathan F.; Knudsen, Karen E.


    The DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery that governs the response to DNA damage, serving to maintain genome integrity. However, the DNA-PK kinase component was initially isolated with transcriptional complexes, and recent findings have illuminated the impact of DNA-PK-mediated transcriptional regulation on tumor progression and therapeutic response. DNA-PK expression has also been correlated with poor outcome in selected tumor types, furthe...

  5. Instructions for using SOW Pk program

    Energy Technology Data Exchange (ETDEWEB)

    Magnoli, D.E.


    PKSOW is a Fortran program developed at Lawrence Livermore National Laboratory to calculate the probability of kill (P{sub k}) of a submarine-launched ASW nuclear standoff weapon. The calculation can be done for a broad spectrum of conditions: the user specifies weapon characteristics (yield, depth of burst), target localization and course and speed errors, target evasion tactics, target damage specifications, and safe standoff parameters. Output from the program includes a table of Pk at various standoff ranges for each of several yields. This version of PKSOW has been adapted to run on the IBM PC using MS/DOS. The output from the program may be used with MS CHART to produce plots of Pk vs standoff range.

  6. DNA-PK inhibition causes a low level of H2AX phosphorylation and homologous recombination repair in Medaka (Oryzias latipes) cells

    Energy Technology Data Exchange (ETDEWEB)

    Urushihara, Yusuke [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan); Kobayashi, Junya [Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto 606-8501 (Japan); Matsumoto, Yoshihisa [Research Laboratory for Nuclear Reactors, Tokyo Institute of Technology, Tokyo 152-8550 (Japan); Komatsu, Kenshi [Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto 606-8501 (Japan); Oda, Shoji [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan); Mitani, Hiroshi, E-mail: [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan)


    Highlights: Black-Right-Pointing-Pointer We investigated the effect of DNA-PK inhibition on DSB repair using fish cells. Black-Right-Pointing-Pointer A radiation sensitive mutant RIC1 strain showed a low level of DNA-PK activity. Black-Right-Pointing-Pointer DNA-PK dysfunction leads defects in HR repair and DNA-PKcs autophosphorylation. Black-Right-Pointing-Pointer DNA-PK dysfunction leads a slight increase in the number of 53BP1 foci after DSBs. Black-Right-Pointing-Pointer DNA-PK dysfunction leads an alternative NHEJ that depends on 53BP1. -- Abstract: Nonhomologous end joining (NHEJ) and homologous recombination (HR) are known as DNA double-strand break (DSB) repair pathways. It has been reported that DNA-PK, a member of PI3 kinase family, promotes NHEJ and aberrant DNA-PK causes NHEJ deficiency. However, in this study, we demonstrate that a wild-type cell line treated with DNA-PK inhibitor and a mutant cell line with dysfunctional DNA-PK showed decreased HR efficiency in fish cells (Medaka, Oryzias latipes). Previously, we reported that the radiation-sensitive mutant RIC1 strain has a defect in the Histone H2AX phosphorylation after {gamma}-irradiation. Here, we showed that a DNA-PK inhibitor, NU7026, treatment resulted in significant reduction in the number of {gamma}H2AX foci after {gamma}-irradiation in wild-type cells, but had no significant effect in RIC1 cells. In addition, RIC1 cells showed significantly lower levels of DNA-PK kinase activity compared with wild-type cells. We investigated NHEJ and HR efficiency after induction of DSBs. Wild-type cells treated with NU7026 and RIC1 cells showed decreased HR efficiency. These results indicated that aberrant DNA-PK causes the reduction in the number of {gamma}H2AX foci and HR efficiency in RIC1 cells. We performed phosphorylated DNA-PKcs (Thr2609) and 53BP1 focus assay after {gamma}-irradiation. RIC1 cells showed significant reduction in the number of phosphorylated DNA-PKcs foci and no deference in the

  7. Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model. (United States)

    Tanoshima, Reo; Bournissen, Facundo Garcia; Tanigawara, Yusuke; Kristensen, Judith H; Taddio, Anna; Ilett, Kenneth F; Begg, Evan J; Wallach, Izhar; Ito, Shinya


    Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX). © 2014 The British Pharmacological Society.

  8. Lumbar extension traction alleviates symptoms and facilitates healing of disc herniation/sequestration in 6-weeks, following failed treatment from three previous chiropractors: a CBP®case report with an 8 year follow-up. (United States)

    Oakley, Paul A; Harrison, Deed E


    [Purpose] To present the outcome of a patient, having sciatica and MRI-verified disc herniation/sequestration who underwent Chiropractic BioPhysics ® (CBP ® ) protocol designed to improve the lumbar lordosis. [Subject and Methods] A 56-year-old male suffered from chronic low back pain and recent sciatica due to lumbar disc herniation despite being under continuous care from three previous chiropractors. Radiographic analysis revealed a lumbar hypolordosis and MRI confirmed disc herniation and sequestration at L4-L5. Generalized decreased lumbar range of motion and multiple positive orthopedic and neurologic tests were present. [Results] After 26 treatments of CBP lumbar extension traction over 9-weeks a total reduction of the disc herniation and sequestration occurred with concomitant improvement in neurologic symptoms. Continuing maintenance treatments, an 8 year follow-up shows no relapse of condition and patient remained in good health. [Conclusion] A patient with lumbar disc herniation/sequestration was successfully treated with CBP technique procedures including lumbar extension traction that achieved a significant healing of herniation and significant reduction in symptoms not obtained following traditional chiropractic procedures alone. The quick reduction in lumbar disc herniation would appear to be related to a segmental disc unloading force produced during extension traction procedures for increasing the lumbar curvature.

  9. Rapid and efficient radiosynthesis of [{sup 123}I]I-PK11195, a single photon emission computed tomography tracer for peripheral benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Pimlott, Sally L. [Department of Clinical Physics, West of Scotland Radionuclide Dispensary, Western Infirmary, G11 6NT Glasgow (United Kingdom)], E-mail:; Stevenson, Louise [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom); Wyper, David J. [Institute of Neurological Sciences, Southern General Hospital, G51 4TF Glasgow (United Kingdom); Sutherland, Andrew [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom)


    Introduction: [{sup 123}I]I-PK11195 is a high-affinity single photon emission computed tomography radiotracer for peripheral benzodiazepine receptors that has previously been used to measure activated microglia and to assess neuroinflammation in the living human brain. This study investigates the radiosynthesis of [{sup 123}I]I-PK11195 in order to develop a rapid and efficient method that obtains [{sup 123}I]I-PK11195 with a high specific activity for in vivo animal and human imaging studies. Methods: The synthesis of [{sup 123}I]I-PK11195 was evaluated using a solid-state interhalogen exchange method and an electrophilic iododestannylation method, where bromine and trimethylstannyl derivatives were used as precursors, respectively. In the electrophilic iododestannylation method, the oxidants peracetic acid and chloramine-T were both investigated. Results: Electrophilic iododestannylation produced [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than achievable using the halogen exchange method investigated. Using chloramine-T as oxidant provided a rapid and efficient method of choice for the synthesis of [{sup 123}I]I-PK11195. Conclusions: [{sup 123}I]I-PK11195 has been successfully synthesized via a rapid and efficient electrophilic iododestannylation method, producing [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than previously achieved.

  10. Classification and Regression Tree Analysis of Clinical Patterns that Predict Survival in 127 Chinese Patients with Advanced Non-small Cell Lung Cancer Treated by Gefitinib Who Failed to Previous Chemotherapy

    Directory of Open Access Journals (Sweden)

    Ziping WANG


    Full Text Available Background and objective It has been proven that gefitinib produces only 10%-20% tumor regression in heavily pretreated, unselected non-small cell lung cancer (NSCLC patients as the second- and third-line setting. Asian, female, nonsmokers and adenocarcinoma are favorable factors; however, it is difficult to find a patient satisfying all the above clinical characteristics. The aim of this study is to identify novel predicting factors, and to explore the interactions between clinical variables and their impact on the survival of Chinese patients with advanced NSCLC who were heavily treated with gefitinib in the second- or third-line setting. Methods The clinical and follow-up data of 127 advanced NSCLC patients referred to the Cancer Hospital & Institute, Chinese Academy of Medical Sciences from March 2005 to March 2010 were analyzed. Multivariate analysis of progression-free survival (PFS was performed using recursive partitioning, which is referred to as the classification and regression tree (CART analysis. Results The median PFS of 127 eligible consecutive advanced NSCLC patients was 8.0 months (95%CI: 5.8-10.2. CART was performed with an initial split on first-line chemotherapy outcomes and a second split on patients’ age. Three terminal subgroups were formed. The median PFS of the three subsets ranged from 1.0 month (95%CI: 0.8-1.2 for those with progressive disease outcome after the first-line chemotherapy subgroup, 10 months (95%CI: 7.0-13.0 in patients with a partial response or stable disease in first-line chemotherapy and age <70, and 22.0 months for patients obtaining a partial response or stable disease in first-line chemotherapy at age 70-81 (95%CI: 3.8-40.1. Conclusion Partial response, stable disease in first-line chemotherapy and age ≥ 70 are closely correlated with long-term survival treated by gefitinib as a second- or third-line setting in advanced NSCLC. CART can be used to identify previously unappreciated patient

  11. PK-sensitive PrPSc is infectious and shares basic structural features with PK-resistant PrPSc (United States)

    One of the main characteristics of the transmissible isoform of the prion protein (PrPSc) is its partial resistance to proteinase K (PK) digestion. Diagnosis of prion disease typically relies upon immunodetection of PK-digested PrPSc following Western blot or ELISA. More recently, researchers determ...

  12. Tools for predicting the PK/PD of therapeutic proteins. (United States)

    Diao, Lei; Meibohm, Bernd


    Assessments of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics are an integral part in the development of novel therapeutic agents. Compared with traditional small molecule drugs, therapeutic proteins possess many distinct PK/PD features that necessitate the application of modified or separate approaches for assessing their PK/PD relationships. In this review, the authors discuss tools that are utilized to describe and predict the PK/PD features of therapeutic proteins and that are valuable additions in the armamentarium of drug development approaches to facilitate and accelerate their successful preclinical and clinical development. A variety of state-of-the-art PK/PD tools is currently being applied and has been adjusted to support the development of proteins as therapeutics, including allometric scaling approaches, target-mediated disposition models, first-in-man dose calculations, physiologically based PK models and empirical and semi-mechanistic PK/PD modeling. With the advent of the next generation of biologics including bioengineered antibody constructs being developed, these tools will need to be further refined and adapted to ensure their applicability and successful facilitation of the drug development process for these novel scaffolds.

  13. Does the MMPI PTSD-PK scale measure robustness? (United States)

    Sinnett, E R; Holen, M C; Heil, M C


    Research evaluating the diagnostic value of the MMPI PK scale for determining Posttraumatic Stress Disorder has been consistently positive. Various cut-off points have been suggested, depending on the population studied. The current study, involving a select group of police candidates from middle-sized midwestern towns, suggests that low PK scores may represent robustness. These subjects as a group made low use of health and mental health services and obtained very low PK scores (T = 41), although they made average scores on the clinical scales.

  14. DNA-PK. The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway

    International Nuclear Information System (INIS)

    Hashimoto, Mitsumasa; Rao, S.; Tokuno, Osamu; Utsumi, Hiroshi; Takeda, Shunichi


    The effect of wortmannin posttreatment was studied in cells derived from different species (hamster, mouse, chicken, and human) with normal and defective DNA-dependent protein kinase (DNA-PK) activity, cells with and without the ataxia telangiectasia mutated (ATM) gene, and cells lacking other regulatory proteins involved in the DNA double-strand break (DSB) repair pathways. Clonogenic assays were used to obtain all results. Wortmannin radiosensitization was observed in Chinese hamster cells (V79-B310H, CHO-K1), mouse mammary carcinoma cells (SR-1), transformed human fibroblast (N2KYSV), chicken B lymphocyte wild-type cells (DT40), and chicken Rad54 knockout cells (Rad54 -/- ). However, mouse mammary carcinoma cells (SX9) with defects in the DNA-PK and chicken DNA-PK catalytic subunit (DNA-PKcs) knockout cells (DNA-PKcs -/-/- ) failed to exhibit wortmannin radiosensitization. On the other hand, severe combined immunodeficiency (SCID) mouse cells (SC3VA2) exposed to wortmannin exhibited significant increases in radiosensitivity, possibly because of some residual function of DNA-PKcs. Moreover, the transformed human cells derived from AT patients (AT2KYSV) and chicken ATM knockout cells (ATM -/- ) showed pronounced wortmannin radiosensitization. These studies demonstrate confirm that the mechanism underlying wortmannin radiosensitization is the inhibition of DNA-PK, but not of ATM, thereby resulting in the inhibition of DSB repair via nonhomologous endjoining (NHEJ). (author)

  15. Dialectical behaviour therapy and an added cognitive behavioural treatment module for eating disorders in women with borderline personality disorder and anorexia nervosa or bulimia nervosa who failed to respond to previous treatments. An open trial with a 15-month follow-up. (United States)

    Kröger, Christoph; Schweiger, Ulrich; Sipos, Valerija; Kliem, Sören; Arnold, Ruediger; Schunert, Tanja; Reinecker, Hans


    There is evidence from case studies suggesting that adapted dialectical behavior therapy (DBT) for borderline personality disorder (BPD) and eating disorders (ED) might improve disorder related complaints. Twenty-four women with BPD (9 with comorbid anorexia nervosa [AN] and 15 with bulimia nervosa [BN]), who already had failed to respond to previous eating-disorder related inpatient treatments were consecutively admitted to an adapted inpatient DBT program. Assessment points were at pre-treatment, post-treatment, and 15-month follow-up. At follow-up, the remission rate was 54% for BN, and 33% for AN. Yet 44% of women with AN crossed over to BN and one woman additionally met the criteria of AN. For women with AN, the mean weight was not significantly increased at post-treatment, but had improved at follow-up. For women with BN, the frequency of binge-eating episodes was reduced at post-treatment as well as at follow-up. Self-rated eating-related complaints and general psychopathology, as well as ratings on global psychosocial functioning, were significantly improved at post-treatment and at follow-up. Although these findings support the assumption that the adapted DBT inpatient program is a potentially efficacious treatment for those who failed to respond to previous eating-disorder related inpatient treatments, remission rates and maintained eating-related psychopathology also suggest that this treatment needs further improvement. 2010 Elsevier Ltd. All rights reserved.

  16. Automated DBS microsampling, microscale automation and microflow LC-MS for therapeutic protein PK. (United States)

    Zhang, Qian; Tomazela, Daniela; Vasicek, Lisa A; Spellman, Daniel S; Beaumont, Maribel; Shyong, BaoJen; Kenny, Jacqueline; Fauty, Scott; Fillgrove, Kerry; Harrelson, Jane; Bateman, Kevin P


    Reduce animal usage for discovery-stage PK studies for biologics programs using microsampling-based approaches and microscale LC-MS. We report the development of an automated DBS-based serial microsampling approach for studying the PK of therapeutic proteins in mice. Automated sample preparation and microflow LC-MS were used to enable assay miniaturization and improve overall assay throughput. Serial sampling of mice was possible over the full 21-day study period with the first six time points over 24 h being collected using automated DBS sample collection. Overall, this approach demonstrated comparable data to a previous study using single mice per time point liquid samples while reducing animal and compound requirements by 14-fold. Reduction in animals and drug material is enabled by the use of automated serial DBS microsampling for mice studies in discovery-stage studies of protein therapeutics.

  17. SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods

    NARCIS (Netherlands)

    Schuitemaker, Alie; van Berckel, Bart N. M.; Kropholler, Marc A.; Veltman, Dick J.; Scheltens, Philip; Jonker, Cees; Lammertsma, Adriaan A.; Boellaard, Ronald


    (R)-[11C]PK11195 has been used for quantifying cerebral microglial activation in vivo. In previous studies, both plasma input and reference tissue methods have been used, usually in combination with a region of interest (ROI) approach. Definition of ROIs, however, can be labourious and prone to

  18. Engaging Future Failing States (United States)


    military missions in the Middle East, the Balkans, Africa, Asia , and South America. There is an increasing proliferation of failed and failing states...disparity, overpopulation , food security, health services availability, migration pressures, environmental degradation, personal and 22 community

  19. SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods. (United States)

    Schuitemaker, Alie; van Berckel, Bart N M; Kropholler, Marc A; Veltman, Dick J; Scheltens, Philip; Jonker, Cees; Lammertsma, Adriaan A; Boellaard, Ronald


    (R)-[11C]PK11195 has been used for quantifying cerebral microglial activation in vivo. In previous studies, both plasma input and reference tissue methods have been used, usually in combination with a region of interest (ROI) approach. Definition of ROIs, however, can be labourious and prone to interobserver variation. In addition, results are only obtained for predefined areas and (unexpected) signals in undefined areas may be missed. On the other hand, standard pharmacokinetic models are too sensitive to noise to calculate (R)-[11C]PK11195 binding on a voxel-by-voxel basis. Linearised versions of both plasma input and reference tissue models have been described, and these are more suitable for parametric imaging. The purpose of this study was to compare the performance of these plasma input and reference tissue parametric methods on the outcome of statistical parametric mapping (SPM) analysis of (R)-[11C]PK11195 binding. Dynamic (R)-[11C]PK11195 PET scans with arterial blood sampling were performed in 7 younger and 11 elderly healthy subjects. Parametric images of volume of distribution (Vd) and binding potential (BP) were generated using linearised versions of plasma input (Logan) and reference tissue (Reference Parametric Mapping) models. Images were compared at the group level using SPM with a two-sample t-test per voxel, both with and without proportional scaling. Parametric BP images without scaling provided the most sensitive framework for determining differences in (R)-[11C]PK11195 binding between younger and elderly subjects. Vd images could only demonstrate differences in (R)-[11C]PK11195 binding when analysed with proportional scaling due to intersubject variation in K1/k2 (blood-brain barrier transport and non-specific binding).

  20. Data analysis & probability task sheets : grades pk-2

    CERN Document Server

    Cook, Tanya


    For grades PK-2, our Common Core State Standards-based resource meets the data analysis & probability concepts addressed by the NCTM standards and encourages your students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

  1. Physiologically-based PK/PD modelling of therapeutic macromolecules. (United States)

    Thygesen, Peter; Macheras, Panos; Van Peer, Achiel


    Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

  2. Distinct genetic difference between the Duffy binding protein (PkDBPαII) of Plasmodium knowlesi clinical isolates from North Borneo and Peninsular Malaysia. (United States)

    Fong, Mun-Yik; Rashdi, Sarah A A; Yusof, Ruhani; Lau, Yee-Ling


    Plasmodium knowlesi is one of the monkey malaria parasites that can cause human malaria. The Duffy binding protein of P. knowlesi (PkDBPαII) is essential for the parasite's invasion into human and monkey erythrocytes. A previous study on P. knowlesi clinical isolates from Peninsular Malaysia reported high level of genetic diversity in the PkDBPαII. Furthermore, 36 amino acid haplotypes were identified and these haplotypes could be separated into allele group I and allele group II. In the present study, the PkDBPαII of clinical isolates from the Malaysian states of Sarawak and Sabah in North Borneo was investigated, and compared with the PkDBPαII of Peninsular Malaysia isolates. Blood samples from 28 knowlesi malaria patients were used. These samples were collected between 2011 and 2013 from hospitals in North Borneo. The PkDBPαII region of the isolates was amplified by PCR, cloned into Escherichia coli, and sequenced. The genetic diversity, natural selection and phylogenetics of PkDBPαII haplotypes were analysed using MEGA5 and DnaSP ver. 5.10.00 programmes. Forty-nine PkDBPαII sequences were obtained. Comparison at the nucleotide level against P. knowlesi strain H as reference sequence revealed 58 synonymous and 102 non-synonymous mutations. Analysis on these mutations showed that PkDBPαII was under purifying (negative) selection. At the amino acid level, 38 different PkDBPαII haplotypes were identified. Twelve of the 28 blood samples had mixed haplotype infections. Phylogenetic analysis revealed that all the haplotypes were in allele group I, but they formed a sub-group that was distinct from those of Peninsular Malaysia. Wright's FST fixation index indicated high genetic differentiation between the North Borneo and Peninsular Malaysia haplotypes. This study is the first to report the genetic diversity and natural selection of PkDBPαII of P. knowlesi from Borneo Island. The PkDBPαII haplotypes found in this study were distinct from those from

  3. A comparison of the structure of the PK-sensitive and PK-resistant forms of PrPSc(Abstract) (United States)

    Background/Introduction. One of the distinctive phenotypes of the infectious isoform of PrP(PrPSc)is its resistance to proteinase K (PK) digestion. The diagnosis of prion diseases is based on this phenotypic observation. More recently, researchers determined that there is a sizeable fraction of PrPS...

  4. Genetic Diversity, Natural Selection and Haplotype Grouping of Plasmodium knowlesi Gamma Protein Region II (PkγRII): Comparison with the Duffy Binding Protein (PkDBPαRII). (United States)

    Fong, Mun Yik; Rashdi, Sarah A A; Yusof, Ruhani; Lau, Yee Ling


    Plasmodium knowlesi is a simian malaria parasite that has been reported to cause malaria in humans in Southeast Asia. This parasite invades the erythrocytes of humans and of its natural host, the macaque Macaca fascicularis, via interaction between the Duffy binding protein region II (PkDBPαRII) and the Duffy antigen receptor on the host erythrocytes. In contrast, the P. knowlesi gamma protein region II (PkγRII) is not involved in the invasion of P. knowlesi into humans. PkγRII, however, mediates the invasion of P. knowlesi into the erythrocytes of M. mulata, a non-natural host of P. knowlesi via a hitherto unknown receptor. The haplotypes of PkDBPαRII in P. knowlesi isolates from Peninsular Malaysia and North Borneo have been shown to be genetically distinct and geographically clustered. Also, the PkDBPαRII was observed to be undergoing purifying (negative) selection. The present study aimed to determine whether similar phenomena occur in PkγRII. Blood samples from 78 knowlesi malaria patients were used. Forty-eight of the samples were from Peninsular Malaysia, and 30 were from Malaysia Borneo. The genomic DNA of the samples was extracted and used as template for the PCR amplification of the PkγRII. The PCR product was cloned and sequenced. The sequences obtained were analysed for genetic diversity and natural selection using MEGA6 and DnaSP (version 5.10.00) programmes. Genetic differentiation between the PkγRII of Peninsular Malaysia and North Borneo isolates was estimated using the Wright's FST fixation index in DnaSP (version 5.10.00). Haplotype analysis was carried out using the Median-Joining approach in NETWORK (version A total of 78 PkγRII sequences was obtained. Comparative analysis showed that the PkγRII have similar range of haplotype (Hd) and nucleotide diversity (π) with that of PkDBPαRII. Other similarities between PkγRII and PkDBPαRII include undergoing purifying (negative) selection, geographical clustering of haplotypes

  5. Widespread and prolonged increase in (R)-(11)C-PK11195 binding after traumatic brain injury

    NARCIS (Netherlands)

    Folkersma, Hedy; Boellaard, Ronald; Yaqub, Maqsood; Kloet, Reina W.; Windhorst, Albert D.; Lammertsma, Adriaan A.; Vandertop, W. Peter; van Berckel, Bart N. M.


    Our objective was to measure (R)-(11)C-PK11195 binding as an indirect marker of neuronal damage after traumatic brain injury (TBI). Dynamic (R)-(11)C-PK11195 PET scans were acquired for 8 patients 6 mo after TBI and for 7 age-matched healthy controls. (R)-(11)C-PK11195 binding was assessed using the

  6. Translational PK/PD of anti-infective therapeutics. (United States)

    Rathi, Chetan; Lee, Richard E; Meibohm, Bernd

    Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses. With this tool set at hand, mechanism-based PK/PD modeling and simulation allows to develop optimal dosing regimens for novel and established antibiotics for maximum efficacy and minimal resistance development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Five strands of math tasks big book : grades pk-2

    CERN Document Server

    Reed, Nat; Forest, Chris


    For grades PK-2, our Common Core State Standards-based resource meets the five strands of math concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Included are challenging problem-solving tasks which will push the boundaries of critical thought and demonstrate to students the importance of mathematical problems in Number & Operations, Geometry, Measurement, Data Analysis & Probability and Algebra using real world situations.

  8. The old and the new in prekallikrein deficiency: historical context and a family from Argentina with PK deficiency due to a new mutation (Arg541Gln) in exon 14 associated with a common polymorphysm (Asn124Ser) in exon 5. (United States)

    Girolami, Antonio; Vidal, Josè; Sabagh, Marcela; Salagh, Marcela; Gervan, Nora; Parody, Maria; Peroni, Edoardo; Sambado, Luisa; Guglielmone, Hugo


    Prekallikrein (PK) is one of the clotting factors involved in the contact phase of blood. PK has an important historical role as its deficiency state represents the second instance of a clotting defect without bleeding manifestations, the first one being factor XII deficiency. PK deficiency is a rare clotting disorder. Moreover, only 11 patients have been investigated so far by molecular biology techniques. In this article, we briefly review some of the history around PK and also present some recent data on a newly identified family from Argentina suffering from PK deficiency. Two patients are homozygous whereas other family members are heterozygous. PK activity and antigen are 1% of normal in the homozygotes and around 60 to 70% of normal in the heterozygotes. As expected, all patients are asymptomatic of bleeding or thrombosis presentations. However, the two homozygotes showed essential hypertension. The PK deficiency in this family is due to a new mutation (Arg541Gln) in exon 14. The defect segregates together with a known polymorphism, Asn124Ser, in exon 5. The significance of the presence of hypertension in the two homozygotes is discussed in view of the extra coagulation effects of PK on vasodilation, vessel permeability, and the control of blood pressure. Structure function analysis indicates that the substitution of Arg with Gln probably impedes the transmembrane diffusion of the molecule, which therefore cannot be secreted in the homozygotes. The presence of hypertension in patients with PK deficiency has been previously reported in some but not all patients. Future research activities will probably concentrate on the effect of PK and other contact phase factors on the vascular system. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  9. The Duffy binding protein (PkDBPαII) of Plasmodium knowlesi from Peninsular Malaysia and Malaysian Borneo show different binding activity level to human erythrocytes. (United States)

    Lim, Khai Lone; Amir, Amirah; Lau, Yee Ling; Fong, Mun Yik


    The zoonotic Plasmodium knowlesi is a major cause of human malaria in Malaysia. This parasite uses the Duffy binding protein (PkDBPαII) to interact with the Duffy antigen receptor for chemokines (DARC) receptor on human and macaque erythrocytes to initiate invasion. Previous studies on P. knowlesi have reported distinct Peninsular Malaysia and Malaysian Borneo PkDBPαII haplotypes. In the present study, the differential binding activity of these haplotypes with human and macaque (Macaca fascicularis) erythrocytes was investigated. The PkDBPαII of Peninsular Malaysia and Malaysian Borneo were expressed on the surface of COS-7 cells and tested with human and monkey erythrocytes, with and without anti-Fy6 (anti-Duffy) monoclonal antibody treatment. Binding activity level was determined by counting the number of rosettes formed between the transfected COS-7 cells and the erythrocytes. Anti-Fy6 treatment was shown to completely block the binding of human erythrocytes with the transfected COS-7 cells, thus verifying the specific binding of human DARC with PkDBPαII. Interestingly, the PkDBPαII of Peninsular Malaysia displayed a higher binding activity with human erythrocytes when compared with the Malaysian Borneo PkDBPαII haplotype (mean number of rosettes formed = 156.89 ± 6.62 and 46.00 ± 3.57, respectively; P < 0.0001). However, no difference in binding activity level was seen in the binding assay using M. fascicularis erythrocytes. This study is the first report of phenotypic difference between PkDBPαII haplotypes. The biological implication of this finding is yet to be determined. Therefore, further studies need to be carried out to determine whether this differential binding level can be associated with severity of knowlesi malaria in human.

  10. Failed endotracheal intubation

    Directory of Open Access Journals (Sweden)

    Sheykhol Islami V


    Full Text Available The incidence of failed intubation is higher in obstetric than other surgical patients. Failed intubation was the 2nd commonest cause of mortality during anesthesia. Bearing in mind that failre to intubate may be unavoidable in certain circumstances, it is worth reviewing. The factors, which may contribute to a disastrous out come. Priorities of subsequent management must include maintaining oxygenation and preventing aspiration of gastric contents. Fiber optic intubation is now the technique of choice with a high success rate and with least trauma to the patient.

  11. Role of DNA-PK in cellular responses to DNA double-strand breaks

    International Nuclear Information System (INIS)

    Chen, D.J.


    DNA double-strand breaks (DSBs) are probably the most dangerous of the many different types of DNA damage that occur within the cell. DSBs are generated by exogenous agents such as ionizing radiation (IR) or by endogenously generated reactive oxygen species and occur as intermediates during meiotic and V(D)J recombination. The repair of DSBs is of paramount importance to the cell as misrepair of DSBs can lead to cell death or promote tumorigenesis. In eukaryotes there exists two distinct mechanisms for DNA DSB repair: homologous recombination (HR) and non-homologous end joining (NHEJ). In mammalian cells, however, it is clear that nonhomologous repair of DSBs is highly active and plays a major role in conferring radiation resistance to the cell. The NHEJ machinery minimally consists of the DNA-dependent Protein Kinase (DNA-PK) and a complex of XRCC4 and DNA Ligase IV. The DNA-PK complex is composed of a 470 kDa catalytic subunit (DNA-PKcs), and the heterodimeric Ku70 and Ku80 DNA end-binding complex. DNA-PKcs is a PI-3 kinase with homology to ATM and ATR in its C-terminal kinase domain. The DNA-PK complex protects and tethers the ends, and directs assembly and, perhaps, the activation of other NHEJ proteins. We have previously demonstrated that the kinase activity of DNA-PK is essential for DNA DSB repair and V(D)J recombination. It is, therefore, of immense interest to determine the in vivo targets of DNA-PKcs and the mechanisms by which phosphorylation of these targets modulates NHEJ. Recent studies have resulted in the identification of a number of protein targets that are phosphorylated by and/or interact with DNA-PKcs. Our laboratory has recently identified autophosphorylation site(s) on DNA-PKcs. We find that phosphorylation at these sites in vivo is an early and essential response to DSBs and demonstrate, for the first time, the localization of DNA-PKcs to the sites of DNA damage in vivo. Furthermore, mutation of these phosphorylation sites in mammalian

  12. Improving the Accuracy of Predicting Maximal Oxygen Consumption (VO2pk) (United States)

    Downs, Meghan E.; Lee, Stuart M. C.; Ploutz-Snyder, Lori; Feiveson, Alan


    Maximal oxygen (VO2pk) is the maximum amount of oxygen that the body can use during intense exercise and is used for benchmarking endurance exercise capacity. The most accurate method to determineVO2pk requires continuous measurements of ventilation and gas exchange during an exercise test to maximal effort, which necessitates expensive equipment, a trained staff, and time to set-up the equipment. For astronauts, accurate VO2pk measures are important to assess mission critical task performance capabilities and to prescribe exercise intensities to optimize performance. Currently, astronauts perform submaximal exercise tests during flight to predict VO2pk; however, while submaximal VO2pk prediction equations provide reliable estimates of mean VO2pk for populations, they can be unacceptably inaccurate for a given individual. The error in current predictions and logistical limitations of measuring VO2pk, particularly during spaceflight, highlights the need for improved estimation methods.

  13. Failed fuel detector

    International Nuclear Information System (INIS)

    Martucci, J.A.


    A failed fuel detection apparatus is described for a nuclear reactor having a liquid cooled core comprising a gas collection hood adapted to engage the top of the suspect assembly and means for delivering a stripping gas to the vicinity of the bottom of the suspect fuel assembly. (U.S.)

  14. Who Really Failed? Commentary (United States)

    Maiuri, Katherine M.; Leon, Raul A.


    Scott Jaschik's (2010) article "Who Really Failed?" details the experience of Dominique Homberger, a tenured faculty member at Louisiana State University (LSU) who was removed from teaching her introductory biology course citing student complaints in regards to "the extreme nature" of the grading policy. This removal has…


    International Nuclear Information System (INIS)



    In May 2004 alpha contamination was found on the lid of the pre-filter housing in the Sodium Removal Ion Exchange System during routine filter change. Subsequent investigation determined that the alpha contamination likely came from a fuel pin(s) contained in an Ident-69 (ID-69) type pin storage container serial number 9 (ID-69-9) that was washed in the Sodium Removal System (SRS) in January 2004. Because all evidence indicated that the wash water interacted with the fuel, this ID49 is designated as containing a failed fuel pin with gross cladding defect and was set aside in the Interim Examination and Maintenance (IEM) Cell until it could be determined how to proceed for long term dry storage of the fuel pin container. This ID49 contained fuel pins from the driver fuel assembly (DFA) 16392, which was identified as a Delayed Neutron Monitor (DNM) leaker assembly. However, this DFA was disassembled and the fuel pin that was thought to be the failed pin was encapsulated and was not located in this ID49 container. This failed fuel disposition study discusses two alternatives that could be used to address long term storage for the contents of ID-69-9. The first alternative evaluated utilizes the current method of identifying and storing DNM leaker fuel pin(s) in tubes and thus, verifying that the alpha contamination found in the SRS came from a failed pin in this pin container. This approach will require unloading selected fuel pins from the ID-69, visually examining and possibly weighing suspect fuel pins to identify the failed pin(s), inserting the failed pin(s) in storage tubes, and reloading the fuel pins into ID49 containers. Safety analysis must be performed to revise the 200 Area Interim Storage Area (ISA) Final Safety Analysis Report (FSAR) (Reference 1) for this fuel configuration. The second alternative considered is to store the failed fuel as-is in the ID-69. This was evaluated to determine if this approach would comply with storage requirements. This


    Energy Technology Data Exchange (ETDEWEB)



    In May 2004 alpha contamination was found on the lid of the pre-filter housing in the Sodium Removal Ion Exchange System during routine filter change. Subsequent investigation determined that the alpha contamination likely came from a fuel pin(s) contained in an Ident-69 (ID-69) type pin storage container serial number 9 (ID-69-9) that was washed in the Sodium Removal System (SRS) in January 2004. Because all evidence indicated that the wash water interacted with the fuel, this ID49 is designated as containing a failed fuel pin with gross cladding defect and was set aside in the Interim Examination and Maintenance (IEM) Cell until it could be determined how to proceed for long term dry storage of the fuel pin container. This ID49 contained fuel pins from the driver fuel assembly (DFA) 16392, which was identified as a Delayed Neutron Monitor (DNM) leaker assembly. However, this DFA was disassembled and the fuel pin that was thought to be the failed pin was encapsulated and was not located in this ID49 container. This failed fuel disposition study discusses two alternatives that could be used to address long term storage for the contents of ID-69-9. The first alternative evaluated utilizes the current method of identifying and storing DNM leaker fuel pin(s) in tubes and thus, verifying that the alpha contamination found in the SRS came from a failed pin in this pin container. This approach will require unloading selected fuel pins from the ID-69, visually examining and possibly weighing suspect fuel pins to identify the failed pin(s), inserting the failed pin(s) in storage tubes, and reloading the fuel pins into ID49 containers. Safety analysis must be performed to revise the 200 Area Interim Storage Area (ISA) Final Safety Analysis Report (FSAR) (Reference 1) for this fuel configuration. The second alternative considered is to store the failed fuel as-is in the ID-69. This was evaluated to determine if this approach would comply with storage requirements. This

  17. Searching for Failed Supernovae (United States)

    Gerke, Jill; Kochanek, C. S.; Stanek, K. Z.


    Understanding the deaths of massive stars is key to understanding both stellar evolution and the chemical enrichment of the universe. Only by monitoring all the massive stars in a large sample over years are we able to take a statistical approach to the deaths of massive stars and possibly observe the rare phenomenon of a failed supernova, a massive star that collapses to form a black hole without a SN explosion. To this end, we have been monitoring 25 galaxies within 10 Mpc with the Large Binocular Telescope for the past 4 years. Analyzing the data using image subtraction, we monitor the fate of all ~106 evolved supergiants in these galaxies to obtain limits on the rate of failed supernovae. We search for stars that have "vanished'' over the course of our survey, by examining all stars showing a decrease in luminosity of ΔνLν ≥ 104L⊙ from the first to the last observation. If we can detect the variable source in our last observation, it is not considered a vanished supergiant or failed supernova. We also identify sources that have increased in luminosity by this same amount, allowing us to estimate our false-positive rates. In addition to the search that does not require a particular signature, we also search for the low luminosity, long period transients predicted by Lovegrove & Woosley (2013) for failed explosions of red supergiants. Among many other applications, the survey also provides photometry of SN progenitors and the first light curves of these stars. Here I present the first results of the survey and provide the first direct limits on the rate of failed supernovae.

  18. Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design. (United States)

    Vozmediano, Valvanera; Sologuren, Ander; Lukas, John C; Leal, Nerea; Rodriguez, Mónica


    Bilastine is an H 1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions. PK/PD simulations supported the selection of 10 mg/day in 2 to PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.

  19. Automatic electromagnetic valve for previous vacuum

    International Nuclear Information System (INIS)

    Granados, C. E.; Martin, F.


    A valve which permits the maintenance of an installation vacuum when electric current fails is described. It also lets the air in the previous vacuum bomb to prevent the oil ascending in the vacuum tubes. (Author)

  20. PD-PK evaluation of freeze-dried atorvastatin calcium-loaded poly-ε-caprolactone nanoparticles. (United States)

    Ahmed, Iman S; El-Hosary, Rania; Shalaby, Samia; Abd-Rabo, Marwa M; Elkhateeb, Dalia G; Nour, Samia


    In this work lyophilized poly-ε-caprolactone nanoparticles (NPs) loaded with atorvastatin calcium (AC) were developed in an attempt to improve the in-vivo performance of AC following oral administration. The individual and combined effects of several formulation variables were previously investigated using step-wise full factorial designs in order to produce optimized AC-NPs with predetermined characteristics including particle size, drug loading capacity, drug release profile and physical stability. Four optimized formulations were further subjected in this work to lyophilization to promote their long-term physical stability and were fully characterized. The pharmacodynamics (PD)/pharmacokinetics (PK) properties of two optimized freeze-dried AC-NPs formulations showing acceptable long-term stability were determined and compared to a marketed AC immediate release tablet (Lipitor(®)) in albino rats. PD results revealed that the two tested formulations were equally effective in reducing low density lipoproteins (LDL) and triglycerides (TG) levels when given in reduced doses compared to Lipitor(®) and showed no adverse effects. PK results, on the other hand, revealed that the two freeze-dried AC-NPs formulations were of significantly lower bioavailability compared to Lipitor(®). Taken together the PD and PK results demonstrate that the improved efficacy obtained at reduced doses from the freeze-dried AC-NPs could be due to increased concentration of AC in the liver rather than in the plasma. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox? (United States)

    Del Bono, Valerio; Giacobbe, Daniele Roberto; Marchese, Anna; Parisini, Andrea; Fucile, Carmen; Coppo, Erika; Marini, Valeria; Arena, Antonio; Molin, Alexandre; Martelli, Antonietta; Gratarola, Angelo; Viscoli, Claudio; Pelosi, Paolo; Mattioli, Francesca


    The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.

  2. Failed fuel detector

    International Nuclear Information System (INIS)

    Kogure, Sumio; Seya, Toru; Watanabe, Masaaki.


    Purpose: To enhance the reliability of a failed fuel detector which detects radioactivity of nuclear fission products leaked out from fuel elements in cooling water. Constitution: Collected specimen is introduced into a separator and co-existing material considered to be an impediment is separated and removed by ion exchange resins, after which this specimen is introduced into a container housing therein a detector to systematically measure radioactivity. Thereby, it is possible to detect a signal lesser in variation in background, and inspection work also becomes simple. (Kawakami, Y.)

  3. Abortion: Strong's counterexamples fail

    DEFF Research Database (Denmark)

    Di Nucci, Ezio


    This paper shows that the counterexamples proposed by Strong in 2008 in the Journal of Medical Ethics to Marquis's argument against abortion fail. Strong's basic idea is that there are cases--for example, terminally ill patients--where killing an adult human being is prima facie seriously morally......'s scenarios have some valuable future or admitted that killing them is not seriously morally wrong. Finally, if "valuable future" is interpreted as referring to objective standards, one ends up with implausible and unpalatable moral claims....

  4. Comparison of Plasma Tu-M2-PK and CA19-9 in Pancreatic Cancer

    DEFF Research Database (Denmark)

    Joergensen, Maiken Thyregod; Heegaard, Niels H H; Schaffalitzky de Muckadell, Ove B


    alone. The presence of chronic pancreatitis or jaundice causes increased levels of CA19-9 but does not influence Tu-M2-PK. CONCLUSIONS:: Tu-M2-PK was inferior to CA19-9 as marker of PDAC. Tu-M2-PK may have a role in diagnosing PDAC because it is not affected by cholestasis or Lewis phenotype. Neither...

  5. PK/DB: database for pharmacokinetic properties and predictive in silico ADME models. (United States)

    Moda, Tiago L; Torres, Leonardo G; Carrara, Alexandre E; Andricopulo, Adriano D


    The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metabolism and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compounds which represent 2973 pharmacokinetic measurements, including five models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water solubility).

  6. Native American Women Perceptions in Pk-12 Administrative Positions in North Dakota Public Schools (United States)

    DeCoteau, Lanelia Irene


    Historically Native American women have experienced barriers in their rise to Pk-12 educational leadership positions. There is limited research available on Native American women in educational leadership. Therefore, the purpose for this survey study was to discover what inspired current Pk-12 Native American women educational leaders to choose…

  7. Why foreign aid fails

    Directory of Open Access Journals (Sweden)

    Prokopijević Miroslav


    Full Text Available The main point of this paper is that foreign aid fails because the structure of its incentives resembles that of central planning. Aid is not only ineffective, it is arguably counterproductive. Contrary to business firms that are paid by those they are supposed to serve (customers, aid agencies are paid by tax payers of developed countries and not by those they serve. This inverse structure of incentives breaks the stream of pressure that exists on the commercial market. It also creates larger loopholes in the principle-agent relationship on each point along the chain of aid delivery. Both factors enhance corruption, moral hazard and negative selection. Instead of promoting development, aid extends the life of bad institutions and those in power. Proposals to reform foreign aid – like aid privatization and aid conditionality – do not change the existing structure of the incentives in aid delivery, and their implementation may just slightly improve aid efficacy. Larger improvement is not possible. For that reason, foreign aid will continue to be a waste of resources, probably serving some objectives different to those that are usually mentioned, like recipient’s development poverty reduction and pain relief.

  8. Using a Matlab Implemented Algorithm for UV-vis spectral Resolution for pk Determination and Multicomponent Analysis

    Directory of Open Access Journals (Sweden)

    Yotam Gonen


    Full Text Available A Matlab implemented computer code for spectral resolution is presented. The code enables the user to resolve the UV-visible absorption spectrum of a mixture of up to 3 previously known components, to the individual components, thus, evaluating their quantities. The resolving procedure is based on searching the combination of the components which yields the spectrum which is the most similar (minimal RMSE to the measured spectrum of the mixture. Examples of using the software for pK a value estimation and multicomponent analysis are presented and other implementations are suggested.

  9. Pharmacological considerations for predicting PK/PD at the site of action for therapeutic proteins. (United States)

    Wang, Weirong; Zhou, Honghui

    For therapeutic proteins whose sites of action are distal to the systemic circulation, both drug and target concentrations at the tissue sites are not necessarily proportional to those in systemic circulation, highlighting the importance of understanding pharmacokinetic/pharmacodynamic (PK/PD) relationship at the sites of action. This review summarizes the pharmacological considerations for predicting local PK/PD and the importance of measuring PK and PD at site of action. Three case examples are presented to show how mechanistic and physiologically based PK/PD (PBPK/PD) models which incorporated the PK and PD at the tissue site can be used to facilitate understanding the exposure-response relationship for therapeutic proteins. Copyright © 2016. Published by Elsevier Ltd.

  10. Uptake of inflammatory cell marker [{sup 11}C]PK11195 into mouse atherosclerotic plaques

    Energy Technology Data Exchange (ETDEWEB)

    Laitinen, Iina; Marjamaeki, Paeivi; Naagren, Kjell; Roivainen, Anne; Knuuti, Juhani [University of Turku, Turku PET Centre, Turku (Finland); Laine, V.J.O. [Turku University Hospital, Department of Pathology, Turku (Finland); Wilson, Ian [GE Healthcare Biosciences, Medical Diagnostics, London (United Kingdom); Leppaenen, Pia; Ylae-Herttuala, Seppo [University of Kuopio, A.I. Virtanen Institute, Kuopio (Finland)


    The ligand [{sup 11}C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [{sup 11}C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [{sup 11}C]PK11195 in imaging inflammation in the atherosclerotic plaques. The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [{sup 3}H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [{sup 11}C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. The [{sup 3}H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [{sup 11}C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of {sup 11}C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Our results indicate that the uptake of [{sup 11}C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [{sup 11}C]PK11195 in clinical imaging of atherosclerotic plaques. (orig.)

  11. Impact of Shed/Soluble targets on the PK/PD of approved therapeutic monoclonal antibodies. (United States)

    Samineni, Divya; Girish, Sandhya; Li, Chunze


    Suboptimal treatment for monoclonal antibodies (mAbs) directed against endogenous circulating soluble targets and the shed extracellular domains (ECD) of the membrane-bound targets is an important clinical concern due to the potential impact of mAbs on the in vivo efficacy and safety. Consequently, there are considerable challenges in the determination of an optimal dose and/or dosing regimen. Areas covered: This review outlines the impact of shed antigen targets from membrane-bound proteins and soluble targets on the PK and/or PD of therapeutic mAbs that have been approved in the last decade. We discuss various bioanalytical techniques that have facilitated the interpretation of the PK/PD properties of therapeutic mAbs and also considered the factors that may impact such measurements. Quantitative approaches include target-mediated PK models and bi- or tri-molecular interaction PK/PD models that describe the relationships between the antibody PK and the ensuing effects on PD biomarkers, to facilitate the mAb PK/PD characterization. Expert commentary: The proper interpretation of PK/PD relationships through the integrated PK/PD modeling and bioanalytical strategy facilitates a mechanistic understanding of the disease processes and dosing regimen optimization, thereby offering insights into developing effective therapeutic regimens. This review provides an overview of the impact of soluble targets or shed ECD on mAb PK/PD properties. We provide examples of quantitative approaches that facilitate the characterization of mAb PK/PD characteristics and their corresponding bioanalytical strategies.

  12. Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining

    Directory of Open Access Journals (Sweden)

    Cynthia L. Hendrickson


    Full Text Available In mammalian cells, DNA double-strand breaks (DSBs are primarily repaired by nonhomologous end joining (NHEJ. The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PKcs to form the active DNA-dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step. Therefore, DNA-PK plays a key role in NHEJ due to its structural and regulatory functions that mediate DSB end joining. However, recent studies show that additional DNA-PK-independent NHEJ pathways also exist. Unfortunately, the presence of DNA-PKcs appears to inhibit DNA-PK-independent NHEJ, and in vitro analysis of DNA-PK-independent NHEJ in the presence of the DNA-PKcs protein remains problematic. We have developed an in vitro assay that is preferentially active for DNA-PK-independent DSB repair based solely on its reaction conditions, facilitating coincident differential biochemical analysis of the two pathways. The results indicate the biochemically distinct nature of the end-joining mechanisms represented by the DNA-PK-dependent and -independent NHEJ assays as well as functional differences between the two pathways.

  13. To fail or not to fail : clinical trials in depression

    NARCIS (Netherlands)

    Santen, Gijs Willem Eduard


    To fail or not to fail – Clinical trials in depression investigates the causes of the high failure rate of clinical trials in depression research. Apart from the difficulties in the search for new antidepressants during drug discovery, faulty clinical trial designs hinder their evaluation during

  14. Cellular response to DNA damage. Link between p53 and DNA-PK

    International Nuclear Information System (INIS)

    Salles-Passador, I.; Fotedar, R.; Fotedar, A.


    Cells which lack DNA-activated protein kinase (DNA-PK) are very susceptible to ionizing radiation and display an inability to repair double-strand DNA breaks. DNA-PK is a member of a protein kinase family that includes ATR and ATM which have strong homology in their carboxy-terminal kinase domain with Pl-3 kinase. ATM has been proposed to act upstream of p53 in cellular response to ionizing radiation. DNA-PK may similarly interact with p53 in cellular growth control and in mediation of the response to ionizing radiation. (author)


    African Journals Online (AJOL)


    PREVIOUS SECOND TRIMESTER ABORTION: A risk factor for third trimester uterine rupture in three ... for accurate diagnosis of uterine rupture. KEY WORDS: Induced second trimester abortion - Previous uterine surgery - Uterine rupture. ..... scarred uterus during second trimester misoprostol- induced labour for a missed ...

  16. Method for repairing failed fuel

    International Nuclear Information System (INIS)

    Shakudo, Taketomi.


    Purpose: To repair fuel elements that became failed during burnup in a reactor or during handling. Method: After the surface in the vicinity of a failed part of a fuel element is cleaned, a socket made of a shape-memory alloy having a ring form or a horseshoe form made by cutting a part of the ring form is inserted into the failed position according to the position of the failed fuel element. The shape memory alloy socket remembers a slightly larger inside diameter in its original phase (high-temperature side) than the outside diameter of the cladding tube and also a slightly larger inside diameter of the socket in the martensite phase (low-temperature side) than the outside diameter of the cladding tube, such that the socket can easily be inserted into the failed position. The socket, inserted into the failed part of the cladding tube, is heated by a heating jig. The socket recovers the original phase, and the shape also tends to recover a smaller diameter than the outside diameter of the cladding tube that has been remembered, and accordingly the failed part of the cladding tube is fastened with a great force and the failed part is fully closed with the socket, thus keeping radioactive materials from going out. (Horiuchi, T.)

  17. Increasing the reach of the PK-3R continuous Miner; Desarrollo y Ensayo de un Sistema para aumentar el alcance de la Pina de Rozado en un Minador PK-3R

    Energy Technology Data Exchange (ETDEWEB)



    The objective of this project is the development and implementation of a system designed to increase the reach of the cutting head of a PK-3R continuous miner working in our coal operations. Justification for the project stems from our method of coal extraction, whereby once the sub-level gallery has been advanced to it`s limit, extraction of the coal is undertaken by retreat mining, using a room and pillar method. In this method the roof is blasted to allow greater coal recovery. Due to it`s short length, the original position of the cutting arm of the PK-3R miner did not permit the total recovery of the blasted coal piled up on the gallery floor. Therefore an increase in the reach of the arm is very beneficial, facilitating the recovery of coal that previously could not be recovered. The system also permits excavation for support methods to be undertaken more rapidly, and a better adaptation of the miner to the irregularities of the wall, thus permitting it to move up or down more quickly, reducing the movements required. The system has not caused significant breakdowns, and the availability of the miner is good. In addition, the substitution of the turret in the case of a breakdown is an easy task, as during the design stage, the ease of mounting and dismounting the turret was considered as a fundamental parameter. (Author)

  18. Mafic inclusions in Yosemite granites and Lassen Pk lavas: records of complex crust-mantle interactions

    Energy Technology Data Exchange (ETDEWEB)

    Reid, J.B. Jr.; Flinn, J.E.


    This study compares three small-scale magmatic systems dominated by mafic/felsic interaction that appear to be analogs to the evolution of their larger host systems: mafic inclusions from modern Lassen Pk lavas along with inclusions and related synplutonic dike materials from granitoids in the Tuolumne Intrusive Series. Each system represents quickly chilled mafic melt previously contaminated by digestion of rewarmed, super-solidus felsic hosts. Contaminants occur in part as megacrysts of reworked oligoclase with lesser hb and biot. Within each group MgO-variation diagrams for Fe, Ca, Ti, Si are strikingly linear (r>.96); alkalis are decidedly less regular, and many hybrid rocks show a curious, pronounced Na enrichment. Field data, petrography, and best fit modeling suggests this may result from flow concentration of oligoclase xenocrysts within contaminated synplutonic dikes, and is preserved in the inclusions when dike cores chill as pillows in their felsic host. Dissolution of mafic inclusions erases these anomalies and creates a more regular series of two-component mafic-felsic mixtures in the large host system. The inclusions and dikes thus appear to record a variety of late-stage mafic-felsic interactive processes that earlier and on a larger scale created much of the compositional variety of their intermediate host rocks.

  19. DNA ligase III is involved in a DNA-PK independent pathway of NHEJ in human cells

    International Nuclear Information System (INIS)

    Wang, H.; Perrault, A.R.; Qin, W.; Wang, H.; Iliakis, G.


    Full text: Double strand breaks (DSB) induced by ionizing radiation (IR) and other cytotoxic agents in the genome of higher eukaryotes are thought to be repaired either by homologous recombination repair (HRR), or non-homologous endjoining (NHEJ). We previously reported the operation of two components of NHEJ in vivo: a DNA-PK dependent component that operates with fast kinetics (D-NHEJ), and a DNA-PK independent component that acts as a backup (basic or B-NHEJ) and operates with kinetics an order of magnitude slower. To gain further insight into the mechanisms of B-NHEJ, we investigated DNA endjoining in extracts 180BR, a human cell line deficient in DNA ligase IV, using an in vitro plasmid-based DNA endjoining assay. An anti DNA ligase III antibody inhibited almost completely DNA endjoining activity in these extracts. On the other hand, an anti DNA ligase I antibody had no measurable effect in DNA endjoining activity. Immunodepletion of DNA ligase III from 180BR cell extracts abolished the DNA endjoining activity, which could be restored by addition of purified human DNA ligase IIIb. Full-length DNA ligase III bound to double stranded DNA and stimulated DNA endjoining in both intermolecular and intramolecular ligation. Furthermore, fractionation of HeLa cell extracts demonstrated the presence of an activity stimulating the function of DNA ligase III. Based on these observations we propose that DNA ligase III is the ligase operating in B-NHEJ

  20. Laparoscopy After Previous Laparotomy

    Directory of Open Access Journals (Sweden)

    Zulfo Godinjak


    Full Text Available Following the abdominal surgery, extensive adhesions often occur and they can cause difficulties during laparoscopic operations. However, previous laparotomy is not considered to be a contraindication for laparoscopy. The aim of this study is to present that an insertion of Veres needle in the region of umbilicus is a safe method for creating a pneumoperitoneum for laparoscopic operations after previous laparotomy. In the last three years, we have performed 144 laparoscopic operations in patients that previously underwent one or two laparotomies. Pathology of digestive system, genital organs, Cesarean Section or abdominal war injuries were the most common causes of previouslaparotomy. During those operations or during entering into abdominal cavity we have not experienced any complications, while in 7 patients we performed conversion to laparotomy following the diagnostic laparoscopy. In all patients an insertion of Veres needle and trocar insertion in the umbilical region was performed, namely a technique of closed laparoscopy. Not even in one patient adhesions in the region of umbilicus were found, and no abdominal organs were injured.

  1. Cytotoxic effects of 125I-labeled PBZr ligand PK 11195 in prostatic tumor cells: therapeutic implications

    International Nuclear Information System (INIS)

    Alenfall, J.; Kant, R.; Batra, S.


    The effect of [ 125 I]PK 11195 was examined in human prostatic tumor cells (DU 145) in culture and compared with Na[ 125 I] and non-radioactive PK 11195. [ 125 I]PK 11195 was clearly cytocidal. The data for dose-related cell survival with [ 125 I]PK 11195 showed a linear relationship. Na[ 125 I] or non-labeled PK 11195 at similar concentrations did not lead to any cell killing. The uptake of [ 125 I]PK 11195 and [ 3 H]PK 11195 in cells was very similar. Fragmentation of DNA measured by agarose gel electrophoresis showed that exposure of DU 145 cells to [ 125 I]PK 11195 for 1, 4 or 24 h caused no fragmentation. These results indicate that nuclear DNA is not the prime binding site for [ 125 I]PK 11195, which is consistent with the presence of specific peripheral benzodiazepine receptors (PBZr) in the mitochondria. The cell killing effect of [ 125 I]PK 11195 suggests the use of PBZr ligand for radiotherapy

  2. Small molecules, inhibitors of DNA-PK, targeting DNA repair and beyond

    Directory of Open Access Journals (Sweden)

    David eDavidson


    Full Text Available Many current chemotherapies function by damaging genomic DNA in rapidly dividing cells ultimately leading to cell death. This therapeutic approach differentially targets cancer cells that generally display rapid cell division compared to normal tissue cells. However, although these treatments are initially effective in arresting tumor growth and reducing tumor burden, resistance and disease progression eventually occur. A major mechanism underlying this resistance is increased levels of cellular DNA repair. Most cells have complex mechanisms in place to repair DNA damage that occurs due to environmental exposures or normal metabolic processes. These systems, initially overwhelmed when faced with chemotherapy induced DNA damage, become more efficient under constant selective pressure and as a result chemotherapies become less effective. Thus, inhibiting DNA repair pathways using target specific small molecule inhibitors may overcome cellular resistance to DNA damaging chemotherapies. Non-homologous end joining (NHEJ a major mechanism for the repair of double strand breaks (DSB in DNA is regulated in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK. The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and recruiting other repair molecules. It also has enzymatic activity that may be involved in DNA damage signaling. Because of its’ central role in repair of DSBs, DNA-PK has been the focus of a number of small molecule studies. In these studies specific DNA-PK inhibitors have shown efficacy in synergizing chemotherapies in vitro. However, compounds currently known to specifically inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor solubility and have high metabolic lability in vivo leading to short serum half-lives. Future improvement in DNA-PK inhibition will likely be achieved by designing new molecules based on the recently reported crystallographic structure of DNA-PK

  3. Sustained release ophthalmic dexamethasone: In vitro in vivo correlations derived from the PK-Eye. (United States)

    Awwad, Sahar; Day, Richard M; Khaw, Peng T; Brocchini, Steve; Fadda, Hala M


    Corticosteroids have long been used to treat intraocular inflammation by intravitreal injection. We describe dexamethasone loaded poly-DL-lactide-co-glycolide (PLGA) microparticles that were fabricated by thermally induced phase separation (TIPS). The dexamethasone loaded microparticles were evaluated using a two-compartment, in vitro aqueous outflow model of the eye (PK-Eye) that estimates drug clearance time from the back of the eye via aqueous outflow by the anterior route. A dexamethasone dose of 0.20±0.02mg in a 50μL volume of TIPS microparticles resulted in a clearance t 1/2 of 9.6±0.3days using simulated vitreous in the PK-Eye. Since corticosteroids can also clear through the retina, it is necessary to account for clearance through the back of the eye. Retinal permeability data, published human ocular pharmacokinetics (PK) and the PK-Eye clearance times were then used to establish in vitro in vivo correlations (IVIVCs) for intraocular clearance times of corticosteroid formulations. A t 1/2 of 48h was estimated for the dexamethasone-TIPS microparticles, which is almost 9 times longer than that reported for dexamethasone suspension in humans. The prediction of human clearance times of permeable molecules from the vitreous compartment can be determined by accounting for drug retinal permeation and determining the experimental clearance via the anterior aqueous outflow pathway using the PK-Eye. Copyright © 2017. Published by Elsevier B.V.

  4. Study of the acid-base properties of mineral soil horizons using pK spectroscopy (United States)

    Shamrikova, E. V.; Vanchikova, E. V.; Ryazanov, M. A.


    The presence of groups 4 and 5 participating in acid-base equilibria was revealed in samples from mineral horizons of the gley-podzolic soil of the Komi Republic using pK spectroscopy (the mathematical processing of potentiometric titration curves for plotting the distribution of acid groups according to their pK values). The specific quantity of acid-base sites in soil samples was calculated. The contribution of organic and mineral soil components to the groups of acid-base sites was estimated. The pK values of groups determining the potential, exchangeable, and unexchangeable acidities were found. The heterogeneity of acid components determining different types of soil acidity was revealed.

  5. Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites -current status

    International Nuclear Information System (INIS)

    Pike, V.W.; Osman, S.; Shah, F.; Turton, D.R.; Waters, S.L.; Crouzel, C.; Nutt, D.J.


    The status of the radiochemical development and biological evaluation of radioligands for PET studies of central benzodiazepine (BZ) receptors and the so-called peripheral benzodiazepine binding sites, here discriminated and referred to as PK binding sites, is reviewed against current pharmacological knowledge, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies, [N-methyl- 11 C]flumazenil for central BZ receptors, and [N-methyl- 11 C]PK 11195 for PK binding sites. Quality assurance and plasma metabolite analysis are also reviewed for these radioligands and practical recommendations are given on methodology for their performance. (Author)

  6. Can the 2014 Comprehensive Agreement on the Bangsamoro (CAB) Succeed in Mindanao Where Previous Agreements Failed? (United States)


    homeless .82 The Moros, once rich in “mineral wealth” and blessed with an abundance of “natural resources,” now found themselves with extreme financial...difficulties and living “in grinding poverty .”83 The fight originally directed towards the migrating Christians eventually targeted the GOP; the GOP led...Moro poverty throughout the region may decrease. If land issues are left unanswered, then Moro “frustrations” may lead into the “resumption of

  7. Applications of the pharmacokinetic/pharmacodynamic (PK/PD) analysis of antimicrobial agents. (United States)

    Asín-Prieto, Eduardo; Rodríguez-Gascón, Alicia; Isla, Arantxazu


    The alarming increase of resistance against multiple currently available antibiotics is leading to a rapid lose of treatment options against infectious diseases. Since the antibiotic resistance is partially due to a misuse or abuse of the antibiotics, this situation can be reverted when improving their use. One strategy is the optimization of the antimicrobial dosing regimens. In fact, inappropriate drug choice and suboptimal dosing are two major factors that should be considered because they lead to the emergence of drug resistance and consequently, poorer clinical outcomes. Pharmacokinetic/pharmacodynamic (PK/PD) analysis in combination with Monte Carlo simulation allows to optimize dosing regimens of the antibiotic agents in order to conserve their therapeutic value. Therefore, the aim of this review is to explain the basis of the PK/PD analysis and associated techniques, and provide a brief revision of the applications of PK/PD analysis from a therapeutic point-of-view. The establishment and reevaluation of clinical breakpoints is the sticking point in antibiotic therapy as the clinical use of the antibiotics depends on them. Two methodologies are described to establish the PK/PD breakpoints, which are a big part of the clinical breakpoint setting machine. Furthermore, the main subpopulations of patients with altered characteristics that can condition the PK/PD behavior (such as critically ill, elderly, pediatric or obese patients) and therefore, the outcome of the antibiotic therapy, are reviewed. Finally, some recommendations are provided from a PK/PD point of view to enhance the efficacy of prophylaxis protocols used in surgery. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  8. DECOFF Probabilities of Failed Operations

    DEFF Research Database (Denmark)

    Gintautas, Tomas


    A statistical procedure of estimation of Probabilities of Failed Operations is described and exemplified using ECMWF weather forecasts and SIMO output from Rotor Lift test case models. Also safety factor influence is investigated. DECOFF statistical method is benchmarked against standard Alpha...

  9. Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC). (United States)

    Chen, Shang-Chiung; Kagedal, Matts; Gao, Yuying; Wang, Bei; Harle-Yge, Marie-Laurence; Girish, Sandhya; Jin, Jin; Li, Chunze


    Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC). Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined. T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V c ) of 4.48 L, distribution clearance (Q) of 0.62 L/day, volume of distribution in the peripheral compartment (V p ) of 1.49 L, nonlinear CL of 2.06 L/day, and KM of 1.63 μg/mL. Parameter uncertainty was low to moderate for fixed effects, except KM (estimated with poor precision). Patients with high body weight and low baseline trastuzumab concentrations had significantly faster linear CL; those with higher body weight had significantly larger V c . In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.

  10. Widespread Dependence of Backup NHEJ on Growth State: Ramifications for the Use of DNA-PK Inhibitors

    International Nuclear Information System (INIS)

    Singh, Satyendra K.; Wu Wenqi; Zhang Lihua; Klammer, Holger; Wang Minli; Iliakis, George


    Purpose: The backup pathway of nonhomologous end joining (B-NHEJ) enables cells to process DNA double-strand breaks (DSBs) when the DNA-PK-dependent pathway of NHEJ (D-NHEJ) is compromised. Our previous results show marked reduction in the activity of B-NHEJ when LIG4 -/- mouse embryo fibroblasts (MEFs) cease to grow and enter a plateau phase. The dependence of B-NHEJ on growth state is substantially stronger than that of D-NHEJ and points to regulatory mechanisms or processing determinants that require elucidation. Because the different D-NHEJ mutants show phenotypes distinct in their details, it is necessary to characterize the dependence of their DSB repair capacity on growth state and to explore species-specific responses. Methods and Materials: DSB repair was measured in cells of different genetic background from various species using pulsed-field gel electrophoresis, or the formation of γ-H2AX foci, at different stages of growth. Results: Using pulsed-field gel electrophoresis, we report a marked reduction of B-NHEJ during the plateau phase of growth in KU and XRCC4, mouse or Chinese hamster, mutants. Notably, this reduction is only marginal in DNA-PKcs-deficient cells. However, reduced B-NHEJ is also observed in repair proficient, plateau-phase cells after treatment with DNA-PK inhibitors. The reduction of B-NHEJ activity in the plateau phase of growth does not derive from the reduced expression of participating proteins, is detectable by γ-H2AX foci analysis, and leads to enhanced cell killing. Conclusions: These results further document the marked dependence on growth state of an essential DSB repair pathway and show the general nature of the effect. Molecular characterization of the mechanism underlying this response will help to optimize the administration of DNA repair inhibitors as adjuvants in radiation therapy.

  11. Neuroinflammation in bipolar disorder : A [C-11]-(R)-PK11195 positron emission tomography study

    NARCIS (Netherlands)

    Haarman, Bartholomeus C.M.; Riemersma -van der Lek, Rixt; de Groot, Jan Cees; Ruhe, Eric; Klein, Hans C; Zandstra, Tjitske E; Burger, Huibert; Schoevers, Robert A.; de Vries, Erik F.J.; Drexhage, Hemmo A; Nolen, Willem A.; Doorduin, Janine

    Background: The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [C-11]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential

  12. Mechanism-based PK/PD modeling of selective serotonin reuptake inhibitors

    NARCIS (Netherlands)

    Geldof, Marian


    The main objective of the investigations was to explore the PK/PD correlations of fluvoxamine, as a prototype for the Selective Serotonin Reuptake Inhibitors (SSRIs). In the various investigations, a spectrum of different biomarkers was used, each reflecting a specific process on the causal path

  13. PK-ISIS: a new superconducting ECR ion source at Pantechnik

    International Nuclear Information System (INIS)

    Villari, A.C.; Bieth, C.; Bougy, W.; Brionne, N.; Donzel, X.; Gaubert, G.; Leroy, R.; Sineau, A.; Tasset, O.; Vallerand, C.; Thuillier, T.


    The new ECR ion source PK-ISIS was recently commissioned at Pantechnik. Three superconducting coils generate the axial magnetic field configuration while the radial magnetic field is done with multi-layer permanent magnets. Special care was devoted in the design of the hexapolar structure, allowing a maximum magnetic field of 1.32 T at the wall of the 82 mm diameter plasma chamber. The three superconducting coils using Low Temperature Superconducting wires are cooled by a single double stage cryo-cooler (4.2 K). Cryogen-free technology is used, providing reliability, easy maintenance at low cost. The maximum installed RF power (18.0 GHz) is of 2 kW. Metallic beams can be produced with an oven (T max = 1400 C) installed with an angle of 5 degrees with respect to the source axis or a sputtering system, mounted in the axis of the source. The beam extraction system is constituted of three electrodes in accel-decel configuration. The new source of Pantechnik is conceived for reaching optimum performances at 18 GHz RF frequencies. PK-ISIS delivers 5 to 10 times more beam intensity than the original PK-DELIS and/or shifting the charge state distribution to higher values. PK-ISIS is built with Low Temperature Superconducting wire technology (LTS), but keeps the He-free concept, extremely important for a reliable and easy operation. The radial field circuit is permanent magnet made. Finally, PK-ISIS is also conceived for using in a High-Voltage platform with minor power consumption. The paper is followed by the slides of the presentation. (A.C.)

  14. Expression of prokineticin-receptor2(PK-R2) is a new prognostic factor in human colorectal cancer. (United States)

    Goi, Takanori; Kurebayashi, Hidetaka; Ueda, Yuki; Naruse, Takayuki; Nakazawa, Toshiyuki; Koneri, Kenji; Hirono, Yasuo; Katayama, Kanji; Yamaguchi, Akio


    The increased invasiveness of colorectal cancer cells is important for progression and metastasis to the surrounding organs. According to recent molecular biological studies, signaling through transmembrane Prokineticin-Receptor2(PK-R2) is likely involved in the ability of tumor cell to invade. However, no studies have evaluated the relationship between PK-R2 expression, ability of cancer to invade/metastasize, and patient prognosis in cases of resected colorectal cancer. Accordingly, we have examined these factors in the present study.Immunohistochemical staining was performed to detect PK-R2 in the primary lesion and adjacent normal large intestine mucosa of 324 colorectal cancer patients who underwent resection surgery at our department. Additionally, we conducted clinicopathologic examinations and analyzed patient prognoses with the Kaplan-Meier method. Further, multivariate analysis was conducted using a cox-proportional hazard model.PK-R2 expression was observed on the cellular membrane of the primary lesion in 147 of 324 cases (45.3%) of human colorectal cancer. PK-R2 expression was associated with a higher incidence of vascular invasion, lymph node metastasis, hepatic metastasis, and hematogenous metastasis. Further, prevalence of PK-R2 expression increased as tumor stage increased. In stage III curative resection cases, where recurrence is the most serious problem, cases that expressed PK-R2 had a significantly lower 5-year survival rate (82.1% versus 66.8%) and higher recurrence compared to those cases with no PK-R2 expression. In the multivariate analysis for prognosis, PK-R2 expression was found to be an independent factor(ratio2.621).PK-R2 expression could be one of the new prognostic factors in human colorectal cancer.

  15. Method of detecting failed fuels

    International Nuclear Information System (INIS)

    Ishizaki, Hideaki; Suzumura, Takeshi.


    Purpose: To enable the settlement of the temperature of an adequate filling high temperature pure water by detecting the outlet temperature of a high temperature pure water filling tube to a fuel assembly to control the heating of the pure water and detecting the failed fuel due to the sampling of the pure water. Method: A temperature sensor is provided at a water tube connected to a sipping cap for filling high temperature pure water to detect the temperature of the high temperature pure water at the outlet of the tube, and the temperature is confirmed by a temperature indicator. A heater is controlled on the basis of this confirmation, an adequate high temperature pure water is filled in the fuel assembly, and the pure water is replaced with coolant. Then, it is sampled to settle the adequate temperature of the high temperature coolant used for detecting the failure of the fuel assembly. As a result, the sipping effect does not decrease, and the failed fuel can be precisely detected. (Yoshihara, H.)

  16. Semi-physiological pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats. (United States)

    Kobuchi, Shinji; Ito, Yukako; Hayakawa, Taro; Nishimura, Asako; Shibata, Nobuhito; Takada, Kanji; Sakaeda, Toshiyuki


    1. The aim of this study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model that could characterize the complete time-course of alterations in platelet counts to predict the onset and degree of thrombocytopenia, which severely limits the use of the anticancer agent 5-fluorouracil (5-FU), in rats. 2. Platelet counts were measured in rats following the intravenous administration of various doses of 5-FU for 4 days to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with three compartments for the PD model and 10 structural PK-PD model parameters. 3. After the 5-FU treatment, platelet counts transiently decreased to a nadir level, showed a rebound to above the baseline level before recovering to baseline levels. Nadir platelet counts and rebounds varied with the AUC0-∞ level. The final PK-PD model effectively characterized platelet count data and final PD parameters were estimated with high certainty. 4. This PK-PD model and simulation may represent a valuable tool for quantifying and predicting the complete time-course of alterations in blood cell counts, and could contribute to the development of therapeutic strategies with 5-FU and assessments of various novel anticancer agents that are difficult to examine in humans.

  17. Diggers failing to become diggers

    DEFF Research Database (Denmark)

    Jensen, Lars

    of mining as a national discourse beg the question how we might begin to assess mining’s actual long-term influence on the national imaginary. Two quite recent interventions – possibly at the tail end of another boom cycle – have sought to address how the ‘story of mining’ as a national narrative could......Mining has in recent years emerged as a national discourse in Australia as the combined result of the mining boom and national anxieties over the GFC featured prominently in references to Australia as a failed competitive state (the folding of manufacturing, where the closure of car factories plays...... a particular iconic role, not to mention perpetually troubled Qantas). Yet mining is not new to Australia, but has been pivotal to the country’s demographic growth post-settlement/post-invasion. Arguably, mining’s boom and bust cycles have given it at times a disproportionate influence on narratives...

  18. Detector for failed fuel elements

    International Nuclear Information System (INIS)

    Ito, Masaru.


    Purpose: To provide automatic monitor for the separation or reactor water and sampling water, in a failed fuel element detector using a sipping chamber. Constitution: A positional detector for the exact mounting of a sipping chamber on a channel box and a level detector for the detection of complete discharge of cooling water in the sipping chamber are provided in the sipping chamber. The positional detector is contacted to the upper end of the channel box and operated when the sipping chamber is correctly mounted to the fuel assemblies. The level detector comprises a float and a limit switch and it is operated when the water in the sipping chamber is discharged by a predetermined amount. Isolation of reactor water and sampling water are automatically monitored by the signal from these two detectors. (Ikeda, J.)

  19. Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors. (United States)

    Ihmaid, Saleh; Ahmed, Hany E A; Al-Sheikh Ali, Adeeb; Sherif, Yousery E; Tarazi, Hamadeh M; Riyadh, Sayed M; Zayed, Mohamed F; Abulkhair, Hamada S; Rateb, Heba S


    Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinski's rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Why good projects fail anyway. (United States)

    Matta, Nadim F; Ashkenas, Ronald N


    Big projects fail at an astonishing rate--more than half the time, by some estimates. It's not hard to understand why. Complicated long-term projects are customarily developed by a series of teams working along parallel tracks. If managers fail to anticipate everything that might fall through the cracks, those tracks will not converge successfully at the end to reach the goal. Take a companywide CRM project. Traditionally, one team might analyze customers, another select the software, a third develop training programs, and so forth. When the project's finally complete, though, it may turn out that the salespeople won't enter in the requisite data because they don't understand why they need to. This very problem has, in fact, derailed many CRM programs at major organizations. There is a way to uncover unanticipated problems while the project is still in development. The key is to inject into the overall plan a series of miniprojects, or "rapid-results initiatives," which each have as their goal a miniature version of the overall goal. In the CRM project, a single team might be charged with increasing the revenues of one sales group in one region by 25% within four months. To reach that goal, team members would have to draw on the work of all the parallel teams. But in just four months, they would discover the salespeople's resistance and probably other unforeseen issues, such as, perhaps, the need to divvy up commissions for joint-selling efforts. The World Bank has used rapid-results initiatives to great effect to keep a sweeping 16-year project on track and deliver visible results years ahead of schedule. In taking an in-depth look at this project, and others, the authors show why this approach is so effective and how the initiatives are managed in conjunction with more traditional project activities.

  1. Statistical disclosure limitation of health data based on Pk-anonymity. (United States)

    Kimura, Eizen; Chida, Koji; Ikarashi, Dai; Hamada, Koki; Ishihara, Ken


    The Act for the Protection of Personal Information in Japan considers as personal information any quasi-identifier that may be used to obtain information that identifies individuals through comparisons with datasets. Studies using health records are not widely conducted because of the concern regarding the safety of anonymized health records. To increase the safety of such records, we used the Pk-anonymity method. In this method, attributes are probabilistically randomized and then reconstructions are performed on the basis of statistical information from perturbed data. Hence, it is expected to provide more precise statistics and more reliably preserve privacy than the traditional "k-anonymity" method. We anonymized health records, performed cross tabulation, and assessed the error rate using original data. This study shows that the Pk-anonymity method can be used to perform safety statistical disclosures with low error rates, even in small cases.

  2. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers

    International Nuclear Information System (INIS)

    Chauveau, Fabien; Camp, Nadja van; Tavitian, Bertrand; Boutin, Herve; Dolle, Frederic


    Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [ 11 C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [ 11 C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents. (orig.)

  3. Determination of the pK for the acid-induced denaturation of ferrocytochrome c. (United States)

    Varhac, Rastislav; Antalík, Marián


    Optical absorption spectroscopy was used to characterize the acid-induced conformational transition of horse heart ferrocytochrome c in the presence of urea. By using linear extrapolation to zero denaturant concentration, an apparent pK value for denaturation was found to be 0.86 +/- 0.07 at 25 degrees C. Visible absorption spectra in the presence of high urea concentration indicate that the dominant population is a high-spin, five-coordinate form under acidic conditions. Ferricytochrome c, used as a model reference system, shows a linear dependence of pK values versus urea concentration in the range from 0 to 4.1 M. Our data also indicate that even at a pH below 2 the iron-sulfur bond in ferrocytochrome c is present.

  4. DNA Damage Triggers Golgi Dispersal via DNA-PK and GOLPH3


    Farber-Katz, Suzette E.; Dippold, Holly C.; Buschman, Matthew D.; Peterman, Marshall C.; Xing, Mengke; Noakes, Christopher J.; Tat, John; Ng, Michelle M.; Rahajeng, Juliati; Cowan, David M.; Fuchs, Greg J.; Zhou, Huilin; Field, Seth J.


    The response to DNA damage, which regulates nuclear processes such as DNA repair, transcription, and cell cycle, has been studied thoroughly. However, the cytoplasmic response to DNA damage is poorly understood. Here, we demonstrate that DNA damage triggers dramatic reorganization of the Golgi, resulting in its dispersal throughout the cytoplasm. We further show that DNA-damage-induced Golgi dispersal requires GOLPH3/MYO18A/F-actin and the DNA damage protein kinase, DNA-PK. In response to DNA...

  5. Critical role of bioanalytical strategies in investigation of clinical PK observations, a Phase I case study (United States)

    Peng, Kun; Xu, Keyang; Liu, Luna; Hendricks, Robert; Delarosa, Reginald; Erickson, Rich; Budha, Nageshwar; Leabman, Maya; Song, An; Kaur, Surinder; Fischer, Saloumeh K


    RG7652 is a human immunoglobulin 1 (IgG1) monoclonal antibody (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and is designed for the treatment of hypercholesterolemia. A target-binding enzyme-linked immunosorbent assay (ELISA) was developed to measure RG7652 levels in human serum in a Phase I study. Although target-binding assay formats are generally used to quantify free therapeutic, the actual therapeutic species being measured are affected by assay conditions, such as sample dilution and incubation time, and levels of soluble target in the samples. Therefore, in the presence of high concentrations of circulating target, the choice of reagents and assay conditions can have a significant effect on the observed pharmacokinetic (PK) profiles. Phase I RG7652 PK analysis using the ELISA data resulted in a nonlinear dose normalized exposure. An investigation was conducted to characterize the ELISA to determine whether the assay format and reagents may have contributed to the PK observation. In addition, to confirm the ELISA results, a second orthogonal method, liquid chromatography tandem mass spectrometry (LC-MS/MS) using a signature peptide as surrogate, was developed and implemented. A subset of PK samples, randomly selected from half of the subjects in the 6 single ascending dose (SAD) cohorts in the Phase I clinical study, was analyzed with the LC-MS/MS assay, and the data were found to be comparable to the ELISA data. This paper illustrates the importance of reagent characterization, as well as the benefits of using an orthogonal approach to eliminate bioanalytical contributions when encountering unexpected observations. PMID:25484037

  6. Nano Copper Induces Apoptosis in PK-15 Cells via a Mitochondria-Mediated Pathway. (United States)

    Zhang, Hui; Chang, Zhenyu; Mehmood, Khalid; Abbas, Rao Zahid; Nabi, Fazul; Rehman, Mujeeb Ur; Wu, Xiaoxing; Tian, Xinxin; Yuan, Xiaodan; Li, Zhaoyang; Zhou, Donghai


    Nano-sized copper particles are widely used in various chemical, physical, and biological fields. However, earlier studies have shown that nano copper particles (40-100 μg/mL) can induce cell toxicity and apoptosis. Therefore, this study was conducted to investigate the role of nano copper in mitochondrion-mediated apoptosis in PK-15 cells. The cells were treated with different doses of nano copper (20, 40, 60, and 80 μg/mL) to determine the effects of apoptosis using acridine orange/ethidium bromide (AO/EB) fluorescence staining and a flow cytometry assay. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the PK-15 cells were examined using commercially available kits. Moreover, the mRNA levels of the Bax, Bid, Caspase-3, and CYCS genes were assessed by real-time PCR. The results revealed that nano copper exposure induced apoptosis and changed the mitochondrial membrane potential. In addition, nano copper significantly altered the levels of the Bax, Bid, Caspase-3, and CYCS genes at a concentration of 40 μg/mL. To summarize, nano copper significantly (P nano copper can play an important role in inducing the apoptotic pathway in PK-15 cells, which may be the mechanism by which nano copper induces nephrotoxicity.

  7. A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim. (United States)

    Niederalt, Christoph; Kuepfer, Lars; Solodenko, Juri; Eissing, Thomas; Siegmund, Hans-Ulrich; Block, Michael; Willmann, Stefan; Lippert, Jörg


    Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies. For model development and evaluation, PK data was used for compounds with a wide range of solute radii. The model supports the integration of knowledge gained during all development phases of therapeutic proteins, enables translation from pre-clinical species to human and allows predictions of tissue concentration profiles which are of relevance for the analysis of on-target pharmacodynamic effects as well as off-target toxicity. The current implementation of the model replaces the generic protein PBPK model available in PK-Sim since version 4.2 and becomes part of the Open Systems Pharmacology Suite.

  8. The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. (United States)

    Fishburn, C Simone


    Conjugation of macromolecules to polyethylene glycol (PEG) has emerged recently as an effective strategy to alter the pharmacokinetic (PK) profiles of a variety of drugs, and thereby to improve their therapeutic potential. PEG conjugation increases retention of drugs in the circulation by protecting against enzymatic digestion, slowing filtration by the kidneys and reducing the generation of neutralizing antibodies. Often, PEGylation leads to a loss in binding affinity due to steric interference with the drug-target binding interaction. This loss in potency is offset by the longer circulating half-life of the drugs, and the resulting change in PK-PD profile has led in some cases to enabling of drugs that otherwise could not be developed, and in others to improvements in existing drugs. Thus, whereas most approaches to drug development seek to increase the activity of drugs directly, the creation of PEGylated drugs seeks to balance the pharmacodynamic (PD) and pharmacokinetic properties to produce novel therapies that will meet with both increased efficacy and greater compliance in the clinical setting. This review examines some of the PEGylated drugs developed in recent years, and highlights some of the different strategies taken to employ PEG to maximize the overall PK-PD profiles of these compounds. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association

  9. PK20, a new opioid-neurotensin hybrid peptide that exhibits central and peripheral antinociceptive effects

    Directory of Open Access Journals (Sweden)

    Tsuda Yuko


    Full Text Available Abstract Background The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor. Results Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia. Conclusions The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.

  10. Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of ceftiofur after a single intravenous, subcutaneous and subcutaneous-LA administration in lactating goats. (United States)

    Fernández-Varón, Emilio; Cárceles-García, Carlos; Serrano-Rodríguez, Juan Manuel; Cárceles-Rodríguez, Carlos M


    Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals. The objectives of the present study were to establish the serum concentration-time profile for ceftiofur in lactating goats after intravenous, subcutaneous and a SC-long-acting ceftiofur formulation; to determine ceftiofur penetration into milk; to determine in vitro and ex vivo activity of ceftiofur establishing MIC, MBC, MPC and time-kill profiles against field strains of M. haemolytica and finally to calculate the main surrogate markers of efficacy. The pharmacokinetics studies revealed an optimal PK properties for the SC-LA formulation tested. Ceftiofur was well absorbed following SC and SC-LA administration, with absolute bioavailabilities (F) of 85.16 and 84.43 %, respectively. After ceftiofur analysis from milk samples, no concentrations were found at any sampling time. The MIC, MBC and MPC data of ceftiofur against five M. haemolytica strains isolated from goats affected by pneumonia were tested showing excelent sensitivity of ceftiofur against this pathogen. For PK-PD analysis, ratios were calculated suggesting a high level of bacterial kill against the five strains of M. haemolytica tested. The systemic ceftiofur exposure achieved in lactating goats following IV, SC and especially with the SC-LA administration is consistent with the predicted PK-PD ratios needed for a positive therapeutic outcome for M. haemolytica

  11. The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections

    NARCIS (Netherlands)

    Tangden, T.; Martin, V.; Felton, T.W.; Nielsen, E.I.; Marchand, S.; Bruggemann, R.J.M.; Bulitta, J.B.; Bassetti, M.; Theuretzbacher, U.; Tsuji, B.T.; Wareham, D.W.; Friberg, L.E.; Waele, J.J. De; Tam, V.H.; Roberts, J.A.


    Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed.

  12. Factors associated with failed spinal anaesthesia for Caesarean ...

    African Journals Online (AJOL)

    Adeyinka Abiodun Alabi

    Results: The incidence of failed spinal anaesthesia was 11.7%, which was slightly higher in emergency Caesarean sections. In univariate analysis, previous anaesthesia, obesity, dry tap of cerebrospinal fluid (CSF), bloody CSF and duration of work experience less than one year were significantly associated with FSA in the ...

  13. Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice. (United States)

    Li, Jing-Yun; Ren, Yu-Peng; Yuan, Yin; Ji, Shuang-Min; Zhou, Shu-Pei; Wang, Li-Jie; Mou, Zhen-Zhen; Li, Liang; Lu, Wei; Zhou, Tian-Yan


    Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research. The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

  14. How pharmacokinetic and pharmacodynamic (PK/PD) principles pave the way for optimal basal insulin therapy in type 2 diabetes


    Arnolds, Sabine; Kuglin, Bernd; Kapitza, Christoph; Heise, Tim


    Abstract This pedagogical review illustrates the differences between pharmacokinetic (PK) and pharmacodynamic (PD) measures, using insulin therapy as the primary example. The main conclusion is that PD parameters are of greater clinical significance for insulin therapy than PK parameters. The glucose-clamp technique, the optimal method for determining insulin PD, is explained so that the reader can understand important studies in the literature. Key glucose-clamp studies that compa...

  15. Absence of mutations in the coding sequence of the potential tumor suppressor 3pK in metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Houben Roland


    Full Text Available Abstract Background Activation of Ras or Raf contributes to tumorigenesis of melanoma. However, constitutive Raf activation is also a characteristic of the majority of benign melanocytic nevi and high intensity signaling of either Ras or Raf was found to induce growth inhibition and senescence rather than transformation. Since the chromosome 3p kinase (3pK is a target of the Ras/Raf/Mek/Erk signaling pathway which antagonizes the function of the oncogene and anti-differentiation factor Bmi-1, 3pK may function as a tumor suppressor in tumors with constitutive Ras/Raf activation. Consequently, we tested whether inactivating 3pK mutations are present in melanoma. Methods 30 metastatic melanoma samples, which were positive for activating mutations of either BRaf or NRas, were analyzed for possible mutations in the 3pk gene. The 10 coding exons and their flanking intron sequences were amplified by PCR and direct sequencing of the PCR products was performed. Results This analysis revealed that besides the presence of some single nucleotide polymorphisms in the 3pk gene, we could not detect any possible loss of function mutation in any of these 30 metastatic melanoma samples selected for the presence of activating mutations within the Ras/Raf/Mek/Erk signaling pathway. Conclusion Hence, in melanoma with constitutively active Ras/Raf inactivating mutations within the 3pk gene do not contribute to the oncogenic phenotype of this highly malignant tumor.

  16. One hundred cases of laparoscopic subtotal hysterectomy using the PK and Lap Loop systems. (United States)

    Erian, John; El-Toukhy, Tarek; Chandakas, Stefanos; Theodoridis, Theo; Hill, Nicholas


    To evaluate the safety and short-term outcomes of laparoscopic subtotal hysterectomy using the PK and Lap Loop systems. Prospective observational study (Canadian Task Force classification II-2). Princess Royal University and Chelsfield Park Hospitals, Kent, UK. One hundred women who underwent laparoscopic subtotal hysterectomy for menorrhagia from February 2003 through July 2004. The procedure was performed using the Plasma Kinetic (PK) system to seal the vascular pedicles and the Lap Loop system to separate the uterus at the level of the internal os. The uterus was removed from the abdominal cavity mainly by morcellation or posterior colpotomy. Of 100 patients, 59 were operated on as outpatients. Mean patient age was 44.6 years, median parity was 2, mean body mass index was 26.8, and mean duration of symptoms was 4 years. Clinically, the uterus was enlarged in 70 patients, and preoperative ultrasound scanning suggested the presence of uterine myomas in 42 patients. In addition to hysterectomy, 47 patients had concomitant pelvic surgery. The mean total operating time was 45.5 minutes, and mean estimated blood loss was 114 mL. The overall major complication rate was 2%; two patients required blood transfusion after surgery. There were no bowel or urinary tract injuries, unintended laparotomy, return to operating room, or anesthetic complications. At follow-up, all patients were satisfied with surgery. Laparoscopic subtotal hysterectomy using the PK and Lap Loop systems for treatment of therapy-resistant menorrhagia is safe, can be performed as an outpatient procedure, and is associated with reduced operating time and high patient satisfaction.

  17. A PK-PD model of ketamine-induced high-frequency oscillations (United States)

    Flores, Francisco J.; Ching, ShiNung; Hartnack, Katharine; Fath, Amanda B.; Purdon, Patrick L.; Wilson, Matthew A.; Brown, Emery N.


    Objective. Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PDs) of ketamine and the observed HFO power. Approach. In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results. We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance. Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent

  18. A Comparison of Decision Methods for C pk When Data are Autocorrelated

    DEFF Research Database (Denmark)

    Lundkvist, Peder; Vannman, Kerstin; Kulahci, Murat


    of this article is to compare decision methods using the process capability index C-pk when data are autocorrelated. This is done through a case study followed by a simulation study. In the simulation study the actual significance level and power of the decision methods are investigated. The outcome......In many industrial applications, autocorrelated data are becoming increasingly common due to, for example, on-line data collection systems with high-frequency sampling. Therefore, the basic assumption of independent observations for process capability analysis is not valid. The purpose...


    Directory of Open Access Journals (Sweden)

    M. Ihwanudin


    Full Text Available The purpose of research to examine (1 significance of correlation between (X1 with (Y; (2 significance of correlation (X2 with (Y; (3 correlation significance of simultaneous between (X1& X2 to (Y. The research was used regression technique. Object of research at UPT-PK east java Surabaya, Jombang, Kediri, Nganjuk, Pasuruan, Singosari and Tulungagung. Result of research (1 correlation between (X1 with (Y of 0,501%; (2 correlation between (X2 with (Y of 0,533%; (3 significance of simultaneous between (X1& X2 to (Y that positive and significant with coefficient R of 0,829 and R square of 68,7%. Tujuan penelitian untuk menguji (1 signifikansi hubungan antara (X1 dengan (Y; (2 signifikansi hubungan antara (X2 dengan (Y; (3 signifikansi hubungan secara simultan antara (X1& X2 terhadap (Y. Metode penelitian menggunakan teknik regresi. Penelitian dilakukan di UPT-PK Jatim terdiri atas Surabaya, Jombang, Kediri, Nganjuk, Pasuruan, Singosari, dan Tulungagung. Hasil penelitian menunjukkan (1 hubungan antara variabel (X1 dengan (Y koefisien sebesar 0,501; (2 hubungan antara variabel (X2 dengan (Y koefisien sebesar 0,533; (3 hubungan simultan antara variabel (X1& X2 dengan (Y merupakan hubungan positif dan signifikan dengan koefisien R sebesar 0,829 dan R square sebesar 68,7%.

  20. DNA-PK-dependent RPA2 hyperphosphorylation facilitates DNA repair and suppresses sister chromatid exchange.

    Directory of Open Access Journals (Sweden)

    Hungjiun Liaw

    Full Text Available Hyperphosphorylation of RPA2 at serine 4 and serine 8 (S4, S8 has been used as a marker for activation of the DNA damage response. What types of DNA lesions cause RPA2 hyperphosphorylation, which kinase(s are responsible for them, and what is the biological outcome of these phosphorylations, however, have not been fully investigated. In this study we demonstrate that RPA2 hyperphosphorylation occurs primarily in response to genotoxic stresses that cause high levels of DNA double-strand breaks (DSBs and that the DNA-dependent protein kinase complex (DNA-PK is responsible for the modifications in vivo. Alteration of S4, S8 of RPA2 to alanines, which prevent phosphorylations at these sites, caused increased mitotic entry with concomitant increases in RAD51 foci and homologous recombination. Taken together, our results demonstrate that RPA2 hyperphosphorylation by DNA-PK in response to DSBs blocks unscheduled homologous recombination and delays mitotic entry. This pathway thus permits cells to repair DNA damage properly and increase cell viability.

  1. Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery. (United States)

    Fang, Yi-Ping; Wu, Pao-Chu; Huang, Yaw-Bin; Tzeng, Cherng-Chyi; Chen, Yeh-Long; Hung, Yu-Han; Tsai, Ming-Jun; Tsai, Yi-Hung


    The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenyl) amino]furo[2,3-b]quinoline (PK-L4) is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection. To utilize solid lipid nanoparticles (SLNs) modified with polyethylene glycol (PEG) to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration. The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE%) of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%-64% in the human lung carcinoma cell line (A549), 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7), and 95% in the human breast adenocarcinoma cell line (MDA-MB-231). The amount of PK-L4 released by SLNs with PEG was significantly higher than that from the PK-L4 solution (P < 0.05). After intravenous bolus of the PK-L4-loaded SLNs with PEG, there was a marked significant difference in half-life alpha (0.136 ± 0.046 hours) when compared with the PK-L4 solution (0.078 ± 0.023 hours); also the area under the curve from zero to infinity did not change in plasma when compared to the PK-L4 solution. This demonstrated that PK-L4-loaded SLNs were rapidly distributed from central areas to tissues and exhibited higher accumulation in specific organs. The highest deposition of PK-L4-loaded SLNs with PEG was found in the

  2. 3D gut-liver chip with a PK model for prediction of first-pass metabolism. (United States)

    Lee, Dong Wook; Ha, Sang Keun; Choi, Inwook; Sung, Jong Hwan


    Accurate prediction of first-pass metabolism is essential for improving the time and cost efficiency of drug development process. Here, we have developed a microfluidic gut-liver co-culture chip that aims to reproduce the first-pass metabolism of oral drugs. This chip consists of two separate layers for gut (Caco-2) and liver (HepG2) cell lines, where cells can be co-cultured in both 2D and 3D forms. Both cell lines were maintained well in the chip, verified by confocal microscopy and measurement of hepatic enzyme activity. We investigated the PK profile of paracetamol in the chip, and corresponding PK model was constructed, which was used to predict PK profiles for different chip design parameters. Simulation results implied that a larger absorption surface area and a higher metabolic capacity are required to reproduce the in vivo PK profile of paracetamol more accurately. Our study suggests the possibility of reproducing the human PK profile on a chip, contributing to accurate prediction of pharmacological effect of drugs.

  3. When Organization Fails: Why Authority Matters

    DEFF Research Database (Denmark)

    Blaschke, Steffen


    Review of: James R. Taylor and Elizabeth J. Van Every / When Organization Fails: Why Authority Matters. (New York: Routledge, 2014. 220 pp. ISBN: 978 0415741668)......Review of: James R. Taylor and Elizabeth J. Van Every / When Organization Fails: Why Authority Matters. (New York: Routledge, 2014. 220 pp. ISBN: 978 0415741668)...

  4. Neglected City Narratives And Failed Rebranding

    DEFF Research Database (Denmark)

    Mousten, Birthe; Locmele, Gunta


    Rīga, Latvia went through a failed rebranding process as the forerunner of its status as a European Capital of Culture (2014). The same thing happened in Aarhus, Denmark. Aarhus will be a European Capital of Culture (2017) and leading to this, it went through a failed rebranding process. Based on...

  5. Is journalism failing on climate? (United States)

    Rahmstorf, Stefan


    How can we build a reliable and affordable energy supply based on renewables? How rapidly do we need to cut greenhouse gas emissions to keep climate change within manageable bounds? What does it take to maintain a stable common currency of different nations? These are just a few examples of questions that are critical for our future and that require an understanding of complex systems—the energy system, the climate system, the financial system. Finding sound answers to these questions requires sophisticated scientific analysis and expert knowledge; a lay person's intuition will clearly not suffice. Yet, decisions in a democracy are (and should be!) taken by politicians and the voting public who are not usually scientific experts. Hence the well-being of our societies—and even more so the living conditions of future generations, which are defined by the decisions we take today—depends on the wider public being well informed about the state of scientific knowledge and discourse. The media are the most important means by which lay people obtain their information about science. Good science journalism is therefore a decisive factor for the long-term success of modern society. Good science journalism clearly must be critical journalism, and it requires journalists who know what is what, who can put things into a perspective, and who are able to make well-informed judgements. After all, the role of science journalism is not simply to act as a 'translator' who conveys the findings of scientists in a language understandable to lay people. Rather, good science journalism will provide the public with a realistic impression of what is well established in science and what are current 'hot topics', uncertainties and controversies. It will also discuss the methods and social context of the scientific endeavour. There is ample evidence that in the area of climate science, journalism too often is failing to deliver this realistic picture to its audience, despite many good

  6. Study of the production of $\\Lambda_b^0$ and $\\overline{B}^0$ hadrons in $pp$ collisions and first measurement of the $\\Lambda_b^0\\rightarrow J/\\psi pK^-$ branching fraction

    CERN Document Server

    Aaij, R.; Adinolfi, Marco; Affolder, Anthony; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio Augusto; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Anderson, Jonathan; Andreassi, Guido; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Aquines Gutierrez, Osvaldo; Archilli, Flavio; d'Argent, Philippe; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Auriemma, Giulio; Baalouch, Marouen; Bachmann, Sebastian; Back, John; Badalov, Alexey; Baesso, Clarissa; Baldini, Wander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Batozskaya, Varvara; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Bel, Lennaert; Bellee, Violaine; Belloli, Nicoletta; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Benton, Jack; Berezhnoy, Alexander; Bernet, Roland; Bertolin, Alessandro; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bien, Alexander; Bifani, Simone; Billoir, Pierre; Bird, Thomas; Birnkraut, Alex; Bizzeti, Andrea; Blake, Thomas; Blanc, Frédéric; Blouw, Johan; Blusk, Steven; Bocci, Valerio; Bondar, Alexander; Bondar, Nikolay; Bonivento, Walter; Borghi, Silvia; Borsato, Martino; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Braun, Svende; Britsch, Markward; Britton, Thomas; Brodzicka, Jolanta; Brook, Nicholas; Buchanan, Emma; Bursche, Albert; Buytaert, Jan; Cadeddu, Sandro; Calabrese, Roberto; Calvi, Marta; Calvo Gomez, Miriam; Campana, Pierluigi; Campora Perez, Daniel; Capriotti, Lorenzo; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carniti, Paolo; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Castillo Garcia, Lucia; Cattaneo, Marco; Cauet, Christophe; Cavallero, Giovanni; Cenci, Riccardo; Charles, Matthew; Charpentier, Philippe; Chefdeville, Maximilien; Chen, Shanzhen; Cheung, Shu-Faye; Chiapolini, Nicola; Chrzaszcz, Marcin; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Coco, Victor; Cogan, Julien; Cogneras, Eric; Cogoni, Violetta; Cojocariu, Lucian; Collazuol, Gianmaria; Collins, Paula; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombes, Matthew; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Crocombe, Andrew; Cruz Torres, Melissa Maria; Cunliffe, Samuel; Currie, Robert; D'Ambrosio, Carmelo; Dall'Occo, Elena; Dalseno, Jeremy; David, Pieter; Davis, Adam; De Bruyn, Kristof; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Simone, Patrizia; Dean, Cameron Thomas; Decamp, Daniel; Deckenhoff, Mirko; Del Buono, Luigi; Déléage, Nicolas; Demmer, Moritz; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Dey, Biplab; Di Canto, Angelo; Di Ruscio, Francesco; Dijkstra, Hans; Donleavy, Stephanie; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Dossett, David; Dovbnya, Anatoliy; Dreimanis, Karlis; Dufour, Laurent; Dujany, Giulio; Dupertuis, Frederic; Durante, Paolo; Dzhelyadin, Rustem; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; El Rifai, Ibrahim; Elsasser, Christian; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Färber, Christian; Farley, Nathanael; Farry, Stephen; Fay, Robert; Ferguson, Dianne; Fernandez Albor, Victor; Ferrari, Fabio; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fiore, Marco; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fohl, Klaus; Fol, Philip; Fontana, Marianna; Fontanelli, Flavio; Forty, Roger; Francisco, Oscar; Frank, Markus; Frei, Christoph; Frosini, Maddalena; Fu, Jinlin; Furfaro, Emiliano; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; García Pardiñas, Julián; Garra Tico, Jordi; Garrido, Lluis; Gascon, David; Gaspar, Clara; Gauld, Rhorry; Gavardi, Laura; Gazzoni, Giulio; Gerick, David; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianì, Sebastiana; Gibson, Valerie; Girard, Olivier Göran; Giubega, Lavinia-Helena; Gligorov, V.V.; Göbel, Carla; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gotti, Claudio; Grabalosa Gándara, Marc; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graverini, Elena; Graziani, Giacomo; Grecu, Alexandru; Greening, Edward; Gregson, Sam; Griffith, Peter; Grillo, Lucia; Grünberg, Oliver; Gui, Bin; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Hadavizadeh, Thomas; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hall, Samuel; Hamilton, Brian; Han, Xiaoxue; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Harrison, Jonathan; He, Jibo; Head, Timothy; Heijne, Veerle; Hennessy, Karol; Henrard, Pierre; Henry, Louis; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hoballah, Mostafa; Hombach, Christoph; Hulsbergen, Wouter; Humair, Thibaud; Hussain, Nazim; Hutchcroft, David; Hynds, Daniel; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jaeger, Andreas; Jalocha, Pawel; Jans, Eddy; Jawahery, Abolhassan; Jing, Fanfan; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kandybei, Sergii; Kanso, Walaa; Karacson, Matthias; Karbach, Moritz; Karodia, Sarah; Kecke, Matthieu; Kelsey, Matthew; Kenyon, Ian; Kenzie, Matthew; Ketel, Tjeerd; Khanji, Basem; Khurewathanakul, Chitsanu; Klaver, Suzanne; Klimaszewski, Konrad; Kochebina, Olga; Kolpin, Michael; Komarov, Ilya; Koopman, Rose; Koppenburg, Patrick; Kozeiha, Mohamad; Kravchuk, Leonid; Kreplin, Katharina; Kreps, Michal; Krocker, Georg; Krokovny, Pavel; Kruse, Florian; Krzemien, Wojciech; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kuonen, Axel Kevin; Kurek, Krzysztof; Kvaratskheliya, Tengiz; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lambert, Dean; Lanfranchi, Gaia; Langenbruch, Christoph; Langhans, Benedikt; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; van Leerdam, Jeroen; Lees, Jean-Pierre; Lefèvre, Regis; Leflat, Alexander; Lefrançois, Jacques; Lemos Cid, Edgar; Leroy, Olivier; Lesiak, Tadeusz; Leverington, Blake; Li, Yiming; Likhomanenko, Tatiana; Liles, Myfanwy; Lindner, Rolf; Linn, Christian; Lionetto, Federica; Liu, Bo; Liu, Xuesong; Loh, David; Longstaff, Iain; Lopes, Jose; Lucchesi, Donatella; Lucio Martinez, Miriam; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Lusiani, Alberto; Machefert, Frederic; Maciuc, Florin; Maev, Oleg; Maguire, Kevin; Malde, Sneha; Malinin, Alexander; Manca, Giulia; Mancinelli, Giampiero; Manning, Peter Michael; Mapelli, Alessandro; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marino, Pietro; Marks, Jörg; Martellotti, Giuseppe; Martin, Morgan; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Martins Tostes, Danielle; Massafferri, André; Matev, Rosen; Mathad, Abhijit; Mathe, Zoltan; Matteuzzi, Clara; Mauri, Andrea; Maurin, Brice; Mazurov, Alexander; McCann, Michael; McCarthy, James; McNab, Andrew; McNulty, Ronan; Meadows, Brian; Meier, Frank; Meissner, Marco; Melnychuk, Dmytro; Merk, Marcel; Michielin, Emanuele; Milanes, Diego Alejandro; Minard, Marie-Noelle; Mitzel, Dominik Stefan; Molina Rodriguez, Josue; Monroy, Ignacio Alberto; Monteil, Stephane; Morandin, Mauro; Morawski, Piotr; Mordà, Alessandro; Morello, Michael Joseph; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Müller, Dominik; Müller, Janine; Müller, Katharina; Müller, Vanessa; Mussini, Manuel; Muster, Bastien; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nandi, Anita; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Anh Duc; Nguyen, Thi-Dung; Nguyen-Mau, Chung; Niess, Valentin; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Ninci, Daniele; Novoselov, Alexey; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Ogilvy, Stephen; Okhrimenko, Oleksandr; Oldeman, Rudolf; Onderwater, Gerco; Osorio Rodrigues, Bruno; Otalora Goicochea, Juan Martin; Otto, Adam; Owen, Patrick; Oyanguren, Maria Aranzazu; Palano, Antimo; Palombo, Fernando; Palutan, Matteo; Panman, Jacob; Papanestis, Antonios; Pappagallo, Marco; Pappalardo, Luciano; Pappenheimer, Cheryl; Parkes, Christopher; Passaleva, Giovanni; Patel, Girish; Patel, Mitesh; Patrignani, Claudia; Pearce, Alex; Pellegrino, Antonio; Penso, Gianni; Pepe Altarelli, Monica; Perazzini, Stefano; Perret, Pascal; Pescatore, Luca; Petridis, Konstantinos; Petrolini, Alessandro; Petruzzo, Marco; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pilař, Tomas; Pinci, Davide; Pistone, Alessandro; Piucci, Alessio; Playfer, Stephen; Plo Casasus, Maximo; Poikela, Tuomas; Polci, Francesco; Poluektov, Anton; Polyakov, Ivan; Polycarpo, Erica; Popov, Alexander; Popov, Dmitry; Popovici, Bogdan; Potterat, Cédric; Price, Eugenia; Price, Joseph David; Prisciandaro, Jessica; Pritchard, Adrian; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Punzi, Giovanni; Qian, Wenbin; Quagliani, Renato; Rachwal, Bartolomiej; Rademacker, Jonas; Rama, Matteo; Rangel, Murilo; Raniuk, Iurii; Rauschmayr, Nathalie; Raven, Gerhard; Redi, Federico; Reichert, Stefanie; Reid, Matthew; dos Reis, Alberto; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vincente; Robbe, Patrick; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Lopez, Jairo Alexis; Rodriguez Perez, Pablo; Roiser, Stefan; Romanovsky, Vladimir; Romero Vidal, Antonio; Ronayne, John William; Rotondo, Marcello; Rouvinet, Julien; Ruf, Thomas; Ruiz Valls, Pablo; Saborido Silva, Juan Jose; Sagidova, Naylya; Sail, Paul; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santimaria, Marco; Santovetti, Emanuele; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrina, Darya; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmelzer, Timon; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schubiger, Maxime; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Semennikov, Alexander; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Shires, Alexander; Siddi, Benedetto Gianluca; Silva Coutinho, Rafael; Silva de Oliveira, Luiz Gustavo; Simi, Gabriele; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Edmund; Smith, Eluned; Smith, Iwan Thomas; Smith, Jackson; Smith, Mark; Snoek, Hella; Sokoloff, Michael; Soler, Paul; Soomro, Fatima; Souza, Daniel; Souza De Paula, Bruno; Spaan, Bernhard; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Stefkova, Slavorima; Steinkamp, Olaf; Stenyakin, Oleg; Stevenson, Scott; Stoica, Sabin; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Straticiuc, Mihai; Straumann, Ulrich; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Swientek, Stefan; Syropoulos, Vasileios; Szczekowski, Marek; Szczypka, Paul; Szumlak, Tomasz; T'Jampens, Stephane; Tayduganov, Andrey; Tekampe, Tobias; Teklishyn, Maksym; Tellarini, Giulia; Teubert, Frederic; Thomas, Christopher; Thomas, Eric; van Tilburg, Jeroen; Tisserand, Vincent; Tobin, Mark; Todd, Jacob; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Topp-Joergensen, Stig; Torr, Nicholas; Tournefier, Edwige; Tourneur, Stephane; Trabelsi, Karim; Tran, Minh Tâm; Tresch, Marco; Trisovic, Ana; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tuning, Niels; Ukleja, Artur; Ustyuzhanin, Andrey; Uwer, Ulrich; Vacca, Claudia; Vagnoni, Vincenzo; Valenti, Giovanni; Vallier, Alexis; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vázquez Sierra, Carlos; Vecchi, Stefania; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Vesterinen, Mika; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Vilasis-Cardona, Xavier; Volkov, Vladimir; Vollhardt, Achim; Volyanskyy, Dmytro; Voong, David; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; de Vries, Jacco; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wandernoth, Sebastian; Wang, Jianchun; Ward, David; Watson, Nigel; Websdale, David; Weiden, Andreas; Whitehead, Mark; Wilkinson, Guy; Wilkinson, Michael; Williams, Mark Richard James; Williams, Matthew; Williams, Mike; Williams, Timothy; Wilson, Fergus; Wimberley, Jack; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wright, Simon; Wyllie, Kenneth; Xie, Yuehong; Xu, Zhirui; Yang, Zhenwei; Yu, Jiesheng; Yuan, Xuhao; Yushchenko, Oleg; Zangoli, Maria; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Yanxi; Zhelezov, Alexey; Zhokhov, Anatoly; Zhong, Liang; Zucchelli, Stefano


    The product of the $\\Lambda_b^0$ ($\\overline{B}^0$) differential production cross-section and the branching fraction of the decay $\\Lambda_b^0\\rightarrow J/\\psi pK^-$ ($\\overline{B}^0\\rightarrow J/\\psi\\overline{K}^*(892)^0$) is measured as a function of the beauty hadron transverse momentum, $p_{\\rm T}$, and rapidity, $y$. The kinematic region of the measurements is $p_{\\rm T}<20~{\\rm GeV}/c$ and $2.0 < y < 4.5$. The measurements use a data sample corresponding to an integrated luminosity of $3~{\\rm fb}^{-1}$ collected by the LHCb detector in $pp$ collisions at centre-of-mass energies $\\sqrt{s}=7~{\\rm TeV}$ in 2011 and $\\sqrt{s}=8~{\\rm TeV}$ in 2012. Based on previous LHCb results of the fragmentation fraction ratio, $f_{\\Lambda_B^0}/f_d$, the branching fraction of the decay $\\Lambda_b^0\\rightarrow J/\\psi pK^-$ is measured to be \\begin{equation*} \\mathcal{B}(\\Lambda_b^0\\rightarrow J/\\psi pK^-)= (3.04\\pm0.04\\pm0.06\\pm0.33^{+0.43}_{-0.27})\\times10^{-4}, \\end{equation*} where the first uncertainty is st...

  7. Search for a narrow baryonic state decaying to ${pK^0_S}$ and ${\\overline{p}K^0_S}$ in deep inelastic scattering at HERA

    CERN Document Server

    Abramowicz, H.; Adamczyk, L.; Adamus, M.; Antonelli, S.; Aushev, V.; Behnke, O.; Behrens, U.; Bertolin, A.; Bhadra, S.; Bloch, I.; Boos, E.G.; Brock, I.; Brook, N.H.; Brugnera, R.; Bruni, A.; Bussey, P.J.; Caldwell, A.; Capua, M.; Catterall, C.D.; Chwastowski, J.; Ciborowski, J.; Ciesielski, R.; Cooper-Sarkar, A.M.; Corradi, M.; Dementiev, R.K.; Devenish, RCE; Dusini, S.; Foster, B.; Gach, G; Gallo, E.; Garfagnini, A.; Geiser, A.; Gizhko, A.; Gladilin, L.K.; Golubkov, Yu.A.; Grzelak, G.; Guzik, M.; Gwenlan, C.; Hain, W.; Hlushchenko, O.; Hochman, D.; Hori, R.; Ibrahim, Z.A.; Iga, Y.; Ishitsuka, M.; Januschek, F.; Jomhari, N.Z.; Kadenko, I.; Kananov, S.; Karshon, U.; Kaur, P.; Kisielewska, D.; Klanner, R.; Klein, U.; Korzhavina, I.A.; Kotański, A.; Kötz, U.; Kovalchuk, N.; Kowalski, H.; Krupa, B.; Kuprash, O.; Kuze, M; Levchenko, B.B.; Levy, A.; Limentani, S.; Lisovyi, M.; Lobodzinska, E.; Löhr, B.; Lohrmann, E.; Longhin, A.; Lontkovskyi, D.; Lukina, O.Yu.; Makarenko, I.; Malka, J.; Mastroberardino, A.; Mohamad Idris, F.; Mohammad Nasir, N; Myronenko, V.; Nagano, K.; Nobe, T.; Nowak, R.J.; Onishchuk, Yu.; Paul, E.; Perlański, W.; Pokrovskiy, N.S.; Polini, A.; Przybycien, M.; Roloff, P.; Ruspa, M.; Saxon, D.H.; Schioppa, M.; Schneekloth, U.; Schörner-Sadenius, T.; Shcheglova, L.M.; Shevchenko, R.; Shkola, O.; Shyrma, Yu.; Singh, I.; Skillicorn, I.O.; Słomiński, W.; Solano, A.; Stanco, L.; Stefaniuk, N.; Stern, A.; Stopa, P.; Sztuk-Dambietz, J.; Tassi, E.; Tokushuku, K.; Tomaszewska, J.; Tsurugai, T.; Turcato, M.; Turkot, O.; Tymieniecka, T.; Verbytskyi, A.; Wan Abdullah, W.A.T.; Wichmann, K.; Wing, M.; Yamada, S.; Yamazaki, Y.; Zakharchuk, N.; Żarnecki, A.F.; Zawiejski, L.; Zenaiev, O.; Zhautykov, B.O.; Zotkin, D.S.; Mastroberardino, A


    A search for a narrow baryonic state in the $pK^0_S$ and $\\overline{p}K^0_S$ system has been performed in $ep$ collisions at HERA with the ZEUS detector using an integrated luminosity of 358 pb$^{-1}$ taken in 2003-2007. The search was performed with deep inelastic scattering events at an $ep$ centre-of-mass energy of 318 GeV for exchanged photon virtuality, $Q^2$, between 20 and 100 $\\rm{} GeV^{2}$. Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb$^{-1}$ taken in 1996-2000, no resonance peak was found in the $p(\\overline{p})K^0_S$ invariant-mass distribution in the range 1.45-1.7 GeV. Upper limits on the production cross section are set.

  8. Differential binding properties of the peripheral-type benzodiazepine ligands (/sup 3/H)PK 11195 and (/sup 3/H)Ro 5-4864 in trout and mouse brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Eshleman, A.J.; Murray, T.F.


    High-affinity binding sites for (/sup 3/H)PK 11195 have been detected in brain membranes of rainbow trout (Salmo gairdneri) and mouse forebrain, where the densities of receptors were 1,030 and 445 fmol/mg of protein, respectively. Ro 5-4864 (4'-chlorodiazepam) was 2,200-fold less potent as a competitor of (/sup 3/H)PK 11195 binding in the piscine than the murine membranes. Investigation of the regional distribution of these sites in trout yielded a rank order of density of spinal cord greater than olfactory bulb = optic tectum = rhombencephalon greater than cerebellum greater than telencephalon. This site in trout shared some of the characteristics of the peripheral-type benzodiazepine receptor (PTBR) (also known as the mitochondrial benzodiazepine receptor) in rodents, i.e., high affinity for PK 11195 and the endogenous ligand protoporphyrin IX, but was unique in the low affinity of Ro 5-4864 (41 microM) and diazepam and the relatively high affinity of the calcium channel ligand diltiazem and two central benzodiazepine ligands, CGS 8216 and CGS 9896. The differential affinity for the two prototypic PTBR ligands in trout is similar to that previously observed in calf and human brain membranes. Structural differences for the trout sites are indicated by the relative inability of diethyl pyrocarbonate to modify histidine residues of the binding site in trout as compared with mouse membranes. Heterogeneity of binding of the two prototypic PTBR ligands in mouse brain membranes was indicated by additivity studies, equilibrium competition experiments, and saturation isotherms, which together support the hypothesis that Ro 5-4864 discriminates between two (/sup 3/H)PK 11195 binding sites having high (nanomolar) and low (micromolar) affinity, respectively.

  9. PK of immunoconjugate anticancer agent CMD-193 in rats: ligand-binding assay approach to determine in vivo immunoconjugate stability. (United States)

    Hussain, Azher; Gorovits, Boris; Leal, Mauricio; Fluhler, Eric


    Antibody-drug conjugates (ADCs) are a new generation of anticancer therapeutics. The objective of this manuscript is to propose a methodology that can be used to assess the stability of the ADCs by using the PK data obtained by ligand-binding assays that measure various components of ADCs. The ligand-binding assays format of different components of ADCs provided unique valuable PK information. The mathematical manipulation of the bioanalytical data provided an insight into the in vivo integrity, indicating that the loading of the calicheamicin on the G193 antibody declines in an apparent slow first-order process. This report demonstrates the value of analyzing various components of the ADC and their PK profiles to better understand the disposition and in vivo stability of ADCs.

  10. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Senderovitz, Thomas


    Aims To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin...... for the population PK/PD data analysis. A systematic population PK/PD model-building framework using stochastic differential equations was applied to the data to identify nonlinear dynamic dependencies and to deconvolve the functional feedback interactions of the HPG axis. Results In our final PK/PD model of the HPG...

  11. Pro-apoptotic effect of a Mycoplasma hyopneumoniae putative type I signal peptidase on PK(15) swine cells. (United States)

    Paes, Jéssica A; Virginio, Veridiana G; Cancela, Martín; Leal, Fernanda M A; Borges, Thiago J; Jaeger, Natália; Bonorino, Cristina; Schrank, Irene S; Ferreira, Henrique B


    Mycoplasma hyopneumoniae is an economically significant swine pathogen that causes porcine enzootic pneumonia (PEP). Important processes for swine infection by M. hyopneumoniae depend on cell surface proteins, many of which are secreted by secretion pathways not completely elucidated so far. A putative type I signal peptidase (SPase I), a possible component of a putative Sec-dependent pathway, was annotated as a product of the sipS gene in the pathogenic M. hyopneumoniae 7448 genome. This M. hyopneumoniae putative SPase I (MhSPase I) displays only 14% and 23% of sequence identity/similarity to Escherichia coli bona fide SPase I, and, in complementation assays performed with a conditional E. coli SPase I mutant, only a partial restoration of growth was achieved with the heterologous expression of a recombinant MhSPase I (rMhSPase I). Considering the putative surface location of MhSPase I and its previously demonstrated capacity to induce a strong humoral response, we then assessed its potential to elicit a cellular and possible immunomodulatory response. In assays for immunogenicity assessment, rMhSPase I unexpectedly showed a cytotoxic effect on murine splenocytes. This cytotoxic effect was further confirmed using the swine epithelial PK(15) cell line in MTT and annexin V-flow cytometry assays, which showed that rMhSPase I induces apoptosis in a dose dependent-way. It was also demonstrated that this pro-apoptotic effect of rMhSPase I involves activation of a caspase-3 cascade. The potential relevance of the rMhSPase I pro-apoptotic effect for M. hyopneumoniae-host interactions in the context of PEP is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Failed fuel action plan guidelines: Special report

    International Nuclear Information System (INIS)


    The objective of this document is to provide a generic guideline that can be used to formulate a failed fuel action plan (FFAP) for specific application by a utility. This document is intended to be part of a comprehensive fuel reliability monitoring, management, and improvement program. The utilities may utilize this document as one resource in developing a failed fuel action plan. This document is not intended to be used as a failed fuel action plan standard. This document is intended to provide guidance on: management responsibilities; fuel performance parameters; cost/benefit analysis; action levels; long-term improvement methods; and data collection, analysis, and trending. 3 refs., 4 figs., 6 tabs

  13. Semiparametric mixed-effects analysis of PK/PD models using differential equations. (United States)

    Wang, Yi; Eskridge, Kent M; Zhang, Shunpu


    Motivated by the use of semiparametric nonlinear mixed-effects modeling on longitudinal data, we develop a new semiparametric modeling approach to address potential structural model misspecification for population pharmacokinetic/pharmacodynamic (PK/PD) analysis. Specifically, we use a set of ordinary differential equations (ODEs) with form dx/dt = A(t)x + B(t) where B(t) is a nonparametric function that is estimated using penalized splines. The inclusion of a nonparametric function in the ODEs makes identification of structural model misspecification feasible by quantifying the model uncertainty and provides flexibility for accommodating possible structural model deficiencies. The resulting model will be implemented in a nonlinear mixed-effects modeling setup for population analysis. We illustrate the method with an application to cefamandole data and evaluate its performance through simulations.

  14. PK-PD modelling of norfloxacin after oral administration in rabbits

    Directory of Open Access Journals (Sweden)

    B.H. Pavithra

    Full Text Available Norfloxacin posses a wide spectrum of activity, excellent tissue penetration and is rapidly bactericidal at low concentrations and hence an attempt was made to integrate reported pharmacodynamic data with pharmacokinetic data of norfloxacin after oral administration in rabbits to determine its effectiveness against common bacterial pathogens infecting rabbits. Pharmacokinetic data were obtained after a single per oral administration of norfloxacin @ 100mg per kg. Plasma drug concentrations were determined using high performance liquid chromatography (HPLC. From PK-PD integration, it is observed that norfloxacin is highly effective against gram negative infections caused by Pasteurella multocida (AUC/MIC and Cmax/MIC ratio of 133.5 and 111.5 respectively, its efficacy against Salmonella spp., E. Coli, Shigella spp. and Haemophilus influenza is moderate. However, per-oral administration of norfloxacin is not suitable to contain tested gram positive bacterial pathogens infecting rabbits. [Veterinary World 2010; 3(12.000: 546-548

  15. Oxidation of Helix-3 methionines precedes the formation of PK resistant PrP.

    Directory of Open Access Journals (Sweden)

    Tamar Canello


    Full Text Available While elucidating the peculiar epitope of the alpha-PrP mAb IPC2, we found that PrPSc exhibits the sulfoxidation of residue M213 as a covalent signature. Subsequent computational analysis predicted that the presence of sulfoxide groups at both Met residues 206 and 213 destabilize the alpha-fold, suggesting oxidation may facilitate the conversion of PrPC into PrPSc. To further study the effect of oxidation on prion formation, we generated pAbs to linear PrP peptides encompassing the Helix-3 region, as opposed to the non-linear complexed epitope of IPC2. We now show that pAbs, whose epitopes comprise Met residues, readily detected PrPC, but could not recognize most PrPSc bands unless they were vigorously reduced. Next, we showed that the alpha-Met pAbs did not recognize newly formed PrPSc, as is the case for the PK resistant PrP present in lines of prion infected cells. In addition, these reagents did not detect intermediate forms such as PK sensitive and partially aggregated PrPs present in infected brains. Finally, we show that PrP molecules harboring the pathogenic mutation E200K, which is linked to the most common form of familial CJD, may be spontaneously oxidized. We conclude that the oxidation of methionine residues in Helix-3 represents an early and important event in the conversion of PrPC to PrPSc. We believe that further investigation into the mechanism and role of PrP oxidation will be central in finally elucidating the mechanism by which a normal cell protein converts into a pathogenic entity that causes fatal brain degeneration.

  16. Pharmacokinetics, bioavailability and PK/PD relationship of cefquinome for Escherichia coli in Beagle dogs. (United States)

    Zhou, Y F; Zhao, D H; Yu, Y; Yang, X; Shi, W; Peng, Y B; Liu, Y H


    The pharmacokinetics and bioavailability of cefquinome in Beagle dogs were determined by intravenous (IV), intramuscular (IM) or subcutaneous (SC) injection at a single dose of 2 mg/kg body weight (BW). The minimum inhibitory concentrations (MIC) of cefquinome against 217 Escherichia coli isolated from dogs were also investigated. After IV injection, the plasma concentration-time curve of cefquinome was analyzed using a two-compartmental model, and the mean values of t1/2α (h), t1/2β (h), Vss (L/kg), ClB (L/kg/h) and AUC (μg·h/mL) were 0.12, 0.98, 0.30, 0.24 and 8.51, respectively. After IM and SC administration, the PK data were best described by a one-compartmental model with first-order absorption. The mean values of t1/2Kel , t1/2Ka , tmax (h), Cmax (μg/mL) and AUC (μg·h/mL) were corresponding 0.85, 0.14, 0.43, 4.83 and 8.24 for IM administration, 0.99, 0.29, 0.72, 3.88 and 9.13 for SC injection. The duration of time that drug levels exceed the MIC (%T > MIC) were calculated using the determined MIC90 (0.125 μg/mL) and the PK data obtained in this study. The results indicated that the dosage regimen of cefquinome at 2 mg/kg BW with 12-h intervals could achieve %T > MIC above 50% that generally produced a satisfactory bactericidal effect against E. coli isolated from dogs in this study. © 2015 John Wiley & Sons Ltd.

  17. Failing hospitals: mission statements to drive service improvement? (United States)

    McDonald, Annabel; Sarfraz, Aamer


    This paper aims to consider whether the hospital mission statement can be used as a management tool to improve service provision in failing hospitals. A literature search into the potential value and harm of hospital mission statements was done, followed by a survey of initial attitudes within a failing hospital. Do they indicate likely success of the tool? Mission statement is a potentially valuable leadership tool in the hospital environment. The success of its implementation is broadly dependent on its being developed with the support of stakeholders and its real application to all management decisions and questions of asset allocation. The potential danger lies in the fact that it can be seen as an expensive expression of politically correct platitudes which leads to cynical alienation of stakeholders. This was a small study within a single UK failing hospital, and extending its range will help to clarify whether its findings are typical of attitudes within such institutions. The likely success of the hospital mission statement as a management tool within a failing hospital is significantly limited by initial attitudes and preconceptions. Our research suggests that implementation is likely to be detrimental without preparatory involvement of the local community and hospital staff at all levels. Hospital management cannot be divorced from the local community where patient confidence must be maintained. This paper complements previous research, which has looked at mission statement acceptance among the upper echelons of hospital management.

  18. Valores, Creencias Y Objectivos: Base del programa de la Escuela Experimental P.K. Yonge. (Values, Beliefs and Objectives: The Basis of Experimental Schools P.K. Yonge's Program.) (United States)

    Florida Univ., Gainesville. Coll. of Education.

    The values, beliefs, and objectives that form the core of the program at the Experimental School P.K. Yonge in the University of Florida are presented in this paper which is written in Spanish. This experimental school serves approximately 900 students from grades one through twelve. The function of the school is to conduct research to solve…

  19. Effect of α1-adrenergic stimulation on phosphoinositide metabolism and protein kinase C (PK-C) in rat cardiomyocytes

    International Nuclear Information System (INIS)

    Kaku, T.; Lakatta, E.; Filburn, C.R.


    Alpha 1 -adrenergic stimulation is known to enhance membrane phospholipid metabolism resulting in increases in inositol phosphates (IP's) and diacylglycerol (DAG). Cardiomyocytes prelabeled with 3 H-myo-inositol were treated with norepinephrine (NE) for 1-15 min, acid extracted, and IP's separated by ion exchange chromatography. Addition of NE (10 -5 M) in the presence of propranolol (10 -5 M) and LiCl (9 mM) enhanced the accumulation of IP's, linearly with time up to 15 min, and reached 7.3, and 1.5-fold at 15 min for IP 1 , IP 2 , and IP 3 , respectively. KCl at 30 mM had no effect on accumulation of IP's, but augmented the effect of NE. PK-C activity was measured in both cytosol (S) and particulate (P) fractions of treated cells. NE alone had a negligible effect on membrane PK-C, while 30 mM KCl caused a small increase. However, pretreatment with KCl followed by NE produced a significant increase above that seen with KCl alone. Dioctanoylglycerol also stimulated membrane association of PK-C in these cells. These data suggest that α 1 -adrenergic stimulation of membrane association of myocardial PK-C is mediated by DAG but may be dependent on membrane potential and/or the extent of Ca 2+ loading


    Directory of Open Access Journals (Sweden)

    Muhammad Fauzan


    Full Text Available This research related to the implementation of good governance, free from corruption, collusion and nepotism. The approach used in this research is a descriptive qualitative approach. The Location of research conducted in the District of Pemalang. Based on the research results can presented that the District of Pemalang is committed and fully supports the government policy in eradicating corruption. District of Pemalang support to efforts to more information accelerate the eradication of corruption stated in the the Regional Action Plan to Accelerate the Eradication of Corruption (RAD-PK in 2011 -2016 which refers to the Medium Term Development Plan (RPJM District of Pemalang from 2011 to 2016 and the National Action Plan for Eradication of Corruption (RAN-PK and the President of Republic of Indonesia Instruction No. 5 Year 2004 on Accelerating the eradication of corruption. RAD-PK 2011-2016 District of Pemalang is a document that contains an action program that aims to accelerate the eradication of corruption. RAD-PK as a program of action containing concrete measures that have been agreed by the stakeholders in the area, so it has been a commitment of local governments prevention efforts corruption through the development of programs and activities aimed at improving public services and the application of the principles of good governance.

  1. The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections. (United States)

    Tängdén, T; Ramos Martín, V; Felton, T W; Nielsen, E I; Marchand, S; Brüggemann, R J; Bulitta, J B; Bassetti, M; Theuretzbacher, U; Tsuji, B T; Wareham, D W; Friberg, L E; De Waele, J J; Tam, V H; Roberts, Jason A


    Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.

  2. 75 FR 39224 - PK Ventures, Inc.; Notice of Intent To File License Application, Filing of Pre-Application... (United States)


    ...: Robert L Rose, President, P.O. Box 35236, Sarasota, FL 34242; (941) 312-0303; e-mail_ [email protected] i. FERC Contact: Sean Murphy at (202) 502-6145; or e-mail at . j. PK...

  3. Identification of RFLP and NBS/PK profiling markers for disease resistance loci in genetic maps of oats

    NARCIS (Netherlands)

    Sanz, M.J.; Loarce, Y.; Fominaya, A.; Vossen, J.H.; Ferrer, E.


    Two of the domains most widely shared among R genes are the nucleotide binding site (NBS) and protein kinase (PK) domains. The present study describes and maps a number of new oat resistance gene analogues (RGAs) with two purposes in mind: (1) to identify genetic regions that contain R genes and (2)

  4. Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor. (United States)

    Kakkar, Tarundeep; Sung, Cynthia; Gibiansky, Leonid; Vu, Thuy; Narayanan, Adimoolam; Lin, Shao-Lee; Vincent, Michael; Banfield, Christopher; Colbert, Alex; Hoofring, Sarah; Starcevic, Marta; Ma, Peiming


    For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.

  5. Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease. (United States)

    Chen, Xiaoying; Farrokhi, Vahid; Singh, Pratap; Ocana, Mireia Fernandez; Patel, Jenil; Lin, Lih-Ling; Neubert, Hendrik; Brodfuehrer, Joanne


    Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application. This model incorporates experimental biomeasures, including concentration of soluble Fn14 (sFn14) in human plasma and membrane Fn14 (mFn14) in human kidney tissue, and turnover rate of human sFn14. Pulse-chase studies using stable isotope-labeled amino acids and mass spectrometry indicated the sFn14 half-life to be approximately 5 hours in healthy volunteers. The biomeasures (concentration, turnover) of sFn14 in plasma reveals a significant hurdle in designing an antibody against Fn14 with desired characteristics. The projected dose (>1 mg/kg/wk for 90% target coverage) derived from the human PK/PD model revealed potential high and frequent dosing requirements under certain conditions. The PK/PD model suggested a unique bell-shaped relationship between target coverage and antibody affinity for anti-Fn14 mAb, which could be applied to direct the antibody engineering towards an optimized affinity. This investigation highlighted potential applications, including assessment of PK/PD risks during early target validation, human dose prediction and drug candidate optimization.

  6. Efficacy of repeated 5-fluorouracil needling for failing and failed filtering surgeries based on simple gonioscopic examination

    Directory of Open Access Journals (Sweden)

    Rashad MA


    Full Text Available Mohammad A RashadOphthalmology Department, Faculty of Medicine, Ain Shams University, Cairo, EgyptPurpose: To evaluate the success rate of a modified bleb needling technique in eyes with previous glaucoma surgery that had elevated intraocular pressure.Methods: A retrospective study of 24 eyes of 24 patients that underwent repeated bleb needling performed for failing and failed blebs on slit lamp with 5-fluorouracil (5-FU injections on demand. This was performed after gonioscopic examination to define levels of filtration block.Results: There was significant reduction of mean IOP from 36.91 mmHg to 14.73 mmHg at the final follow-up (P < 0.001. The overall success rate was 92%.Conclusion: Repeated needling with adjunctive 5-FU proved a highly effective, safe alternative to revive filtration surgery rather than another medication or surgery.Keywords: bleb, failure, 5-FU, needling, gonioscopy

  7. Arthroscopic deepening trochleoplasty for chronic anterior knee pain after previous failed conservative and arthroscopic treatment. Report of two cases. (United States)

    Blønd, Lars


    A proportion of patients having years of chronic anterior knee pain(AKP) that have not responded to non-operative modalities. Trochlear dysplasia have been found to be a cause for AKP. By restoring the anatomy with a trochleoplasty procedure the patellofemoral joint is unloaded. This study is a prospective 2year follow-up study, based on two cases with chronic AKP for several years and having severe trochlear dysplasia and both were successfully treated by arthroscopic deepening trochleoplasty. Case one was a 46year old women with chronic anterior knee pain (AKP). Imaging showed lateral trochlear inclination angle of 2°, trochlear asymmetry 0.36, central height 81% and medial height 83%. Thepreoperative Kujala score was 70 and Knee injury and Osteoarthritis Outcome Score (KOOS) subscale for pain was 67. Case two was a 26year old man troubled by AKP and knee knee joint effusion for >8years without any instability in the history. Imaging showed lateral trochlear inclination angle of 6°, trochlear asymmetry 0.25, central height 76% and medial height 78%. The preoperative Kujala score was 49 and KOOS subscale for pain was 72. The postoperative Kujala score was for case one 82 and for case two 81. The postoperative KOOS subscale for pain was for case one 89 and for case two 92. Improvement in the KOOS subscale for sport and recreational activities and quality of living were also found. This is the first case report to demonstrate that patient having had years of chronic AKP and trochlear dysplasia can be successfully treated by arthroscopic trochleoplasty. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  8. Amnioinfusion for women with a singleton breech presentation and a previous failed external cephalic version: a randomized controlled trial. (United States)

    Diguisto, Caroline; Winer, Norbert; Descriaud, Celine; Tavernier, Elsa; Weymuller, Victoire; Giraudeau, Bruno; Perrotin, Franck


    Our trial aimed to assess the effectiveness of amnioinfusion for a second attempt at external cephalic version (ECV). This open randomized controlled trial was planned with a sequential design. Women at a term ≥36 weeks of gestation with a singleton fetus in breech presentation and a first unsuccessful ECV were recruited in two level-3 maternity units. They were randomly allocated to transabdominal amnioinfusion with a 500-mL saline solution under ultrasound surveillance or no amnioinfusion before the second ECV attempt. Trained senior obstetricians performed all procedures. The primary outcome was the cephalic presentation rate at delivery. Analyses were conducted according to intention to treat (NCT00465712). Recruitment difficulties led to stopping the trial after a 57-month period, 119 women were randomized: 59 allocated to amnioinfusion + ECV and 60 to ECV only. Data were analyzed without applying the sequential feature of the design. The rate of cephalic presentation at delivery did not differ significantly according to whether the second version attempt was or was not preceded by amnioinfusion (20 versus 12%, p = .20). Premature rupture of the membranes occurred for 15% of the women in the amnioinfusion group. Amnioinfusion before a second attempt to external version does not significantly increase the rate of cephalic presentation at delivery.

  9. Why Do Large Infrastructure Projects Often Fail?

    DEFF Research Database (Denmark)

    Lando, Henrik

    The paper reports, in a systematic manner, the views of a group of experienced practitioners on why large infrastructure projects often fail. The views, centering on the role played by the Owner (the Client or Buyer), can be summarized as follows:The owner should be aware of the need of clarity...... elements in securing successful projects....

  10. Systems with randomly failing repairable components

    DEFF Research Database (Denmark)

    Der Kiureghian, Armen; Ditlevsen, Ove Dalager; Song, Junho


    Closed-form expressions are derived for the steady-state availability, mean rate of failure, mean duration of downtime and reliability of a general system with randomly and independently failing repairable components. Component failures are assumed to be homogeneous Poisson events in time and rep...

  11. Log-binomial models: exploring failed convergence. (United States)

    Williamson, Tyler; Eliasziw, Misha; Fick, Gordon Hilton


    Relative risk is a summary metric that is commonly used in epidemiological investigations. Increasingly, epidemiologists are using log-binomial models to study the impact of a set of predictor variables on a single binary outcome, as they naturally offer relative risks. However, standard statistical software may report failed convergence when attempting to fit log-binomial models in certain settings. The methods that have been proposed in the literature for dealing with failed convergence use approximate solutions to avoid the issue. This research looks directly at the log-likelihood function for the simplest log-binomial model where failed convergence has been observed, a model with a single linear predictor with three levels. The possible causes of failed convergence are explored and potential solutions are presented for some cases. Among the principal causes is a failure of the fitting algorithm to converge despite the log-likelihood function having a single finite maximum. Despite these limitations, log-binomial models are a viable option for epidemiologists wishing to describe the relationship between a set of predictors and a binary outcome where relative risk is the desired summary measure. Epidemiologists are encouraged to continue to use log-binomial models and advocate for improvements to the fitting algorithms to promote the widespread use of log-binomial models.

  12. I Failed the edTPA (United States)

    Kuranishi, Adam; Oyler, Celia


    In this article, co-written by a teacher and a professor, the authors examine possible explanations for why Adam (first author), a New York City public school special educator, failed the edTPA, a teacher performance assessment required by all candidates for state certification. Adam completed a yearlong teaching residency where he was the special…

  13. Underachievement, Failing Youth and Moral Panics (United States)

    Smith, Emma


    This paper considers contemporary "moral panics" around the underachievement of boys in school examinations in the UK and America. In the UK, in particular, the underachievement of boys is central to current "crisis accounts" about falling standards and failing pupils. "Underachievement" is a familiar word to those…

  14. Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies (United States)


    Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure–activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17–0.0072 μM against H37Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (RifR and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (RifR and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development. PMID:26487909

  15. Critical thinking: are the ideals of OBE failing us or are we failing the ...

    African Journals Online (AJOL)

    Critical thinking: are the ideals of OBE failing us or are we failing the ideals of OBE? K Lombard, M Grosser. Abstract. No Abstract. South African Journal of Education Vol. 28 (4) 2008: pp. 561-580. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT.

  16. Semi quantification study of [{sup 11}C]-(R)-PK11195 PET brain images in multiple sclerosis; Estudo da semiquantificacao de imagens PET cerebrais de [{sup 11}C]-(R)-PK11195 na esclerose multipla

    Energy Technology Data Exchange (ETDEWEB)

    Narciso, Lucas D.L.; Schuck, Phelipi N.; Dartora, Caroline M.; Matushita, Cristina S.; Becker, Jefferson; Silva, Ana M. Marques da, E-mail: [Pontificia Universidade Catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil)


    PET brain images with [{sup 11}C]-(R)-PK11195 are being widely used to visualize microglial activation in vivo in neuro degenerative diseases, such as multiple sclerosis (MS). The aim of this study is to investigate the uptake behavior in justacortical and periventricular regions of [{sup 11}C]-(R)-PK11195 PET brain images reformatted in different time intervals by applying three methods, seeking method and time interval that significantly differentiate MS patients from healthy controls. Semi-quantitative SUV and uptake relative to a reference region methods were applied to PET images from different time intervals acquired from 10 patients with MS and 5 healthy controls. The results show significant SUV values difference (p = 0.01, 40 to 60 min) in justacortical and periventricular regions between groups and using the normalization method in which the uptake is relative to the mean concentration activity in the white matter (p <0.01, 10 to 60 min). (author)

  17. Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling

    DEFF Research Database (Denmark)

    Bodenlenz, Manfred; Höfferer, Christian; Magnes, Christoph


    BACKGROUND: Methodologies for continuous sampling of lipophilic drugs and high-molecular solutes in the dermis are currently lacking. We investigated the feasibility of sampling a lipophilic topical drug and the locally released biomarker in the dermis of non-lesional and lesional skin of psoriatic......OFM sampling was performed for 25 h from each site on day 1 and day 8. Patients were mobile as dOFM probes were operated by a novel light-weight push-pull pump. Ultrasound was used to verify intradermal probe placement, cap-LC-MS/MS for BCT194 and ELISA for TNFα analysis. RESULTS: dOFM was well tolerated......-channel pumps allowed prolonged intradermal PK/PD profiling of a lipophilic topical drug in psoriatic patients. This initial study shows that dOFM overcomes limitations of microdialysis sampling methodology, and it demonstrates the potential for PK/PD studies of topical products and formulations in a clinical...

  18. Rasagiline prevents cyclosporine A-sensitive superoxide flashes induced by PK11195, the initial signal of mitochondrial membrane permeabilization and apoptosis. (United States)

    Wu, Yuqiu; Shamoto-Nagai, Masayo; Maruyama, Wakako; Osawa, Toshihiko; Naoi, Makoto


    Rasagiline, a neuroprotective inhibitor of type B monoamine oxidase, prevented PK111195-induced apoptosis in SH-SY5Y cells through inhibition of mitochondrial apoptosis signaling (J Neural Transm 120:1539-1551, 2013, J Neural Transm 122:1399-1407, 2015). This paper presents that PK11195 induced superoxide flashes, the transit production burst, mediated by cyclosporine A-sensitive membrane permeability transition. Rasagiline prevented superoxide flashes, calcium efflux, and cell death by PK11195. Regulation of the initial pore formation at the inner mitochondrial membrane was confirmed as the decisive mechanism of neuroprotection by rasagiline.

  19. Dual Identification and Analysis of Differentially Expressed Transcripts of Porcine PK-15 Cells and Toxoplasma gondii during in vitro Infection

    Directory of Open Access Journals (Sweden)

    Chun-Xue eZhou


    Full Text Available Toxoplasma gondii is responsible for causing toxoplasmosis, one of the most prevalent zoonotic parasitoses worldwide. The mechanisms that mediate T. gondii infection of pigs (the most common source of human infection and renal tissues are still unknown. To identify the critical alterations that take place in the transcriptome of both porcine kidney (PK-15 cells and T. gondii following infection, infected cell samples were collected at 1, 3, 6, 9, 12, 18, and 24 h post infection and RNA-Seq data were acquired using Illumina Deep Sequencing. Differential Expression of Genes (DEGs analysis was performed to study the concomitant gene-specific temporal patterns of induction of mRNA expression of PK-15 cells and T. gondii. High sequence coverage enabled us to thoroughly characterize T. gondii transcriptome and identify the activated molecular pathways in host cells. More than 6G clean bases/ sample, including > 40 million clean reads were obtained. These were aligned to the reference genome of T. gondii and wild boar (Sus scrofa. DEGs involved in metabolic activities of T. gondii showed time-dependent down-regulation. However, DEGs involved in immune or disease related pathways of PK-15 cells peaked at 6 h PI, and were highly enriched as evidenced by KEGG analysis. Protein-protein interaction analysis revealed that TGME49_120110 (PCNA, TGME49_049180 (DHFR-TS, TGME49_055320 and TGME49_002300 (ITPase are the four hub genes with most interactions with T. gondii at the onset of infection. These results reveal altered profiles of gene expressed by PK-15 cells and T. gondii during infection and provide the groundwork for future virulence studies to uncover the mechanisms of T. gondii interaction with porcine renal tissue by functional analysis of these DEGs.

  20. Effects on field- and bottom-layer species in an experiment with repeated PK- and NPK-fertilization

    International Nuclear Information System (INIS)

    Nohrstedt, H.Oe.


    Long-term changes in forest ground vegetation because of repeated PK- and NPK-fertilization were examined in an old field experiment, located in a 85-year-old Pinus sylvestris stand in northern Sweden. Fertilizers were added at 5-(PK, NPK) or 10-(PK) year intervals, beginning 26 years prior to the study. The treatments were tested in two replicates on plots sized 40 x 40 m. The total doses added were N 720 kg/ha, P 222-380 kg/ha and K 318-620 kg/ha. N was given as ammonium nitrate, P as superphosphate and K as potassium chloride. The vegetation on control plots was of the Vaccinium vitis-idaea type. The field layer was dominated by V.vitis-idaea and V.myrtillus, and the bottom layer by Pleurozium schreberi. The effect of fertilization was quantified by examining the areal cover of individual species. This was done in 25 0.25 m 2 frames systematically placed in a grid over each treatment plot. The only pronounced effect in the field layer was on V.myrtillus. The cover was strongly reduced by fertilization with PK. The reduction was 70% for the 5-year interval and 34% for the 10-year interval. The cover more than doubled after NPK-fertilization. Among the cryptogams, a reduction in cover was indicated for Cladina arbuscula and C.rangiferina because of fertilization with NPK. NPK reduced the number of species that were found, totally depending on negative effects on several lichen species. For species absent in the examined frame areas but present somewhere else on the treatment plots, it was seen that Deschampsia flexuosa increased after NPK-fertilization, while Peltigera apthosa and Steroecaulon tomentosum decreased. Hylocomium splendens occurred on both control plots, but only on one fertilized plot. 30 refs, 1 fig, 5 tabs

  1. Effects on field- and bottom-layer species in an experiment with repeated PK- and NPK-fertilization

    Energy Technology Data Exchange (ETDEWEB)

    Nohrstedt, H.Oe.


    Long-term changes in forest ground vegetation because of repeated PK- and NPK-fertilization were examined in an old field experiment, located in a 85-year-old Pinus sylvestris stand in northern Sweden. Fertilizers were added at 5-(PK, NPK) or 10-(PK) year intervals, beginning 26 years prior to the study. The treatments were tested in two replicates on plots sized 40 x 40 m. The total doses added were N 720 kg/ha, P 222-380 kg/ha and K 318-620 kg/ha. N was given as ammonium nitrate, P as superphosphate and K as potassium chloride. The vegetation on control plots was of the Vaccinium vitis-idaea type. The field layer was dominated by V.vitis-idaea and V.myrtillus, and the bottom layer by Pleurozium schreberi. The effect of fertilization was quantified by examining the areal cover of individual species. This was done in 25 0.25 m[sup 2] frames systematically placed in a grid over each treatment plot. The only pronounced effect in the field layer was on V.myrtillus. The cover was strongly reduced by fertilization with PK. The reduction was 70% for the 5-year interval and 34% for the 10-year interval. The cover more than doubled after NPK-fertilization. Among the cryptogams, a reduction in cover was indicated for Cladina arbuscula and C.rangiferina because of fertilization with NPK. NPK reduced the number of species that were found, totally depending on negative effects on several lichen species. For species absent in the examined frame areas but present somewhere else on the treatment plots, it was seen that Deschampsia flexuosa increased after NPK-fertilization, while Peltigera apthosa and Steroecaulon tomentosum decreased. Hylocomium splendens occurred on both control plots, but only on one fertilized plot. 30 refs, 1 fig, 5 tabs

  2. Vitamin E protects against the mitochondrial damage caused by cyclosporin A in LLC-PK1 cells

    International Nuclear Information System (INIS)

    Arriba, G. de; Perez de Hornedo, J.; Ramirez Rubio, S.; Calvino Fernandez, M.; Benito Martinez, S.; Maiques Camarero, M.; Parra Cid, T.


    Cyclosporin A (CsA) has nephrotoxic effects known to involve reactive oxygen species (ROS), since antioxidants prevent the kidney damage induced by this drug. Given that mitochondria are among the main sources of intracellular ROS, the aims of our study were to examine the mitochondrial effects of CsA in the porcine renal endothelial cell line LLC-PK1 and the influence of the antioxidant Vitamin E (Vit E). Following the treatment of LLC-PK1 cells with CsA, we assessed the mitochondrial synthesis of superoxide anion, permeability transition pore opening, mitochondrial membrane potential, cardiolipin peroxidation, cytochrome c release and cellular apoptosis, using flow cytometry and confocal microscopy procedures. Similar experiments were done after Vit E preincubation of cells. CsA treatment increased superoxide anion in a dose-dependent way. CsA opened the permeability transition pores, caused Bax migration to mitochondria, and decreased mitochondrial membrane potential and cardiolipin content. Also CsA released cytochrome c into cytosol and provoked cellular apoptosis. Vit E pretreatment inhibited the effects that CsA induced on mitochondrial structure and function in LLC-PK1 cells and avoided apoptosis. CsA modifies mitochondrial LLC-PK1 cell physiology with loss of negative electrochemical gradient across the inner mitochondrial membrane and increased lipid peroxidation. These features are related to apoptosis and can explain the cellular damage that CsA induces. As Vit E inhibited these effects, our results suggest that they were mediated by an increase in ROS production by mitochondria.

  3. Porcine parvovirus infection induces apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Hongling; Huang, Yong; Du, Qian; Luo, Xiaomao; Zhang, Liang; Zhao, Xiaomin; Tong, Dewen, E-mail:


    Highlights: • PPV reduces PK-15 cells viability by inducing apoptosis. • PPV infection induces apoptosis through mitochondria-mediated pathway. • PPV infection activates p53 to regulate the mitochondria apoptotic signaling. - Abstract: Porcine parvovirus (PPV) infection has been reported to induce the cytopathic effects (CPE) in some special host cells and contribute the occurrence of porcine parvovirus disease, but the molecular mechanisms underlying PPV-induced CPE are not clear. In this study, we investigated the morphological and molecular changes of porcine kidney cell line (PK-15 cells) infected with PPV. The results showed that PPV infection inhibited the viability of PK-15 cells in a time and concentration dependent manner. PPV infection induced typical apoptotic features including chromatin condensation, apoptotic body formation, nuclear fragmentation, and Annexin V-binding activity. Further studies showed that Bax was increased and translocated to mitochondria, whereas Bcl-2 was decreased in PPV-infected cells, which caused mitochondrial outer-membrane permeabilization, resulting in the release of mitochondrial cytochrome c, followed by caspase-9 and caspase-3 activation. However, the expression of Fas and Fas ligand (FasL) did not appear significant changes in the process of PPV-induced apoptosis. Moreover, PPV infection activated p53 signaling, which was involved in the activation of apoptotic signaling induced by PPV infection via regulation of Bax and Bcl-2. Taken together, our results demonstrated that PPV infection induced apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated apoptosis pathway. This study may contribute to shed light on the molecular pathogenesis of PPV infection.

  4. Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4 to enhance solubility for injection delivery

    Directory of Open Access Journals (Sweden)

    Fang YP


    Full Text Available Yi-Ping Fang,1 Pao-Chu Wu,2 Yaw-Bin Huang,3 Cherng-Chyi Tzeng,4 Yeh-Long Chen,4 Yu-Han Hung,2 Ming-Jun Tsai,5,6 Yi-Hung Tsai31Department of Biotechnology, Yuanpei University, Hsinchu, Taiwan; 2School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Graduate Institute of Clinical Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 4School of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Neurology, China Medical University Hospital, Taichung, Taiwan; 6School of Medicine, Medical College, China Medical University, Taichung, TaiwanBackground: The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenylamino]furo[2,3-b]quinoline (PK-L4 is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection.Aims: To utilize solid lipid nanoparticles (SLNs modified with polyethylene glycol (PEG to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration.Results: The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE% of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%–64% in the human lung carcinoma cell line (A549, 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7, and 95% in

  5. Analysis of failed nuclear plant components

    International Nuclear Information System (INIS)

    Diercks, D.R.


    Argonne National Laboratory has conducted analyses of failed components from nuclear power generating stations since 1974. The considerations involved in working with and analyzing radioactive components are reviewed here, and the decontamination of these components is discussed. Analyses of four failed components from nuclear plants are then described to illustrate the kinds of failures seen in service. The failures discussed are (a) intergranular stress corrosion cracking of core spray injection piping in a boiling water reactor, (b) failure of canopy seal welds in adapter tube assemblies in the control rod drive head of a pressure water reactor, (c) thermal fatigue of a recirculation pump shaft in a boiling water reactor, and (d) failure of pump seal wear rings by nickel leaching in a boiling water reactor

  6. Recommended protocol for failed back surgery syndrome

    Directory of Open Access Journals (Sweden)

    Fakhr Tabatabaei SA


    Full Text Available Failed back surgery syndrome (FBSS is many a times an intractable problem confronted in patients with surgical disease of lumbar spine and at the same time is a pressing problem for the physicians as well. This clinical entity is defined as continuation of pain in the lumbar region and lower extremities following surgery of the lumbar spine. Knowledge of the etiological factors and their prevention is the best line of treatment to overcome the evolution of this syndrome. During this study, which was conducted in Imam Khomeini hospital Tehran from the year 1989 till 1990, 43 out of 114 patients developed "FBSS". 23 cases responded to conservative treatment and psychotherapy whereas medical treatment failed to achieve fruitful results in the rest. The latter underwent extensive radiological investigations and repeat surgery. According to this study, we recommend that in the initial management of these patients. The surgeon should observe the dictum of "5-mis" to overcome and minimize the "FBSS" entity

  7. Latest Results on Complex Plasmas with the PK-3 Plus Laboratory on Board the International Space Station (United States)

    Schwabe, M.; Du, C.-R.; Huber, P.; Lipaev, A. M.; Molotkov, V. I.; Naumkin, V. N.; Zhdanov, S. K.; Zhukhovitskii, D. I.; Fortov, V. E.; Thomas, H. M.


    Complex plasmas are low temperature plasmas that contain microparticles in addition to ions, electrons, and neutral particles. The microparticles acquire high charges, interact with each other and can be considered as model particles for effects in classical condensed matter systems, such as crystallization and fluid dynamics. In contrast to atoms in ordinary systems, their movement can be traced on the most basic level, that of individual particles. In order to avoid disturbances caused by gravity, experiments on complex plasmas are often performed under microgravity conditions. The PK-3 Plus Laboratory was operated on board the International Space Station from 2006 - 2013. Its heart consisted of a capacitively coupled radio-frequency plasma chamber. Microparticles were inserted into the low-temperature plasma, forming large, homogeneous complex plasma clouds. Here, we review the results obtained with recent analyzes of PK-3 Plus data: We study the formation of crystallization fronts, as well as the microparticle motion in, and structure of crystalline complex plasmas. We investigate fluid effects such as wave transmission across an interface, and the development of the energy spectra during the onset of turbulent microparticle movement. We explore how abnormal particles move through, and how macroscopic spheres interact with the microparticle cloud. These examples demonstrate the versatility of the PK-3 Plus Laboratory.

  8. Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity

    International Nuclear Information System (INIS)

    Dittmann, Klaus; Mayer, Claus; Rodemann, Hans-Peter


    Background and purpose: Inhibition of EGFR-function can induce radiosensitization in tumor cells. Purpose of our investigation was to identify the possible molecular mechanism of radiosensitization following treatment with anti-EGFR-antibody C225 (Cetuximab). Materials and methods: The effect of C225 on radiation response was determined in human cell lines of bronchial carcinoma (A549) and breast adenoma cells (MDA MB 231). The molecular effects of C225 on EGFR-function after irradiation were analyzed applying western blotting, immune-precipitation and kinase assays. Effects on DNA-repair were detected by quantification of γ-H2AX positive foci 24 h after irradiation. Results: The EGFR specific antibody C225 induced radiosensitization in A549 and also in MDA MB 231 cells. Radiosensitization in A549 was associated with blockage of radiation-induced EGFR transport into the nucleus, and immobilized the complex of EGFR with DNA-dependent protein kinase (DNA-PK) in the cytoplasm. As a consequence radiation-induced DNA-PK activation was abolished, a process that is essential for DNA-repair after radiation exposure. Likewise C225 treatment increased the residual amount of γ-H2AX-positive foci 24 h after irradiation in A549 and in MDA MB 231 cells. Conclusions: Our results suggest that irradiation induced DNA-PK activation-essential for DNA repair-may be hampered specifically by use of the anti-EGFR-antibody C225. This process is associated with radiosensitization

  9. Protective effect of α-mangostin against iodixanol-induced apoptotic damage in LLC-PK1 cells. (United States)

    Lee, Dahae; Choi, Young Ok; Kim, Ki Hyun; Chin, Young-Won; Namgung, Hojin; Yamabe, Noriko; Jung, Kiwon


    Radiographic contrast media facilitate the visibility of internal body structures, but its use to patients with lowered renal function needs to be careful because of severe side effect in kidney. The present study aims to evaluate potential protective effect and mechanism of Alpha mangostin (α-mangostin) against contrast-induced apoptotic damage in LLC-PK1 cells. As a result, α-mangostin in non-toxic concentrations improved the viability of the iodixanol-treated cells up to 90.42% against contrast-induced damage in LLC-PK1 cells. Iodixanol treatment increased the phosphorylation of p38, ERK and cleavage of caspase-3 in LLC-PK1 cells, which were significantly decreased by co-treatment with α-mangostin (2.5 and 5μM). The protective effect of α-mangostin on contrast-induced apoptotic damage was mediated by the inhibition of MAPKs and caspase activation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Aged garlic extract induces proliferation and ameliorates gentamicin-induced toxicity in LLC-PK1 cells. (United States)

    Velasco-Velázquez, Marco A; Maldonado, Perla D; Barrera, Diana; Torres, Víctor; Zentella-Dehesa, Alejandro; Pedraza-Chaverrí, José


    Gentamicin (GM)-induced nephrotoxicity limits the use of this antibiotic. It has been shown that aged garlic extract (AGE) and S-allylcysteine (SAC), the most abundant organosulfur compound in AGE, ameliorate GM-induced nephrotoxicity in rats. The present communication evaluated the effect of AGE and SAC on proliferation and on GM-induced toxicity and genotoxicity of porcine kidney epithelial cell line (LLC-PK1 cells). The cells were preincubated with different concentrations of AGE or SAC for 12 h before incubation with 8 mm GM for an additional 72 h. At the end of this time, cell viability, genotoxicity and proliferation were evaluated. AGE stimulated cell proliferation and protected LLC-PK1 cells from GM-mediated toxicity and genotoxicity. SAC partially prevented only GM-induced genotoxicity. These results suggest that the stimulation of cell proliferation could possibly be one of the mechanisms involved in the in vitro protective effect of AGE in GM-induced toxicity of LLC-PK1 cells. Copyright 2006 John Wiley & Sons, Ltd.

  11. Removal of failed crown and bridge


    Sharma, Ashu; Rahul, G.R.; Poduval, Soorya T.; Shetty, Karunakar


    Crown and bridge have life span of many years but they fail for a number of reasons. Over the years, many devices have been designed to remove crowns and bridges from abutment teeth. While the removal of temporary crowns and bridges is usually very straightforward, the removal of a definitive cast crown with unknown cement is more challenging. Removal is often by destructive means. There are a number of circumstances, however, in which conservative disassembly would aid the practitioner in co...

  12. Mexico: Failing State or Emerging Democracy? (United States)


    argue that President Calderón’s current counter-drug strategy actually triggered the displacement of malign actors throughout Mexico by aggravating...increasing violence in Mexico along the nearly 2,000-mile long U.S. southern border as greater than Iraq and on par with Iran as the greatest...USJFCOM), said either Mexico or Pakistan were “worst case scenarios” for U.S. national security should either nation rapidly fail or collapse.2 Tension

  13. FidFail: Coverage and Precision Enhancement (United States)


    command line argument optionally disables static field analysis in order to reduce DidFail’s memory usage and analysis time. These new features make...unanalyzed taint flows. Finally, a new command line argument optionally disables static field analysis in order to reduce DidFail’s memory usage of the apps has permission for. Unknown to the Android user, sensitive data could be exfiltrated to the Internet , if an app with permission to

  14. Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). (United States)

    Joerger, M; von Pawel, J; Kraff, S; Fischer, J R; Eberhardt, W; Gauler, T C; Mueller, L; Reinmuth, N; Reck, M; Kimmich, M; Mayer, F; Kopp, H-G; Behringer, D M; Ko, Y-D; Hilger, R A; Roessler, M; Kloft, C; Henrich, A; Moritz, B; Miller, M C; Salamone, S J; Jaehde, U


    Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. NCT01326767 ( © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:

  15. Revision of the Failed Thumb Carpometacarpal Arthroplasty. (United States)

    Papatheodorou, Loukia K; Winston, Jonathan D; Bielicka, Deidre L; Rogozinski, Benjamin J; Lourie, Gary M; Sotereanos, Dean G


    To evaluate the outcome of revision surgery for failed thumb carpometacarpal (CMC) arthroplasty. We retrospectively analyzed 32 patients with failed thumb CMC arthroplasty. The primary reason for revision was pain caused by metacarpal subsidence. Revision surgery included soft tissue interposition and distraction pinning to address the metacarpal subsidence. Additional ligament reconstruction was performed in patients with thumb instability. Eight patients required additional metacarpophalangeal joint fusion for concomitant joint hyperextension. Eleven required additional partial excision of the trapezoid for concomitant scaphotrapezoidal joint arthritis. All patients were evaluated clinically and radiographically. Mean follow-up was 57 months (range, 24-121 months). Pain levels evaluated by visual analog scale were significantly reduced in all patients after revision surgery. Mean grip strength and key pinch strength significantly increased. Twenty-seven patients achieved good functional results; those for 5 patients were fair. This study showed that revision surgery with distraction pinning and soft tissue interposition with or without ligament reconstruction was an effective treatment for failed CMC arthroplasty of the thumb. Therapeutic IV. Copyright © 2017 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  16. Implant failure and history of failed endodontic treatment: A retrospective case-control study


    Chatzopoulos, Georgios S.; Wolff, Larry F.


    Background Residual bacterial biofilm and/or bacteria in planktonic form may be survived in the bone following an extraction of an infected tooth that was endodontically treated unsuccessfully Failed endodontic treatment may be associated with failure of implants to osseointegrate in the same sites. Therefore, the aim of this retrospective case-control study is to examine the risk of implant failure in previous failed endodontic sites. Material and Methods This retrospective case-control stud...

  17. The Failed Image and the Possessed

    DEFF Research Database (Denmark)

    Suhr, Christian


    This article asks if the recurrent queries regarding the value of images in visual anthropology could find new answers by exploring responses to visual media in neo-orthodox Islam. It proposes that the visual display of the photographic image shares a curious resemblance to the bodies of people...... possessed by invisible spirits called jinn. The image as a failed example or model of reality works like the possessed body as an amplifier of invisibility pointing towards that which cannot be seen, depicted visually, or represented in writing. This suggests a negative epistemology in which images obtain...

  18. PK-PD Integration Modeling and Cutoff Value of Florfenicol against Streptococcus suis in Pigs. (United States)

    Lei, Zhixin; Liu, Qianying; Yang, Shuaike; Yang, Bing; Khaliq, Haseeb; Li, Kun; Ahmed, Saeed; Sajid, Abdul; Zhang, Bingzhou; Chen, Pin; Qiu, Yinsheng; Cao, Jiyue; He, Qigai


    The aims of the present study were to establish optimal doses and provide an alternate CO PD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w.) were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of C max , AUC 0-24h , AUC, Ke, t 1/2ke , MRT, T max, and Cl b , were estimated as 4.44 μg/ml, 88.85 μg⋅h/ml, 158.56 μg⋅h/ml, 0.048 h -1 , 14.46 h, 26.11 h, 4 h and 0.185 L/h⋅kg, respectively. The bioavailability of florfenicol was calculated to be 99.14% after I.M administration. A total of 124 Streptococcus suis from most cities of China were isolated to determine the minimum inhibitory concentration (MIC) of florfenicol. The MIC 50 and MIC 90 were calculated as 1 and 2 μg/ml. A serotype 2 Streptococcus suis (WH-2), with MIC value similar to MIC 90 , was selected as a representative for an in vitro and ex vivo pharmacodynamics study. The MIC values of WH-2 in TSB and plasma were 2 μg/ml, and the MBC/MIC ratios were 2 in TSB and plasma. The MPC was detected to be 3.2 μg/ml. According to inhibitory sigmoid E max model, plasma AUC 0-24h /MIC values of florfenicol versus Streptococcus suis were 37.89, 44.02, and 46.42 h for the bactericidal, bacteriostatic, and elimination activity, respectively. Monte Carlo simulations the optimal doses for bactericidal, bacteriostatic, and elimination effects were calculated as 16.5, 19.17, and 20.14 mg/kg b.w. for 50% target attainment rates (TAR), and 21.55, 25.02, and 26.85 mg/kg b.w. for 90% TAR, respectively. The PK-PD cutoff value (CO PD ) analyzed from MCS for florfenicol against Streptococcus suis was 1 μg/ml which could provide a sensitivity cutoff value. These results contributed an optimized alternative to clinical veterinary medicine and showed that the dose of 25.02 mg/kg florfenicol for 24 h could have a bactericidal action against

  19. PK-PD Integration Modeling and Cutoff Value of Florfenicol against Streptococcus suis in Pigs

    Directory of Open Access Journals (Sweden)

    Zhixin Lei


    Full Text Available The aims of the present study were to establish optimal doses and provide an alternate COPD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w. were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of Cmax, AUC0-24h, AUC, Ke, t1/2ke, MRT, Tmax, and Clb, were estimated as 4.44 μg/ml, 88.85 μg⋅h/ml, 158.56 μg⋅h/ml, 0.048 h-1, 14.46 h, 26.11 h, 4 h and 0.185 L/h⋅kg, respectively. The bioavailability of florfenicol was calculated to be 99.14% after I.M administration. A total of 124 Streptococcus suis from most cities of China were isolated to determine the minimum inhibitory concentration (MIC of florfenicol. The MIC50 and MIC90 were calculated as 1 and 2 μg/ml. A serotype 2 Streptococcus suis (WH-2, with MIC value similar to MIC90, was selected as a representative for an in vitro and ex vivo pharmacodynamics study. The MIC values of WH-2 in TSB and plasma were 2 μg/ml, and the MBC/MIC ratios were 2 in TSB and plasma. The MPC was detected to be 3.2 μg/ml. According to inhibitory sigmoid Emax model, plasma AUC0-24h/MIC values of florfenicol versus Streptococcus suis were 37.89, 44.02, and 46.42 h for the bactericidal, bacteriostatic, and elimination activity, respectively. Monte Carlo simulations the optimal doses for bactericidal, bacteriostatic, and elimination effects were calculated as 16.5, 19.17, and 20.14 mg/kg b.w. for 50% target attainment rates (TAR, and 21.55, 25.02, and 26.85 mg/kg b.w. for 90% TAR, respectively. The PK-PD cutoff value (COPD analyzed from MCS for florfenicol against Streptococcus suis was 1 μg/ml which could provide a sensitivity cutoff value. These results contributed an optimized alternative to clinical veterinary medicine and showed that the dose of 25.02 mg/kg florfenicol for 24 h could have a bactericidal action against

  20. A double-blind study of the efficacy and safety of the ICP10deltaPK vaccine against recurrent genital HSV-2 infections. (United States)

    Casanova, Gerardo; Cancela, Rosalia; Alonzo, Lourdes; Benuto, Rosa; Magana, Maria del Carmen; Hurley, Dennis R; Fishbein, Eugenia; Lara, Claudia; Gonzalez, Teresa; Ponce, Rebeca; Burnett, Joseph W; Calton, Gary J


    A randomized double-blind trial to evaluate the safety of a novel recombinant virus, ICP10deltaPK, for reduction or prevention of recurrent herpes simplex virus type 2 (HSV-2) infection was carried out in public hospitals in Mexico City. Persons having a minimum of 5 documented herpetic recurrences in the previous year were randomized for vaccination. Patients were examined within 72 hours of lesion occurrence. If accepted into the study, the patient was inoculated subcutaneously in the upper deltoid muscle area at days 7, 17, and 28 after initiation of lesion occurrence. Recurrences were recorded by patient diary and physician examination. During the observation period (extending from 10 to 180 days after the last booster dose), recurrences in the vaccine (V) group were prevented completely in 37.5% of the patients, whereas in the placebo (P) group, 100% of the patients had at least one recurrence (P = .068). Vaccinated patients had fewer recurrences (V, 1.58; P, 3.13 [P = .028]). The mean number of illness days was 10 for the vaccine group and 18 for the placebo group (P = .028). Further studies to evaluate this vaccine and its dosimetry for the treatment of genital herpes infections appear warranted.

  1. Observation of the Decays Λ_{b}^{0}→χ_{c1}pK^{-} and Λ_{b}^{0}→χ_{c2}pK^{-}. (United States)

    Aaij, R; Adeva, B; Adinolfi, M; Ajaltouni, Z; Akar, S; Albrecht, J; Alessio, F; Alexander, M; Ali, S; Alkhazov, G; Alvarez Cartelle, P; Alves, A A; Amato, S; Amerio, S; Amhis, Y; An, L; Anderlini, L; Andreassi, G; Andreotti, M; Andrews, J E; Appleby, R B; Archilli, F; d'Argent, P; Arnau Romeu, J; Artamonov, A; Artuso, M; Aslanides, E; Auriemma, G; Baalouch, M; Babuschkin, I; Bachmann, S; Back, J J; Badalov, A; Baesso, C; Baker, S; Balagura, V; Baldini, W; Baranov, A; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; Baryshnikov, F; Baszczyk, M; Batozskaya, V; Battista, V; Bay, A; Beaucourt, L; Beddow, J; Bedeschi, F; Bediaga, I; Beiter, A; Bel, L J; Bellee, V; Belloli, N; Belous, K; Belyaev, I; Ben-Haim, E; Bencivenni, G; Benson, S; Beranek, S; Berezhnoy, A; Bernet, R; Bertolin, A; Betancourt, C; Betti, F; Bettler, M-O; van Beuzekom, M; Bezshyiko, Ia; Bifani, S; Billoir, P; Birnkraut, A; Bitadze, A; Bizzeti, A; Blake, T; Blanc, F; Blouw, J; Blusk, S; Bocci, V; Boettcher, T; Bondar, A; Bondar, N; Bonivento, W; Bordyuzhin, I; Borgheresi, A; Borghi, S; Borisyak, M; Borsato, M; Bossu, F; Boubdir, M; Bowcock, T J V; Bowen, E; Bozzi, C; Braun, S; Britton, T; Brodzicka, J; Buchanan, E; Burr, C; Bursche, A; Buytaert, J; Cadeddu, S; Calabrese, R; Calvi, M; Calvo Gomez, M; Camboni, A; Campana, P; Campora Perez, D H; Capriotti, L; Carbone, A; Carboni, G; Cardinale, R; Cardini, A; Carniti, P; Carson, L; Carvalho Akiba, K; Casse, G; Cassina, L; Castillo Garcia, L; Cattaneo, M; Cavallero, G; Cenci, R; Chamont, D; Charles, M; Charpentier, Ph; Chatzikonstantinidis, G; Chefdeville, M; Chen, S; Cheung, S F; Chobanova, V; Chrzaszcz, M; Chubykin, A; Cid Vidal, X; Ciezarek, G; Clarke, P E L; Clemencic, M; Cliff, H V; Closier, J; Coco, V; Cogan, J; Cogneras, E; Cogoni, V; Cojocariu, L; Collins, P; Comerma-Montells, A; Contu, A; Cook, A; Coombs, G; Coquereau, S; Corti, G; Corvo, M; Costa Sobral, C M; Couturier, B; Cowan, G A; Craik, D C; Crocombe, A; Cruz Torres, M; Cunliffe, S; Currie, R; D'Ambrosio, C; Da Cunha Marinho, F; Dall'Occo, E; Dalseno, J; Davis, A; De Aguiar Francisco, O; De Bruyn, K; De Capua, S; De Cian, M; De Miranda, J M; De Paula, L; De Serio, M; De Simone, P; Dean, C T; Decamp, D; Deckenhoff, M; Del Buono, L; Dembinski, H-P; Demmer, M; Dendek, A; Derkach, D; Deschamps, O; Dettori, F; Dey, B; Di Canto, A; Di Nezza, P; Dijkstra, H; Dordei, F; Dorigo, M; Dosil Suárez, A; Dovbnya, A; Dreimanis, K; Dufour, L; Dujany, G; Dungs, K; Durante, P; Dzhelyadin, R; Dziewiecki, M; Dziurda, A; Dzyuba, A; Déléage, N; Easo, S; Ebert, M; Egede, U; Egorychev, V; Eidelman, S; Eisenhardt, S; Eitschberger, U; Ekelhof, R; Eklund, L; Ely, S; Esen, S; Evans, H M; Evans, T; Falabella, A; Farley, N; Farry, S; Fay, R; Fazzini, D; Ferguson, D; Fernandez, G; Fernandez Prieto, A; Ferrari, F; Ferreira Rodrigues, F; Ferro-Luzzi, M; Filippov, S; Fini, R A; Fiore, M; Fiorini, M; Firlej, M; Fitzpatrick, C; Fiutowski, T; Fleuret, F; Fohl, K; Fontana, M; Fontanelli, F; Forshaw, D C; Forty, R; Franco Lima, V; Frank, M; Frei, C; Fu, J; Funk, W; Furfaro, E; Färber, C; Gabriel, E; Gallas Torreira, A; Galli, D; Gallorini, S; Gambetta, S; Gandelman, M; Gandini, P; Gao, Y; Garcia Martin, L M; García Pardiñas, J; Garra Tico, J; Garrido, L; Garsed, P J; Gascon, D; Gaspar, C; Gavardi, L; Gazzoni, G; Gerick, D; Gersabeck, E; Gersabeck, M; Gershon, T; Ghez, Ph; Gianì, S; Gibson, V; Girard, O G; Giubega, L; Gizdov, K; Gligorov, V V; Golubkov, D; Golutvin, A; Gomes, A; Gorelov, I V; Gotti, C; Govorkova, E; Graciani Diaz, R; Granado Cardoso, L A; Graugés, E; Graverini, E; Graziani, G; Grecu, A; Greim, R; Griffith, P; Grillo, L; Gruber, L; Gruberg Cazon, B R; Grünberg, O; Gushchin, E; Guz, Yu; Gys, T; Göbel, C; Hadavizadeh, T; Hadjivasiliou, C; Haefeli, G; Haen, C; Haines, S C; Hamilton, B; Han, X; Hansmann-Menzemer, S; Harnew, N; Harnew, S T; Harrison, J; Hatch, M; He, J; Head, T; Heister, A; Hennessy, K; Henrard, P; Henry, L; van Herwijnen, E; Heß, M; Hicheur, A; Hill, D; Hombach, C; Hopchev, P H; Huard, Z-C; Hulsbergen, W; Humair, T; Hushchyn, M; Hutchcroft, D; Idzik, M; Ilten, P; Jacobsson, R; Jalocha, J; Jans, E; Jawahery, A; Jiang, F; John, M; Johnson, D; Jones, C R; Joram, C; Jost, B; Jurik, N; Kandybei, S; Karacson, M; Kariuki, J M; Karodia, S; Kecke, M; Kelsey, M; Kenzie, M; Ketel, T; Khairullin, E; Khanji, B; Khurewathanakul, C; Kirn, T; Klaver, S; Klimaszewski, K; Klimkovich, T; Koliiev, S; Kolpin, M; Komarov, I; Kopecna, R; Koppenburg, P; Kosmyntseva, A; Kotriakhova, S; Kozachuk, A; Kozeiha, M; Kravchuk, L; Kreps, M; Krokovny, P; Kruse, F; Krzemien, W; Kucewicz, W; Kucharczyk, M; Kudryavtsev, V; Kuonen, A K; Kurek, K; Kvaratskheliya, T; Lacarrere, D; Lafferty, G; Lai, A; Lanfranchi, G; Langenbruch, C; Latham, T; Lazzeroni, C; Le Gac, R; van Leerdam, J; Leflat, A; Lefrançois, J; Lefèvre, R; Lemaitre, F; Lemos Cid, E; Leroy, O; Lesiak, T; Leverington, B; Li, T; Li, Y; Li, Z; Likhomanenko, T; Lindner, R; Lionetto, F; Liu, X; Loh, D; Longstaff, I; Lopes, J H; Lucchesi, D; Lucio Martinez, M; Luo, H; Lupato, A; Luppi, E; Lupton, O; Lusiani, A; Lyu, X; Machefert, F; Maciuc, F; Maev, O; Maguire, K; Malde, S; Malinin, A; Maltsev, T; Manca, G; Mancinelli, G; Manning, P; Maratas, J; Marchand, J F; Marconi, U; Marin Benito, C; Marinangeli, M; Marino, P; Marks, J; Martellotti, G; Martin, M; Martinelli, M; Martinez Santos, D; Martinez Vidal, F; Martins Tostes, D; Massacrier, L M; Massafferri, A; Matev, R; Mathad, A; Mathe, Z; Matteuzzi, C; Mauri, A; Maurice, E; Maurin, B; Mazurov, A; McCann, M; McNab, A; McNulty, R; Meadows, B; Meier, F; Melnychuk, D; Merk, M; Merli, A; Michielin, E; Milanes, D A; Minard, M-N; Mitzel, D S; Mogini, A; Molina Rodriguez, J; Monroy, I A; Monteil, S; Morandin, M; Morello, M J; Morgunova, O; Moron, J; Morris, A B; Morris, A P; Mountain, R; Muheim, F; Mulder, M; Mussini, M; Müller, D; Müller, J; Müller, K; Müller, V; Naik, P; Nakada, T; Nandakumar, R; Nandi, A; Nasteva, I; Needham, M; Neri, N; Neubert, S; Neufeld, N; Neuner, M; Nguyen, T D; Nguyen-Mau, C; Nieswand, S; Niet, R; Nikitin, N; Nikodem, T; Nogay, A; O'Hanlon, D P; Oblakowska-Mucha, A; Obraztsov, V; Ogilvy, S; Oldeman, R; Onderwater, C J G; Ossowska, A; Otalora Goicochea, J M; Owen, P; Oyanguren, A; Pais, P R; Palano, A; Palutan, M; Papanestis, A; Pappagallo, M; Pappalardo, L L; Pappenheimer, C; Parker, W; Parkes, C; Passaleva, G; Pastore, A; Patel, M; Patrignani, C; Pearce, A; Pellegrino, A; Penso, G; Pepe Altarelli, M; Perazzini, S; Perret, P; Pescatore, L; Petridis, K; Petrolini, A; Petrov, A; Petruzzo, M; Picatoste Olloqui, E; Pietrzyk, B; Pikies, M; Pinci, D; Pistone, A; Piucci, A; Placinta, V; Playfer, S; Plo Casasus, M; Poikela, T; Polci, F; Poli Lener, M; Poluektov, A; Polyakov, I; Polycarpo, E; Pomery, G J; Ponce, S; Popov, A; Popov, D; Popovici, B; Poslavskii, S; Potterat, C; Price, E; Prisciandaro, J; Prouve, C; Pugatch, V; Puig Navarro, A; Punzi, G; Qian, C; Qian, W; Quagliani, R; Rachwal, B; Rademacker, J H; Rama, M; Ramos Pernas, M; Rangel, M S; Raniuk, I; Ratnikov, F; Raven, G; Ravonel Salzgeber, M; Reboud, M; Redi, F; Reichert, S; Dos Reis, A C; Remon Alepuz, C; Renaudin, V; Ricciardi, S; Richards, S; Rihl, M; Rinnert, K; Rives Molina, V; Robbe, P; Rodrigues, A B; Rodrigues, E; Rodriguez Lopez, J A; Rodriguez Perez, P; Rogozhnikov, A; Roiser, S; Rollings, A; Romanovskiy, V; Romero Vidal, A; Ronayne, J W; Rotondo, M; Rudolph, M S; Ruf, T; Ruiz Valls, P; Saborido Silva, J J; Sadykhov, E; Sagidova, N; Saitta, B; Salustino Guimaraes, V; Sanchez Gonzalo, D; Sanchez Mayordomo, C; Sanmartin Sedes, B; Santacesaria, R; Santamarina Rios, C; Santimaria, M; Santovetti, E; Sarti, A; Satriano, C; Satta, A; Saunders, D M; Savrina, D; Schael, S; Schellenberg, M; Schiller, M; Schindler, H; Schlupp, M; Schmelling, M; Schmelzer, T; Schmidt, B; Schneider, O; Schopper, A; Schreiner, H F; Schubert, K; Schubiger, M; Schune, M-H; Schwemmer, R; Sciascia, B; Sciubba, A; Semennikov, A; Sergi, A; Serra, N; Serrano, J; Sestini, L; Seyfert, P; Shapkin, M; Shapoval, I; Shcheglov, Y; Shears, T; Shekhtman, L; Shevchenko, V; Siddi, B G; Silva Coutinho, R; Silva de Oliveira, L; Simi, G; Simone, S; Sirendi, M; Skidmore, N; Skwarnicki, T; Smith, E; Smith, I T; Smith, J; Smith, M; Soares Lavra, L; Sokoloff, M D; Soler, F J P; Souza De Paula, B; Spaan, B; Spradlin, P; Sridharan, S; Stagni, F; Stahl, M; Stahl, S; Stefko, P; Stefkova, S; Steinkamp, O; Stemmle, S; Stenyakin, O; Stevens, H; Stoica, S; Stone, S; Storaci, B; Stracka, S; Stramaglia, M E; Straticiuc, M; Straumann, U; Sun, L; Sutcliffe, W; Swientek, K; Syropoulos, V; Szczekowski, M; Szumlak, T; T'Jampens, S; Tayduganov, A; Tekampe, T; Tellarini, G; Teubert, F; Thomas, E; van Tilburg, J; Tilley, M J; Tisserand, V; Tobin, M; Tolk, S; Tomassetti, L; Tonelli, D; Topp-Joergensen, S; Toriello, F; Tourinho Jadallah Aoude, R; Tournefier, E; Tourneur, S; Trabelsi, K; Traill, M; Tran, M T; Tresch, M; Trisovic, A; Tsaregorodtsev, A; Tsopelas, P; Tully, A; Tuning, N; Ukleja, A; Ustyuzhanin, A; Uwer, U; Vacca, C; Vagnoni, V; Valassi, A; Valat, S; Valenti, G; Vazquez Gomez, R; Vazquez Regueiro, P; Vecchi, S; van Veghel, M; Velthuis, J J; Veltri, M; Veneziano, G; Venkateswaran, A; Verlage, T A; Vernet, M; Vesterinen, M; Viana Barbosa, J V; Viaud, B; Vieira, D; Vieites Diaz, M; Viemann, H; Vilasis-Cardona, X; Vitti, M; Volkov, V; Vollhardt, A; Voneki, B; Vorobyev, A; Vorobyev, V; Voß, C; de Vries, J A; Vázquez Sierra, C; Waldi, R; Wallace, C; Wallace, R; Walsh, J; Wang, J; Ward, D R; Wark, H M; Watson, N K; Websdale, D; Weiden, A; Whitehead, M; Wicht, J; Wilkinson, G; Wilkinson, M; Williams, M; Williams, M P; Williams, M; Williams, T; Wilson, F F; Wimberley, J; Winn, M A; Wishahi, J; Wislicki, W; Witek, M; Wormser, G; Wotton, S A; Wraight, K; Wyllie, K; Xie, Y; Xu, Z; Yang, Z; Yang, Z; Yao, Y; Yin, H; Yu, J; Yuan, X; Yushchenko, O; Zarebski, K A; Zavertyaev, M; Zhang, L; Zhang, Y; Zhelezov, A; Zheng, Y; Zhu, X; Zhukov, V; Zonneveld, J B; Zucchelli, S


    The first observation of the decays Λ_{b}^{0}→χ_{c1}pK^{-} and Λ_{b}^{0}→χ_{c2}pK^{-} is reported using a data sample corresponding to an integrated luminosity of 3.0  fb^{-1}, collected by the LHCb experiment in pp collisions at center-of-mass energies of 7 and 8 TeV. The following ratios of branching fractions are measured: B(Λ_{b}^{0}→χ_{c1}pK^{-})/B(Λ_{b}^{0}→J/ψpK^{-})=0.242±0.014±0.013±0.009,B(Λ_{b}^{0}→χ_{c2}pK^{-})/B(Λ_{b}^{0}→J/ψpK^{-})=0.248±0.020±0.014±0.009,B(Λ_{b}^{0}→χ_{c2}pK^{-})/B(Λ_{b}^{0}→χ_{c1}pK^{-})=1.02±0.10±0.02±0.05,where the first uncertainty is statistical, the second systematic, and the third due to the uncertainty on the branching fractions of the χ_{c1}→J/ψγ and χ_{c2}→J/ψγ decays. Using both decay modes, the mass of the Λ_{b}^{0} baryon is also measured to be m_{Λ_{b}^{0}}=5619.44±0.28±0.26  MeV/c^{2}, where the first and second uncertainties are statistical and systematic, respectively.

  2. Sequence specific DNA binding by P53 is enhanced by ionizing radiation and is mediated via DNA-PK activity

    International Nuclear Information System (INIS)

    Kachnic, L.A.; Wunsch, H.; Mekeel, K.L.; De Frank, J.S.; Powell, S.N.


    Purpose: P53 is known to be involved in the cellular response to DNA damage. It mediates many of its effects by acting as a transcription factor via sequence-specific DNA binding. The half-life of p53 is prolonged following DNA damage, and this results in elevated levels of p53 for a period of 2-8 hours. The increase in p53 is often relatively small, but this produces significant stimulation of a downstream gene such as p21(WAF1/cip1). We investigated post-translational modification of p53 following ionizing radiation damage. Materials and Methods: The response of normal Balb-C mouse fibroblasts (FC) to ionizing radiation (IR, 8 Gy) was measured at 0,3,6,9 and 24 hours, by the levels of p53, p21, flow cytometry and the electrophoretic mobility shift assay (EMSA). EMSA utilized a 26 bp consensus sequence end-labeled oligonucleotide to measure sequence-specific p53 binding. P53 specificity was confirmed by an enhanced mobility shift (retardation) when using p53 antibody. Comparison was made with scid fibroblasts (FS) and FC cells transfected with a plasmid (CX3) containing mutant p53 (alanine-143) or infected with a retrovirus containing the E6 protein of human papilloma virus type 16. Results: The response of p53 to DNA damage shows a 3-fold increase at 3-6 hours, and was not significantly different between FC and FS. FC-CX3 showed detectable basal levels of p53, and a 2-fold further induction of p53 after IR. FC-E6 showed no detectable levels of p53 before or after IR. No induction of p21 or G1/S arrest was seen in FC-CX3 or FC-E6, as has been observed previously. The induction of p21 in FS cells was attenuated and delayed: a 2-3-fold increase seen maximally at 9 hours, compared with a 5-fold increase seen maximally at 3-6 hours in FC cells. The accumulation of cells at the G1/S junction after IR showed the same kinetics as p21 induction: the peak of cells in G1 occurs at 3-6 hours in FC, but not until 9-24 hours in FS. The response is reminiscent of that seen in

  3. Protective Effects of the Fermented Laminaria japonica Extract on Oxidative Damage in LLC-PK1 Cells (United States)

    Park, Min-Jung; Han, Ji-Sook


    This study investigated the protective effect of the butanol (BuOH) fraction from fermented Laminaria japonica extract (BFLJ) on AAPH-induced oxidative stress in porcine kidney epithelial cells (LLC-PK1 cells). L. japonica was fermented by Aspergillus oryzae at 35±1°C for 72 h. Freeze-dried fermented L. japonica was extracted with distilled water, and the extracted solution was mixed with ethanol and then centrifuged. The supernatant was subjected to sequential fractionation with various solvents. The BuOH fraction was used in this study because it possessed the strongest antioxidant activity among the various solvent fractions. The BuOH fraction of fermented L. japonica had a protective effect against the AAPH-induced LLC-PK1 cells damage and increased cell viability while reducing lipid peroxidation formation and increased activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. The inhibitory effect of BFLJ on lipid peroxidation formation had a higher value of 0.11±0.01 nmol MDA at 100 μg/mL concentration in comparison with intact BuOH fraction showing 0.22±0.08 nmol MDA at the same concentration. Furthermore, BFLJ treatment increased glutathione concentration. GSH concentration in the cell treated with BFLJ of 100 μg/mL was 1.80 pmol/L×105 cells. These results indicate that BFLJ protects the LLC-PK1 cells against AAPH-induced cell damage by inhibiting lipid peroxidation formation and increasing antioxidant enzyme activities and glutathione concentration. PMID:24551823

  4. The effects of PK11195 on the MCF-7 and T47D were associated with the allopregnanolone biosynthesis, which was mediated by Translocator Protein 18 KDa. (United States)

    Xu, Jia-Ning; Shen, Dong; Mao, Wei-Dong; Lin, Qing-Fen; Lin, Feng; Lu, Chao


    Breast cancer is currently the most common malignancy affecting women worldwide. It had been shown that the allopregnanolone biosynthesis was associated with tumorigenesis and PK11195, the Translocator Protein 18 KDa (TSPO) antagonist, had the effects of the allopregnanolone biosynthesis. However, little is known about the association between the effects of PK11195 on the breast cancer and the allopregnanolone biosynthesis. To evaluate this, the breast cancer cell lines MCF-7 and T47D were cultured. Cell viability and proliferation were determined by CCK-8 assay. The IC50 of PK11195 on the MCF-7 and T47D were 5.4 nM and 6 nM. The cell viability and proliferation of AC-5216 (TSPO selective ligand, 3 and 6 nM) was blocked by PK11195 (5.4 nM and 6 nM). Moreover, we evaluated the role of allopregnanolone biosynthesis in the effects of TSPO on breast cancer. Enzyme-Linked ImmunoSorbent Assay (ELISA) was used in the measurement of the allopregnanolone level. We found that the allopregnanolone level was increased by AC-5216 (3 and 6 nM) and the increase was reversed by PK11195 (5.4 nM and 6 nM, resepectively) in MCF-7 and T47D. The TSPO mRNA level was determined by real time polymerase chain reaction (PCR). The TSPO mRNA level were increased by AC-5216 (6 nM), which the increases were reversed by PK11195 (5.4 nM and 6 nM, resepectively) in MCF-7 and T47D. Collectedly, it firstly indicated that the effects of PK11195 on MCF-7 and T47D were associated with the decrease of allopregnanolone biosynthesis, which was mediated by TSPO.

  5. Lesions inflammatory activity quantification in multiple sclerosis using [{sup 11}C]-(R)-PK11195 PET brain images; Quantificacao da atividade inflamatoria em lesoes na esclerose multipla usando imagens PET cerebrais com [{sup 11}C]-(R)-PK11195

    Energy Technology Data Exchange (ETDEWEB)

    Schuck, Phelipi N.; Narciso, Lucas D.L.; Dartora, Caroline M.; Silva, Ana M. Marques da, E-mail: [Pontificia Universidade Catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil). Nucleo de Pesquisa em Imagens Medicas


    The criteria for multiple sclerosis (MS) diagnosis include the presence of lesions in brain regions called black holes (BH), characterized by low signal on magnetic resonance imaging T1-weighted. Studies suggest that lesions in MS, if there is an inflammatory process, can be detected in PET imaging with [{sup 11}C]- (R)-PK11195. The aim of this study is to investigate the uptake of [{sup 11}C]-(R)-PK11195 in BH in PET images, searching for inflammation activity in lesions and neighborhoods. Semiquantitative methods of SUV and uptake normalization were applied to PET images, in different time intervals, acquired from 8 MS patients and 5 healthy controls. Higher uptake was identified in BH and its edges, when compared with health controls white matter, when the SUV method is applied (p < 0,01, 40 to 60 min). When uptake normalization method is applied, smaller uptake in black holes and its your edges is observed, when compared with white matter apparently healthy (p < 0,01, 0 to 60 min). (author)

  6. Closed External Fixation for Failing or Failed Femoral Shaft Plating in a Developing Country. (United States)

    Aliakbar, Adil; Witwit, Ibrahim; Al-Algawy, Alaa A Hussein


    Femoral shaft fractures are one of the common injuries that is treated by open reduction, with internal fixation by plate and screws or intramedullary nailing, which can achieve a high union rate. To evaluate the outcome of using closed external fixation to augment a failing plate; with signs of screw loosening and increasing bone/plate gap; a failed plate; broken plate; screws completely out of bone with redisplacement of fracture. A retrospective study on 18 patients, aged between 17-42 years, who presented between 6-18 weeks after initial surgical fixation, with pain, difficulty in limb function, deformity and abnormal movement at fracture site, was done. X-Rays showed plating failure with acceptable amount of callus, which unfortunately had refractured. Cases associated with infection and no radiological evidence of callus formation were excluded from this study. Closed reduction was done by manipulation, then fracture fixation by AO external fixator. The patients were encouraged for full weight bearing as early as possible with dynamization later on. Of the 18 patients who underwent external fixation after close reduction, 15 cases showed bone healing in a period between 11-18 weeks (mean of 14.27 weeks) with good alignment (Radiologically). Removal of external fixator was done followed by physical therapy thereafter. Closed external fixation for treatment of failing or failed femoral plating, achieves good success rate and has less complications, is a short time procedure, especially in a hospital with limited resources.

  7. Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Hauke Rühs

    Full Text Available Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

  8. Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers. (United States)

    Park, Sunny; Hyun, Yang Jin; Kim, Yu Ran; Lee, Ju Hyun; Ryu, Sunae; Kim, Jeong Mi; Oh, Woo Yong; Na, Han Sung; Lee, Jong Gu; Seo, Doo Won; Hwang, In Yeong; Park, Zewon; Jang, In Jin; Oh, Jaeseong; Choi, Seung Eun


    The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers. © 2017 The Korean Academy of Medical Sciences.

  9. DNA-dependent protein kinase (DAN-PK), a key enzyme in the re-ligation of DNA double-strand breaks

    International Nuclear Information System (INIS)

    Hennequin, C.; Averbeck, D.


    Repair pathways of DNA are now defined and some important findings have been discovered in the last few years. DNA non-homologous end-joining (NEH) is a crucial process in the repair of radiation-induced double-strand breaks (DSBs). NHEj implies at least three steps: the DNA free-ends must get closer, preparation of the free-ends by exonucleases and then a transient hybridization in a region of DNA with weak homology. DNA-dependent protein kinase (DNA-PK) is the key enzyme in this process. DNA-PK is a nuclear serine/threonine kinase that comprises three components: a catalytic subunit (DNA-PK cs ) and two regulatory subunits, DNA-binding proteins, Ku80 and Ku70. The severe combined immuno-deficient (scid) mice are deficient in DNA-PK cs : this protein is involved both in DNA repair and in the V(D)J recombination of immunoglobulin and T-cell receptor genes. It is a protein-kinase of the P13-kinase family and which can phosphorylate Ku proteins, p53 and probably some other proteins still unknown. DNA-PK is an important actor of DSBs repair (induced by ionising radiations or by drugs like etoposide), but obviously it is not the only mechanism existing in the cell for this function. Some others, like homologous recombination, seem also to have a great importance for cell survival. (authors)

  10. Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study. (United States)

    Giannetti, Paolo; Politis, Marios; Su, Paul; Turkheimer, Federico; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Reynolds, Richard; Nicholas, Richard; Piccini, Paola


    The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. Out of a total of 1242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; pholes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf. (United States)

    Toutain, P-L; Potter, T; Pelligand, L; Lacroix, M; Illambas, J; Lees, P


    The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller-Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC (0-24 h) /MIC) to achieve a bactericidal effect was estimated from in vitro time-kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single-dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts. © 2016 John Wiley & Sons Ltd.

  12. Fail forward: Mitigating failure in energy research and innovation

    DEFF Research Database (Denmark)

    Brix, Jacob


    on participant observation and empirical field research in three case companies, the OFEI model is developed to identify inappropriate behaviors that cause energy research and innovation to fail. The OFEI model can be used to give failed (or failing) projects a second chance and the article concludes...

  13. Data mining and diagnosing IC fails

    CERN Document Server

    Huisman, Leendert M


    This book grew out of an attempt to describe a variety of tools that were developed over a period of years in IBM to analyze Integrated Circuit fail data. The selection presented in this book focuses on those tools that have a significant statistical or datamining component. The danger of describing sta­ tistical analysis methods is the amount of non-trivial mathematics that is involved and that tends to obscure the usually straigthforward analysis ideas. This book is, therefore, divided into two roughly equal parts. The first part contains the description of the various analysis techniques and focuses on ideas and experimental results. The second part contains all the mathematical details that are necessary to prove the validity of the analysis techniques, the existence of solutions to the problems that those techniques engender, and the correctness of several properties that were assumed in the first part. Those who are interested only in using the analysis techniques themselves can skip the second part, b...

  14. Salvage microdissection testicular sperm extraction after failed conventional testicular sperm extraction in patients with nonobstructive azoospermia. (United States)

    Tsujimura, Akira; Miyagawa, Yasushi; Takao, Tetsuya; Takada, Shingo; Koga, Minoru; Takeyama, Masami; Matsumiya, Kiyomi; Fujioka, Hideki; Okuyama, Akihiko


    TESE is considered the best procedure for identifying a tubule for spermatozoa retrieval. This technique improves the SRR to around 50%. However, it has been unclear whether it is useful in patients in whom conventional TESE has failed. We compared the outcome of microdissection TESE in patients in whom conventional TESE failed to that in patients who did not undergo conventional TESE. We also evaluated relations between the outcome of salvage microdissection TESE and the characteristics of previous conventional TESE. A total of 46 patients with nonobstructive azoospermia in whom salvage microdissection TESE was performed after failed conventional TESE were included. Patient characteristics and the SRR were compared between these patients and 134 in whom conventional TESE had not been performed previously. The previous TESE procedure, testicular histology and interval between TESEs were also evaluated. Patient characteristics did not differ significantly between the groups. The microdissection TESE SRR also did not differ significantly between the groups (45.7% vs 44.0%). The possibility of successful spermatozoa retrieval by salvage microdissection TESE remained regardless of the previous failure of any other TESE procedure and regardless of testicular histology. The salvage microdissection TESE SRR was not related to the interval between TESEs. Because salvage microdissection TESE is effective in patients in whom conventional TESE has failed, this option should be made available to them with the understanding that extended followup after salvage microdissection TESE is necessary due to the risk of hypogonadism.

  15. Physical and Emotional Development, Appetite and Body Image in Adolescents Who Failed to Thrive as Infants (United States)

    Drewett, R. F.; Corbett, S. S.; Wright, C. M.


    Background: Previous studies suggest that failure to thrive in infancy may be associated with adverse sequelae in childhood. Although cognitive abilities have been extensively investigated, little systematic research is available on other aspects of development. Methods: Eighty-nine children who failed to thrive as infants and 91 controls were…

  16. Effects of failed commissuration on the septum pellucidum and fornix: implications for fetal imaging

    International Nuclear Information System (INIS)

    Griffiths, Paul D.; Batty, Ruth; Connolly, Dan A.J.; Reeves, Michael J.


    In the previous article, we considered the normal appearances of the midline stuctures of the brain as they appear on high-resolution magnetic resonance imaging. In this article, we discuss the effects of failed commissuration on the midline structures. We highlight some of the misconceptions of this process that may lead to misdiagnosis of agenesis of the corpus callosum in utero. (orig.)

  17. Effects of failed commissuration on the septum pellucidum and fornix: implications for fetal imaging

    Energy Technology Data Exchange (ETDEWEB)

    Griffiths, Paul D. [University of Sheffield, Academic Unit of Radiology, Sheffield (United Kingdom); Royal Hallamshire Hospital, Academic Unit of Radiology, C Floor, Sheffield (United Kingdom); Batty, Ruth; Connolly, Dan A.J. [University of Sheffield, Academic Unit of Radiology, Sheffield (United Kingdom); Sheffield Teaching Hospitals NHS Foundation Trust, Department of Radiology, Sheffield (United Kingdom); Reeves, Michael J. [University of Sheffield, Academic Unit of Radiology, Sheffield (United Kingdom)


    In the previous article, we considered the normal appearances of the midline stuctures of the brain as they appear on high-resolution magnetic resonance imaging. In this article, we discuss the effects of failed commissuration on the midline structures. We highlight some of the misconceptions of this process that may lead to misdiagnosis of agenesis of the corpus callosum in utero. (orig.)

  18. Why Do First-Generation Students Fail? (United States)

    Mehta, Sanjay S.; Newbold, John J.; O'Rourke, Matthew A.


    Previous studies have determined factors contributing to first-generation student success. This study finds that first-generation students are less involved, have less social and financial support, and do not show a preference for active coping strategies. First-generation students report less social and academic satisfaction as well as lower…

  19. Why Small Businesses Fail in Tunisia?


    Anis Omri; Mohamed Frikha


    This paper aims at drawing up an average cognitive map in order to explain the failure factors of Tunisian small businesses. The method adopted in our study is the cognitive approach. Our study extends entrepreneurship literature and previous literature by proposing a new approach in order to build an average cognitive map for the explanation of small businesses failures.

  20. Money Talks: Why Nigeria’s Petroleum Industry Bill will Fail to End Gas Flaring (United States)


    Industry Bill ( PIB ) that if enacted would ban gas flaring. However, as currently written the PIB will not end flaring for the same reasons that...previous legislation failed. Loopholes in the PIB combined with corruption, lack of effective enforcement mechanisms and lack of incentives to develop...Bill ( PIB ) that if enacted would ban gas flaring. However, as currently written, the PIB will not end flaring for the same reasons that previous

  1. Pass/fail patterns of candidates who failed COMLEX-USA level 2-PE because of misrepresentation of clinical findings on postencounter notes. (United States)

    Langenau, Erik E; Sandella, Jeanne M


    In 2007, The National Board of Osteopathic Medical Examiners (NBOME) instituted a policy to address the accuracy and integrity of postencounter written documentation recorded during the Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation (COMLEX-USA Level 2-PE). This policy was instituted not only to protect the integrity of the examination, but also to highlight that overdocumentation of clinical findings not obtained during patient encounters may jeopardize patient safety. To investigate overall and domain pass/fail patterns of candidates who misrepresented clinical findings with regard to past and subsequent performance on COMLEX-USA Level 2-PE. Specifically, to investigate what percentage of candidates failed because of misrepresentation on first attempts and how they performed on subsequent administrations, as well as the previous performance patterns of candidates who failed because of misrepresentation on examination retakes. Historical records from NBOME's COMLEX-USA Level 2-PE database (testing cycles 2007-2008, 2008-2009, and 2009-2010) were used to analyze overall and domain pass/fail patterns of candidates who failed at least once because of misrepresentation of clinical findings. Of the 24 candidates who failed because of misrepresentation of postencounter (SOAP) notes, 20 candidates (83%) were first-time examinees. Four candidates (17%) were repeating the examination, 2 of whom were making a third attempt to pass. Among these 20 candidates who failed because of misrepresentation of clinical findings on their first attempt, 19 passed on their next attempt. At the time of study analysis, all but 2 candidates eventually passed the examination in subsequent attempts. Among candidates found to have misrepresented clinical findings on postencounter written documentation on COMLEX-USA Level 2-PE, no pattern existed between their past or subsequent performance with regard to overall or domain pass/fail results. The vast

  2. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Vowinckel, E; Reutens, D; Becher, B


    examined the utility of using in vitro and in vivo ligand binding to the PBR as a measure of lesion activity in autoimmune CNS demyelinating diseases. Applying a combined autoradiography and immunohistochemical approach to spinal cord and brain tissues from mice with EAE, we found a correlation at sites...... tomography (PET) imaging with [11C]-PK11195 showed ligand uptake only at sites of active MS lesions defined by magnetic resonance imaging criteria. Our results indicate the potential to develop markers suitable for both in vitro and in vivo use, which will serve to help correlate phenotypic and functional...... of inflammatory lesions between [3H]-PK11195 binding and immunoreactivity for the activated microglial/macrophage marker Mac-1/CD11b. In MS tissues, [3H]-PK11195 binding correlated with sites of immunoreactivity for the microglial/macrophage marker CD68, at the edges of chronic active plaques. Positron emission...

  3. Disorganized junior doctors fail the MRCP (UK). (United States)

    Stanley, Adrian G; Khan, Khalid M; Hussain, Walayat; Tweed, Michael


    Career progression during undergraduate and early postgraduate years is currently determined by successfully passing examinations. Both academic factors (secondary school examination results, learning style and training opportunities) and non-academic factors (maturity, ethnic origin, gender and motivation) have been identified as predicting examination outcome. Few studies have examined organization skills. Disorganized medical students are more likely to perform poorly in end-of-year examinations but this observation has not been examined in junior doctors. This study asked whether organization skills relate to examination outcome amongst junior doctors taking the clinical Part II examination for the Membership of the Royal College of Physicians (Practical Assessment of Clinical Examination Skills). The study was conducted prospectively at four consecutive clinical courses that provided clinical teaching and practice to prepare trainees for the examination. Arrival time at registration for the course was the chosen surrogate for organization skills. Trainees were advised that they should arrive promptly at 8.00 a.m. for registration and it was explained that the course would start at 8.30 a.m. Recorded arrival times were compared with the pass lists published by the Royal College of Physicians. The mean arrival time was 8.17 a.m. A total of 81 doctors (53.3%) passed the examination with a mean arrival time of 8.14 a.m. However, 71 doctors failed the exam and arrived, on average, six minutes later than doctors who passed (p?=?0.006). Better-prepared junior doctors were more likely to pass the final examination. Arriving on time represents a composite of several skills involved in the planning of appropriate travel arrangements and is therefore a valid marker of organization skills and preparation. This novel study has shown that good time-keeping skills are positively associated with examination outcome.

  4. Imaging studies for failed back surgery syndrome

    International Nuclear Information System (INIS)

    Cosnard, G.; Cordoliani, Y.S.; Sarrazin, J.L.; Soulie, D.


    In patients with failed back surgery syndrome, magnetic resonance imaging (MRI) can be the best first-line imaging study because it simplifies the diagnosis. This update is based on over 600 cases. MRI shows the scar tissue at the surgical site, persistent evidence of disk herniation for several weeks after surgery, and evidence of local and regional edema in one-fourth of cases. The edema is most marked between two months and two years after the operation and can misleadingly suggest discitis. MRI is the best investigation for detecting recurrent herniation at the same vertebral level or another level. Herniated disk material is seen as a mass that does not enhance after gadolinium, in contrast to the vascularized scar tissue. Free fragments are often clearly visible within the scar tissue. Fragments that migrate to the epidural space can give rise to granulomatous reactions. Scar tissue can be seen in the epidural space and within the disk; it can show enhancement after gadolinium for several years. The scar can be atrophic or hypertrophic and can encase or impinge on the dural sac and nerve roots. Pathological fibrosis cannot be differentiated from ordinary scar tissue. Arachnoiditis causing adherence of the nerve roots to the dura mater or to each other occurs in 5 % to 10 % of cases. Nerve root enhancement after gadolinium is seen in three-fourths of cases. Bone lesions are common, especially some time after surgery; they are usually accompanied with other lesions. Hematomas are seen in less than 10 % of cases. Infections are similarly rare (0.25 % each for discitis and epiduritis). The diagnosis of discitis is difficult and requires percutaneous biopsy of the disk, especially when MRI shows fluid within the disk, with decreased signal intensity on T2 images, and non enhancement after intravenous gadolinium. (authors). 19 refs., 7 figs

  5. The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant α1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker

    International Nuclear Information System (INIS)

    Lockhart, Andrew; Davis, Bill; Matthews, Julian C.; Rahmoune, Hassan; Hong, Guizhu; Gee, Antony; Earnshaw, David; Brown, John


    The peripheral benzodiazepine receptor ligand PK11195 has been used as an in vivo marker of neuroinflammation in positron emission tomography studies in man. One of the methodological issues surrounding the use of the ligand in these studies is the highly variable kinetic behavior of [ 11 C]PK11195 in plasma. We therefore undertook a study to measure the binding of [ 3 H]PK11195 to whole human blood and found a low level of binding to blood cells but extensive binding to plasma proteins. Binding assays using [ 3 H]PK11195 and purified human plasma proteins demonstrated a strong binding to α1-acid glycoprotein (AGP) and a much weaker interaction with albumin. Immunodepletion of AGP from plasma resulted in the loss of plasma [ 3 H]PK11195 binding demonstrating: (i) the specificity of the interaction and (ii) that AGP is the major plasma protein to which PK11195 binds with high affinity. PK11195 was able to displace fluorescein-dexamethasone from AGP with IC 50 of 11 C]PK11195 to the brain parenchyma in diseases with blood brain barrier breakdown. Finally, local synthesis of AGP at the site of brain injury may contribute the pattern of [ 11 C]PK11195 binding observed in neuroinflammatory diseases

  6. Salvage of Failed Protein Targets by Reductive Alkylation (United States)

    Tan, Kemin; Kim, Youngchang; Hatzos-Skintges, Catherine; Chang, Changsoo; Cuff, Marianne; Chhor, Gekleng; Osipiuk, Jerzy; Michalska, Karolina; Nocek, Boguslaw; An, Hao; Babnigg, Gyorgy; Bigelow, Lance; Joachimiak, Grazyna; Li, Hui; Mack, Jamey; Makowska-Grzyska, Magdalena; Maltseva, Natalia; Mulligan, Rory; Tesar, Christine; Zhou, Min; Joachimiak, Andrzej


    The growth of diffraction-quality single crystals is of primary importance in protein X-ray crystallography. Chemical modification of proteins can alter their surface properties and crystallization behavior. The Midwest Center for Structural Genomics (MCSG) has previously reported how reductive methylation of lysine residues in proteins can improve crystallization of unique proteins that initially failed to produce diffraction-quality crystals. Recently, this approach has been expanded to include ethylation and isopropylation in the MCSG protein crystallization pipeline. Applying standard methods, 180 unique proteins were alkylated and screened using standard crystallization procedures. Crystal structures of 12 new proteins were determined, including the first ethylated and the first isopropylated protein structures. In a few cases, the structures of native and methylated or ethylated states were obtained and the impact of reductive alkylation of lysine residues was assessed. Reductive methylation tends to be more efficient and produces the most alkylated protein structures. Structures of methylated proteins typically have higher resolution limits. A number of well-ordered alkylated lysine residues have been identified, which make both intermolecular and intramolecular contacts. The previous report is updated and complemented with the following new data; a description of a detailed alkylation protocol with results, structural features, and roles of alkylated lysine residues in protein crystals. These contribute to improved crystallization properties of some proteins. PMID:24590719

  7. Outcome After Salvage Arthrodesis for Failed Total Ankle Replacement. (United States)

    Kamrad, Ilka; Henricson, Anders; Magnusson, Håkan; Carlsson, Åke; Rosengren, Björn E


    In cases with total ankle replacement (TAR) failure, a decision between revision TAR and salvage arthrodesis (SA) must be made. In a previous study, we analyzed revision TAR and found low functional outcome and satisfaction. The aims of the current study were to analyze SA concerning failure rate and patient-related outcome measures (PROMs). Until September 2014, a total of 1110 primary TARs were recorded in the Swedish Ankle Registry. Of the 188 failures, 118 were revised with SA (and 70 with revision TAR). Patient- and implant-specific data for SA cases were analyzed as well as arthrodesis techniques. Failure of SA was defined as repeat arthrodesis or amputation. Generic and region-specific PROMs of 68 patients alive with a solid unilateral SA performed more than 1 year before were analyzed. The first-attempt solid arthrodesis rate of SA was 90%. Overall, 25 of 53 (47%) patients were very satisfied or satisfied. Mean Self-reported Foot and Ankle Score (SEFAS) was 22 (95% confidence interval 20-24), Euro Qol-5 Dimensions 0.57 (0.49-0.65), Euro Qol-Visual Analogue Scale 59 (53-64), Short Form-36 physical 34 (31-37) and mental 50 (46-54). The scores and satisfaction were similar to those after revision TAR but the reoperation rate was significantly lower in SA (P < .05). Salvage arthrodesis after failed TAR had a solid arthrodesis rate of 90% at first attempt, but similar to revision TAR, less than 50% of the patients were satisfied and the functional scores were low. Until studies show true benefit of revision TAR over SA, we favor SA for failed TAR. Level IV, retrospective case series. © The Author(s) 2015.

  8. Role of XRCC4 phosphorylation by DNA-PK in the regulation of NHEJ repair pathway of DNA double strand break

    International Nuclear Information System (INIS)

    Sharma, Mukesh Kumar; Imamichi, Shoji; Fukuchi, Mikoto; Kamdar, Radhika P.; Sicheng, Liu; Wanotayan, Rujira; Matsumoto, Yoshihisa


    Non-homologous end-joining (NHEJ) is the predominant pathway of DNA double strand breaks in higher eukaryotes and is active throughout the cell cycle. NHEJ repair includes many factors as Ku70/86, DNA-PKcs, XRCC4-Ligase IV complex and XLF (also known as Cernunnos). In these factors, DNA-PKcs acts as central regulator in NHEJ repair. It recruited at the DNA damages site after DNA damage and after association with Ku its kinase activity is activated. It phosphorylates many of important NHEJ proteins in vitro including XRCC4, Ku 70/86, Artemis, and even DNA-PKcs but till now, very less studies have been done to know the role and significance of phosphorylation in the NHEJ repair. Studies by other researchers identified various phosphorylation sites in XRCC4 by DNA-PK using mass spectrometry but these phosphorylation sites were shown to be dispensable for DSB repair. In the present investigation, we identified 3 serine and one new threonine phosphorylation sites in XRCC4 protein by DNA-PK. In vivo phosphorylation at these sites was verified by generating phosphorylation specific antibodies and the requirement for DNA-PK therein was verified by using DNA-PK inhibitor and DNA-PK proficient and deficient cell lines in response to radiation and zeocin treatment. We have also found that phosphorylation at these sites showed dose dependency in response to radiation treatment. The two serine and one threonine phosphorylation site is also biological important as their mutation into alanine significantly elevated radiosensitivity as measured by colony formation assay. Neutral comet assay showed delayed kinetics in DSB repair of these mutants. Furthermore, we have found a protein, with putative DSB repair function, which interacts with domain including the phosphorylation sites.These results indicate that these phosphorylation sites would mediate functional link between XRCC4 and DNA-PK. (author)

  9. Systemic injection of kainic acid: Gliosis in olfactory and limbic brain regions quantified with [3H]PK 11195 binding autoradiography

    International Nuclear Information System (INIS)

    Altar, C.A.; Baudry, M.


    Neurodegenerative diseases may result from excessive stimulation of excitatory amino acid receptors by endogenous ligands. Because neuronal degeneration is associated with glial proliferation and hypertrophy, the degenerative changes throughout rat brain following the systemic administration of kainic acid (12 mg/kg) were mapped with quantitative autoradiography of [3H]PK 11195. This radioligand binds to a mitochondrial benzodiazepine binding site (MBBS) on microglia and astrocytes. Analysis of eight horizontal and four coronal brain levels revealed up to 16-fold increases in [3H]PK 11195 binding from 1 to 5 weeks but not 1 day after kainate injection. Increases in [3H]PK 11195 binding were predominantly in ventral limbic brain regions and olfactory projections to neocortical areas, with the olfactory cortex greater than subiculum/CA1 greater than anterior olfactory nucleus, medial thalamic nucleus, and piriform cortex greater than cingulate cortex and rostral hippocampus greater than dentate gyrus, septum, and amygdala greater than entorhinal cortex and temporal cortex. Little or no enhancement of [3H]PK 11195 binding was observed in numerous regions including the caudate-putamen, substantia nigra, nucleus accumbens, olfactory tubercle, cerebellum, thalamic nuclei, choroid plexus, medulla, parietal or occipital cortex, or pons. A 2-fold greater extent of neurodegeneration was obtained in ventral portions of the olfactory bulb, entorhinal cortex, temporal cortex, and dentate gyrus compared with the dorsal portions of these structures. The pattern of increase in [3H]PK 11195 binding closely matched the patterns of neuronal degeneration reported following parenteral kainate injection. These findings strengthen the notion that quantitative autoradiography of [3H]PK 11195 is a valuable tool to quantify the extent of neuronal degeneration

  10. Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Woillard


    Full Text Available Tacrolimus (Tac is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD] profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics®. Patients were genotyped for the CYP3A4∗22 and CYP3A5∗3 alleles and were classified into 3 different categories [poor-metabolizers (PM, Intermediate-metabolizers (IM or extensive-metabolizers (EM]. A one-compartment model with double gamma absorption route described very accurately the tacrolimus PK. In covariate analysis, only CYP3A genotype was retained in the final model (Δ-2LL = -73. Our model estimated that tacrolimus concentrations were 33% IC95%[20–26%], 41% IC95%[36–45%] lower in CYP3A IM and EM when compared to PM, respectively. Virtually, we proved that defining different starting doses for PM, IM and EM would be beneficial by ensuring better probability of target concentrations attainment allowing us to define new dosage recommendations according to patient CYP3A genetic profile.

  11. Lentviral-mediated RNAi to inhibit target gene expression of the porcine integrin αv subunit, the FMDV receptor, and against FMDV infection in PK-15 cells

    Directory of Open Access Journals (Sweden)

    Lin Tong


    Full Text Available Abstract Background shRNA targeting the integrin αv subunit, which is the foot-and-mouth disease virus (FMDV receptor, plays a key role in virus attachment to susceptible cells. We constructed a RNAi lentiviral vector, iαv pLenti6/BLOCK -iT™, which expressed siRNA targeting the FMDV receptor, the porcine integrin αv subunit, on PK-15 cells. We also produced a lentiviral stock, established an iαv-PK-15 cell line, evaluated the gene silencing efficiency of mRNA using real-time qRT-PCR, integrand αv expression by indirect immunofluorescence assay (IIF and cell enzyme linked immunosorbent assays (cell ELISA, and investigated the in vivo inhibitory effect of shRNA on FMDV replication in PK-15 cells. Results Our results indicated successful establishment of the iαv U6 RNAi entry vector and the iαv pLenti6/BLOCK -iT expression vector. The functional titer of obtained virus was 1.0 × 106 TU/mL. To compare with the control and mock group, the iαv-PK-15 group αv mRNA expression rate in group was reduced by 89.5%, whilst IIF and cell ELISA clearly indicated suppression in the experimental group. Thus, iαv-PK-15 cells could reduce virus growth by more than three-fold and there was a > 99% reduction in virus titer when cells were challenged with 102 TCID50 of FMDV. Conclusions Iαv-PK-15 cells were demonstrated as a cell model for anti-FMDV potency testing, and this study suggests that shRNA could be a viable therapeutic approach for controlling the severity of FMD infection and spread.

  12. Establishing in vitro-in vivo correlation for antibody drug conjugate efficacy: a PK/PD modeling approach. (United States)

    Shah, Dhaval K; Loganzo, Frank; Haddish-Berhane, Nahor; Musto, Sylvia; Wald, Hallie S; Barletta, Frank; Lucas, Judy; Clark, Tracey; Hansel, Steve; Betts, Alison


    The objective of this manuscript was to establish in vitro-in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as 'in vitro tumor static concentration' (TSC in vitro ). TSC in vitro is a theoretical concentration at continuous exposure of which the number of cells will neither increase nor decrease, compared to the initial cell number in the experiment. The in vivo efficacy of ADCs was evaluated using tumor growth inhibition (TGI) studies performed on human tumor xenograft bearing mice. The TGI data obtained from in vivo studies was characterized using a PK/PD model, parameter estimates from which were used to derive an in vivo efficacy matrix for each ADC, termed as 'in vivo tumor static concentration' (TSC in vivo ). TSC in vivo is a theoretical concentration if one were to maintain in the plasma of a tumor bearing mouse, the tumor volume will neither increase nor decrease compared to the initial tumor volume. Comparison of the TSC in vitro and TSC in vivo values from 19 ADCs provided a linear and positive IVIVC. The Spearman's rank correlation coefficient for TSC in vitro and TSC in vivo was found to be 0.82. On average TSC in vivo was found to be ~ 27 times higher than TSC in vitro . The reasonable IVIVC for ADCs suggests that in vitro efficacy data was correctly able to differentiate ADCs for their in vivo efficacy. Thus, IVIVC can be used as a tool to triage ADC molecules in the discovery stage, thereby preventing unnecessary scaling-up of ADCs and waste of time and resources. An ability to predict the concentration of ADC that is

  13. Placental complications after a previous cesarean section


    Milošević Jelena; Lilić Vekoslav; Tasić Marija; Radović-Janošević Dragana; Stefanović Milan; Antić Vladimir


    Introduction The incidence of cesarean section has been rising in the past 50 years. With the increased number of cesarean sections, the number of pregnancies with the previous cesarean section rises as well. The aim of this study was to establish the influence of the previous cesarean section on the development of placental complications: placenta previa, placental abruption and placenta accreta, as well as to determine the influence of the number of previous cesarean sections on the complic...

  14. {sup 18}F-GE-180: a novel TSPO radiotracer compared to {sup 11}C-R-PK11195 in a preclinical model of stroke

    Energy Technology Data Exchange (ETDEWEB)

    Boutin, Herve; Gerhard, Alexander [University of Manchester, Faculty of Medical and Human Sciences, Manchester (United Kingdom); University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Murray, Katie [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Pradillo, Jesus [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Universidad Complutense/Politecnica de Madrid, Madrid (Spain); Maroy, Renaud [SHFJ - CEA Orsay, Orsay (France); Smigova, Alison [University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Jones, Paul A.; Trigg, William [GE Healthcare Ltd., Amersham (United Kingdom)


    Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer {sup 11}C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer {sup 18}F-GE-180 in a rat model of stroke. Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with {sup 11}C-R-PK11195 and {sup 18}F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). {sup 18}F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of {sup 11}C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BP{sub ND} = 3.5 ± 0.4 and 2.4 ± 0.5 for {sup 18}F-GE-180 and {sup 11}C-R-PK11195, respectively, with R{sub 1} = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180 significantly displaced {sup 18}F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. The in vivo binding characteristics of {sup 18}F-GE-180 demonstrate a better signal to noise ratio than {sup 11}C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in

  15. PET-derived biodistribution and dosimetry of the benzodiazepine receptor-binding radioligand (11)C-(R)-PK11195 in children and adults. (United States)

    Kumar, Ajay; Muzik, Otto; Chugani, Diane; Chakraborty, Pulak; Chugani, Harry T


    The PET tracer (11)C-(R)-PK11195 (PK) is an antagonist of the peripheral-type benzodiazepine binding site and allows the noninvasive imaging of microglial activation seen in several neurologic disorders affecting the mature and developing brain. The objective of this study was to derive the biodistribution and in vivo radiation dose estimates of PK in children studied for brain inflammatory conditions and in healthy adults. Twenty-two children (mean age +/- SD, 9.5 +/- 4 y; range, 4-17 y; 10 girls) who underwent dynamic PK PET for conditions involving brain inflammation were studied. Seven healthy adults (age, 27.4 +/- 7.5 y; range, 22-41 y; 3 women) were evaluated using the same protocol. Normal-organ time-activity curves and residence times were derived and absorbed doses then calculated using the OLINDA software. Two other healthy young adults (1 man, 1 woman) also underwent sequential whole-body PET using a PET/CT scanner to obtain corresponding CT images and PK pharmacokinetics. PK uptake was highest in the gallbladder and urinary bladder, followed by the liver, kidney, bone marrow, salivary gland, and heart wall, with minimal localization in all other organs including normal brain and lungs. PK was excreted through the hepatobiliary and renal systems. The average effective dose equivalent was 11.6 +/- 0.6 microSv/MBq (mean +/- SD) for young children (age, 4-7 y), 7.7 +/- 1.0 microSv/MBq for older children (age, 8-12 y), 5.3 +/- 0.5 muSv/MBq for adolescents (age, 13-17 y), and 4.6 +/- 2.7 microSv/MBq for adults. The gallbladder wall received the highest radiation dose in children younger than 12 y, whereas the urinary bladder wall received the highest dose in older children and adults. For an administered activity of 17 MBq/kg (0.45 mCi/kg), the effective dose equivalent was about 5 mSv or below for all age groups. At clinically practical administered activities, the radiation dose from (11)C-PK11195 in both children and adults is comparable to that from other

  16. 4D monitoring of actively failing rockslopes (United States)

    Rosser, Nick; Williams, Jack; Hardy, Richard; Brain, Matthew


    Assessing the conditions which promote rockfall to collapse relies upon detailed monitoring, ideally before, during and immediately after failure. With standard repeat surveys it is common that surveys do not coincide with or capture precursors, or that surveys are widely spaced relative to the timing and duration of driving forces such as storms. As a result gaining insight into the controls on failure and the timescales over which precursors operate remains difficult to establish with certainty, and establishing direct links between environmental conditions and rock-falls, or sequences of events prior to rockfall, remain difficult to define. To address this, we present analysis of a high-frequency 3D laser scan dataset captured using a new permanently installed system developed to constantly monitor actively failing rock slopes. The system is based around a time of flight laser scanner, integrated with and remotely controlled by dedicated controls and analysis software. The system is configured to capture data at 0.1 m spacing across > 22,000 m3 at up to 30 minute intervals. Here we present results captured with this system over a period of 9 months, spanning spring to winter 2015. Our analysis is focussed upon improving the understanding of the nature of small (< 1m^3) rockfalls falling from near vertical rock cliffs. We focus here on the development of a set of algorithms for differencing that trade-off the temporal resolution of frequent surveys (hourly) against high spatial resolution point clouds (< 0.05 m) to enhance the precision of change detection, allowing both deformation and detachments to be monitored through time. From this dataset we derive rockfall volume frequency distributions based upon short-interval surveys, and identify the presence and/or absence of precursors, in what we believe to be the first constant volumetric measurement of rock face erosion. The results hold implications for understanding of rockfall mechanics, but also for how

  17. DNA-PK dependent targeting of DNA-ends to a protein complex assembled on matrix attachment region DNA sequences

    International Nuclear Information System (INIS)

    Mauldin, S.K.; Getts, R.C.; Perez, M.L.; DiRienzo, S.; Stamato, T.D.


    Full text: We find that nuclear protein extracts from mammalian cells contain an activity that allows DNA ends to associate with circular pUC18 plasmid DNA. This activity requires the catalytic subunit of DNA-PK (DNA-PKcs) and Ku since it was not observed in mutants lacking Ku or DNA-PKcs but was observed when purified Ku/DNA-PKcs was added to these mutant extracts. Competition experiments between pUC18 and pUC18 plasmids containing various nuclear matrix attachment region (MAR) sequences suggest that DNA ends preferentially associate with plasmids containing MAR DNA sequences. At a 1:5 mass ratio of MAR to pUC18, approximately equal amounts of DNA end binding to the two plasmids were observed, while at a 1:1 ratio no pUC18 end-binding was observed. Calculation of relative binding activities indicates that DNA-end binding activities to MAR sequences was 7 to 21 fold higher than pUC18. Western analysis of proteins bound to pUC18 and MAR plasmids indicates that XRCC4, DNA ligase IV, scaffold attachment factor A, topoisomerase II, and poly(ADP-ribose) polymerase preferentially associate with the MAR plasmid in the absence or presence of DNA ends. In contrast, Ku and DNA-PKcs were found on the MAR plasmid only in the presence of DNA ends. After electroporation of a 32P-labeled DNA probe into human cells and cell fractionation, 87% of the total intercellular radioactivity remained in nuclei after a 0.5M NaCl extraction suggesting the probe was strongly bound in the nucleus. The above observations raise the possibility that DNA-PK targets DNA-ends to a repair and/or DNA damage signaling complex which is assembled on MAR sites in the nucleus

  18. Event sequence variability in healthy swallowing: building on previous findings. (United States)

    Molfenter, Sonja M; Leigh, Chelsea; Steele, Catriona M


    This study builds on previous work by Kendall, Leonard, and McKenzie, which investigated event sequence variability for 12 paired events during swallowing by healthy volunteers. They identified four event pairs that always occurred in a stereotyped order and a most common occurring overall order of events during swallowing. In the current study, we investigated overall event sequencing and the same four paired events in a sample of swallows by healthy young (under 45 years old) volunteers. Data were collected during a 16-swallow lateral videofluoroscopy protocol, which included manipulations of bolus volume, barium density, bolus viscosity, and swallow cueing. Our results agreed with previous findings that variable event sequencing is found in healthy swallowing, and, in regard to obligatory sequencing of two paired events, movement of the arytenoids toward the base of the epiglottis begins prior to upper esophageal sphincter (UES) opening and maximum hyolaryngeal approximation occurs after UES opening. However, our data failed to replicate the previous findings that there is obligatory sequencing of maximum pharyngeal constriction after maximal UES distension and the UES opens before bolus arrival at the UES. The most common observed overall event sequence reported by Kendall et al. was observed in only 4/293 swallows in our dataset. Manipulations of bolus volume, bolus viscosity, barium concentration, swallow cueing, and swallow repetitions could not completely account for the differences observed between the two studies.

  19. Preoperative screening: value of previous tests. (United States)

    Macpherson, D S; Snow, R; Lofgren, R P


    To determine the frequency of tests done in the year before elective surgery that might substitute for preoperative screening tests and to determine the frequency of test results that change from a normal value to a value likely to alter perioperative management. Retrospective cohort analysis of computerized laboratory data (complete blood count, sodium, potassium, and creatinine levels, prothrombin time, and partial thromboplastin time). Urban tertiary care Veterans Affairs Hospital. Consecutive sample of 1109 patients who had elective surgery in 1988. At admission, 7549 preoperative tests were done, 47% of which duplicated tests performed in the previous year. Of 3096 previous results that were normal as defined by hospital reference range and done closest to the time of but before admission (median interval, 2 months), 13 (0.4%; 95% CI, 0.2% to 0.7%), repeat values were outside a range considered acceptable for surgery. Most of the abnormalities were predictable from the patient's history, and most were not noted in the medical record. Of 461 previous tests that were abnormal, 78 (17%; CI, 13% to 20%) repeat values at admission were outside a range considered acceptable for surgery (P less than 0.001, frequency of clinically important abnormalities of patients with normal previous results with those with abnormal previous results). Physicians evaluating patients preoperatively could safely substitute the previous test results analyzed in this study for preoperative screening tests if the previous tests are normal and no obvious indication for retesting is present.

  20. Rescue of failed filtering blebs with ab interno trephination. (United States)

    Shihadeh, Wisam A; Ritch, Robert; Liebmann, Jeffrey M


    We evaluated the effectiveness of ab interno automated trephination as a technique for rescuing failed mature filtering blebs. A retrospective chart review of 40 failed blebs of 38 patients who had a posttrephination follow-up period of at least 3 months was done. With success defined as intraocular pressure (IOP) control with other modalities of management. Complications were few. We believe that ab interno trephination is an excellent option for rescuing selected failed filtering blebs.

  1. Development of failed fuel detection system for PWR (III)

    International Nuclear Information System (INIS)

    Hwang, Churl Kew; Kang, Hee Dong; Jeong, Seung Ho; Cho, Byung Sub; Yoon, Byeong Joo; Yoon, Jae Seong


    Ultrasonic transducers satisfying the conditions for failed fuel rod detection for failed fuel rod detection have been designed and built. And performance tests for them have been carried out. Ultrasonic signal processing units, a manipulator guiding the ultrasonic probe through the fuel assembly lanes and its control units have been constructed. The performance of the system has been verified experimentally to be successful in failed fuel rod detection. (Author)

  2. Biomass Yield and N Uptake in Tall Fescue and Reed Canary Grass Depending on N and PK Fertilization on Two Marginal Sites in Denmark

    DEFF Research Database (Denmark)

    Ugilt Larsen, Søren; Jørgensen, Uffe; Lærke, Poul Erik


    areas with limited suitability for cereal production. Plots with TF and RCG were sown in April 2011, and fertilization trials were established in spring 2012 with three factors: (a) grass species, (b) PK fertilization (either no P and K or 24 and 250 kg ha−1 y−1 of P and K, respectively), and (c) N...... fertilization (0, 150, 300, or 450 kg ha−1 y−1 N). Three cuts were taken annually from 2012 to 2014. Both species responded strongly to N fertilization. In TF, 450 kg ha−1 y−1 N combined with PK fertilization gave DM yields of 19.3, 12.1, and 14.2 t ha−1 y−1 in the 3 years, respectively, and corresponding...... yields for RCG were 17.3, 14.4, and 14.3 t ha−1 y−1. Without PK fertilization yields were significantly lower: 15.2, 7.5, and 7.3 t ha−1 y−1 in TF and 16.3, 8.7, and 4.8 ha−1 y−1 in RCG. When fertilized with PK, N uptake in harvested biomass balanced with N fertilization at rates of 244, 187, and 172 kg...

  3. Feline and canine coronaviruses are released from the basolateral side of polarized epithelial LLC-PK1 cells expressing the recombinant feline aminopeptidase-N cDNA

    NARCIS (Netherlands)

    Rossen, J W; Kouame, J; Goedheer, A J; Vennema, H; Rottier, P J


    In this study feline (FECV and FIPV) and canine (CCoV) coronavirus entry into and release from polarized porcine epithelial LLC-PK1 cells, stably expressing the recombinant feline aminopeptidase-N cDNA, were investigated. Virus entry appeared to occur preferentially through the apical membrane,

  4. Predictive performance of two PK-PD models of D2 receptor occupancy of the antipsychotics risperidone and paliperidone in rats

    NARCIS (Netherlands)

    Kozielska, Magdalena; Johnson, Martin; Pilla Reddy, Venkatesh; Vermeulen, An; de Greef, Rik; Li, Cheryl; Grimwood, Sarah; Liu, Jing; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes


    Objectives: The level of dopamine D2 receptor occupancy is predictive of efficacy and safety in schizophrenia. Population PK-PD modelling has been used to link observed plasma and brain concentrations to receptor occupancy. The objective of this study was to compare the predictive performance of two

  5. Differential effect of detergents on [3H]Ro 5-4864 and [3H]PK 11195 binding to peripheral-type benzodiazepine-binding sites

    International Nuclear Information System (INIS)

    Awad, M.; Gavish, M.


    The present study demonstrates a differential effect of various detergent treatments on [ 3 H]Ro 5-4864 and [ 3 H]PK 11195 binding to peripheral benzodiazepine binding sites (PBS). Triton X-100 caused a decrease of about 70% in [ 3 H]Ro 5-4864 binding to membranes from various peripheral tissues of rat, but had only a negligible effect on [ 3 H]PK 11195 binding. A similar effect of Triton X-100 was observed on guinea pig and rabbit kidney membranes. The decrease in [ 3 H]Ro 5-4864 binding after treatment with Triton X-100 was apparently due to a decrease in the density of PBS, since the affinity remained unaltered. The detergents 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate (CHAPS), Tween 20, deoxycholic acid, or digitonin (0.0125%) caused only a minor change in [ 3 H]Ro 5-4864 and [ 3 H]PK 11195 binding to rat kidney membranes; but when concentrations were substantially increased (0.1%), all detergents caused a decrease of at least 50% in [ 3 H]Ro 5-4864 binding, while [ 3 H]PK 11195 binding to rat kidney membranes remained unaffected by the first three detergents, with only a minor decrease (15%) after treatment with digitonin

  6. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography - A Pilot Study

    NARCIS (Netherlands)

    Versijpt, JJ; Dumont, F; Van Laere, KJ; Decoo, D; Santens, P; Audenaert, K; Achten, E; Slegers, G; Dierckx, RA; Korf, J


    Objectives: Inflammation contributes to degeneration in Alzheimer's disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [I-123]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor,

  7. Overexpression of pig selenoprotein S blocks OTA-induced promotion of PCV2 replication by inhibiting oxidative stress and p38 phosphorylation in PK15 cells (United States)

    Gan, Fang; Hu, Zhihua; Huang, Yu; Xue, Hongxia; Huang, Da; Qian, Gang; Hu, Junfa; Chen, Xingxiang; Wang, Tian; Huang, Kehe


    Porcine circovirus type 2 (PCV2) is the primary cause of porcine circovirus disease, and ochratoxin A (OTA)-induced oxidative stress promotes PCV2 replication. In humans, selenoprotein S (SelS) has antioxidant ability, but it is unclear whether SelS affects viral infection. Here, we stably transfected PK15 cells with pig pCDNA3.1-SelS to overexpress SelS. Selenium (Se) at 2 or 4 μM and SelS overexpression blocked the OTA-induced increases of PCV2 DNA copy number and infected cell numbers. SelS overexpression also increased glutathione (GSH), NF-E2-related factor 2 (Nrf2) mRNA, and γ-glutamyl-cysteine synthetase mRNA levels; decreased reactive oxygen species (ROS) levels; and inhibited p38 phosphorylation in PCV2-infected PK15 cells, regardless of OTA treatment. Buthionine sulfoximine reversed all of the above SelS-induced changes. siRNA-mediated SelS knockdown decreased Nrf2 mRNA and GSH levels, increased ROS levels, and promoted PCV2 replication in OTA-treated PK15 cells. These data indicate that pig SelS blocks OTA-induced promotion of PCV2 replication by inhibiting the oxidative stress and p38 phosphorylation in PK15 cells. PMID:26943035

  8. [18F]DPA-714: Direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats

    International Nuclear Information System (INIS)

    Boutin, Herve; Prenant, Christian; Smigova, Alison; Cawthorne, Christopher; Brown, Gavin; Herholz, Karl; Maroy, Renaud; Galea, James; Greenhalgh, Andrew D.; Rothwell, Nancy J.; Julyan, Peter; Wilkinson, Shane M.; Banister, Samuel D.; Kassiou, Michael


    Neuro-inflammation is involved in several brain disorders and can be monitored through expression of the translocator protein 18 kDa (TSPO) on activated micro-glia. In recent years, several new PET radioligands for TSPO have been evaluated in disease models. [ 18 F]DPA-714 is a TSPO radiotracer with great promise; however results vary between different experimental models of neuro-inflammation. To further examine the potential of [ 18 F]DPA-714, it was compared directly to [ 11 C]PK11195 in experimental cerebral ischaemia in rats. Under anaesthesia, the middle cerebral artery of adult rats was occluded for 60 min using the filament model. Rats were allowed recovery for 5 to 7 days before one hour dynamic PET scans with [ 11 C]PK11195 and/or [ 18 F]DPA-714 under anaesthesia. Uptake of [ 11 C]PK11195 vs [ 18 F]DPA-714 in the ischemic lesion was similar (core/contralateral ratio: 2.8460.67 vs 2.2860.34 respectively), but severity of the brain ischemia and hence ligand uptake in the lesion appeared to vary greatly between animals scanned with [ 11 C]PK11195 or with [ 18 F]DPA-714. To solve this issue of inter-individual variability, we performed a direct comparison of [ 11 C]PK11195 and [ 18 F]DPA-714 by scanning the same animals sequentially with both tracers within 24 h. In this direct comparison, the core/contralateral ratio (3.3561.21 vs 4.6662.50 for [ 11 C]PK11195 vs [ 18 F]DPA-714 respectively) showed a significantly better signal-to-noise ratio (1.6 (1.3-1.9, 95%CI) fold by linear regression) for [ 18 F]DPA-714. In a clinically relevant model of neuro-inflammation, uptake for both radiotracers appeared to be similar at first, but a high variability was observed in our model. Therefore, to truly compare tracers in such models, we performed scans with both tracers in the same animals. By doing so, our result demonstrated that [ 18 F]DPA-714 displayed a higher signal-to-noise ratio than [ 11 C]PK11195. Our results suggest that, with the longer half-life of [ 18 F

  9. Concordant and opposite roles of DNA-PK and the "facilitator of chromatin transcription" (FACT in DNA repair, apoptosis and necrosis after cisplatin

    Directory of Open Access Journals (Sweden)

    Calkins Anne S


    Full Text Available Abstract Background Platinum-containing chemotherapy produces specific DNA damage and is used to treat several human solid tumors. Tumors initially sensitive to platinum-based drugs frequently become resistant. Inhibition of DNA repair is a potential strategy to enhance cisplatin effectiveness. After cisplatin treatment, a balance between repair and apoptosis determines whether cancer cells proliferate or die. DNA-dependent protein kinase (DNA-PK binds to DNA double strand breaks (DSBs through its Ku subunits and initiates non-homologous end joining. Inhibition of DNA-PK sensitizes cancer cells to cisplatin killing. The goal of this study is to elucidate the mechanism underlying the effects of DNA-PK on cisplatin sensitivity. Results Silencing the expression of the catalytic subunit of DNA-PK (DNA-PKcs increased sensitivity to cisplatin and decreased the appearance of γH2AX after cisplatin treatment. We purified DNA-PK by its Ku86 subunit and identified interactors by tandem mass spectrometry before and after cisplatin treatment. The structure specific recognition protein 1 (SSRP1, Spt16 and γH2AX appeared in the Ku86 complex 5 hours after cisplatin treatment. SSRP1 and Spt16 form the facilitator of chromatin transcription (FACT. The cisplatin-induced association of FACT with Ku86 and γH2AX was abrogated by DNase treatment. In living cells, SSRP1 and Ku86 were recruited at sites of DSBs induced by laser beams. Silencing SSRP1 expression increased sensitivity to cisplatin and decreased γH2AX appearance. However, while silencing SSRP1 in cisplatin-treated cells increased both apoptosis and necrosis, DNA-PKcs silencing, in contrast, favored necrosis over apoptosis. Conclusions DNA-PK and FACT both play roles in DNA repair. Therefore both are putative targets for therapeutic inhibition. Since DNA-PK regulates apoptosis, silencing DNA-PKcs redirects cells treated with cisplatin toward necrosis. Silencing FACT however, allows both apoptosis and

  10. Recurrent failings of medical humanitarianism: intractable, ignored, or just exaggerated? (United States)

    Colombo, Sandro; Pavignani, Enrico


    Humanitarian health workers operate in dangerous and uncertain contexts, in which mistakes and failures are common, often have severe consequences, and are regularly repeated, despite being documented by many reviews. This Series paper aims to discuss the failures of medical humanitarianism. We describe why some of these recurrent failings, which are often not identified until much later, seem intractable: they are so entrenched in humanitarian action that they cannot be addressed by simple technical fixes. We argue that relief health-care interventions should be contextualised. Perhaps medical humanitarianism deserves a better reputation than the one at times tarnished by unfair criticism, resulting from inapplicable guiding principles and unrealistic expectations. The present situation is not conducive to radical reforms of humanitarian medicine; complex crises multiply and no political, diplomatic, or military solutions are in sight. Relief agencies have to compete for financial resources that do not increase at the same pace as health needs. Avoiding the repetition of failures requires recognising previous mistakes and addressing them through different policies by donors, stronger documentation and analysis of humanitarian programmes and interventions, increased professionalisation, improved, opportunistic relationships with the media, and better ways of working together with local health stakeholders and through indigenous institutions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Concomitant and previous osteoporotic vertebral fractures. (United States)

    Lenski, Markus; Büser, Natalie; Scherer, Michael


    Background and purpose - Patients with osteoporosis who present with an acute onset of back pain often have multiple fractures on plain radiographs. Differentiation of an acute osteoporotic vertebral fracture (AOVF) from previous fractures is difficult. The aim of this study was to investigate the incidence of concomitant AOVFs and previous OVFs in patients with symptomatic AOVFs, and to identify risk factors for concomitant AOVFs. Patients and methods - This was a prospective epidemiological study based on the Registry of Pathological Osteoporotic Vertebral Fractures (REPAPORA) with 1,005 patients and 2,874 osteoporotic vertebral fractures, which has been running since February 1, 2006. Concomitant fractures are defined as at least 2 acute short-tau inversion recovery (STIR-) positive vertebral fractures that happen concomitantly. A previous fracture is a STIR-negative fracture at the time of initial diagnostics. Logistic regression was used to examine the influence of various variables on the incidence of concomitant fractures. Results - More than 99% of osteoporotic vertebral fractures occurred in the thoracic and lumbar spine. The incidence of concomitant fractures at the time of first patient contact was 26% and that of previous fractures was 60%. The odds ratio (OR) for concomitant fractures decreased with a higher number of previous fractures (OR =0.86; p = 0.03) and higher dual-energy X-ray absorptiometry T-score (OR =0.72; p = 0.003). Interpretation - Concomitant and previous osteoporotic vertebral fractures are common. Risk factors for concomitant fractures are a low T-score and a low number of previous vertebral fractures in cases of osteoporotic vertebral fracture. An MRI scan of the the complete thoracic and lumbar spine with STIR sequence reduces the risk of under-diagnosis and under-treatment.

  12. Implant failure and history of failed endodontic treatment: A retrospective case-control study. (United States)

    Chatzopoulos, Georgios S; Wolff, Larry F


    Residual bacterial biofilm and/or bacteria in planktonic form may be survived in the bone following an extraction of an infected tooth that was endodontically treated unsuccessfully Failed endodontic treatment may be associated with failure of implants to osseointegrate in the same sites. Therefore, the aim of this retrospective case-control study is to examine the risk of implant failure in previous failed endodontic sites. This retrospective case-control study is based on 94 dental records of implants placed at the University of Minnesota School of Dentistry. Dental records of patients who received an implant in sites with previously failed endodontic therapy in the dental school were identified from the electronic database, while control subjects were obtained from the same pool of patients with the requirement to have received an implant in a site that was not endodontically treated. The mean age of the population was 62.89±14.17 years with 57.4% of the sample being females and 42.6% of them being males. In regards to the socio-economic status and dental insurance, 84.0% of this population was classified as low socio-economic status and 68.1% had dental insurance. Tobacco use was self-reported by 9.6% and hypercholesterolemia was the most prevalent systemic medical condition. Dental implant failure was identified in two of the included records (2.1%), both of which were placed in sites with a history of failed endodontic treatment. Within the limitations of this retrospective case-control study, further investigation with a larger population group into implant failure of sites that previously had unsuccessful endodontic treatment would be warranted. Implant failure may be associated with a history of failed endodontic treatment. Key words: Implantology, endodontics, osseointegration, treatment outcome, case-control study.

  13. Native kidney reincarnation following a failed transplant

    International Nuclear Information System (INIS)

    Mansberg, R.; Roberts, J.M.


    Full text: A 51-year-old woman with end stage renal failure secondary to Haemolytic Uraemic syndrome underwent a cadaveric renal transplant. A routine post transplant DTPA scan was performed which demonstrated satisfactory renal transplant perfusion and function. Incidental note was made of tracer uptake in the pelvis in the mid-line, which was suspected to be a uterine fibroid. This was confirmed on ultrasonography and at surgery. One week post transplantation the patient became acutely unwell and at laparotomy a perforated diverticular abscess was drained. Intraoperatively the transplant kidney was examined and the surgeon thought there was a area of infarction. This was confirmed on biopsy. As the patient's creatinine was rising a repeat DTPA study was performed. Perfusion and function of the transplant kidney was virtually absent while Doppler studies showed no flow. The patient however continued to produce urine and the creatinine was stable. Subsequently a mercaptoacetyltriglycine (MAG) 3 study was performed which again confirmed absent perfusion and function by the the transplanted kidney as well as the previous noted uterine fibroid. The native kidneys however demonstrated good perfusion and function. The patient's renal function remained stable and she did not require dialysis. A necrotic infarcted transplant kidney was removed uneventfully. This case illustrates the importance of imaging the native kidneys as well as the transplant kidney when there are puzzling clinical features. The presumed cause of the recovery of native renal function was the immunosuppression given for the transplant. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

  14. Uterine rupture without previous caesarean delivery

    DEFF Research Database (Denmark)

    Thisted, Dorthe L. A.; H. Mortensen, Laust; Krebs, Lone


    OBJECTIVE: To determine incidence and patient characteristics of women with uterine rupture during singleton births at term without a previous caesarean delivery. STUDY DESIGN: Population based cohort study. Women with term singleton birth, no record of previous caesarean delivery and planned...... vaginal delivery (n=611,803) were identified in the Danish Medical Birth Registry (1997-2008). Medical records from women recorded with uterine rupture during labour were reviewed to ascertain events of complete uterine rupture. Relative Risk (RR) and adjusted Relative Risk Ratio (aRR) of complete uterine...... rupture with 95% confidence intervals (95% CI) were ascertained according to characteristics of the women and of the delivery. RESULTS: We identified 20 cases with complete uterine rupture. The incidence of complete uterine rupture among women without previous caesarean delivery was about 3...

  15. Ultrasonics aids the identification of failed fuel rods

    International Nuclear Information System (INIS)



    Over a number of years Brown Boveri Reaktor of West Germany has developed and commercialized an ultrasonic failed fuel rod detection system. Sipping has up to now been the standard technique for failed fuel detection, but sipping can only indicate whether or not an assembly contains defective rods; the BBR system can tell which rod is defective. (author)

  16. 7 CFR 983.52 - Failed lots/rework procedure. (United States)


    ... Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE PISTACHIOS GROWN IN CALIFORNIA.... Each lot of substandard pistachios may be reworked to meet aflatoxin or quality requirements. The... reporting. If a lot fails to meet the aflatoxin and/or the quality requirements of this part, a failed lot...

  17. Management for failed back surgery syndrome: three-in-one ...

    African Journals Online (AJOL)

    Management for failed back surgery syndrome: three-in-one procedure versus percutaneous spinal fixation alone .... unchanged; Fair: definite relief of some preoperative symptoms, while other symptoms were either .... spinal fixation procedure alone for management of pain and handicap after failed back spinal surgery ...

  18. 75 FR 76321 - Source of Income From Qualified Fails Charges (United States)


    ... Source of Income From Qualified Fails Charges AGENCY: Internal Revenue Service (IRS), Treasury. ACTION... source of income attributable to qualified fails charges. This action is necessary to provide guidance...-basis taxation of foreign persons not otherwise subject to U.S. net-basis taxation and the withholding...

  19. Simulating fail-stop in asynchronous distributed systems (United States)

    Sabel, Laura; Marzullo, Keith


    The fail-stop failure model appears frequently in the distributed systems literature. However, in an asynchronous distributed system, the fail-stop model cannot be implemented. In particular, it is impossible to reliably detect crash failures in an asynchronous system. In this paper, we show that it is possible to specify and implement a failure model that is indistinguishable from the fail-stop model from the point of view of any process within an asynchronous system. We give necessary conditions for a failure model to be indistinguishable from the fail-stop model, and derive lower bounds on the amount of process replication needed to implement such a failure model. We present a simple one-round protocol for implementing one such failure model, which we call simulated fail-stop.

  20. INTRODUCTION Previous reports have documented a high ...

    African Journals Online (AJOL)

    pregnancy if they were married, educated, had dental insurance, previously used dental services when not pregnant, or had knowledge about the possible connection between oral health and pregnancy outcome8. The purpose of this study was to explore the factors determining good oral hygiene among pregnant women ...

  1. Empowerment perceptions of educational managers from previously ...

    African Journals Online (AJOL)

    The perceptions of educational manag ers from previously disadvantaged primary and high schools in the Nelson Mandela Metropole regarding the issue of empowerment are outlined and the perceptions of educational managers in terms of various aspects of empowerment at different levels reflected. A literature study ...

  2. Management of choledocholithiasis after previous gastrectomy. (United States)

    Anwer, S; Egan, R; Cross, N; Guru Naidu, S; Somasekar, K


    Common bile duct stones in patients with a previous gastrectomy can be a technical challenge because of the altered anatomy. This paper presents the successful management of two such patients using non-traditional techniques as conventional endoscopic retrograde cholangiopancreatography was not possible.

  3. Laboratory Grouping Based on Previous Courses. (United States)

    Doemling, Donald B.; Bowman, Douglas C.


    In a five-year study, second-year human physiology students were grouped for laboratory according to previous physiology and laboratory experience. No significant differences in course or board examination performance were found, though correlations were found between predental grade-point averages and grouping. (MSE)

  4. Indiscriminate behaviors in previously institutionalized young children. (United States)

    Gleason, Mary Margaret; Fox, Nathan A; Drury, Stacy S; Smyke, Anna T; Nelson, Charles A; Zeanah, Charles H


    This study included 54-month-old children with a history of institutional care. Our goal was to: (1) examine differences in indiscriminate social behaviors in children with a history of institutional care compared with home-reared children; (2) test whether foster care reduces indiscriminate social behaviors in a randomized controlled trial; and (3) examine early predictors of indiscriminate behaviors. Participants were 58 children with a history of institutional care and 31 never-institutionalized control (NIG) subjects enrolled in a randomized controlled trial of foster care for institutional care, assessed from toddlerhood to 54 months. Indiscriminate social behaviors were measured naturalistically by using the Stranger at the Door procedure. In the Stranger at the Door procedure, children with a history of institutional care left with a stranger at higher rates than NIG subjects (33% vs. 3.5%; P Children in the care as usual group left more than NIG subjects (41.9% vs. 3.6%; P ≤ .001). The differences between the foster care group (24.1%) and the care as usual group and between foster care group and NIG were not significant. In a logistic regression, early disorganized attachment behaviors, baseline developmental quotient, and caregiving quality after randomization contributed to variance at 54 months. In the same analysis using only children with a history of institutional care, only disorganized attachment contributed significantly to 54-month indiscriminate social behaviors (Exp[B] = 1.6 [95% confidence interval: 1.1-2.5]). Observed socially indiscriminate behaviors at 54 months were associated with prolonged exposure to institutional care. Young children raised in conditions of deprivation who fail to develop organized attachments as toddlers are at increased risk for subsequent indiscriminate behaviors.

  5. Previously unknown organomagnesium compounds in astrochemical context


    Ruf, Alexander


    We describe the detection of dihydroxymagnesium carboxylates (CHOMg) in astrochemical context. CHOMg was detected in meteorites via ultrahigh-resolving chemical analytics and represents a novel, previously unreported chemical class. Thus, chemical stability was probed via quantum chemical computations, in combination with experimental fragmentation techniques. Results propose the putative formation of green-chemical OH-Grignard-type molecules and triggered fundamental questions within chemica...

  6. [Placental complications after a previous cesarean section]. (United States)

    Milosević, Jelena; Lilić, Vekoslav; Tasić, Marija; Radović-Janosević, Dragana; Stefanović, Milan; Antić, Vladimir


    The incidence of cesarean section has been rising in the past 50 years. With the increased number of cesarean sections, the number of pregnancies with the previous cesarean section rises as well. The aim of this study was to establish the influence of the previous cesarean section on the development of placental complications: placenta previa, placental abruption and placenta accreta, as well as to determine the influence of the number of previous cesarean sections on the complication development. The research was conducted at the Clinic of Gynecology and Obstetrics in Nis covering 10-year-period (from 1995 to 2005) with 32358 deliveries, 1280 deliveries after a previous cesarean section, 131 cases of placenta previa and 118 cases of placental abruption. The experimental groups was presented by the cases of placenta previa or placental abruption with prior cesarean section in obstetrics history, opposite to the control group having the same conditions but without a cesarean section in medical history. The incidence of placenta previa in the control group was 0.33%, opposite to the 1.86% incidence after one cesarean section (pcesarean sections and as high as 14.28% after three cesarean sections in obstetric history. Placental abruption was recorded as placental complication in 0.33% pregnancies in the control group, while its incidence was 1.02% after one cesarean section (pcesarean sections. The difference in the incidence of intrapartal hysterectomy between the group with prior cesarean section (0.86%) and without it (0.006%) shows a high statistical significance (pcesarean section is an important risk factor for the development of placental complications.

  7. hSSB1 phosphorylation is dynamically regulated by DNA-PK and PPP-family protein phosphatases. (United States)

    Ashton, Nicholas W; Paquet, Nicolas; Shirran, Sally L; Bolderson, Emma; Kariawasam, Ruvini; Touma, Christine; Fallahbaghery, Azadeh; Gamsjaeger, Roland; Cubeddu, Liza; Botting, Catherine; Pollock, Pamela M; O'Byrne, Kenneth J; Richard, Derek J


    The maintenance of genomic stability is essential for cellular viability and the prevention of diseases such as cancer. Human single-stranded DNA-binding protein 1 (hSSB1) is a protein with roles in the stabilisation and restart of stalled DNA replication forks, as well as in the repair of oxidative DNA lesions and double-strand DNA breaks. In the latter process, phosphorylation of threonine 117 by the ATM kinase is required for hSSB1 stability and efficient DNA repair. The regulation of hSSB1 in other DNA repair pathways has however remained unclear. Here we report that hSSB1 is also directly phosphorylated by DNA-PK at serine residue 134. While this modification is largely suppressed in undamaged cells by PPP-family protein phosphatases, S134 phosphorylation is enhanced following the disruption of replication forks and promotes cellular survival. Together, these data thereby represent a novel mechanism for hSSB1 regulation following the inhibition of replication. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Urinary Excretion of Tetrodotoxin Modeled in a Porcine Renal Proximal Tubule Epithelial Cell Line, LLC-PK1

    Directory of Open Access Journals (Sweden)

    Takuya Matsumoto


    Full Text Available This study examined the urinary excretion of tetrodotoxin (TTX modeled in a porcine renal proximal tubule epithelial cell line, LLC-PK1. Time course profiles of TTX excretion and reabsorption across the cell monolayers at 37 °C showed that the amount of TTX transported increased linearly for 60 min. However, at 4 °C, the amount of TTX transported was approximately 20% of the value at 37 °C. These results indicate that TTX transport is both a transcellular and carrier-mediated process. Using a transport inhibition assay in which cell monolayers were incubated with 50 µM TTX and 5 mM of a transport inhibitor at 37 °C for 30 min, urinary excretion was significantly reduced by probenecid, tetraethylammonium (TEA, l-carnitine, and cimetidine, slightly reduced by p-aminohippuric acid (PAH, and unaffected by 1-methyl-4-phenylpyridinium (MPP+, oxaliplatin, and cefalexin. Renal reabsorption was significantly reduced by PAH, but was unaffected by probenecid, TEA and l-carnitine. These findings indicate that TTX is primarily excreted by organic cation transporters (OCTs and organic cation/carnitine transporters (OCTNs, partially transported by organic anion transporters (OATs and multidrug resistance-associated proteins (MRPs, and negligibly transported by multidrug and toxic compound extrusion transporters (MATEs.

  9. Predictors of failed attendances in a multi-specialty outpatient centre using electronic databases

    Directory of Open Access Journals (Sweden)

    Chen Mark I


    Full Text Available Abstract Background Failure to keep outpatient medical appointments results in inefficiencies and costs. The objective of this study is to show the factors in an existing electronic database that affect failed appointments and to develop a predictive probability model to increase the effectiveness of interventions. Methods A retrospective study was conducted on outpatient clinic attendances at Tan Tock Seng Hospital, Singapore from 2000 to 2004. 22864 patients were randomly sampled for analysis. The outcome measure was failed outpatient appointments according to each patient's latest appointment. Results Failures comprised of 21% of all appointments and 39% when using the patients' latest appointment. Using odds ratios from the mutliple logistic regression analysis, age group (0.75 to 0.84 for groups above 40 years compared to below 20 years, race (1.48 for Malays, 1.61 for Indians compared to Chinese, days from scheduling to appointment (2.38 for more than 21 days compared to less than 7 days, previous failed appointments (1.79 for more than 60% failures and 4.38 for no previous appointments, compared with less than 20% failures, provision of cell phone number (0.10 for providing numbers compared to otherwise and distance from hospital (1.14 for more than 14 km compared to less than 6 km were significantly associated with failed appointments. The predicted probability model's diagnostic accuracy to predict failures is more than 80%. Conclusion A few key variables have shown to adequately account for and predict failed appointments using existing electronic databases. These can be used to develop integrative technological solutions in the outpatient clinic.

  10. Childhood obesity: parents fail to recognise, general practitioners fail to act.

    LENUS (Irish Health Repository)

    White, A


    General Practitioners (GPs) have an important role to play in recognition of and intervention against childhood obesity in Ireland. Data were collected prospectively on a cohort of children aged 4-14 and their parents (n = 101 pairs) who attended consecutively to a semi-rural group general practice. Parents estimated their child\\'s weight status. Actual weight status was determined for both parent and child using the United States Centres\\' for Disease Control\\'s BMI-for-age references. 15 (14.9%) of the children and 49 (51.6%) of the parents were overweight or obese. While 71 (95.5%) of normal weight status children were correctly identified, parents showed poor concordance in identifying their children as overweight 2 (18.2%) or obese 0 (0%). BMI was only evidently recorded in the clinical records of 1 out of 15 cases of overweight children identified. With parents failing to recognise childhood obesity, GPs have a responsibility in tackling this problem at a family level.

  11. Securing Failed Inner-City Communities: The Military's Role

    National Research Council Canada - National Science Library

    Khan, Oral


    This study examines the threat to internal security posed by violent gangs. This threat was found to be particularly acute in inner-city communities that have over time devolved to a status that the author classified as failed communities...

  12. Pharmacokinetics (PK), Pharmacodynamics (PD) and Integrated PK/PD Modeling of a Novel Long Acting FGF21 Clinical Candidate PF-05231023 in Diet-Induced Obese and Leptin-Deficient Obese Mice (United States)

    Bernardo, Barbara; Yan, Qingyun; Zhu, Yimin; Brenner, Martin B.; Vage, Chandra; Logan, Alison; Calle, Roberto; Talukdar, Saswata


    Pharmacological administration of fibroblast growth factor 21 (FGF21) improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB)/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C- and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (SC) bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability). Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW) loss and glucose reduction during an oral glucose tolerance test (OGTT) following SC and intravenous (IV) administration in diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C-terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C-terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits. PMID:25790234

  13. Why military personnel fail to keep medical appointments. (United States)

    Thornton, R; Ballard, K


    Failure to keep medical appointments, commonly referred to as 'Did Not Attend' (DNA), is a frequent problem in both primary and secondary health care and leads to a waste of valuable resources. Although the reasons for DNA within the general population are well documented, little is known about this behaviour amongst people serving in the armed forces. In this paper we report the findings of a questionnaire-based study investigating the reasons why military personnel fail to keep hospital appointments. A postal questionnaire asking questions about the reasons for not attending the appointment and how they perceived the condition for which treatment had been sought, were sent to 167 military patients known to have missed appointments in either a hospital outpatient department or regional rehabilitation unit. 162 controls, who attended appointments, were also sent a questionnaire asking them about factors leading to their appointment and how they perceived the condition that they attended the appointment for. Illness perception was measured using a previously validated Illness perception Questionnaire (IPQ-R). The controls were matched by rank, gender and corps. The overall response rate was 51.5%, with 46% response in the DNA group and 55% in the controls. A previous history of hospital DNA (though not DNA in primary care) and attempting to change the appointment date were associated with DNA (p = 0.01). Those who received a reminder about the appointment were less likely to DNA (p IPQ-R, was not associated with appointment attendance. The most frequent reasons cited for missed appointments were due to administrative problems, with many (38%) respondents being simply unaware that they had an appointment at all or believing that they had cancelled it (14%). Forgetting the appointment (8%) or mixing up the date (21%) were also cited by respondents as reasons for not attending. Only 11% of respondents gave reasons that were specific to a military population, most

  14. Failing the market, failing deliberative democracy: How scaling up corporate carbon reporting proliferates information asymmetries

    Directory of Open Access Journals (Sweden)

    Ingmar Lippert


    Full Text Available Corporate carbon footprint data has become ubiquitous. This data is also highly promissory. But as this paper argues, such data fails both consumers and citizens. The governance of climate change seemingly requires a strong foundation of data on emission sources. Economists approach climate change as a market failure, where the optimisation of the atmosphere is to be evidence based and data driven. Citizens or consumers, state or private agents of control, all require deep access to information to judge emission realities. Whether we are interested in state-led or in neoliberal ‘solutions’ for either democratic participatory decision-making or for preventing market failure, companies’ emissions need to be known. This paper draws on 20 months of ethnographic fieldwork in a Fortune 50 company’s environmental accounting unit to show how carbon reporting interferes with information symmetry requirements, which further troubles possibilities for contesting data. A material-semiotic analysis of the data practices and infrastructures employed in the context of corporate emissions disclosure details the situated political economies of data labour along the data processing chain. The explicit consideration of how information asymmetries are socially and computationally shaped, how contexts are shifted and how data is systematically straightened out informs a reflexive engagement with Big Data. The paper argues that attempts to automatise environmental accounting’s veracity management by means of computing metadata or to ensure that data quality meets requirements through third-party control are not satisfactory. The crossover of Big Data with corporate environmental governance does not promise to trouble the political economy that hitherto sustained unsustainability.

  15. National intelligence estimates and the Failed State Index. (United States)

    Voracek, Martin


    Across 177 countries around the world, the Failed State Index, a measure of state vulnerability, was reliably negatively associated with the estimates of national intelligence. Psychometric analysis of the Failed State Index, compounded of 12 social, economic, and political indicators, suggested factorial unidimensionality of this index. The observed correspondence of higher national intelligence figures to lower state vulnerability might arise through these two macro-level variables possibly being proxies of even more pervasive historical and societal background variables that affect both.

  16. DNA-PK/Ku complex binds to latency-associated nuclear antigen and negatively regulates Kaposi's sarcoma-associated herpesvirus latent replication

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Seho [Department of Life Science, Dongguk Univ-Seoul, Seoul 100-715 (Korea, Republic of); Lim, Chunghun [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701 (Korea, Republic of); Lee, Jae Young [Department of Life Science, Dongguk Univ-Seoul, Seoul 100-715 (Korea, Republic of); Song, Yoon-Jae [Department of Life Science, Kyungwon University, Seongnam-Si, Kyeonggi-Do 461-701 (Korea, Republic of); Park, Junsoo [Division of Biological Science and Technology, Yonsei University, Wonju 220-100 (Korea, Republic of); Choe, Joonho [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701 (Korea, Republic of); Seo, Taegun, E-mail: [Department of Life Science, Dongguk Univ-Seoul, Seoul 100-715 (Korea, Republic of)


    During latent infection, latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) plays important roles in episomal persistence and replication. Several host factors are associated with KSHV latent replication. Here, we show that the catalytic subunit of DNA protein kinase (DNA-PKcs), Ku70, and Ku86 bind the N-terminal region of LANA. LANA was phosphorylated by DNA-PK and overexpression of Ku70, but not Ku86, impaired transient replication. The efficiency of transient replication was significantly increased in the HCT116 (Ku86 +/-) cell line, compared to the HCT116 (Ku86 +/+) cell line, suggesting that the DNA-PK/Ku complex negatively regulates KSHV latent replication.

  17. Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model. (United States)

    Mohamed, Ami F; Kristoffersson, Anders N; Karvanen, Matti; Nielsen, Elisabet I; Cars, Otto; Friberg, Lena E


    Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa. In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem. A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h. The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:

  18. Books average previous decade of economic misery. (United States)

    Bentley, R Alexander; Acerbi, Alberto; Ormerod, Paul; Lampos, Vasileios


    For the 20(th) century since the Depression, we find a strong correlation between a 'literary misery index' derived from English language books and a moving average of the previous decade of the annual U.S. economic misery index, which is the sum of inflation and unemployment rates. We find a peak in the goodness of fit at 11 years for the moving average. The fit between the two misery indices holds when using different techniques to measure the literary misery index, and this fit is significantly better than other possible correlations with different emotion indices. To check the robustness of the results, we also analysed books written in German language and obtained very similar correlations with the German economic misery index. The results suggest that millions of books published every year average the authors' shared economic experiences over the past decade.

  19. Induced vaginal birth after previous caesarean section

    Directory of Open Access Journals (Sweden)

    Akylbek Tussupkaliyev


    Full Text Available Introduction The rate of operative birth by Caesarean section is constantly rising. In Kazakhstan, it reaches 27 per cent. Research data confirm that the percentage of successful vaginal births after previous Caesarean section is 50–70 per cent. How safe the induction of vaginal birth after Caesarean (VBAC remains unclear. Methodology The studied techniques of labour induction were amniotomy of the foetal bladder with the vulsellum ramus, intravaginal administration of E1 prostaglandin (Misoprostol, and intravenous infusion of Oxytocin-Richter. The assessment of rediness of parturient canals was conducted by Bishop’s score; the labour course was assessed by a partogram. The effectiveness of labour induction techniques was assessed by the number of administered doses, the time of onset of regular labour, the course of labour and the postpartum period and the presence of complications, and the course of the early neonatal period, which implied the assessment of the child’s condition, described in the newborn development record. The foetus was assessed by medical ultrasound and antenatal and intranatal cardiotocography (CTG. Obtained results were analysed with SAS statistical processing software. Results The overall percentage of successful births with intravaginal administration of Misoprostol was 93 per cent (83 of cases. This percentage was higher than in the amniotomy group (relative risk (RR 11.7 and was similar to the oxytocin group (RR 0.83. Amniotomy was effective in 54 per cent (39 of cases, when it induced regular labour. Intravenous oxytocin infusion was effective in 94 per cent (89 of cases. This percentage was higher than that with amniotomy (RR 12.5. Conclusions The success of vaginal delivery after previous Caesarean section can be achieved in almost 70 per cent of cases. At that, labour induction does not decrease this indicator and remains within population boundaries.

  20. Measurement of $CP$ asymmetries in $\\Lambda_{b}^{0} \\to pK^{-}$ and $\\Lambda_{b}^{0} \\to p\\pi^-$ decays at LHCb

    CERN Document Server

    Ferrari, F


    The LHCb experiment has been designed to perform precision measurements in the flavour physics sector at the Large Hadron Collider (LHC). The measurement of the CP-violating observable defined as ΔACP = ACP (Λ0b → pK − ) − ACP (Λ0b → pπ − ), where ACP (Λ0b → pK − ) and ACP (Λ0b → pπ − ) are the direct CP asymmetries in Λ0b → pK − and Λ0b → pπ − decays, is presented for the first time using LHCb data. Using the full 2011 and 2012 data sets of pp collisions collected with the LHCb detector, corresponding to an integrated luminosity of about 3 fb −1, the value ΔACP = (0.8 ± 2.1 ± 0.2)% is obtained. The first uncertainty is statistical and the second corresponds to one of the dominant systematic effects. As the result is compatible with zero, no evidence of CP violation is found. This is the most precise measurement of CP violation in the decays of baryons containing the b quark to date. Once the analysis will be completed with an exhaustive study of systematic uncertainti...

  1. Naxos disease in an Arab family is not caused by the Pk2157del2 mutation; evidance for exclusion of the plakoglobin gene

    International Nuclear Information System (INIS)

    Stuhmann, M.; El-Harith, A.; Bukhari, Iqbal A.


    Nax os disease is a rare hereditary disorder characterized by palmoplantar keratoderma, woolly hair and cardiomyopathy. This study aims to determine whether Naxos disease in a Saudi Arab family is caused by the Pk2157del2 mutation that was identified in Greek families from Naxos Island where the disease had originally been described. This study was undertaken at King Fahad Hospital of the University, Al-Khobar, and the Medical University of Hannover, in the spring of 2003. Naxos disease has been encountered in a 2-year-old girl and her 30-year-old aunt of a Saudi Arab family. Deoxyribonucleic acid samples of this family were analyzed by polymerase chain-reaction (PCR) amplification of the respective region of the plakoglobin gene, and direct nucleotide sequencing of the PCR-products. Segregation analysis was performed employing the newly detected IVS11+22G/A polymorphism. Molecular genetic analysis of the DNA sample of the child diagnosed with Naxos disease showed absence of the Pk2157del2 mutation. In addition, the segregation analysis revealed heterozygosity for IVS11+22G/A in the affected girl. Absence of the Pk2157del2 frameshift in the affected child proved that Naxos disease in this Saudi Arab family is not caused by the same mutation that was identified in the Greek families. Furthermore, heterozygosity for the IVS11+22G/A polymorphism provided evidence for exclusion of the plakoglobin gene in this consanguineous family. (author)

  2. Phytochemicals prevent mitochondrial membrane permeabilization and protect SH-SY5Y cells against apoptosis induced by PK11195, a ligand for outer membrane translocator protein. (United States)

    Wu, Yuqiu; Shamoto-Nagai, Masayo; Maruyama, Wakako; Osawa, Toshihiko; Naoi, Makoto


    Epidemiological studies present the beneficial effects of dietary habits on prevention of aging-associated decline of brain function. Phytochemicals, the second metabolites of food, protect neuronal cells from cell death in cellular models of neurodegenerative disorders, and the neuroprotective activity has been ascribed to the anti-oxidant and anti-inflammatory functions. In this paper, the cellular mechanism of neuroprotection by phytochemicals was investigated, using the cellular model of mitochondrial apoptosis induced by PK11195, a ligand of outer membrane translocator protein, in SH-SY5Y cells. PK11195 induced mitochondrial membrane permeabilization with rapid transit production of superoxide (superoxide flashes) and calcium release from mitochondria, and activated apoptosis signal pathway. Study on the structure-activity relationship of astaxanthin, ferulic acid derivatives, and sesame lignans revealed that these phytochemicals inhibited mitochondrial membrane permeabilization and protected cells from apoptosis. Ferulic acid derivatives and sesame lignans inhibited or enhanced the mitochondrial pore formation and cell death by PK11195 according to their amphiphilic properties, not directly depending on the antioxidant activity. Regulation of pore formation at mitochondrial membrane is discussed as a novel mechanism behind neuroprotective activity of phytochemicals in aging and age-associated neurodegenerative disorders, and also behind dual functions of phytochemicals in neuronal and cancer cells.

  3. A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Delta24, for the treatment of advanced breast cancer. (United States)

    Ranki, T; Kanerva, A; Ristimäki, A; Hakkarainen, T; Särkioja, M; Kangasniemi, L; Raki, M; Laakkonen, P; Goodison, S; Hemminki, A


    Conditionally replicating adenoviruses (CRAds) that replicate in tumor but less in normal cells are promising anticancer agents. A major determinant of their potency is their capacity for infecting target cells. The primary receptor for serotype 5 adenovirus (Ad5), the most widely used serotype in gene therapy, is the coxsackie-adenovirus receptor (CAR). CAR is expressed variably and often at low levels in various tumor types including advanced breast cancer. We generated a novel p16/retinoblastoma pathway-dependent CRAd, Ad5.pK7-Delta24, with a polylysine motif in the fiber C-terminus, enabling CAR-independent binding to heparan sulfate proteoglycans (HSPG). Ad5.pK7-Delta24 mediated effective oncolysis of all breast cancer cell lines tested. Further, we utilized noninvasive, fluorescent imaging for analysis of antitumor efficacy in an orthotopic model of advanced hormone refractory breast cancer. A therapeutic benefit was seen following both intratumoral and intravenous delivery. Murine biodistribution similar to Ad5, proven safe in trials, suggests feasibility of clinical safety testing. Interestingly, upregulation of CAR was seen in low-CAR M4A4-LM3 breast cancer cells in vivo, which resulted in better than expected efficacy also with an isogenic CRAd with an unmodified capsid. These results suggest utility of Ad5.pK7-Delta24 and the orthotopic model for further translational studies.

  4. Generation of static PET images with [{sup 11}C]-(R)-PK11195: Defining time interval; Geração de imagens PET Estáticas com [{sup 11}C]-(R)-PK11195: definição do intervalo temporal

    Energy Technology Data Exchange (ETDEWEB)

    Schuck, Phelipi Nunes; Dartora, Caroline Machado; Silva, Ana Maria Marques da, E-mail: [Pontificia Universidade catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil). Núcleo de Pesquisa em Imagens Médicas


    [{sup 11}C]-(R)-PK11195 radiotracer shows microglia affinity in PET images and can be used as neuro inflammatory disease indicator, such as in Multiple Sclerosis (MS). There is no consensus about appropriate time interval to generate static PET images with [{sup 11}C]-(R)-PK11195. The aim of this study is to define the most appropriate time interval to generate static brain PET images with [{sup 11}C]-(R)-PK11195 for quantification. For this study, images from 10 remittent-recurrent MS patients and 5 healthy controls were used. Static images were generated from list-mode dynamic acquisition in the following time intervals: 0-60min, 5-20min, 5-30min, 10-60min, 30-60min e 40-60min. The ratio between SUV mean of juxtacortical and periventricular regions and normal appearing white matter, denominated SUVR{sup WM}, was used for image quantification. Results shown high variation in time intervals that include radiotracer perfusion. SUVRWM higher stability was observed in two time intervals (30-60min and 40-60min), for both control and MS patients groups. In conclusion, the best acquisition time interval to generate static PET images for quantification is from 40 to 60 minutes after administration, meaning an image acquired 40 minutes after [{sup 11}C]-(R)-PK11195 injection, during 20 min. (author)

  5. Optimalisasi Pengelolaan dan Pemanfaatan Aset Tanah dan Bangunan Perguruan Tinggi Negeri (PTN yang Melaksanakan Pengelolaan Keuangan Badan Layanan Umum (PK BLU0 dalam Rangka Meningkatkan Pelayanan Pendidikan

    Directory of Open Access Journals (Sweden)

    Dewi Kania Sugiharti


    Full Text Available Abstrak Perguruan Tinggi Negeri Pengelolaan Keuangan Badan Layanan Umum (PTN-PK BLU merupakan instansi pemerintah yang diberi kewenangan untuk melakukan pengelolaan keuangan badan layanan umum, dengan tujuan untuk meningkatkan pelayanan bidang pendidikan kepada masyarakat dalam rangka mencerdaskan kehidupan bangsa. Fleksibilitas dalam pengelolaan keuangan PTNPKBLU berdasarkan prinsip ekonomi dan produktivitas, serta penerapan praktik bisnis yang sehat. Berdasarkan PP Nomor 23 Tahun 2005 dan PP Nomor 6 Tahun 2006 sebagaimana telah diubah dengan PP Nomor 38 Tahun 2008, fleksibilitas tersebut hanya berlaku dalam pengelolaan keuangan. Tanah dan bangunan yang berada dalam penguasaan PTNPKBLU, wajib dipergunakan sesuai dengan tugas pokok dan fungsi PTNPKBLU tersebut. Secara normatif, tidak ada ketentuan yang memberikan wewenang kepada kuasa pengguna barang untuk memanfaatkannya untuk tujuan lain. Aturan memberi peluang untuk mendayagunakan barang milik negara yang tidak dipergunakan sesuai dengan tugas pokok dan fungsi, yaitu dalam bentuk sewa, pinjam pakai, kerja sama pemanfaatan, dan bangun serah guna/bangun guna serah dengan tidak mengubah status kepemilikan, namun pemanfaatan tersebut hanya dapat dilakukan oleh pengelola barang, bukan oleh kuasa pengguna barang. Dalam hal ini, kuasa pengguna barang milik negara hanya berwenang dan bertanggung jawab untuk menyerahkan tanah dan/atau bangunan yang tidak dimanfaatkan untuk kepentingan penyelenggaraan tugas pokok dan fungsi kantor yang dipimpinnya tersebut, kepada pengguna barang. Abstract State University implementing PK BLU is a government agency with the right to use Pengelolaan Keuangan Badan Layanan Umum (PK BLU to better increase educational service in order to improve the intellectual life of the people of Indonesia. Flexibility in a State University implementing PK BLU has to be based on economic principles, productivity, and fairness. Based on Government Regulation 23/2005 and Government

  6. Thermal analysis of the failed equipment storage vault system

    International Nuclear Information System (INIS)

    Jerrell, J.; Lee, S.Y.; Shadday, A.


    A storage facility for failed glass melters is required for radioactive operation of the Defense Waste Processing Facility (DWPF). It is currently proposed that the failed melters be stored in the Failed Equipment Storage Vaults (FESV's) in S area. The FESV's are underground reinforced concrete structures constructed in pairs, with adjacent vaults sharing a common wall. A failed melter is to be placed in a steel Melter Storage Box (MSB), sealed, and lowered into the vault. A concrete lid is then placed over the top of the FESV. Two melters will be placed within the FESV/MSB system, separated by the common wall. There is no forced ventilation within the vault so that the melter is passively cooled. Temperature profiles in the Failed Equipment Storage Vault Structures have been generated using the FLOW3D software to model heat conduction and convection within the FESV/MSB system. Due to complexities in modeling radiation with FLOW3D, P/THERMAL software has been used to model radiation using the conduction/convection temperature results from FLOW3D. The final conjugate model includes heat transfer by conduction, convection, and radiation to predict steady-state temperatures. Also, the FLOW3D software has been validated as required by the technical task request

  7. Pharmacokinetics (PK, pharmacodynamics (PD and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice.

    Directory of Open Access Journals (Sweden)

    Yan Weng

    Full Text Available Pharmacological administration of fibroblast growth factor 21 (FGF21 improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C- and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (s.c. bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability. Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW loss and glucose reduction during an oral glucose tolerance test (OGTT following SC and intravenous (i.v. administration in diet-induced obese (DIO and leptin-deficient obese (ob/ob mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C-terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C-terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits.

  8. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed

    NARCIS (Netherlands)

    Sands, Bruce E.; Feagan, Brian G.; Rutgeerts, Paul; Colombel, Jean-Frédéric; Sandborn, William J.; Sy, Richmond; D'Haens, Geert; Ben-Horin, Shomron; Xu, Jing; Rosario, Maria; Fox, Irving; Parikh, Asit; Milch, Catherine; Hanauer, Stephen


    There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody

  9. In vivo imaging of ''neuroinflammation''. Principles and applications; In-vivo-Darstellung ''neuroinflammatorischer'' Veraenderungen mit [{sup 11}C] PK11195-PET. Grundlagen und Anwendung

    Energy Technology Data Exchange (ETDEWEB)

    Gerhard, A.; Banati, R.B. [MRC Clinical Sciences Centre and Div. of Neuroscience, Faculty of Medicine, Imperial Coll., London (United Kingdom)


    Microglia are the brains' resident immunocompetent cells that can be activated by acute as well as chronic pathological stimuli. When activated they express the peripheral benzodiazepine binding site to which the isoquinolin PK11195 binds with high specificity. Labelled with [{sup 11}C], the R-enatiomer [{sup 11}C] PK1195 has been used for positron emission tomography (PET) studies to demonstrate neuroinflammatory changes in vivo. [{sup 11}C](R) PK11195-PET has been successfully used to show in vivo microglial activation in ischemic (stroke), inflammatory (multiple sclerosis) and degenerative (Alzheimer's and Parkinson's disease). Longitudinal studies are in progress to help to clarify the relationship between localisation and extent of microglial activation and the clinical presentations in these disorders. This will help to determine the role of [{sup 11}C](R) PK11195 PET as a diagnostic tool and a surrogate marker of ''neuroinflammation'' in therapeutic trials. (orig.) [German] Mikroglia sind residente immunkompetente Zellen des Gehirns, die durch akute, aber auch langsam voranschreitende, chronische Schaedigungprozesse aktiviert werden. Im aktivierten Zustand exprimieren sie den peripheren Benzodiazepinrezeptor, an den das Isoquinolin PK11195 spezifisch bindet. Radioaktiv markiert kann das R-Enantiomer [{sup 11}C] PK11195 als Ligand in der Positronenemissionstomographie (PET) genutzt werden und ermoeglicht so die In-vivo-Darstellung aktiver ''neuroinflammatorischer'', d.h. die Mikroglia aktivierender, Veraenderungen. Mit der [{sup 11}C](R) PK11195-PET konnte bisher In-vivo-Mikrogliaaktivierung bei ischaemischen (Schlaganfall), entzuendlichen (multiple Sklerose) und degenerativen (Morbus Alzheimer- und Parkinson-Erkrankung) demonstriert werden. Laufende longitudinale Studien werden dazu beitragen, die Beziehung zwischen Lokalisation und Ausmass der Mikrogliaaktivierung und klinischer Krankheitsauspraegung

  10. Fail-safe reactivity compensation method for a nuclear reactor

    Energy Technology Data Exchange (ETDEWEB)

    Nygaard, Erik T.; Angelo, Peter L.; Aase, Scott B.


    The present invention relates generally to the field of compensation methods for nuclear reactors and, in particular to a method for fail-safe reactivity compensation in solution-type nuclear reactors. In one embodiment, the fail-safe reactivity compensation method of the present invention augments other control methods for a nuclear reactor. In still another embodiment, the fail-safe reactivity compensation method of the present invention permits one to control a nuclear reaction in a nuclear reactor through a method that does not rely on moving components into or out of a reactor core, nor does the method of the present invention rely on the constant repositioning of control rods within a nuclear reactor in order to maintain a critical state.

  11. Resolution of temporomandibular joint dysfunction (TMJD) by correcting a lateral head translation posture following previous failed traditional chiropractic therapy: a CBP®case report. (United States)

    Jaeger, Jason O; Oakley, Paul A; Moore, Robert R; Ruggeroli, Edward P; Harrison, Deed E


    [Purpose] To present the case of the resolution of right temporomandibular joint dysfunction (TMJD) following the correction of a right lateral head translation posture. [Subject and Methods] A 24 year old female reported facial pain and jaw clicking in the right TMJ. Radiography revealed a 19 mm right head (shift) translation posture. TMJ vibration analysis showed characteristic abnormalities for the right TMJ. The patient was treated with CBP ® technique mirror image ® left sided exercises, and traction methods as well as spinal manipulative therapy (SMT). [Results] After 36 treatments over a 12-week time period, a complete correction of the lateral head posture was achieved corresponding with a complete resolution of jaw pain and clicking. TMJ vibration analysis demonstrated normal right side TMJ characteristics following treatment. [Conclusion] Abnormal head/neck postures, such as lateral head translation, may be an unrealized source of TMJD and may be explained through the 'regional interdependence' model or by how seemingly unrelated anatomy may be associated with a primary complaint.

  12. Failed MTR Fuel Element Detect in a Sipping Tests

    International Nuclear Information System (INIS)

    Zeituni, C.A.; Terremoto, L.A.A.; Silva, J.E.R. da


    This work describes sipping tests performed on Material Testing Reactor (MTR) fuel elements of the IEA-R1 research reactor, in order to find out which one failed in the core during a routine operation. Radioactive iodine isotopes 131 I and 133 I, employed as failure monitors, were detected in samples corresponding to the failed fuel element. The specific activity of each sample, as well as the average leaking rate, were measured for 137 Cs. The nuclear fuels U 3 O 8 - Al dispersion and U - Al alloy were compared concerning their measured average leaking rates of 137 Cs

  13. Failed MTR Fuel Element Detect in a Sipping Tests

    Energy Technology Data Exchange (ETDEWEB)

    Zeituni, C.A.; Terremoto, L.A.A.; da Silva, J.E.R.


    This work describes sipping tests performed on Material Testing Reactor (MTR) fuel elements of the IEA-R1 research reactor, in order to find out which one failed in the core during a routine operation. Radioactive iodine isotopes {sup 131}I and {sup 133}I, employed as failure monitors, were detected in samples corresponding to the failed fuel element. The specific activity of each sample, as well as the average leaking rate, were measured for {sup 137}Cs. The nuclear fuels U{sub 3}O{sub 8} - Al dispersion and U - Al alloy were compared concerning their measured average leaking rates of {sup 137}Cs.

  14. Sipping tests on a failed irradiated MTR fuel element

    International Nuclear Information System (INIS)

    Zeituni, C. A.; Terremoto, L. A. A.; Da Silva, J. E. R.


    This work describes sipping tests performed on Material Testing Reactor (MTR) fuel elements of the IEA-R1 research reactor, in order to find out which one failed in the core during a routine operation. Radioactive iodine isotopes 131 I and 133 I, employed as failure monitors, were detected in samples corresponding to the failed fuel element. The specific activity of each sample, as well as the average leaking rate, were measured for 137 Cs. The nuclear fuels U 3 O 8 - Al dispersion and U - Al alloy were compared concerning their measured average leaking rates of 137 Cs. (authors)

  15. 77 FR 9846 - Source of Income From Qualified Fails Charges (United States)


    ... Administration for comment on its impact on small business. Drafting Information The principal author of these... unit if it satisfies the principles of Sec. 1.864-4(c)(5)(iii) (substituting ``qualified business unit... income, with two exceptions. Qualified fails charge income earned by a qualified business unit (QBU) of a...

  16. Failing Boys! Beyond Crisis, Moral Panic and Limiting Stereotypes (United States)

    Martino, Wayne


    For some time now, school boards, Ministries of Education, and the popular media have been expressing concerns about failing boys and how best to meet their needs, framing these concerns in terms of a crisis in which boys are the "new disadvantaged". This perspective does not provide an accurate representation of the problem and, in fact, detracts…

  17. When Consensus Decision-Making Fails: A Case Study. (United States)

    Savage, Grant T.

    Habermas's theory of dialogue was used to evaluate the process of decision making that occurred in a labor-management committee's meeting to discuss flextime. The study attempted to determine why, at that meeting, the committee's consensus process of decision making failed. W.R. Bion's theory of unconscious group motives was also used to…

  18. Reversing Polarities: Anarchical (Failed States versus International Progress

    Directory of Open Access Journals (Sweden)

    Marta Fernandez Moreno


    Full Text Available The article explores how the literature on 'failed states' (reproduces the modern state as a regulatory ideal, obscuring its contingent character and its violent foundation. So, discursive practices, based on an Eurocentric account, construct the 'failed state' as deviant. The resultant hierarchy of states, in turn, creates favorable conditions for interventionist practices, whose agents are depicted as members of a 'progressive' and 'benevolent' 'international community'. As state failure is interpreted as exclusively domestic process, a well-demarcated boundary between the domestic level of 'anarchy' and the international realm of 'order' and 'progress' results. This article shows that the traditional image of an anarchical system versus an ordered and progressive state is turned on its head when viewed from the perspective of 'failed states'. In the latter, domestic anarchy is contrary to a modernizing international realm. By labelling the 'other' as 'traditional', 'failed', and 'backward' in distinction to a 'modern', 'successful' and 'progressive' international, the dominant discourse conditions us to conceive of these realms as homogeneous in themselves and radically different from each other, rather than as liminal areas with numerous ambiguities and overlaps.

  19. Chloroquine in the Ugandan market fails quality test: a ...

    African Journals Online (AJOL)

    Background: Antimalaria treatment failure has been partly attributed to poor quality antimalarials in the drug market. A 1998 survey in Kampala showed that 55 % of tablets and 62 % of injection forms of chloroquine failed the quality test. Objective: This study was carried out as a follow-up to establish the quality of ...

  20. Why does Centralisation fail to internalise Policy Externalities?

    NARCIS (Netherlands)

    A.J. Dur (Robert); H.J. Roelfsema (Hein)


    textabstractCentralisation of political decision making often fails to produce the desired results. For instance, it is frequently argued that decision making within the European Union results in overspending and overregulation in some policy areas, while too low spending and too little regulation

  1. "It's All Human Error!": When a School Science Experiment Fails (United States)

    Viechnicki, Gail Brendel; Kuipers, Joel


    This paper traces the sophisticated negotiations to re-inscribe the authority of Nature when a school science experiment fails during the enactment of a highly rated science curriculum unit. Drawing on transcriptions from classroom videotapes, we identify and describe four primary patterns of interaction that characterize this process, arguing…

  2. Post-deportation risks for failed asylum seekers

    Directory of Open Access Journals (Sweden)

    Jill Alpes


    Full Text Available What happens to people who are deported after their asylum applications have failed? Many who are deported are at risk of harm when they return to their country of origin but there is little monitoring done of deportation outcomes.

  3. Refections of an Industrial Sociologist on the Failed Attempts to ...

    African Journals Online (AJOL)

    Locating privatisation within the theoretical context of neo-liberalism, this paper reflects on the causes of the failed attempt to privatise NITEL as well as the reasons for dismal performances of most public enterprises in Nigeria. Reflecting on the utility or otherwise of privatising state-owned enterprises in Nigeria, the paper ...

  4. Factors associated with failed spinal anaesthesia for Caesarean ...

    African Journals Online (AJOL)

    Background: The use of spinal anaesthesia has increased in the last three decades, given that it is the recommended anaesthetic of choice for better foetal and maternal outcomes in Caesarean section. Failed spinal anaesthesia (FSA) exposes patients to unfavourable experience of pain and the potential complications of ...

  5. The ugly twins: Failed global sourcing projects and their substitutes

    NARCIS (Netherlands)

    Schiele, Holger; Horn, Philipp; Horn, Philipp; Werner, Welf


    Purpose of the paper and literature addressed: Analyzing the impact of failed global sourcing projects on the entire commodity group and exploring isomorphism as potential antecedent to the observed phenomenon. The paper is embedded in the global sourcing literature, as well as isomorphism and total

  6. Organization Theory: Bright Prospects for a Permanently Failing Field

    NARCIS (Netherlands)

    P.P.M.A.R. Heugens (Pursey)


    textabstractOrganization theory is a paradoxical field of scientific inquiry. It has struggled for more than fifty years to develop a unified theory of organizational effectiveness under girded by a coherent set of assumptions, and it has thus far failed to produce one. Yet, by other standards it is

  7. Therapeutic options after failed Helicobacter pylori eradication therapy

    NARCIS (Netherlands)

    van der Hulst, R. W.; Weel, J. F.; van der Ende, A.; ten Kate, F. J.; Dankert, J.; Tytgat, G. N.


    OBJECTIVES: Many of the currently used Helicobacter pylori eradication regimens fail to cure 5-20% of the patients. Those patients will remain at risk of developing a potentially fatal complication of peptic ulcer disease. Therefore, a new attempt to cure H. pylori infection after initial failure of

  8. Why pediatricians fail to diagnose hypertension: a multicenter survey

    NARCIS (Netherlands)

    Bijlsma, Merijn W.; Blufpand, Hester N.; Kaspers, Gertjan J. L.; Bökenkamp, Arend


    To elucidate why pediatricians fail to diagnose childhood hypertension, with special emphasis on the use of blood pressure (BP) reference data. We hypothesized that pediatricians frequently omit BP measurements and do not routinely relate BP measurements to reference data. We conducted a multicenter

  9. Age of failed restorations: A deceptive longevity parameter

    NARCIS (Netherlands)

    Opdam, N.J.M.; Bronkhorst, E.M.; Cenci, M.S.; Huysmans, M.C.D.N.J.M.; Wilson, N.H.F.


    There is pressing need to enhance evidence base in respect of longevity of restorations. Currently, there is lack of appreciation of differences between survival data based on the age of failed restorations as compared to gold standard Kaplan-Meier statistics. OBJECTIVES: This study was undertaken

  10. Delay factors in failed construction projects in southwestern Nigeria ...

    African Journals Online (AJOL)

    This study was carried out with a view to showing the contribution of delay factors in the overall consideration of failed construction projects in south western Nigeria. This is considered necessary because the traditional view of construction project failure as consisting mainly of structural or functional failures tends to excuse ...

  11. Failed total carpometacarpal joint prosthesis of the thumb

    DEFF Research Database (Denmark)

    Hansen, Torben Bæk; Homilius, Morten


    Total joint prosthesis in carpometacarpal joint arthritis of the thumb often fails. Loosening of the implant is often treated by resection arthroplasty, and we reviewed 10 patients, mean age 54 years (range 47-63) who were treated by resection arthroplasty after a failed total joint prosthesis. T...... in eight of 10 patients, but the mean Disabilities of the arm, shoulder, and hand (DASH) scores, self-reported pinch-grip-related function, and pain were comparable with our earlier published results with the Elektra carpometacarpal total joint prosthesis.......Total joint prosthesis in carpometacarpal joint arthritis of the thumb often fails. Loosening of the implant is often treated by resection arthroplasty, and we reviewed 10 patients, mean age 54 years (range 47-63) who were treated by resection arthroplasty after a failed total joint prosthesis....... The male:female ratio was 1:4 and the mean duration of observation 32 months (range 6-52). In three patients the revised implant was a MOJE uncemented carpometacarpal joint prosthesis and in seven patients an Elektra uncemented one. At follow-up grip strength was reduced to less than 90% of the other hand...

  12. Counselor Liability for Failing to Report Child Abuse. (United States)

    Knapp, Samuel


    Describes the laws regarding counselor liability for failure to report child abuse and state laws designating mandated reporters of suspected child abuse. Notes how the law protects mandated reporters. Discusses criminal penalties for those who fail to report suspected abuse. (RC)

  13. Heterotopic Pregnancy in a Natural Conception Following Failed ...

    African Journals Online (AJOL)

    This report presents another rare case of spontaneous simultaneous intrauterine and extrauterine tubal pregnancies following failed progestogen-only injectable contraceptive. The ruptured heterotopic pregnancy was diagnosed in unruptured state but could not be treated because the couple did not believe/accept the ...

  14. Rulers against Writers, Writers against Rulers: The Failed Promise of ...

    African Journals Online (AJOL)

    Various literary critics have dwelt on the nature, tenets and trends of commitment in Nigeria literature. However, there is paucity of scholarly studies on the representations of the failed promise to the public sphere in postcolonial Nigerian fiction. This paper, therefore, examines the strategies and technicalities of representing ...

  15. Civil Liability for Failing to Report Child Abuse. (United States)

    Lehto, Neil J.


    The article examines the Landeros decision (which ruled that a doctor who fails to report a child abuse victim can be held liable for subsequent injuries inflicted on the child) and discusses three theories of proving civil liability for the failure to report child abuse victims. Addressed are the following topics: the problem of child abuse and…


    African Journals Online (AJOL)


    Jun 6, 2011 ... BENEFITS OF SHIRODKAR STITCH IN WOMEN WITH FAILED McDONALD STITCH. Omondi-Ogutu, MBChB, MMed (O/G) PGDRM, ... advanced cervical changes (dilatation) are present on visual (speculum) and digital .... length at 23 weeks of gestation: the value of. Shirodkar Suture for the short cervix.

  17. Finite element analysis of bone loss around failing implants

    NARCIS (Netherlands)

    Wolff, J.E.H.; Narra, N.; Antalainen, A.K.; Valasek, J.; Kaiser, J.; Sandor, G.K.; Marcian, P.


    Dental implants induce diverse forces on their surrounding bone. However, when excessive unphysiological forces are applied, resorption of the neighbouring bone may occur. The aim of this study was to assess possible causes of bone loss around failing dental implants using finite element analysis. A

  18. Characteristics of failed fertilized oocytes in patients with severe obesity

    Directory of Open Access Journals (Sweden)

    E A Pigarova


    Full Text Available Реферат по статье: Machtinger R, Combelles CM, Missmer SA, Correia KF, Fox JH, Racowsky C. The association between severe obesity and characteristics of failed fertilized oocytes. Hum Reprod. 2012 Nov;27(11:3198-207.

  19. Rates of induced abortion in Denmark according to age, previous births and previous abortions

    Directory of Open Access Journals (Sweden)

    Marie-Louise H. Hansen


    Full Text Available Background: Whereas the effects of various socio-demographic determinants on a woman's risk of having an abortion are relatively well-documented, less attention has been given to the effect of previous abortions and births. Objective: To study the effect of previous abortions and births on Danish women's risk of an abortion, in addition to a number of demographic and personal characteristics. Data and methods: From the Fertility of Women and Couples Dataset we obtained data on the number of live births and induced abortions by year (1981-2001, age (16-39, county of residence and marital status. Logistic regression analysis was used to estimate the influence of the explanatory variables on the probability of having an abortion in a relevant year. Main findings and conclusion: A woman's risk of having an abortion increases with the number of previous births and previous abortions. Some interactions were was found in the way a woman's risk of abortion varies with calendar year, age and parity. The risk of an abortion for women with no children decreases while the risk of an abortion for women with children increases over time. Furthermore, the risk of an abortion decreases with age, but relatively more so for women with children compared to childless women. Trends for teenagers are discussed in a separate section.

  20. High Prevalence of Abacavir-associated L74V/I Mutations in Kenyan Children Failing Antiretroviral Therapy. (United States)

    Dziuban, Eric J; DeVos, Joshua; Ngeno, Bernadette; Ngugi, Evelyn; Zhang, Guoqing; Sabatier, Jennifer; Wagar, Nick; Diallo, Karidia; Nganga, Lucy; Katana, Abraham; Yang, Chunfu; Rivadeneira, Emilia D; Mukui, Irene; Odhiambo, Francesca; Redfield, Robert; Raizes, Elliot


    A survey of 461 HIV-infected Kenyan children receiving antiretroviral therapy found 143 (31%) failing virologically. Drug resistance mutations were found in 121; 37 had L74V/I mutations, with 95% receiving abacavir (ABC)-containing regimens. L74V/I was associated with current ABC usage (P = 0.0001). L74V/I may be more prevalent than previously realized in children failing ABC-containing regimens, even when time on treatment has been short. Ongoing rigorous pediatric drug resistance surveillance is needed.

  1. Conversion of failed modern unicompartmental arthroplasty to total knee arthroplasty. (United States)

    Levine, W N; Ozuna, R M; Scott, R D; Thornhill, T S


    Between January 1983 and January 1991, 29 patients (31 knees) with a failed Robert Brigham metal-backed knee arthroplasty (Johnson & Johnson, Raynham, MA) underwent revision to a total knee arthroplasty (TKA). Twenty-five patients had osteoarthritis, three avascular necrosis, and one rheumatoid arthritis. The average patient age was 72.3 years (range, 49-88 years), and the average weight was 179 lb. (range, 112-242 lb.). The interval between the primary and secondary index procedures averaged 62 months (range, 7-106 months), and mean postrevision follow-up period was 45 months (range, 24-104 months). The primary mechanism of failure of the UKA was tibial polyethylene wear in 21 knees and opposite compartment progression of arthritis in 10 knees. Sixteen knees had particulate synovitis with dense metallic staining of the synovium. At revision, the posterior cruciate ligament was spared in 30 knees and substituted in 1 knee. Restoration of bony deficiency at revision required cancellous bone-graft for contained defects in seven knees, tibial wedges in four knees, and femoral wedges in two knees. No defects received structural allografts. The data suggest that failed, modern unicompartmental knee arthroplasty can successfully be converted to TKA. In most cases, the posterior cruciate ligament can be spared and bone defects corrected with simple wedges or cancellous grafts. Moreover, the results of revision of failed unicompartmental knee arthroplasty are superior to those of failed TKA and failed high tibial osteotomy and comparable to the authors' results of primary TKA with similar-length follow-up periods. Although these results are encouraging, longer-term follow-up evaluation is required to determine survivorship of these revision arthroplasties.

  2. Proximal femoral reconstruction for failed internal fixation of a bisphosphonate-related femur fracture

    Directory of Open Access Journals (Sweden)

    Rishabh G. Jethanandani, BSE


    Full Text Available We present a case of a bisphosphonate-related femur fracture in an elderly woman, who failed treatment with both cephalomedullary nail and proximal femoral locking plate, leading to successful treatment with total hip arthroplasty. Hardware failure should be included in the differential of patients with previous internal fixation of bisphosphonate-related femur fracture that present with hip or groin pain. Arthroplasty can be an acceptable salvage option in an active elderly patient with a bisphosphonate-related femur fracture.

  3. Comparison of nutritional status in hemodialysis patients with and without failed renal allografts. (United States)

    Yelken, B M; Gorgulu, N; Caliskan, Y; Yazici, H; Turkmen, A; Yildiz, A; Sever, M S


    The survival of patients returning to hemodialysis (HD) following kidney transplant failure is unfavorable. However, the factors responsible for this poor outcome are largely unknown; chronic inflammation due to failed allograft and malnutrition may contribute to morbidity and mortality. We aimed to compare the nutritional status and its relation with inflammation in patients on HD with and without previous kidney transplantation. Forty-three patients with failed renal allografts (27 males; mean age 36±9 yr) and 40 never transplanted HD patients (24 males; mean age 39±9 yr) were included in the study. Body weight, triceps (TSF), biceps (BSF), subscapular (SSSF), and suprailiac skinfold thicknesses (SISF); mid-arm, mid-arm muscle, hip and waist circumferences; as well as body mass indices (BMIs) were determined as anthropometric parameters. Moreover, biochemical markers of nutritional status, including serum cholesterol and albumin as well as high-sensitive C-reactive protein (hs-CRP), as a marker of inflammation, were measured. Associations among these variables were analyzed. There were no significant differences considering age, gender or duration of renal replacement therapy between the two groups. The TSF (pfailed renal allografts were significantly lower than those of the never transplanted HD patients. Waist circumference was significantly lower as well (p=0.028). Patients with failed transplants were characterized by lower serum albumin (pfailed allografts may induce chronic inflammation in chronic HD patients which may result in a worse nutritional status. © 2009 John Wiley & Sons A/S.

  4. Salvage Percutaneous Vertebral Augmentation Using Polymethyl Methacrylate in Patients with Failed Interbody Fusion. (United States)

    Yun, Dong-Ju; Hwang, Byeong-Wook; Oh, Hyeong-Seok; Kim, Jin-Sung; Jeon, Sang-Hyeop; Lee, Sang-Ho


    Percutaneous vertebral augmentation with cement is used as a salvage procedure for failed instrumentation. Few studies have reported the use of this procedure for failed anterior lumbar fusion in elderly patients with osteoporosis and other complicated diseases who have undergone a previous major operation. Between January 2007 and December 2015, the clinical and radiographic results of 8 patients with osteoporosis who showed subsidence and migration of the implant after an initial operation were examined. After the development of implant failure, the patients underwent vertebral augmentation with polymethyl methacrylate. Mean patient age was 73.4 years (range, 67-78 years), and mean bone mineral density was -2.96 (range, -2.1 to -3.8). The mean radiologic follow-up period between augmentation and the last follow-up examination was 16 months (range, 3-38 months). Although the subjective clinical outcome was not satisfying to the patients, no loss of correction, fractures, or screw loosening occurred during the follow-up period. The injection of cement around the instrument might help to stabilize it by providing strength to the axis and preventing further loosening. This salvage procedure could be an alternative in the management of cases with failed interbody fusion. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Placenta Percreta in First Trimester after Multiple Rounds of Failed Medical Management for a Missed Abortion

    Directory of Open Access Journals (Sweden)

    Jaimin Shah


    Full Text Available Background. The detection of a morbidly adherent placenta (MAP in the first trimester is rare. Risk factors such as multiparity, advanced maternal age, prior cesarean delivery, prior myomectomy, placenta previa, or previous uterine evacuation place patients at a higher risk for having abnormal placental implantation. If these patients have a first trimester missed abortion and fail medical management, it is important that providers have a heightened suspicion for a MAP. Case. A 24-year-old G4P3003 with 3 prior cesarean deliveries underwent multiple rounds of failed medical management for a missed abortion. She had a dilation and curettage that was complicated by a significant hemorrhage and ultimately required an urgent hysterectomy. Conclusion. When patients fail medical management for a missed abortion, providers need to assess the patient’s risk factors for a MAP. If risk factors are present, a series of specific evaluations should be triggered to rule out a MAP and help further guide management. Early diagnosis of a MAP allows providers to coordinate a multidisciplinary treatment approach and thoroughly counsel patients. Ensuring adequate resources and personnel at a tertiary hospital is essential to provide the highest quality of care and improve outcomes.

  6. Medium pressure boiler water chemistry optimization using neutralizing amines mixture reagent AMINAT™ PK-2 at CEPP “Borovichi Refractories Plant” of JSC “BKO” (United States)

    Guseva, O. V.; Butakova, M. V.; Orlov, K. A.; Vinogradov, S. V.; Pavlenko, L. S.


    An overview of the neutralizing amine based reagent AMINAT PK-2 usage for water chemistry of steam boilers for medium pressure boiler was given. Long term experiment showed that new reagent allows to decrease corrosion rate comparing with old water chemistry based on ammonia only. Two dosage schemes in different cycle places discussed. Scheme with two points on injection showed better results. Results of corrosion rates experiments and photos of tubes inner surfaces are presented. Based on fuel savings due to reducing scale formation the total annual economy for last year was 5.1 million Russian roubles.

  7. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. (United States)

    Kohlhaas, Michael; Liu, Ting; Knopp, Andreas; Zeller, Tanja; Ong, Mei Fang; Böhm, Michael; O'Rourke, Brian; Maack, Christoph


    Oxidative stress is causally linked to the progression of heart failure, and mitochondria are critical sources of reactive oxygen species in failing myocardium. We previously observed that in heart failure, elevated cytosolic Na(+) ([Na(+)](i)) reduces mitochondrial Ca(2+) ([Ca(2+)](m)) by accelerating Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger. Because the regeneration of antioxidative enzymes requires NADPH, which is indirectly regenerated by the Krebs cycle, and Krebs cycle dehydrogenases are activated by [Ca(2+)](m), we speculated that in failing myocytes, elevated [Na(+)](i) promotes oxidative stress. We used a patch-clamp-based approach to simultaneously monitor cytosolic and mitochondrial Ca(2+) and, alternatively, mitochondrial H(2)O(2) together with NAD(P)H in guinea pig cardiac myocytes. Cells were depolarized in a voltage-clamp mode (3 Hz), and a transition of workload was induced by beta-adrenergic stimulation. During this transition, NAD(P)H initially oxidized but recovered when [Ca(2+)](m) increased. The transient oxidation of NAD(P)H was closely associated with an increase in mitochondrial H(2)O(2) formation. This reactive oxygen species formation was potentiated when mitochondrial Ca(2+) uptake was blocked (by Ru360) or Ca(2+) efflux was accelerated (by elevation of [Na(+)](i)). In failing myocytes, H(2)O(2) formation was increased, which was prevented by reducing mitochondrial Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger. Besides matching energy supply and demand, mitochondrial Ca(2+) uptake critically regulates mitochondrial reactive oxygen species production. In heart failure, elevated [Na(+)](i) promotes reactive oxygen species formation by reducing mitochondrial Ca(2+) uptake. This novel mechanism, by which defects in ion homeostasis induce oxidative stress, represents a potential drug target to reduce reactive oxygen species production in the failing heart.

  8. Congruency sequence effects are driven by previous-trial congruency, not previous-trial response conflict


    Weissman, Daniel H.; Carp, Joshua


    Congruency effects in distracter interference tasks are often smaller after incongruent trials than after congruent trials. However, the sources of such congruency sequence effects (CSEs) are controversial. The conflict monitoring model of cognitive control links CSEs to the detection and resolution of response conflict. In contrast, competing theories attribute CSEs to attentional or affective processes that vary with previous-trial congruency (incongruent vs. congruent). The present study s...

  9. Important biological information uncovered in previously unaligned reads from chromatin immunoprecipitation experiments (ChIP-Seq) (United States)

    Ouma, Wilberforce Zachary; Mejia-Guerra, Maria Katherine; Yilmaz, Alper; Pareja-Tobes, Pablo; Li, Wei; Doseff, Andrea I.; Grotewold, Erich


    Establishing the architecture of gene regulatory networks (GRNs) relies on chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) methods that provide genome-wide transcription factor binding sites (TFBSs). ChIP-Seq furnishes millions of short reads that, after alignment, describe the genome-wide binding sites of a particular TF. However, in all organisms investigated an average of 40% of reads fail to align to the corresponding genome, with some datasets having as much as 80% of reads failing to align. We describe here the provenance of previously unaligned reads in ChIP-Seq experiments from animals and plants. We show that a substantial portion corresponds to sequences of bacterial and metazoan origin, irrespective of the ChIP-Seq chromatin source. Unforeseen was the finding that 30%–40% of unaligned reads were actually alignable. To validate these observations, we investigated the characteristics of the previously unaligned reads corresponding to TAL1, a human TF involved in lineage specification of hemopoietic cells. We show that, while unmapped ChIP-Seq read datasets contain foreign DNA sequences, additional TFBSs can be identified from the previously unaligned ChIP-Seq reads. Our results indicate that the re-evaluation of previously unaligned reads from ChIP-Seq experiments will significantly contribute to TF target identification and determination of emerging properties of GRNs. PMID:25727450

  10. An optimal inspection strategy for randomly failing equipment

    International Nuclear Information System (INIS)

    Chelbi, Anis; Ait-Kadi, Daoud


    This paper addresses the problem of generating optimal inspection strategies for randomly failing equipment where imminent failure is not obvious and can only be detected through inspection. Inspections are carried out following a condition-based procedure. The equipment is replaced if it has failed or if it shows imminent signs of failure. The latter state is indicated by measuring certain predetermined control parameters during inspection. Costs are associated with inspection, idle time and preventive or corrective actions. An optimal inspection strategy is defined as the inspection sequence minimizing the expected total cost per time unit over an infinite span. A mathematical model and a numerical algorithm are developed to generate an optimal inspection sequence. As a practical example, the model is applied to provide a machine tool operator with a time sequence for inspecting the cutting tool. The tool life time distribution and the trend of one control parameter defining its actual condition are supposed to be known

  11. A survey of failed post-retained restorations

    DEFF Research Database (Denmark)

    Peutzfeldt, A; Sahafi, A; Asmussen, E


    functioned for 10 years or less. Fracture of the tooth was the most common type of failure reported, followed by loosening of the post and fracture of the post. Tapered posts implied an increased risk of tooth fracture compared to loosening or fracture of the post, and the relative risk of tooth fracture...... increased with the functioning time until failure. Fracture of the post was more common among male than female patients. On the basis of this survey of failed post-retained restorations, it was concluded that tapered posts were associated with a higher risk of tooth fracture than were parallel-sided posts......., the tooth, the restorative materials, and the techniques. Two-hundred and sixty questionnaires were collected from 171 practitioners over a 3-year period. Functioning time until failure varied between 3 months and 38 years. Mean survival time until failure was 11 years. Of the failed restorations, 61% had...

  12. 'HAs fail to consult Irish people in UK'. (United States)


    Health authorities are failing to consult local people on their health needs, a conference on the mental health of Irish people living in the UK heard last week. Consulting Irish people was often only 'symbolic', despite the requirements of the NHS and Community Care Act, conference Chair Padraic Kenna, Director of Innisfree Housing Association, told delegates. 'The Irish caught the boat in the 1950s only to miss the boat ever since,' he said.

  13. Amount of meniscal resection after failed meniscal repair. (United States)

    Pujol, Nicolas; Barbier, Olivier; Boisrenoult, Philippe; Beaufils, Philippe


    The failure rate after arthroscopic meniscal repair ranges from 5% to 43.5% (mean, 15%) in the literature. But little is known about the amount of meniscal tissue removed after failed meniscal repair. The volume of subsequent meniscectomy after failed meniscal repair is not increased when compared with the volume of meniscectomy that would have been performed if not initially repaired. Case series; Level of evidence, 4. From January 2000 to December 2009, 295 knees underwent arthroscopic meniscal repair for unstable peripheral vertical tears. When present (219 cases), all anterior cruciate ligament (ACL) tears underwent reconstruction. Patients with multiple ligament injuries and posterior cruciate ligament injuries were excluded from the analysis. Thirty-two medial and 5 lateral menisci underwent subsequent meniscectomy after failed repair at a mean of 26 months postoperatively (range, 3-114 months). Five parameters were specifically evaluated: the amount of meniscectomy related to the initial tear, the ACL status, the appearance of chondral lesions, the time from the initial injury to meniscal repair, and the time from repair to meniscectomy. The posterior segment of the meniscus was involved in all tears and retears. Among failures, resection of the meniscal segments primarily repaired occurred for 17 medial and 2 lateral meniscal tears (52%); the tear extended in 5 cases (all medial menisci), and healing of some repaired segments led to a partial resection of the initial lesion in 35% of cases (10 medial menisci, 3 lateral menisci). The time from injury to meniscal repair was correlated with an increasing volume of meniscus removed (P lesions at revision (P meniscal lesion, even if it fails. The amount of meniscectomy is rarely increased when compared with the initial lesion. This study supports the hypothesis that the meniscus can be partially saved and that a risk of a partial failure should be taken when possible.

  14. Agrobacterium rhizogenes mutants that fail to bind to plant cells.


    Crews, J L; Colby, S; Matthysse, A G


    Transposon insertion mutants of Agrobacterium rhizogenes were screened to obtain mutant bacteria that failed to bind to carrot suspension culture cells. A light microscope binding assay was used. The bacterial isolates that were reduced in binding to carrot cells were all avirulent on Bryophyllum diagremontiana leaves and on carrot root disks. The mutants did not appear to be altered in cellulose production. The composition of the medium affected the ability of the parent and mutant bacteria ...

  15. When in vitro fertilization fails: a prospective view. (United States)

    Black, R B; Walther, V N; Chute, D; Greenfeld, D A


    New reproductive technologies such as in vitro fertilization (IVF) offer much hope to infertile couples, yet the odds for success are not high. In this study we examine the experiences of a cohort of women undergoing IVF or a related technology at three points in time: before technological intervention, approximately one month after the first failed cycle, and six months later. We consider the women's expectations and experiences and discuss implications of the findings for social work practice.

  16. Management of Failed Laparoscopic Roux-en-Y Gastric Bypass. (United States)

    Elnahas, Ahmad Ibrahim; Jackson, Timothy D; Hong, Dennis


    Background: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has emerged as the gold standard for the management of morbid obesity. Accordingly, patients who fail to lose weight after LRYGB present a difficult problem for the bariatric surgeons. A literature review was performed to evaluate the management options for this select bariatric population. Methods: A literature search was conducted in the EMBASE and MEDLINE databases using the most comprehensive timeline. All relevant articles were identified and full texts were obtained and reviewed. Results: Thirteen articles were retrieved based on key word searches. Management for weight failure following LRYGB included revision using the following options: laparoscopic adjustable gastric banding, pouch/anastomotic revision with or without endoluminal techniques, laparoscopic distal Roux-en-Y gastric bypass, and laparoscopic biliopancreatic diversion with duodenal switch. Laparoscopic sleeve gastrectomy may be considered in patients who fail LRYGB with nutritional deficiencies. Conclusion: Failed LRYGB should be managed based on the patient presentation and diagnostic evaluation. Patients may present with significant nutritional deficiencies/complications, failure to lose weight, or weight recidivism. A treatment algorithm is proposed based on the literature to guide bariatric surgeons with respect to management options. However, given the paucity of research with respect to this problem, additional studies are needed to provide more insight on the optimal surgical management.

  17. Failed magnetic resonance imaging examinations due to claustrophobia

    International Nuclear Information System (INIS)

    Sarji, S.A.; Abdullah, B.J.J.; Kumar, G.; Tan, A.H.; Narayanan, P.


    A recognised cause of incomplete or cancelled MRI examinations is anxiety and claustrophobic symptoms in patients undergoing MR scanning. This appears to be a problem in many MRI centres in Western Europe and North America, where it is said to be costly in terms of loss of valuable scan time, and has led to researchers suggesting several anxiety reducing approaches for MRI. To determine the incidence of failed MRI examination among our patients and if there are any associations with a patient's sex, age and education level, we studied claustrophobia that led to premature termination of the MRI examination in the University Malaya Medical Centre (UMMC) in 3324 patients over 28 months. The incidence of failed MRI examinations due to claustrophobia in the UMMC was found to be only 0.54%. There are associations between claustrophobia in MRI with the patients' sex, age and level of education. The majority of those affected were male patients and young patients in the 25-45-year age group. The patients' education level appears to be the strongest association with failed MRI examinations due to claustrophobia, where the majority of the affected were highly educated individuals. Claustrophobia in MRI is more of a problem among the educated individuals or patients from a higher socio-economic group, which may explain the higher incidence in Western European and North American patients. Copyright (1998) Blackwell Science Pty Ltd

  18. Hip arthroplasty in failed intertrochanteric fractures in elderly

    Directory of Open Access Journals (Sweden)

    Javahir A Pachore


    Full Text Available Background: Failed intertrochanteric fractures in elderly patients are surgical challenge with limited options. Hip arthroplasty is a good salvage procedure even though it involves technical issues such as implant removal, bone loss, poor bone quality, trochanteric nonunion and difficulty of surgical exposure. Materials and Methods: 30 patients of failed intertrochanteric fractures where hip arthroplasty was done between May 2008 and December 2011 were included in study. 13 were males and 17 were females with average age of 67.3 years. There were 2 cemented bipolar arthroplasties, 19 uncemented bipolar, 4 cemented total hip arthroplasty and 5 uncemented total hip arthroplasties. 16 patients had a trochanteric nonunion, which was treated by tension band principles. Total hip was considered where there was acetabular damage due to the penetration of implant. Results: The average followup was 20 months (range 6-48 months. Patients were followed up from 6 to 48 months with average followup of 20 months. None of the patients were lost to followup. There was no dislocation. All patients were ambulatory at the final followup. Conclusion: A predictable functional outcome can be achieved by hip arthroplasty in elderly patients with failed intertrochanteric fractures. Though technically demanding, properly performed hip arthroplasty can be a good salvage option for this patient group.

  19. Reasons why patients fail screening in Indian breast cancer trials

    Directory of Open Access Journals (Sweden)

    P Mahajan


    Full Text Available Introduction: An increased number of screen failure patients in a clinical trial increases time and cost required for the recruitment. Assessment of reasons for screen failure can help reduce screen failure rates and improve recruitment. Materials and Methods: We collected retrospective data of human epidermal growth factor receptor (HER2 positive Indian breast cancer patients, who failed screening for phase 3 clinical trials and ascertained their reasons for screen failure from screening logs. Statistical comparison was done to ascertain if there are any differences between private and public sites. Results: Of 727 patients screened at 14 sites, 408 (56.1% failed screening. The data on the specific reasons for screen failures was not available at one of the public sites (38 screen failures out of 83 screened patients. Hence, after excluding that site, further analysis is based on 644 patients, of which 370 failed screening. Of these, 296 (80% screen failure patients did not meet selection criteria. The majority -266 were HER2 negative. Among logistical issues, 39 patients had inadequate breast tissue sample. Sixteen patients withdrew their consent at private sites as compared to six at public sites. The difference between private and public sites for the above three reasons was statistically significant. Conclusion: Use of prescreening logs to reduce the number of patients not meeting selection criteria and protocol logistics, and patient counseling to reduce consent withdrawals could be used to reduce screen failure rate.

  20. Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome

    Directory of Open Access Journals (Sweden)

    Antonella Paladini


    Full Text Available Introduction. This observational study was designed to evaluate the efficacy of ultramicronized palmitoylethanolamide (um-PEA (Normast® administration, as add-on therapy for chronic pain, in the management of pain-resistant patients affected by failed back surgery syndrome. Methods. A total of 35 patients were treated with tapentadol (TPD and pregabalin (PGB. One month after the start of standard treatment, um-PEA was added for the next two months. Pain was evaluated by the Visual Analogue Scale (VAS at the time of enrollment (T0 and after one (T1, two (T2, and three (T3 months. Results. After the first month with TDP + PGB treatment only, VAS score decreased significantly from 5.7±0.12 at the time of enrollment (T0 to 4.3 ± 0.11 (T1 (p<0.0001; however, it failed to provide significant subjective improvement in pain symptoms. Addition of um-PEA led to a further and significant decrease in pain intensity, reaching VAS scores of 2.7 ± 0.09 (T2 and 1.7 ± 0.11 (T3, end of treatment (p<0.0001 without showing any side effects. Conclusions. This observational study provides evidence, albeit preliminary, for the efficacy and safety of um-PEA (Normast as part of a multimodal therapeutic regimen in the treatment of pain-resistant patients suffering from failed back surgery syndrome.

  1. Failed magnetic resonance imaging examinations due to claustrophobia

    Energy Technology Data Exchange (ETDEWEB)

    Sarji, S.A.; Abdullah, B.J.J.; Kumar, G.; Tan, A.H.; Narayanan, P. [University of malaya Centre, Kuala Lumpar (Malaysia). Department of Radiology


    A recognised cause of incomplete or cancelled MRI examinations is anxiety and claustrophobic symptoms in patients undergoing MR scanning. This appears to be a problem in many MRI centres in Western Europe and North America, where it is said to be costly in terms of loss of valuable scan time, and has led to researchers suggesting several anxiety reducing approaches for MRI. To determine the incidence of failed MRI examination among our patients and if there are any associations with a patient`s sex, age and education level, we studied claustrophobia that led to premature termination of the MRI examination in the University Malaya Medical Centre (UMMC) in 3324 patients over 28 months. The incidence of failed MRI examinations due to claustrophobia in the UMMC was found to be only 0.54%. There are associations between claustrophobia in MRI with the patients` sex, age and level of education. The majority of those affected were male patients and young patients in the 25-45-year age group. The patients` education level appears to be the strongest association with failed MRI examinations due to claustrophobia, where the majority of the affected were highly educated individuals. Claustrophobia in MRI is more of a problem among the educated individuals or patients from a higher socio-economic group, which may explain the higher incidence in Western European and North American patients. Copyright (1998) Blackwell Science Pty Ltd 9 refs.

  2. Integrated pharmacokinetic-Pharmacodynamic (PK/PD) model to evaluate the in vivo antimicrobial activity of Marbofloxacin against Pasteurella multocida in piglets. (United States)

    Zeng, Qing Lin; Mei, Xian; Su, Jia; Li, Xiao Hong; Xiong, Wen Guang; Lu, Yan; Zeng, Zhen Ling


    Marbofloxacin is a veterinary fluoroquinolone with high activity against Pasteurella multocida. We evaluated it's in vivo activity against P. multocida based on in vivo time-kill data in swine using a tissue-cage model. A series of dosages ranging from 0.15 to 2.5 mg/kg were administered intramuscularly after challenge with P. multocida type B, serotype 2. The ratio of the 24 h area under the concentration-time curve divided by the minimum inhibitory concentration (AUC 24 TCF/MIC) was the best PK/PD index correlated with the in vivo antibacterial effectiveness of marbofloxacin (R2 = 0.9279). The AUC 24 TCF/MIC necessary to achieve a 1-log 10 CFU/ml reduction and a 3-log 10 CFU/ml (90% of the maximum response) reduction as calculated by an inhibitory sigmoid E max model were 13.48 h and 57.70 h, respectively. Marbofloxacin is adequate for the treatment of swine infected with P. multocida. The tissue-cage model played a significant role in achieving these PK/PD results.

  3. Determining the pk(a) of N,N-dimethylsphingosine and the flip-flop rate of related compounds with deuterium nuclear magnetic resonance

    International Nuclear Information System (INIS)

    Lau, Bienca


    Deuterium nuclear magnetic resonance ( 2 H-NMR) spectroscopy was applied to determine the pk(a) of the protein kinase C (PKC) inhibitor, N,N-dimethylsphingosine (DMS), when bound to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. The quadrupolar splittings from deuterium labels at the α- and the β-positions of the POPC headgroup responded in a manner indicative of a positive surface charge density at pH 7.0. Conversely, at pH 10.0 DMS had virtually no influence on either quadrupolar splitting, an effect attributed to titration of the dimethylamino group of DMS to its neutral form. A DMS titration curve was obtained by quantifying the charge in the quadrupolar splittings as a function of pH. Simulation of this curve yielded a pk(a) of 8.8 of membrane-bound DMS. Using a similar approach, the dynamic process of flip-flop was examined in two DMS analogues. We discuss here the quantitative and the qualitative aspects as well as the limitations of this application. (author)

  4. Identification and Analysis of Novel Viral and Host Dysregulated MicroRNAs in Variant Pseudorabies Virus-Infected PK15 Cells.

    Directory of Open Access Journals (Sweden)

    Fei Liu

    Full Text Available Pseudorabies (PR is one of the most devastating diseases in the pig industry. To identify changes in microRNA (miRNA expression and post-transcriptional regulatory responses to PRV infection in porcine kidney epithelial (PK15 cells, we sequenced a small RNA (sRNA library prepared from infected PK15 cells and compared it to a library prepared from uninfected cells using Illumina deep sequencing. Here we found 25 novel viral miRNAs by high-throughput sequencing and 20 of these miRNAs were confirmed through stem-loop RT-qPCR. Intriguingly, unlike the usual miRNAs encoded by the α-herpesviruses, which are found clustered in the large latency transcript (LLT, these novel viral miRNAs are throughout the PRV genome like β-herpesviruses. Viral miRNAs are predicted to target multiple genes and form a complex regulatory network. GO analysis on host targets of viral miRNAs were involved in complex cellular processes, including the metabolic pathway, biological regulation, stimulus response, signaling process and immune response. Moreover, 13 host miRNAs were expressed with significant difference after infection with PRV: 8 miRNAs were up-regulated and 5 miRNAs were down-regulated, which may affect viral replication in host cell. Our results provided new insight into the characteristic of miRNAs in response to PRV infection, which is significant for further study of these miRNAs function.

  5. Pharmacokinetics of enrofloxacin HCl-2H2O (ENRO-C) in dogs and PK/PD Monte Carlo simulations against Leptospira sp. (United States)

    Sumano, Hector; Ocampo, Luis; Tapia, Graciela; Mendoza, C de Jesus; Gutierrez, Lilia


    Pharmacokinetics/pharmacodynamics (PK/PD) ratios of reference enrofloxacin (Enro-R) and enrofloxacin as HCl-2H 2 O (Enro-C), as well as Monte Carlo simulations based on composite MIC 50 and MIC 90 vs. Leptospira sp., were carried out in dogs after their IM and oral administration (10 mg/kg). Plasma determination of enrofloxacin was achieved by means of high performance liquid chromatography (HPLC). Maximum plasma concentration values after oral administration were 1.47 ± 0.19 µg/mL and 5.3 ± 0.84 µg/mL for Enro-R and Enro-C, respectively, and 1.6 ± 0.12 µg/mL and 7.6 ± 0.93 µg/mL after IM administration. Area under the plasma vs. time concentrations in 24 h (AUC 0-24 ) were 8.02 µg/mL/h and 36.2 µg/mL/h for Enro-R oral and Enro-C oral , respectively, and 8.55 ± 0.85 µg/mL/h and 56.4 ± 6.21 µg/mL/h after IM administration of these drugs. Only PK/PD ratios and Monte Carlo simulations obtained with Enro-C, anticipate that its IM administration to dogs will result in therapeutic concentrations to treat leptospirosis. This is the first time enrofloxacin has been recommended to treat this disease in dogs.

  6. The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism

    International Nuclear Information System (INIS)

    Pajonk, Frank; Ophoven, Arndt van; Weissenberger, Christian; McBride, William H


    By modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition. Prostate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay. Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity. We conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132

  7. "Too big to fail" or "Too non-traditional to fail"?: The determinants of banks' systemic importance


    Moore, Kyle; Zhou, Chen


    This paper empirically analyzes the determinants of banks' systemic importance. In constructing a measure on the systemic importance of financial institutions we find that size is a leading determinant. This confirms the usual "Too big to fail'' argument. Nevertheless, banks with size above a sufficiently high level have equal systemic importance. In addition to size, we find that the extent to which banks engage in non-traditional banking activities is also positively related to ...

  8. [Vaginal delivery after previous cesarean: comparison between own method and Weinstein's predictive score]. (United States)

    Poreba, R; Dudkiewicz, D; Drygalski, M; Poreba, A; Sipiński, A


    121 women after previous caesarean section were examined. The amount of successful labours were compared (according to the own diagnostic card) with the foreseeing probability of vaginal labours according to Weinstein's score. 63% pregnant woman was classified to the natural labour on the base of the own diagnostic card, probability of natural labour according to Weinstein's score were more or equal than 67%. There were no agreement between prognostic Weinstein's scale and our own method in the cases of failed attempt of labour followed by caesarean section.

  9. [Bronchiolitis obliterans in a patient previously working as a printer in a textile factory]. (United States)

    Pérez Fernández, A M; Gómez de Tejada, R; Castañar Jover, A; Checa Pinilla, J M; Fuentes Otero, F


    We report the case of a 24-year-old man with a diagnosis of bronchiolitis obliterans, a rare clinical condition; the similarity to Ardystil syndrome was striking. Relevant occupational history included work in a textile air-brushing factory. Also noteworthy were lesions observed by CT scan in the form of cystic formations measuring less than 1 cm, a finding not previously described in the context of bronchiolitis obliterans. The patient improved immediately after starting corticoid treatment although scans failed to improve over several months of follow-up.

  10. Failed magmatic eruptions: Late-stage cessation of magma ascent (United States)

    Moran, S.C.; Newhall, C.; Roman, D.C.


    When a volcano becomes restless, a primary question is whether the unrest will lead to an eruption. Here we recognize four possible outcomes of a magmatic intrusion: "deep intrusion", "shallow intrusion", "sluggish/viscous magmatic eruption", and "rapid, often explosive magmatic eruption". We define "failed eruptions" as instances in which magma reaches but does not pass the "shallow intrusion" stage, i. e., when magma gets close to, but does not reach, the surface. Competing factors act to promote or hinder the eventual eruption of a magma intrusion. Fresh intrusion from depth, high magma gas content, rapid ascent rates that leave little time for enroute degassing, opening of pathways, and sudden decompression near the surface all act to promote eruption, whereas decreased magma supply from depth, slow ascent, significant enroute degassing and associated increases in viscosity, and impingement on structural barriers all act to hinder eruption. All of these factors interact in complex ways with variable results, but often cause magma to stall at some depth before reaching the surface. Although certain precursory phenomena, such as rapidly escalating seismic swarms or rates of degassing or deformation, are good indicators that an eruption is likely, such phenomena have also been observed in association with intrusions that have ultimately failed to erupt. A perpetual difficulty with quantifying the probability of eruption is a lack of data, particularly on instances of failed eruptions. This difficulty is being addressed in part through the WOVOdat database. Papers in this volume will be an additional resource for scientists grappling with the issue of whether or not an episode of unrest will lead to a magmatic eruption.

  11. Fail-safe computer-based plant protection systems

    International Nuclear Information System (INIS)

    Keats, A.B.


    A fail-safe mode of operation for computers used in nuclear reactor protection systems was first evolved in the UK for application to a sodium cooled fast reactor. The fail-safe properties of both the hardware and the software were achieved by permanently connecting test signals to some of the multiplexed inputs. This results in an unambiguous data pattern, each time the inputs are sequentially scanned by the multiplexer. The ''test inputs'' simulate transient excursions beyond defined safe limits. The alternating response of the trip algorithms to the ''out-of-limits'' test signals and the normal plant measurements is recognised by hardwired pattern recognition logic external to the computer system. For more general application to plant protection systems, a ''Test Signal Generator'' (TSG) is used to compute and generate test signals derived from prevailing operational conditions. The TSG, from its knowledge of the sensitivity of the trip algorithm to each of the input variables, generates a ''test disturbance'' which is superimposed upon each variable in turn, to simulate a transient excursion beyond the safe limits. The ''tripped'' status yielded by the trip algorithm when using data from a ''disturbed'' input forms part of a pattern determined by the order in which the disturbances are applied to the multiplexer inputs. The data pattern formed by the interleaved test disturbances is again recognised by logic external to the protection system's computers. This fail-safe mode of operation of computer-based protection systems provides a powerful defence against common-mode failure. It also reduces the importance of software verification in the licensing procedure. (author)

  12. Clinical Outcomes Associated with a Failed Infant Car Seat Challenge. (United States)

    Shah, Malika D; Dookeran, Keith A; Khan, Janine Y


    To assess comorbid conditions and clinical outcomes among late preterm and low birth weight term infants (Baby Unit. This was a retrospective chart review of consecutive infants who failed ICSC on the Mother-Baby Unit and were subsequently admitted to the neonatal intensive care unit at Prentice Women's Hospital between January 1, 2009, and December 31, 2015. Regression models were used to estimate risk differences (RDs) with 95% CIs for factors related to length of stay. A total of 148 infants were studied (43% male; 37% delivered via cesarean). ICSC failure in the Mother-Baby Unit was due to desaturation, bradycardia, and tachypnea in 59%, 37%, and 4% of infants, respectively. During monitoring on the neonatal intensive care unit, 39% of infants experienced apnea (48% in preterm vs 17% in term infants) in the supine position, 19% received phototherapy, and 2% and 6.8% received nasogastric and thermoregulatory support, respectively. Univariate predictors of increased duration of stay (days) were younger gestational age, apnea, nasogastric support, intravenous fluids, and antibiotics (all P < .05). In multivariable analysis adjusted for gestational age and discharge weight, only apnea (RD, 4.87; 95% CI, 2.99-6.74; P < .001), administration of antibiotics (RD, 3.25; 95% CI, 0.29-6.21; P < .032), and intravenous fluid support (RD, 4.87; 95% CI, 0.076-9.66; P < .047) remained independent predictors of a longer duration of stay. Infants who failed ICSC were at risk for comorbid conditions that prolonged hospital stay beyond the neonatal intensive care unit observation period. Almost one-half of late preterm infants who failed ICSC had apnea events in the supine position. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. In Silico Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetics (ADME-PK): Utility and Best Practices. An Industry Perspective from the International Consortium for Innovation through Quality in Pharmaceutical Development. (United States)

    Lombardo, Franco; Desai, Prashant V; Arimoto, Rieko; Desino, Kelly E; Fischer, Holger; Keefer, Christopher E; Petersson, Carl; Winiwarter, Susanne; Broccatelli, Fabio


    In silico tools to investigate absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK) properties of new chemical entities are an integral part of the current industrial drug discovery paradigm. While many companies are active in the field, scientists engaged in this area do not necessarily share the same background and have limited resources when seeking guidance on how to initiate and maintain an in silico ADME-PK infrastructure in an industrial setting. This work summarizes the views of a group of industrial in silico and experimental ADME scientists, participating in the In Silico ADME Working Group, a subgroup of the International Consortium for Innovation through Quality in Pharmaceutical Development (IQ) Drug Metabolism Leadership Group. This overview on the benefits, caveats, and impact of in silico ADME-PK should serve as a resource for medicinal chemists, computational chemists, and DMPK scientists working in drug design to increase their knowledge in the area.

  14. Fail-safe neutron shutter used for thermal neutron radiography

    International Nuclear Information System (INIS)

    Sachs, R.D.; Morris, R.A.


    A fail-safe, reliable, easy-to-use neutron shutter was designed, built, and put into operation at the Omega West Reactor, Los Alamos Scientific Laboratory. The neutron shutter will be used primarily to perform thermal neutron radiography, but is also available for a highly collimated source of thermal neutrons [neutron flux = 3.876 x 10 6 (neutrons)/(cm 2 .s)]. Neutron collimator sizes of either 10.16 by 10.16 cm or 10.16 by 30.48 cm are available

  15. A Perplexed Economist Confronts 'too Big to Fail'

    Directory of Open Access Journals (Sweden)

    Scherer, F. M.


    Full Text Available This paper examines premises and data underlying the assertion that some financial institutions in the U.S. economy were "too big to fail" and hence warranted government bailout. It traces the merger histories enhancing the dominance of six leading firms in the U. S. banking industry and he sharp increases in the concentration of financial institution assets accompanying that merger wave. Financial institution profits are found to have soared in tandem with rising concentration. The paper advances hypotheses why these phenomena might be related and surveys relevant empirical literature on the relationships between market concentration, interest rates received and charged by banks, and economies of scale in banking.

  16. Sipping test on a failed MTR fuel element

    International Nuclear Information System (INIS)

    Terremoto, Luis Antonio Albiac; Zeituni, Carlos Alberto; Silva, Antonio Teixeira e; Perrotta, Jose Augusto; Silva, Jose Eduardo Rosa da


    This work describes sipping tests performed on MTR fuel elements of the IEA-R1 research reactor, in order to determinate which one failed in the core during a routine operation of the reactor. radioactive iodine isotopes 131 I and 133 I, employed as failure indicators, were detected in samples corresponding to the fuel element IEA-156. The specific activity of each sample, as well as the average leaking rate, were measured for 137 Cs. The nuclear fuels U 3 O 8 - Al dispersion and U - Al alloy were compared concerning their measured average leaking rates of 137 Cs. (author)

  17. Has Multiculturalism Really Failed? A Canadian Muslim Perspective

    Directory of Open Access Journals (Sweden)

    Baljit Nagra


    Full Text Available In recent years, claims that multiculturalism has created segregated communities, encouraged terrorism, and failed to foster shared national identities in western nations have gained popularity. In this paper, we use young Canadian Muslims’ lived experience of multiculturalism to reflect on this debate. Contrary to popular rhetoric, our interviews of 50 young Muslim adults show that many maintain a dual Canadian-Muslim identity by utilizing the ideology of multiculturalism, even though they are increasingly stigmatized for their religion. These findings lead us to problematize the discourse surrounding the ‘failure’ of multiculturalism and to highlight the contradictions within it.

  18. Establishing Pass/Fail Criteria for Bronchoscopy Performance

    DEFF Research Database (Denmark)

    Konge, Lars; Clementsen, Paul; Larsen, Klaus Richter


    Background: Several tools have been created to assess competence in bronchoscopy. However, educational guidelines still use an arbitrary number of performed procedures to decide when basic competency is acquired. Objectives: The purpose of this study was to define pass/fail scores for two...... method. In the first we compared bronchoscopy performance scores of 14 novices with the scores of 14 experienced consultants to find the score that best discriminated between the two groups. In the second we asked an expert group of 7 experienced bronchoscopists to judge how a borderline trainee would...

  19. [Hospitals failing minimum volumes in 2004: reasons and consequences]. (United States)

    Geraedts, M; Kühnen, C; Cruppé, W de; Blum, K; Ohmann, C


    In 2004 Germany introduced annual minimum volumes nationwide on five surgical procedures: kidney, liver, stem cell transplantation, complex oesophageal, and pancreatic interventions. Hospitals that fail to reach the minimum volumes are no longer allowed to perform the respective procedures unless they raise one of eight legally accepted exceptions. The goal of our study was to investigate how many hospitals fell short of the minimum volumes in 2004, whether and how this was justified, and whether hospitals that failed the requirements experienced any consequences. We analysed data on meeting the minimum volume requirements in 2004 that all German hospitals were obliged to publish as part of their biannual structured quality reports. We performed telephone interviews: a) with all hospitals not achieving the minimum volumes for complex oesophageal, and pancreatic interventions, and b) with the national umbrella organisations of all German sickness funds. In 2004, one quarter of all German acute care hospitals (N=485) performed 23,128 procedures where minimum volumes applied. 197 hospitals (41%) did not meet at least one of the minimum volumes. These hospitals performed N=715 procedures (3.1%) where the minimum volumes were not met. In 43% of these cases the hospitals raised legally accepted exceptions. In 33% of the cases the hospitals argued using reasons that were not legally acknowledged. 69% of those hospitals that failed to achieve the minimum volumes for complex oesophageal and pancreatic interventions did not experience any consequences from the sickness funds. However, one third of those hospitals reported that the sickness funds addressed the issue and partially announced consequences for the future. The sickness funds' umbrella organisations stated that there were only sparse activities related to the minimum volumes and that neither uniform registrations nor uniform proceedings in case of infringements of the standards had been agreed upon. In spite of the

  20. Recognizing and treating delayed or failed lactogenesis II. (United States)

    Hurst, Nancy M


    Delayed or failed achievement of lactogenesis II--the onset of copious milk volume--occurs as a result of various maternal and/or infant factors. Early recognition of these risk factors is critical for clinicians who interact with breastfeeding women so that intervention and achievement of full or partial breastfeeding can be preserved. This article describes the maternal and infant conditions that contribute to the unsuccessful establishment of a full lactation. Treatment modalities that can maximize maternal lactation capacity and infant growth rates are offered.

  1. Looked-but-failed-to-see-errors in traffic

    DEFF Research Database (Denmark)

    Herslund, Mai-Britt; Jørgensen, N O


    Danish studies of traffic accidents at priority intersections have shown a particular type of accidents. In these accidents a car driver supposed to give way has collided with a bicycle rider on the priority road. Often the involved car drivers have maintained that they did not see the bicycle...... looking in the direction where the other parties were but have not seen (i.e. perceived the presence of) the other road user. This paper describes two studies approaching this problem.One study is based on 10 self-reported near accidents. It does show that "looked-but-failed-to-see" events do occur...

  2. Analysis of failed ramps during the RHIC FY09 run

    Energy Technology Data Exchange (ETDEWEB)

    Minty, M. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.


    The Relativistic Heavy Ion Collider (RHIC) is a versatile accelerator that supports operation with polarized protons of up to 250 GeV and ions with up to 100 GeV/nucleon. During any running period, various operating scenarios with different particle species, beam energies or accelerator optics are commissioned. In this report the beam commissioning periods for establishing full energy beams (ramp development periods) from the FY09 run are summarized and, for the purpose of motivating further developments, we analyze the reasons for all failed ramps.

  3. Fail-safe storage rack for irradiated fuel rod assemblies (United States)

    Lewis, D.R.


    A fail-safe storage rack is provided for interim storage of spent but radioactive nuclear fuel rod assemblies. The rack consists of a checkerboard array of substantially square, elongate receiving tubes fully enclosed by a double walled container, the outer wall of which is imperforate for liquid containment and the inner wall of which is provided with perforations for admitting moderator liquid flow to the elongate receiving tubes, the liquid serving to take up waste heat from the stored nuclear assemblies and dissipate same to the ambient liquid reservoir. A perforated cover sealing the rack facilitates cooling liquid entry and dissipation.

  4. How energy efficiency fails in the building industry

    International Nuclear Information System (INIS)

    Ryghaug, Marianne; Sorensen, Knut H.


    This paper examines how energy efficiency fails in the building industry based on many years of research into the integration of energy efficiency in the construction of buildings and sustainable architecture in Norway. It argues that energy-efficient construction has been seriously restrained by three interrelated problems: (1) deficiencies in public policy to stimulate energy efficiency, (2) limited governmental efforts to regulate the building industry, and (3) a conservative building industry. The paper concludes that innovation and implementation of new, energy-efficient technologies in the building industry requires new policies, better regulations and reformed practices in the industry itself

  5. On fail-safe principle and safety for reactor control

    International Nuclear Information System (INIS)

    Kawaguchi, Chiyozi; Ito, Taiju


    Fail-safe technique is not systematically established yet in the safety technology in reactor operation, though the concept has been incorporated in design. The safey measures taken are multifold, with emphasis placed on the fair margin of design making sacrifice of economy and availability, and the policy of using multiplicity, independency and reliability freely is taken. The following matters are described: distinction between accidents and failures; principles for reactor safety and safety measures against radiation and accidents of cooling system, foolproof and interlock; the relation between safety and plant availability; safety manipulation and scram; reactor safety instrumentation; reliability of measuring instrumentation; and system reliability. (Mori, K.)

  6. John 21:24-25: A case of failed attestation?

    Directory of Open Access Journals (Sweden)

    D.F. Tolmie


    Full Text Available John 21:24-25: A case of� failed attestation In� this article� the� tendency� to� interpret John� 21:24-25 narratologically as a highly sophisticated and effective� technique� is disputed.� Instead it is argued that� the Beloved Disciple� is� identified in� these� verses as� the� real author of the� Gospel� and� that� the� dominating� function� in� John� 21� :24-25� is� the testimonial function� (also� known� as� the function� of attestation.� It� is� also argued� that� the� intended� effect� of this� junction� is� undermined� by� the awkward manner in which� it is� fulfilled.

  7. The Epstein-Barr virus (EBV)-encoded protein kinase, EBV-PK, but not the thymidine kinase (EBV-TK), is required for ganciclovir and acyclovir inhibition of lytic viral production. (United States)

    Meng, Qiao; Hagemeier, Stacy R; Fingeroth, Joyce D; Gershburg, Edward; Pagano, Joseph S; Kenney, Shannon C


    Ganciclovir (GCV) and acyclovir (ACV) are guanine nucleoside analogues that inhibit lytic herpesvirus replication. GCV and ACV must be monophosphorylated by virally encoded enzymes to be converted into nucleotides and incorporated into viral DNA. However, whether GCV and/or ACV phosphorylation in Epstein-Barr virus (EBV)-infected cells is mediated primarily by the EBV-encoded protein kinase (EBV-PK), the EBV-encoded thymidine kinase (EBV-TK), or both is controversial. To examine this question, we constructed EBV mutants containing stop codons in either the EBV-PK or EBV-TK open reading frame and selected for stable 293T clones latently infected with wild-type EBV or each of the mutant viruses. Cells were induced to the lytic form of viral replication with a BZLF1 expression vector in the presence and absence of various doses of GCV and ACV, and infectious viral titers were determined by a green Raji cell assay. As expected, virus production in wild-type EBV-infected 293T cells was inhibited by both GCV (50% inhibitory concentration [IC(50)] = 1.5 microM) and ACV (IC(50) = 4.1 microM). However, the EBV-PK mutant (which replicates as well as the wild-type (WT) virus in 293T cells) was resistant to both GCV (IC(50) = 19.6 microM) and ACV (IC(50) = 36.4 microM). Expression of the EBV-PK protein in trans restored GCV and ACV sensitivity in cells infected with the PK mutant virus. In contrast, in 293T cells infected with the TK mutant virus, viral replication remained sensitive to both GCV (IC(50) = 1.2 microM) and ACV (IC(50) = 2.8 microM), although susceptibility to the thymine nucleoside analogue, bromodeoxyuridine, was reduced. Thus, EBV-PK but not EBV-TK mediates ACV and GCV susceptibilities.

  8. A Physical Model of Mass Ejection in Failed Supernovae (United States)

    Coughlin, Eric R.; Quataert, Eliot; Fernández, Rodrigo; Kasen, Daniel


    During the core collapse of massive stars, the formation of the protoneutron star is accompanied by the emission of a significant amount of mass-energy (˜0.3 M⊙) in the form of neutrinos. This mass-energy loss generates an outward-propagating pressure wave that steepens into a shock near the stellar surface, potentially powering a weak transient associated with an otherwise-failed supernova. We analytically investigate this mass-loss-induced wave generation and propagation. Heuristic arguments provide an accurate estimate of the amount of energy contained in the outgoing sound pulse. We then develop a general formalism for analyzing the response of the star to centrally concentrated mass loss in linear perturbation theory. To build intuition, we apply this formalism to polytropic stellar models, finding qualitative and quantitative agreement with simulations and heuristic arguments. We also apply our results to realistic pre-collapse massive star progenitors (both giants and compact stars). Our analytic results for the sound pulse energy, excitation radius, and steepening in the stellar envelope are in good agreement with full time-dependent hydrodynamic simulations. We show that prior to the sound pulses arrival at the stellar photosphere, the photosphere has already reached velocities ˜20 - 100% of the local sound speed, thus likely modestly decreasing the stellar effective temperature prior to the star disappearing. Our results provide important constraints on the physical properties and observational appearance of failed supernovae.

  9. Electromechanical Dyssynchrony and Resynchronization of the Failing Heart (United States)

    Kirk, Jonathan A.; Kass, David A.


    Patients with heart failure and depressed function frequently develop discoordinate contraction due to electrical activation delay. Often termed dyssynchrony, this further depresses systolic function and chamber efficiency, and worsens morbidity and mortality. In the mid-1990s, a pacemaker-based treatment termed cardiac resynchronization therapy (CRT) was developed to restore mechanical synchrony by electrically activating both right and left sides of the heart. It is a major therapeutic advance for the new millennium.. Acute chamber-effects of CRT include increased cardiac output and mechanical efficiency, and reduced mitral regurgitation, while reduction in chamber volumes ensues more chronically. Patient candidates for CRT have a prolonged QRS duration and discoordinate wall-motion, although other factors may also be important as ∼30% of such selected subjects fail to respond to the treatment. In contrast to existing pharmacological inotropes, CRT both acutely and chronically increases cardiac systolic function and work yet it also reduces long-term mortality. Recent studies reveal unique molecular/cellular changes from CRT that may also contribute to this success. Heart failure with dyssynchrony displays depressed myocyte and myofilament function, calcium handling, beta-adrenergic responsiveness, mitochondrial ATP-synthase activity, cell survival signaling, and other changes. CRT reverses many of these abnormalities often by triggering entirely new pathways. In this review, we discuss chamber, circulatory, and basic myocardial effects of dyssynchrony and CRT in the failing heart, and highlight new research aiming to better target and implement CRT as well as leverage its molecular effects. PMID:23989718

  10. Mass Ejection in Failed Supernovae: Variation with Stellar Progenitor (United States)

    Fernández, Rodrigo; Quataert, Eliot; Kashiyama, Kazumi; Coughlin, Eric R.


    We study the ejection of mass during stellar core-collapse when the stalled shock does not revive and a black hole forms. Neutrino emission during the protoneutron star phase causes a decrease in the gravitational mass of the core, resulting in an outward going sound pulse that steepens into a shock as it travels out through the star. We explore the properties of this mass ejection mechanism over a range of stellar progenitors using spherically-symmetric, time-dependent hydrodynamic simulations that treat neutrino mass loss parametrically and follow the shock propagation over the entire star. We find that all types of stellar progenitor can eject mass through this mechanism. The ejected mass is a decreasing function of the surface gravity of the star, ranging from several M⊙ for red supergiants to ˜0.1M⊙ for blue supergiants and ˜10-3M⊙ for Wolf-Rayet stars. We find that the final shock energy at the surface is a decreasing function of the core-compactness, and is ≲ 1047 - 1048 erg in all cases. In progenitors with a sufficiently large envelope, high core-compactness, or a combination of both, the sound pulse fails to unbind mass. Successful mass ejection is accompanied by significant fallback accretion that can last from hours to years. We predict the properties of shock breakout and thermal plateau emission produced by the ejection of the outer envelope of blue supergiant and Wolf-Rayet progenitors in otherwise failed supernovae.

  11. We still fail to account for Mendel's observations

    Directory of Open Access Journals (Sweden)

    Porteous John W


    Full Text Available Abstract Background The present article corrects common textbook accounts of Mendel's experiments by re-establishing what he wrote and how he accounted for his observations. It notes the long-established tests for the validity of any explanations that purport to explain observations obtained by experiment. Application of these tests to Mendel's paper shows that the arguments he used to explain his observations were internally consistent but were, on one crucial issue, implausible. The same tests are applied to the currently accepted explanation for Mendel's observations. Conclusions The currently favoured explanation for Mendel's observations is untenable. It misrepresents Mendel, fails to distinguish between the parameters and the variables of any system of interacting components, its arguments are inconsistent, it repeats the implausibility in Mendel's paper, fails to give a rational explanation for his observed 3:1 trait ratio and cannot explain why this ratio is not always observed in experimental practice. A rational explanation for Mendel's observations is initiated. Readers are challenged to complete the process before a further article appears.

  12. Mechanical and Spectroscopic Analysis of Retrieved/Failed Dental Implants

    Directory of Open Access Journals (Sweden)

    Umer Daood


    Full Text Available The purpose of this study was to examine surface alterations and bone formation on the surface of failed dental implants (Straumann [ST] and TiUnite [TiUn] removed due to any biological reason. In addition, failure analysis was performed to test mechanical properties. Dental implants (n = 38 from two manufacturers were collected and subjected to chemical cleaning. The presence of newly formed hydroxyapatite bone around failed implants was evaluated using micro-Raman spectroscopy. Scanning electron microscopy was used to identify surface defects. Mechanical testing was performed using a Minneapolis servo-hydraulic system (MTS along with indentation using a universal testing machine and average values were recorded. A statistical analysis of mechanical properties was done using an unpaired t test, and correlation between observed defects was evaluated using Chi-square (p = 0.05. Apatite-formation was evident in both implants, but was found qualitatively more in the ST group. No significant difference was found in indentation between the two groups (p > 0.05. The percentage of “no defects” was significantly lower in the ST group (71%. Crack-like and full-crack defects were observed in 49% and 39% of TiUn. The ST group showed 11,061 cycles to failure as compared with 10,021 cycles in the TiUnite group. Implant failure mechanisms are complex with a combination of mechanical and biological reasons and these factors are variable with different implant systems.

  13. [Spinal cord stimulation and failed back surgery syndrome. Clinical results with laminectomy electrodes]. (United States)

    García March, Guillermo; Bordes, Vicente; Roldán, Pedro; Real, Luis; González Darder, José Manuel


    Spinal cord stimulation is a widely-accepted technique in the treatment of back pain resulting from failed back surgery. Classically, stimulation has been carried out with percutaneous electrodes implanted under local anaesthesia and sedation. However, the ease of migration and the difficulty of reproducing electrical paresthesias in large areas with such electrodes has led to increasing use of surgical plate leads, which have the disadvantage of the need for general anaesthesia and a laminectomy for implantation. Our objective was to report the clinical results, technical details, advantages and benefits of laminectomy lead placement under epidural anaesthesia in failed back surgery syndrome cases. Spinal cord stimulation was performed in a total of 119 patients (52 men and 67 women), aged between 31 and 73 years (average, 47.3). Epidural anaesthesia was induced with ropivacaine. In all cases we inserted the octapolar or 16-polar lead in the epidural space through a small laminectomy. The final position of the leads was the vertebral level that provided coverage of the patient's pain. The electrodes were connected at dual-channel or rechargeable pulse generators. After a mean follow-up of 4.7 years, the results in terms of improvement of the previous painful situation was satisfactory, with an analgesia level of 58% of axial pain and 60% of radicular pain in more than 70% of cases. None of the patients said that the surgery stage was painful or unpleasant. No serious complications were included in the group, but in 6 cases the system had to be explanted because of ineffectiveness or intolerance of long-term neurostimulation. This study, with a significant number of patients, used epidural anaesthesia for spinal cord stimulation of lead implants by laminectomy in failed back surgery syndromes. The technique seems to be safe and effective. Copyright © 2014 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

  14. PK/PD modelling of glucose-insulin-glucagon dynamics in healthy dogs after a subcutaneous bolus administration of native glucagon or a novel glucagon analogue

    DEFF Research Database (Denmark)

    Wendt, Sabrina Lyngbye; Møller, Jan Kloppenborg; Boye Knudsen, Carsten

    received two subcutaneous (SC) bolus injections of low and high doses of glucagon and ZP-GA-1 (20 and 120 nmol/kg). Results We report posterior probability distributions and correlations for all identifiable model parameters. Based on visual inspection and residual analysis, the PD model described data...... by Zealand Pharma A/S. Research Design and Methods We expanded a physiological model of endogenous glucose production with multiplicative effects of insulin and glucagon and combined it with the Hovorka glucoregulatory model. We used a Bayesian framework to perform multidimensional MAP estimation of model......Objective We aim to develop a simulation model of the complex glucose-insulin-glucagon dynamics based on physiology and data. Furthermore, we compare pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of marketed reconstituted glucagon with a stable liquid glucagon analogue invented...

  15. A novel ViewRNA in situ hybridization method for the detection of the dynamic distribution of Classical Swine Fever Virus RNA in PK15 cells. (United States)

    Zhang, Qianyi; Xu, Lu; Zhang, Yujie; Wang, Tuanjie; Zou, Xingqi; Zhu, Yuanyuan; Zhao, Yan; Li, Cui; Chen, Kai; Sun, Yongfang; Sun, Junxiang; Zhao, Qizu; Wang, Qin


    Classical swine fever (CSF) is a highly contagious fatal infectious disease caused by classical swine fever virus (CSFV). A better understanding of CSFV replication is important for the study of pathogenic mechanism of CSF. With the development of novel RNA in situ Hybridization method, quantitatively localization and visualization of the virus RNA molecular in cultured cell or tissue section becomes very important tool to address these pivotal pathogenic questions. In this study, we established ViewRNA ISH method to reveal the dynamic distribution of CSFV RNA in PK15 cells. We designed several specific probes of CSFV RNA and reference gene β-actin for host PK15 cells to monitor the relative location of CSFV RNA and house-keeping gene in the infected cells. After determining the titer of reference strain CSFV (HeBHH1/95) with the 50% tissue culture infective dose (TCID50), we optimized the protease K concentration and formalin fixation time to analyze the hybridization efficiency, fluorescence intensity and repeatability. In order to measure the sensitivity of this assay, we compared it with the fluorescent antibody test (FAT) and immunohistochemical(IHC) method. Specificity of the ViewRNA ISH was tested by detecting several sub genotypes of CSFV (sub genotype 1.1, 2.1, 2.2 and 2.3) which are present in China and other normal pig infectious virus (bovine viral diarrhea virus (BVDV), porcine parvovirus (PPV), porcine pseudorabies virus (PRV) and porcine circovirusII(PCV-2). The lowest detection threshold of the ViewRNA ISH method was 10 -8 , while the sensitivity of FAT and IHC were 10 -5 and 10 -4 , respectively. The ViewRNA ISH was specific for CSFV RNA including 1.1, 2.1, 2.2 and 2.3 subtypes, meanwhile, there was no cross-reaction with negative control and other viruses including BVDV, PPV, PRV and PCV-2. Our results showed that after infection at 0.5 hpi (hours post inoculation, hpi), the CSFV RNA can be detected in nucleus and cytoplasm; during 3-9 hpi, RNA

  16. Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection. (United States)

    Wu, Yuqiu; Kazumura, Kimiko; Maruyama, Wakako; Osawa, Toshihiko; Naoi, Makoto


    Rasagiline and selegiline, inhibitors of type B monoamine oxidase (MAO-B), protect neurons from cell death in cellular and animal models. Suppression of mitochondrial membrane permeabilization and subsequent activation of apoptosis cascade, and induction of anti-apoptotic, pro-survival genes are proposed to contribute the anti-apoptotic function. Rasagiline suppresses neurotoxin- and oxidative stress-induced membrane permeabilization in isolated mitochondria, but the mechanism has been not fully clarified. In this paper, regulation of the mitochondrial permeability transition pore by rasagiline and selegiline was examined in apoptosis induced by PK11195, a ligand of the outer membrane translocator protein 18 kDa (TSPO) in SH-SY5Y cells. The pore opening was quantitatively measured using a simultaneous monitoring system for calcium (Ca(2+)) and superoxide (O2(-)) (Ishibashi et al. in Biochem Biophys Res Commun 344:571-580, 2006). The association of the pore opening with Ca(2+) efflux and ROS increase was proved by the inhibition of Bcl-2 overexpression and cyclosporine A treatment. Potency to release Ca(2+) was correlated with the cytotoxicity of TSPO antagonists, PK11195, FGIN-1-27 and protoporphyrin IX, whereas a TSPO agonist, 4-chloro-diazepamine, did not significantly increase Ca(2+) or cause cell death. Rasagiline and selegiline inhibited mitochondrial Ca(2+) efflux through the mitochondrial permeability transition pore dose dependently. Ca(2+) efflux was confirmed as the initial signal in mitochondrial apoptotic cascade, and the suppression of Ca(2+) efflux may account for the neuroprotective function of rasagiline and selegiline. The quantitative measurement of Ca(2+) efflux can be applied to determine anti-apoptotic activity of neuroprotective compounds. The role of mitochondrial Ca(2+) release in neuronal death and also in neuroprotection by MAO-B inhibitors is discussed.

  17. Assessment of In Vivo Efficacy of Eravacycline against Enterobacteriaceae Exhibiting Various Resistance Mechanisms: A Dose-Ranging Study and PK/PD Analysis. (United States)

    Thabit, Abrar K; Monogue, Marguerite L; Newman, Joseph V; Nicolau, David P


    After the pharmacokinetic (PK) profile of eravacycline as a novel fluorocycline was defined, understanding its pharmacodynamic (PD) profile became essential. The aim of this study was to assess the correlation of the PK/PD index of the area under free drug concentration-time curve above the minimum inhibitory concentration (fAUC/MIC) and its magnitude with eravacycline's efficacy against Enterobacteriaceae isolates using the immunocompetent murine thigh infection model to resemble the immunocompetent environment in eravacycline's clinical trials. Eight Enterobacteriaceae isolates with various resistance mechanisms were selected and tested. Eravacycline doses ranged 1-10 mg/kg/day and were given either once daily or divided into q12h doses over the 24h treatment period. Antibacterial efficacy was measured as the change in log 10 CFU at 24h compared with 0h controls. Composite data were modeled using a sigmoid E max model. Eravacycline MICs ranged 0.125-0.5 µg/ml. The mean fAUC/MIC magnitudes required for stasis and 1-log reduction for the eight isolates were 2.9 ± 3.1 and 5.6 ± 5.0, respectively. While the humanized eravacycline regimen (2.5 mg/kg q12h) pharmacokinetically achieves a fAUC 0-24 that is higher than the fAUC 0-24 achieved with the 5 mg/kg q24h dose, the latter was associated with higher efficacy raising a suggestive correlation of the free peak drug concentration to the MIC (fC max /MIC) index with eravacycline's efficacy. This study showed that the magnitudes associated with the efficacy of eravacycline in the immunocompetent murine thigh model appear to be close to achievable targets in human. These data support further development of eravacycline for the treatment of infections caused by drug-resistant Enterobacteriaceae. Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  18. Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand [3H]PK 14105

    International Nuclear Information System (INIS)

    Benavides, J.; Dubois, A.; Dennis, T.; Hamel, E.; Scatton, B.


    The anatomical distribution of omega 3 (peripheral type benzodiazepine binding) sites in the immune system organs of the rat has been studied autoradiographically at both macroscopic and microscopic levels of resolution using either reversible or irreversible (UV irradiation) labeling with [ 3 H]PK 14105. In thymus sections, [ 3 H]PK 14105 labeled with high affinity (Kd, derived from saturation experiments = 10.8 nM) a single population of sites which possessed the pharmacological characteristics of omega 3 sites. In the thymus gland, higher omega 3 site densities were detected in the cortex than in the medulla; in these subregions, silver grains were associated to small (10-18 microns diameter) cells. In the spleen, omega 3 sites were more abundant in the white than in the red pulp. In the white pulp, silver grains were denser in the marginal zone than in the vicinity of the central artery and labeling was, as in the thymus, associated to small cytoplasm-poor cells. In the red pulp, omega 3 site associated silver grains were observed mainly in the Bilroth cords. In the lymph nodes, the medullary region showed a higher labeling than the surrounding follicles and paracortex. A significant accumulation of silver grains was observed in the lymph node medullary cords. In the intestine, Peyer patches were particularly enriched in omega 3 sites (especially in the periphery of the follicles). The distribution of omega 3 sites in the immune system organs suggests a preferential labeling of cells of T and monocytic lineages. This is consistent with the proposed immunoregulatory properties of some omega 3 site ligands

  19. [Pharmacokinetics/pharmacodinamic (PK/PD) evaluation of a short course of oral administration of metronidazole for the management of infections caused by Bacteroides fragilis]. (United States)

    Morales-León, Felipe; von Plessing-Rossel, Carlos; Villa-Zapata, Lorenzo; Fernández-Rocca, Pola; Sanhueza-Sanhueza, Cindy; Bello-Toledo, Helia; Mella-Montecinos, Sergio


    Metronidazole is the antibiotic of choice for the management of infections caused by anaerobes. Its administration requires multiple daily doses causing increased medication errors. Due to its high post-antibiotic effect and rapid concentration-dependent bactericidal activity, administration of this antibiotic in an extended dosing interval would achieve PK/PD parameters effectively. To assess the probability of achieving effective PK/PD relationship with the administration of 1,000 mg every 24 hours of metronidazole for Bacteroides fragilis infections. A clinical trial was conducted in a group of volunteers who received a single oral dose of 500 or 1,000 mg of metronidazole. Determinations of values of Cmax, t max, and AUCC0-24 h. determined using the trapezoidal method, were obtained for a Markov simulation that would allow for determining the likelihood of achieving a AUC0-24 h/MIC ratio above 70 for infections caused by susceptible B. fragilis. Cmax (24,03 ± 6,89 mg/L) and t max (1,20 ± 0.80 hrs) and the value of AUC0-24 h (241.91 ± 48.14 mg * h/L) were determined. The probability of obtaining a AUC0-24 h/MIC ratio greater than 70 was greater than 99%. From a pharmacokinetic perspective, with the administration of a daily dose of 1,000 mg of metronidazole, it is possible to achieve a therapeutic goal of AUC0-24 h/MIC ratio above 70 for the treatment of anaerobic infections.

  20. Role of the sodium-dependent phosphate co-transporters and of the phosphate complexes of uranyl in the cytotoxicity of uranium in LLC-PK1 cells

    International Nuclear Information System (INIS)

    Muller, D.; Houpert, P.; Cambar, J.; Henge-Napoli, M-H.


    Although uranium is a well-characterized nephrotoxic agent, very little is known at the cellular and molecular level about the mechanisms underlying the uptake and toxicity of this element in proximal tubule cells. The aim of this study was thus to characterize the species of uranium that are responsible for its cytotoxicity and define the mechanism which is involved in the uptake of the cytotoxic fraction of uranium using two cell lines derived from kidney proximal (LLC-PK 1 ) and distal (MDCK) tubule as in vitro models. Treatment of LLC-PK 1 cells with colchicine, cytochalasin D, concanavalin A and PMA increased the sodium-dependent phosphate co-transport and the cytotoxicity of uranium. On the contrary, replacement of the extra-cellular sodium with N-methyl-D-glucamine highly reduced the transport of phosphate and the cytotoxic effect of uranium. Uranium cytotoxicity was also dependent upon the extra-cellular concentration of phosphate and decreased in a concentration-dependent manner by 0.1-10 mM phosphonoformic acid, a competitive inhibitor of phosphate uptake. Consistent with these observations, over-expression of the rat proximal tubule sodium-dependent phosphate co-transporter NaPi-IIa in stably transfected MDCK cells significantly increased the cytotoxicity of uranium, and computer modeling of uranium speciation showed that uranium cytotoxicity was directly dependent on the presence of the phosphate complexes of uranyl UO 2 (PO 4 ) - and UO 2 (HPO 4 ) aq . Taken together, these data suggest that the cytotoxic fraction of uranium is a phosphate complex of uranyl whose uptake is mediated by a sodium-dependent phosphate co-transporter system

  1. Hsp27, Hsp70, and metallothionein in MDCK and LLC-PK1 renal epithelial cells: effects of prolonged exposure to cadmium

    International Nuclear Information System (INIS)

    Bonham, Rita T.; Fine, Michael R.; Pollock, Fiona M.; Shelden, Eric A.


    Cadmium is a widely distributed industrial and environmental toxin. The principal target organ of chronic sublethal cadmium exposure is the kidney. In renal epithelial cells, acute high-dose cadmium exposure induces differential expression of proteins, including heat shock proteins. However, few studies have examined heat shock protein expression in cells after prolonged exposure to cadmium at sublethal concentrations. Here, we assayed total cell protein, neutral red uptake, cell death, and levels of metallothionein and heat shock proteins Hsp27 and inducible Hsp70 in cultures of MDCK and LLC-PK1 renal epithelial cells treated with cadmium for 3 days. Treatment with cadmium at concentrations equal to or greater than 10 μM (LLC-PK1) or 25 μM (MDCK) reduced measures of cell vitality and induced cell death. However, a concentration-dependent increase in Hsp27 was detected in both cell types treated with as little as 5 μM cadmium. Accumulation of Hsp70 was correlated only with cadmium treatment at concentrations also causing cell death. Metallothionein was maximally detected in cells treated with cadmium at concentrations that did not reduce cell vitality, and further increases were not detected at greater concentrations. These results reveal that heat shock proteins accumulate in renal epithelial cells during prolonged cadmium exposure, that cadmium induces differential expression of heat shock protein in epithelial cells, and that protein expression patterns in epithelial cells are specific to the cadmium concentration and degree of cellular injury. A potential role for Hsp27 in the cellular response to sublethal cadmium-induced injury is also implicated by our results

  2. Characterization of polarized expression of point- or deletion-mutated human BCRP/ABCG2 in LLC-PK1 cells. (United States)

    Takada, Tappei; Suzuki, Hiroshi; Sugiyama, Yuichi


    In polarized cells, such as hepatocytes and intestinal epithelial cells, transporters are localized on the apical or basolateral membranes and play important roles in the vectorial transport of their substrates. In the current study, we have aimed to clarify the mechanism for the cellular sorting of human breast cancer resistance protein (BCRP/ABCG2), which is expressed on the apical membrane of many tissues and functions as an efflux transporter. After the expression vector, including wild type or mutants of human BCRP cDNA, was transfected into LLC-PK1 cells, immunohistochemical staining and Western blot analyses were performed to characterize the cellular localization and the status of BCRP, respectively. The transfected cDNA product of wild-type BCRP was expressed on the apical membrane in LLC-PK1 cells. Glycosylation consensus sequences-disrupted mutants showed the apical localization as the wild type, whereas the apical-selective expression disappeared when disulfide bonds could not be formed. Furthermore, examination of the localization of deletion mutants of human BCRP emphasized the importance of some peptide sequences. The region between the N-terminal and ATP-binding cassette and proximal C-terminal region, both of which are well conserved in various animal species, were found to be significant for proper localization. These results suggest that, although the presence of N-glycan does not affect the localization of BCRP, disulfide bonds and some peptide sequences in both the N- and C-terminals are necessary for the apical expression of BCRP.

  3. Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model.

    Directory of Open Access Journals (Sweden)

    Shamim H Rahman


    Full Text Available In vitro disease modeling based on induced pluripotent stem cells (iPSCs provides a powerful system to study cellular pathophysiology, especially in combination with targeted genome editing and protocols to differentiate iPSCs into affected cell types. In this study, we established zinc-finger nuclease-mediated genome editing in primary fibroblasts and iPSCs generated from a mouse model for radiosensitive severe combined immunodeficiency (RS-SCID, a rare disorder characterized by cellular sensitivity to radiation and the absence of lymphocytes due to impaired DNA-dependent protein kinase (DNA-PK activity. Our results demonstrate that gene editing in RS-SCID fibroblasts rescued DNA-PK dependent signaling to overcome radiosensitivity. Furthermore, in vitro T-cell differentiation from iPSCs was employed to model the stage-specific T-cell maturation block induced by the disease causing mutation. Genetic correction of the RS-SCID iPSCs restored T-lymphocyte maturation, polyclonal V(DJ recombination of the T-cell receptor followed by successful beta-selection. In conclusion, we provide proof that iPSC-based in vitro T-cell differentiation is a valuable paradigm for SCID disease modeling, which can be utilized to investigate disorders of T-cell development and to validate gene therapy strategies for T-cell deficiencies. Moreover, this study emphasizes the significance of designer nucleases as a tool for generating isogenic disease models and their future role in producing autologous, genetically corrected transplants for various clinical applications.

  4. Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

    International Nuclear Information System (INIS)

    Chen, Chien-Liang; Chou, Kang-Ju; Lee, Po-Tsang; Chen, Ying-Shou; Chang, Tsu-Yuan; Hsu, Chih-Yang; Huang, Wei-Chieh; Chung, Hsiao-Min; Fang, Hua-Chang


    Purpose: Tumor growth factor-β1 (TGF-β1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-β1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-β1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-β1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-β1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-β1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-β1-mediated apoptosis and also partially inhibited TGF-β1-mediated EMT. We showed that EPO treatment suppressed TGF-β1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-β1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-β1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

  5. Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand [3H]PK 14105. (United States)

    Benavides, J; Dubois, A; Dennis, T; Hamel, E; Scatton, B


    The anatomical distribution of omega 3 (peripheral type benzodiazepine binding) sites in the immune system organs of the rat has been studied autoradiographically at both macroscopic and microscopic levels of resolution using either reversible or irreversible (UV irradiation) labeling with [3H]PK 14105. In thymus sections, [3H]PK 14105 labeled with high affinity (Kd, derived from saturation experiments = 10.8 nM) a single population of sites which possessed the pharmacological characteristics of omega 3 sites. In the thymus gland, higher omega 3 site densities were detected in the cortex than in the medulla; in these subregions, silver grains were associated to small (10-18 microns diameter) cells. In the spleen, omega 3 sites were more abundant in the white than in the red pulp. In the white pulp, silver grains were denser in the marginal zone than in the vicinity of the central artery and labeling was, as in the thymus, associated to small cytoplasm-poor cells. In the red pulp, omega 3 site associated silver grains were observed mainly in the Bilroth cords. In the lymph nodes, the medullary region showed a higher labeling than the surrounding follicles and paracortex. A significant accumulation of silver grains was observed in the lymph node medullary cords. In the intestine, Peyer patches were particularly enriched in omega 3 sites (especially in the periphery of the follicles). The distribution of omega 3 sites in the immune system organs suggests a preferential labeling of cells of T and monocytic lineages. This is consistent with the proposed immunoregulatory properties of some omega 3 site ligands.

  6. Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand (/sup 3/H)PK 14105

    Energy Technology Data Exchange (ETDEWEB)

    Benavides, J.; Dubois, A.; Dennis, T.; Hamel, E.; Scatton, B.


    The anatomical distribution of omega 3 (peripheral type benzodiazepine binding) sites in the immune system organs of the rat has been studied autoradiographically at both macroscopic and microscopic levels of resolution using either reversible or irreversible (UV irradiation) labeling with (/sup 3/H)PK 14105. In thymus sections, (/sup 3/H)PK 14105 labeled with high affinity (Kd, derived from saturation experiments = 10.8 nM) a single population of sites which possessed the pharmacological characteristics of omega 3 sites. In the thymus gland, higher omega 3 site densities were detected in the cortex than in the medulla; in these subregions, silver grains were associated to small (10-18 microns diameter) cells. In the spleen, omega 3 sites were more abundant in the white than in the red pulp. In the white pulp, silver grains were denser in the marginal zone than in the vicinity of the central artery and labeling was, as in the thymus, associated to small cytoplasm-poor cells. In the red pulp, omega 3 site associated silver grains were observed mainly in the Bilroth cords. In the lymph nodes, the medullary region showed a higher labeling than the surrounding follicles and paracortex. A significant accumulation of silver grains was observed in the lymph node medullary cords. In the intestine, Peyer patches were particularly enriched in omega 3 sites (especially in the periphery of the follicles). The distribution of omega 3 sites in the immune system organs suggests a preferential labeling of cells of T and monocytic lineages. This is consistent with the proposed immunoregulatory properties of some omega 3 site ligands.

  7. The use of a prosthetic inlay resurfacing as a salvage procedure for a failed cartilage repair. (United States)

    Dhollander, Aad Alfons Maria; Almqvist, Karl Fredrik; Moens, Kris; Vandekerckhove, Pieter-Jan; Verdonk, René; Verdonk, Peter; Victor, Jan


    This study was designed to describe the clinical and radiographical outcome of the HemiCAP(®) resurfacing system as a salvage treatment for a failed index cartilage procedure. Fourteen patients were treated consecutively and clinically prospectively followed for a mean period of 26.1 ± 12.8 months. All patients were previously treated for their cartilage lesion. Radiographical data were analysed based on the Kellgren and Lawrence system. The patients involved in this study demonstrated a gradual clinical improvement in time. However, radiographically significant osteoarthritic changes were observed during the follow-up period. The position of the HemiCAP(®) resurfacing system was adequate in all cases, and no signs of loosening were observed during the follow-up period. The HemiCAP(®) resurfacing system is feasible as a salvage treatment for a failed index cartilage procedure and resulted in a gradual clinical improvement. However, the favourable clinical outcome was not confirmed by the radiographical findings. IV.

  8. Identifying Demographic and Academic Issues that Influence the Passing or Failing of the Physiology Course in the Medicine Study Program of UCIMED (University of Medical Sciences

    Directory of Open Access Journals (Sweden)

    Juan Carlos Vanegas-Pissa


    Full Text Available (This paper, product of a research project, analyzes some academic and demographic issues that might influence students passing or failing Physiology in the Licentiate Study Program in Medicine and Surgery at UCIMED (University of Medical Sciences between 2008 and 2011. This was a retrospective cohort study. We analyzed the grades obtained by the students who were taking Physiology for the first, second or third time during the research period, the semesters in which the grades were obtained, who passed or failed the course, their sociodemographic characteristics, and other courses passed or failed previously with their corresponding grades. For the data analysis, we used the Stata 13 software (Data Analysis and Statistical Software with a logistic regression model to determine the variables, which explain the passing or failing of the Physiology course. The results showed that the variables with a greater effect on the probability of p


    Directory of Open Access Journals (Sweden)

    Matej Andoljšek


    When conservative treatment fails, operative treatment is indicated in most patients withbone and joint problems. The goals of surgical treatment are pain relief and restoration oftalocalcaneal alignment. In lateral impingement, when subtalar joint and general alignmentof the tuber are preserved, removal of the bulged lateral wall could suffice. In suchcases a corrective osteotomy of the tuber is rarely indicated. In painfull subtalar arthrosisfusion is the only option. Limited fusion is preferable. »In situ« subtalar fusion is advisablein cases without malalignment or deformity. When we have arthrosis and varus/valgusdeformity with preserved height, arthrodesis with corrective osteotomy is indicated. In mostcases, where complex deformity is present, corrective subtalar distraction bone-blockarthrodesis should be done

  10. A Novel Endoscopic Technique for Failed Nasogastric Tube Placement. (United States)

    Boston, Andrew G


    Direct visualization of the nasopharynx gives the otolaryngologist a unique advantage for addressing difficult nasopharyngeal anatomy. One common situation is being consulted to assist when the blind placement of a nasogastric tube has failed. A novel technique for managing a patient with a nasogastric tube embedded in the adenoid remnant is described with illustrations. The atraumatic method is easily employed by a resident armed with a portable nasolaryngoscope and plain suture. By using a repeated pull-through technique, the nasogastric tube can be guided past difficult nasopharyngeal anatomy and into a position from where it can be advanced into the patient's esophagus. © American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.

  11. Trending a New Normal: Is Nigeria becoming a failed Nation?

    Directory of Open Access Journals (Sweden)

    Emmanuel Olusegun Stober


    Full Text Available Judging from every economic parameter, Nigeria will suggest being a failed nation. Not so long ago international investors identified Nigeria as one of the world’s most promising investment opportunities, but things have changed drastically in the meantime. The slump in the price of crude oil has hit Nigerian economy hard, the twin curses of insecurity and corruption have not gone away either. The Nigerian currency - naira has also lost its value by 170% from its value in 2015. The question most analysts and citizens are now asking is if Nigeria will ever fulfil its potential. This study empirically analyses the current economic situation of Nigeria, and gives recommendations on what government should do in getting the country out of recession.

  12. Failed rapid sequence induction in an achondroplastic dwarf

    Directory of Open Access Journals (Sweden)

    Jasleen Kaur


    Full Text Available Achondroplasia, a common cause of short limbed type of dwarfism is due to quantitative decrease in rate of endochondral ossification. This abnormal bone growth leads to disproportionate body and head structure, thus placing them under high risk for anaesthetic management. There is paucity in literatures, regarding appropriate drug dosage selection in these patients. Use of drugs as per standard dosage recommendations based on body weight or body surface area, may not be adequate in these patients owing to discrepancies in overall body weight and lean body weight, especially during rapid sequence induction. Here, we report a case of failed rapid sequence induction due to abnormal response to administered drugs in an adult achondroplastic dwarf. Standard doses of thiopentone and rocuronium had to be repeated thrice to achieve adequate conditions for intubation.

  13. The ambivert: A failed attempt at a normal personality. (United States)

    Davidson, Ian J


    Recently, attention has been drawn toward an overlooked and nearly forgotten personality type: the ambivert. This paper presents a genealogy of the ambivert, locating the various contexts it traversed in order to highlight the ways in which these places and times have interacted and changed-ultimately elucidating our current situation. Proposed by Edmund S. Conklin in 1923, the ambivert only was meant for normal persons in between the introvert and extravert extremes. Although the ambivert could have been taken up by early personality psychologists who were transitioning from the study of the abnormal to the normal, it largely failed to gain traction. Whether among psychoanalysts, psychiatrists, or applied and personality psychologists, the ambivert was personality non grata. It was only within the context of Eysenck's integrative view of types and traits that the ambivert marginally persisted up to the present day and is now the focus of sales management and popular psychology. © 2017 Wiley Periodicals, Inc.

  14. Looked-but-failed-to-see-errors in traffic

    DEFF Research Database (Denmark)

    Herslund, Mai-Britt; Jørgensen, N O


    Danish studies of traffic accidents at priority intersections have shown a particular type of accidents. In these accidents a car driver supposed to give way has collided with a bicycle rider on the priority road. Often the involved car drivers have maintained that they did not see the bicycle...... until immediately before the collision even though the bicycle must have been clearly visible.Similar types of accidents have been the subject of studies elsewhere. In literature they are labelled "looked-but-failed-to-see", because it seems clear that in many cases the car drivers have actually been......, especially for well experienced drivers. The other study based on Gap Acceptance shows that the car driver acceptance of gaps towards cyclists depends on whether or not another car is present. Hypotheses for driver perception and for accident countermeasures are discussed....

  15. Failed manual removal of the placenta after vaginal delivery

    DEFF Research Database (Denmark)

    Bjurström, Johanna; Collins, Sally; Langhoff-Roos, Jens


    and the UK provide examples of various treatment strategies such as ultrasound-guided vaginal removal, removal of the placenta through a hysterotomy and just leaving the placenta in situ. The placentas were all retained, but it was only possible to diagnose abnormal invasion in the one case, which had......PURPOSE: A retained placenta after vaginal delivery where manual removal of placenta fails is a clinical challenge. We present six cases that illustrate the heterogeneity of the condition and discuss the etiology and terminology as well as the clinical management. METHODS: Members of the European...... a histopathological diagnosis of increta. Based on these cases we present a flow chart to aid clinical management for future cases. CONCLUSION: We need properly defined stringent terminology for the different types of retained placenta, as well as improved tools to predict and diagnose both abnormally invasive...

  16. Mutuality: clinical and metapsychological potentials of a failed experiment. (United States)

    Castillo Mendoza, Carlos Alberto


    Ferenczi's experiments with mutual analysis are often dismissed, without acknowledging the results obtained from them and his own cautionary remarks about their limits. Though ultimately failed, Ferenczi's experiments with mutual analysis were a source of clinical and metapsychological knowledge, despite the fact that he was unable to elaborate them in his lifetime. In this paper I connect mutuality to the development of the psyche, especially to the constitutive core of the intrapsychic. To understand the latter, it is necessary to take into account, among others, issues such as the common attribute, the mutual flux between the unconsciouses, the dialogue of unconsciouses, the maternal profundity, the primal relationship with the mother, and, above all, the primal unity between mother and child, which are fundamental for the emergence and development of the primary psychic forces. Incidences of rupture, distortion of the core of mutuality in the psychic life, its loss and disadjustment, by means of external traumatizing forces, and some clinical implications are described.

  17. Ranking nodes in growing networks: When PageRank fails. (United States)

    Mariani, Manuel Sebastian; Medo, Matúš; Zhang, Yi-Cheng


    PageRank is arguably the most popular ranking algorithm which is being applied in real systems ranging from information to biological and infrastructure networks. Despite its outstanding popularity and broad use in different areas of science, the relation between the algorithm's efficacy and properties of the network on which it acts has not yet been fully understood. We study here PageRank's performance on a network model supported by real data, and show that realistic temporal effects make PageRank fail in individuating the most valuable nodes for a broad range of model parameters. Results on real data are in qualitative agreement with our model-based findings. This failure of PageRank reveals that the static approach to information filtering is inappropriate for a broad class of growing systems, and suggest that time-dependent algorithms that are based on the temporal linking patterns of these systems are needed to better rank the nodes.

  18. Ranking nodes in growing networks: When PageRank fails (United States)

    Mariani, Manuel Sebastian; Medo, Matúš; Zhang, Yi-Cheng


    PageRank is arguably the most popular ranking algorithm which is being applied in real systems ranging from information to biological and infrastructure networks. Despite its outstanding popularity and broad use in different areas of science, the relation between the algorithm’s efficacy and properties of the network on which it acts has not yet been fully understood. We study here PageRank’s performance on a network model supported by real data, and show that realistic temporal effects make PageRank fail in individuating the most valuable nodes for a broad range of model parameters. Results on real data are in qualitative agreement with our model-based findings. This failure of PageRank reveals that the static approach to information filtering is inappropriate for a broad class of growing systems, and suggest that time-dependent algorithms that are based on the temporal linking patterns of these systems are needed to better rank the nodes.

  19. Why did ISO 9001:2008 system fail to deliver? (United States)

    Langford, Melvyn


    This article is based on an actual investigation undertaken, and summarises the subsequent report's findings and observations. It has been anonymised for obvious reasons. In May 2013 an analysis was undertaken by a multidisciplinary team that compared an NHS Trust estates department's managerial systems against the NHS national recommendations. The conclusions stated that: 'There was a systemic failure across a large number of topics generating intolerable/substantial risks to the organisation, its staff, and patients; this despite the department's managerial systems being accredited to the International Standard ISO 9001:2008'. The natural question raised when presented with this demonstrable and auditable evidence was: 'Why did the ISO 9001:2008 system fail?'

  20. Alternative Splicing of NOX4 in the Failing Human Heart

    Directory of Open Access Journals (Sweden)

    Zoltán V. Varga


    Full Text Available Increased oxidative stress is a major contributor to the development and progression of heart failure, however, our knowledge on the role of the distinct NADPH oxidase (NOX isoenzymes, especially on NOX4 is controversial. Therefore, we aimed to characterize NOX4 expression in human samples from healthy and failing hearts. Explanted human heart samples (left and right ventricular, and septal regions were obtained from patients suffering from heart failure of ischemic or dilated origin. Control samples were obtained from donor hearts that were not used for transplantation. Deep RNA sequencing of the cardiac transcriptome indicated extensive alternative splicing of the NOX4 gene in heart failure as compared to samples from healthy donor hearts. Long distance PCR analysis with a universal 5′-3′ end primer pair, allowing amplification of different splice variants, confirmed the presence of the splice variants. To assess translation of the alternatively spliced transcripts we determined protein expression of NOX4 by using a specific antibody recognizing a conserved region in all variants. Western blot analysis showed up-regulation of the full-length NOX4 in ischemic cardiomyopathy samples and confirmed presence of shorter isoforms both in control and failing samples with disease-associated expression pattern. We describe here for the first time that NOX4 undergoes extensive alternative splicing in human hearts which gives rise to the expression of different enzyme isoforms. The full length NOX4 is significantly upregulated in ischemic cardiomyopathy suggesting a role for NOX4 in ROS production during heart failure.

  1. Evaluation and Management of Failed Shoulder Instability Surgery (United States)

    Cartucho, António; Moura, Nuno; Sarmento, Marco


    Background: Failed shoulder instability surgery is mostly considered to be the recurrence of shoulder dislocation but subluxation, painful or non-reliable shoulder are also reasons for patient dissatisfaction and should be considered in the notion. Methods: The authors performed a revision of the literature and online contents on evaluation and management of failed shoulder instability surgery. Results: When we look at the reasons for failure of shoulder instability surgery we point the finger at poor patient selection, technical error and an additional traumatic event. More than 80% of surgical failures, for shoulder instability, are associated with bone loss. Quantification of glenoid bone loss and investigation of an engaging Hill-Sachs lesion are determining facts. Adequate imaging studies are determinant to assess labrum and capsular lesions and to rule out associated pathology as rotator cuff tears. CT-scan is the method of choice to diagnose and quantify bone loss. Arthroscopic soft tissue procedures are indicated in patients with minimal bone loss and no contact sports. Open soft tissue procedures should be performed in patients with small bone defects, with hiperlaxity and practicing contact sports. Soft tissue techniques, as postero-inferior capsular plication and remplissage, may be used in patients with less than 25% of glenoid bone loss and Hill-Sachs lesions. Bone block procedures should be used for glenoid larger bone defects in the presence of an engaging Hill-Sachs lesion or in the presence of poor soft tissue quality. A tricortical iliac crest graft may be used as a primary procedure or as a salvage procedure after failure of a Bristow or a Latarjet procedure. Less frequently, the surgeon has to address the Hill-Sachs lesion. When a 30% loss of humeral head circumference is present a filling graft should be used. Conclusion: Reasons for failure are multifactorial. In order to address this entity, surgeons must correctly identify the causes and

  2. Remembering past exchanges: Apes fail to use social cues

    Directory of Open Access Journals (Sweden)

    Amy Lewis


    Full Text Available Nonhuman primates can remember events from their distant past. Furthermore, they can distinguish between very similar events by the process of binding. So far, research into long-term memory and binding has focused on the binding of contextual information, such as spatial surroundings. As such, we aimed to investigate if apes can bind and retrieve other types of information, specifically, social information. We presented great apes with three different object types; they learnt to exchange (via reinforcement one of the object types with one experimenter and another type with a second, different, experimenter. The remaining object type was not reinforced by either of the experimenters. After a delay of two or ten weeks, we assessed the apes’ memory of which object type was exchanged with which experimenter. Additionally, we introduced a new experimenter to see if the apes could infer by exclusion that the remaining object type should be exchanged with the new experimenter. The apes successfully remembered which object types were exchanged, but failed to distinguish which object type was exchanged with whom. This failure to bind an object type to a specific person may have resulted from the apes learning to use a rule based on recency, as opposed to learning a conditional rule involving social information. However, results from a second experiment suggested they fail to incorporate social information even when no other information could guide successful performance. Our findings are consistent with research showing long-term memory in primates, but suggest that social information may not be bound in memory as readily as spatial or contextual information.

  3. Rotationplasty as a salvage of failed primary limb reconstruction: up to date review and case report. (United States)

    Canavese, Federico; Samba, Antoine; Khan, Ahmad; Dechelotte, Pierre; Krajbich, Joseph I


    We report a case of a 15-year-old girl who is a known case for proximal focal femoral deficiency. She underwent several surgical lengthening procedures. Her course was complicated by femur nonunion, knee joint dislocation, stiff knee, and final lower limb discrepancy of over 15 cm. Rotationplasty was performed to salvage her previous surgical failures and restore her function. Surgery was uneventful and the patient was able to walk with the prosthesis in a few months after index surgery. Although the outcome of rotationplasty is visually unusual, for some children restored function and physical capabilities outweigh cosmetic concerns. The aim of the present study was to report a case of rotationplasty in salvaging a failed primary limb reconstruction in a patient with proximal femur focal deficiency.

  4. Failed fertilization with conventional oocyte insemination can be overcome with the ability of ICSI according to binding or failing to bind to the zona pellucida. (United States)

    Check, J H; Bollendorf, A; Wilson, C


    To determine the frequency of failed fertilization with conventional oocyte insemination and to determine the ability of intracytoplasmic sperm injection (ICSI) to overcome the failed fertilization according to binding or failing to bind to the zona pellucida. Retrospective review of 12,448 in vitro fertilization (IVF) cycle to identify cycles where failed fertilization occurred following conventional oocyte insemination with seemingly normal sperm. A number of three oocytes retrieved was required. There were only 12 cases of failed fertilization (0.1%). Six were related to failure of any or few sperm attaching to the zona pellucida These six had high fertilization rates with ICSI. Six had normal attachment and five attempted another cycle, this time with ICSI. Only 60% had good fertilization. When there is failed fertilization with normal sperm oocyte binding following conventional oocyte insemination, ICSI may still be effective in 60% of the cases, but it would be probably recommended to combine ICSI with artificial oocyte activation by calcium ionophore.

  5. A triple-helix forming oligonucleotide targeting genomic DNA fails to induce mutation. (United States)

    Reshat, Reshat; Priestley, Catherine C; Gooderham, Nigel J


    Purine tracts in duplex DNA can bind oligonucleotide strands in a sequence specific manner to form triple-helix structures. Triple-helix forming oligonucleotides (TFOs) targeting supFG1 constructs have previously been shown to be mutagenic raising safety concerns for oligonucleotide-based pharmaceuticals. We have engineered a TFO, TFO27, to target the genomic Hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus to define the mutagenic potential of such structures at genomic DNA. We report that TFO27 was resistant to nuclease degradation and readily binds to its target motif in a cell free system. Contrary to previous studies using the supFG1 reporter construct, TFO27 failed to induce mutation within the genomic HPRT locus. We suggest that it is possible that previous reports of triplex-mediated mutation using the supFG1 reporter construct could be confounded by DNA quadruplex formation. Although the present study indicates that a TFO targeting a genomic locus lacks mutagenic activity, it is unclear if this finding can be generalised to all TFOs and their targets. For the present, we suggest that it is prudent to avoid large purine stretches in oligonucleotide pharmaceutical design to minimise concern regarding off-target genotoxicity.

  6. Optimizing an online SPE-HPLC method for analysis of (R)-[11C]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide [(R)-[11C]PK11195] and its metabolites in humans

    NARCIS (Netherlands)

    Greuter, Henri J. N. M.; van Ophemert, Patricia L B; Luurtsema, Gert; van Berckel, Bart N. M.; Franssen, Eric J F; Windhorst, Bert D; Lammertsma, Adriaan A.

    (R)-[11C]PK11195 is used as a positron emission tomography tracer for activated microglia in several neurological disorders. Quantification of specific binding requires a metabolite-corrected plasma input function. In this study, a high-performance liquid chromatography (HPLC) procedure with online

  7. Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous Staphylococcus aureus osteomyelitis model

    DEFF Research Database (Denmark)

    Nielsen, Ole Lehberg; Afzelius, Pia; Bender, Dirk


    characterized as abscesses/cellulitis, arthritis in three joints and five enlarged lymph nodes. None of the tracers accumulated in joints with arthritis. By comparing the 10 infectious lesions, 18F-FDG accumulated in nine, 111In-leukocytes in eight, 11C-methionine in six, 68Ga-citrate in four and 11C-PK11195...

  8. Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous Staphylococcus aureus osteomyelitis model

    DEFF Research Database (Denmark)

    Nielsen, Ole L.; Afzelius, Pia; Bender, Dirk

    characterized as abscesses/cellulitis, arthritis in three joints and five enlarged lymph nodes. None of the tracers accumulated in joints with arthritis. By comparing the 10 infectious lesions, 18F-FDG accumulated in nine, 111In-leukocytes in eight, 11C-methionine in six, 68Ga-citrate in four and 11C-PK11195...

  9. Population PK Modeling and Target Attainment Simulations to Support Dosing of Ceftaroline Fosamil in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia. (United States)

    Riccobene, Todd A; Khariton, Tatiana; Knebel, William; Das, Shampa; Li, James; Jandourek, Alena; Carrothers, Timothy J; Bradley, John S


    Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to ceftaroline fosamil were combined with PK data from adults to update a population PK model for ceftaroline and ceftaroline fosamil. This model, based on a data set including 305 children, was used to conduct simulations to estimate ceftaroline exposures and percentage of time that free drug concentrations were above the minimum inhibitory concentration (%fT>MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to 90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to <18 years by the FDA and EMA, which are presented. © 2016, The American College of Clinical Pharmacology.

  10. 22 CFR 40.91 - Certain aliens previously removed. (United States)


    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Certain aliens previously removed. 40.91... IMMIGRANTS UNDER THE IMMIGRATION AND NATIONALITY ACT, AS AMENDED Aliens Previously Removed § 40.91 Certain aliens previously removed. (a) 5-year bar. An alien who has been found inadmissible, whether as a result...

  11. Determining root correspondence between previously and newly detected objects (United States)

    Paglieroni, David W.; Beer, N Reginald


    A system that applies attribute and topology based change detection to networks of objects that were detected on previous scans of a structure, roadway, or area of interest. The attributes capture properties or characteristics of the previously detected objects, such as location, time of detection, size, elongation, orientation, etc. The topology of the network of previously detected objects is maintained in a constellation database that stores attributes of previously detected objects and implicitly captures the geometrical structure of the network. A change detection system detects change by comparing the attributes and topology of new objects detected on the latest scan to the constellation database of previously detected objects.

  12. Utility of Covered Stents for Revision of Aging Failing Synthetic Hemodialysis Grafts: A Report of Three Cases

    International Nuclear Information System (INIS)

    Silas, Anne M.; Bettmann, Michael A.


    Three aging failing hemodialysis polytetrafluoroethylene bypass shunts, average age 44 months, previously percutaneously revised with balloon angioplasty, presented with pseudoaneurysms and recurrent thrombosis. All were treated with percutaneous covered stent placement within their affected limbs. One graft was ligated 1 month after treatment for infected overlying skin ulcer, though this graft was subsequently surgically revised with interposition graft and the covered stent portion remains functional at 19 month follow-up. The 18- and 13- month follow- up of the remaining 2 patients shows that the covered stents remained patent and they are functional and being successfully and routinely punctured for dialysis. In this elderly population, the use of covered stents may prolong the functional life of failing hemodialysis bypass grafts, reducing the number of percutaneous and surgical interventions and further sparing other vascular access sites

  13. 7 CFR 1951.264 - Action when borrower fails to cooperate, respond or graduate. (United States)


    ... Analyzing Credit Needs and Graduation of Borrowers § 1951.264 Action when borrower fails to cooperate, respond or graduate. (a) When borrowers with other than FCP loans fail to: (1) Provide information... appeal the decision. (b) If an FCP borrower fails to cooperate after a lender expresses a willingness to...

  14. Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients. (United States)

    Reinders, Mattheus K; van Roon, Eric N; Houtman, Pieternella M; Brouwers, Jacobus R B J; Jansen, Tim L Th A


    In 2003, the uricosuric drug benzbromarone was withdrawn from the market. The first alternative drug of choice was the xanthine oxidase inhibitor allopurinol. The purpose was to (1) investigate the efficacy of allopurinol (standard dosage) compared with previous treatment with benzbromarone; and (2) investigate the combination therapy allopurinol-probenecid as an effective alternative treatment compared with previous benzbromarone treatment. A prospective, open study was carried out in a cohort of 51 gout patients who discontinued benzbromarone therapy because of market withdrawal. Patients were given 200-300 mg allopurinol (stage 1). When allopurinol failed to attain the target serum urate (sUr) levels probenecid 1,000 mg/day was added (stage 2). Treatment with benzbromarone monotherapy (range: 100-200 mg/day; mean 138 mg/day) resulted in 92% of patients reaching target levels sUr probenecid combination therapy, which resulted in 86% of patients attaining target sUr levels (after failure on allopurinol monotherapy), which was comparable to previous treatment with benzbromarone (p = 0.81). Decrease in sUr levels was 53[9]% (CI 95%: 48-58%), which was a non-significant difference compared to previous treatment with benzbromarone (p = 0.23). Benzbromarone is a very effective antihyperuricemic drug with 91% success in attainment of target sUr levels probenecid proves to be an effective treatment strategy for attaining sUr target levels (86% success).

  15. Requirements: Towards an understanding on why software projects fail (United States)

    Hussain, Azham; Mkpojiogu, Emmanuel O. C.


    Requirement engineering is at the foundation of every successful software project. There are many reasons for software project failures; however, poorly engineered requirements process contributes immensely to the reason why software projects fail. Software project failure is usually costly and risky and could also be life threatening. Projects that undermine requirements engineering suffer or are likely to suffer from failures, challenges and other attending risks. The cost of project failures and overruns when estimated is very huge. Furthermore, software project failures or overruns pose a challenge in today's competitive market environment. It affects the company's image, goodwill, and revenue drive and decreases the perceived satisfaction of customers and clients. In this paper, requirements engineering was discussed. Its role in software projects success was elaborated. The place of software requirements process in relation to software project failure was explored and examined. Also, project success and failure factors were also discussed with emphasis placed on requirements factors as they play a major role in software projects' challenges, successes and failures. The paper relied on secondary data and empirical statistics to explore and examine factors responsible for the successes, challenges and failures of software projects in large, medium and small scaled software companies.

  16. Experimenting `learn by doing' and `learn by failing' (United States)

    Pozzi, Rossella; Noè, Carlo; Rossi, Tommaso


    According to the literature, in recent years, developing experiential learning has fulfilled the requirement of a deep understanding of lean philosophy by engineering students, demonstrating the advantages and disadvantages of some of the key principles of lean manufacturing. On the other hand, the literature evidences how some kinds of game-based experiential learning overlook daily difficulties, which play a central role in manufacturing systems. To fill the need of a game overcoming such lack of vision, an innovative game direct in-field, named Kart Factory, has been developed. Actual production shifts are simulated, while keeping all the elements peculiar to a real production set (i.e. complexity, effort, safety). The working environment is a real pedal car assembly department, the products to be assembled have relevant size and weight (i.e. up to 35 kg approximately), and the provided tools are real production equipment (e.g. keys, screwdrivers, trans-pallets, etc.). Due to the need to maximise the impact on students, a labour-intensive process characterises the production department. The whole training process is based on three educational principles: Experience Value Principle, Error Value Principle, and Team Value Principle. As the 'learn by doing' and 'learn by failing' are favoured, the theory follows the practice, while crating the willingness to 'do' instead of just designing or planning. The gathered data prove the Kart Factory's effectiveness in reaching a good knowledge of lean concepts, notwithstanding the students' initial knowledge level.

  17. Excisional Bleb Revision for Management of Failed Ahmed Glaucoma Valve. (United States)

    Eslami, Yadollah; Fakhraie, Ghasem; Moghimi, Sasan; Zarei, Reza; Mohammadi, Masoud; Nabavi, Amin; Yaseri, Mehdi; Izadi, Ali


    To evaluate the outcome of excisonal bleb revision in patients with failed Ahmed glaucoma valve (AGV). In total, 29 patients with uncontrolled intraocular pressure (IOP) despite of maximal tolerated medical therapy at least 6 months after AGV implantation were enrolled in this prospective interventional case series. Excision of fibrotic tissue around the reservoir with application of mitomycin C 0.02% was performed. IOP, number of glaucoma medications were evaluated at baseline and 1 week and 1, 3, 6, and 12 months postoperatively. Complete and qualified success was defined as IOP≤21 mm Hg with or without glaucoma medications, respectively. Intraoperative and postopervative complications were also recorded. Mean IOP was reduced from 30±4.2 mm Hg at baseline to 19.2±3.1 mm Hg at 12-month follow-up visit (Pglaucoma medications was decrease from 3.2±0.5 at baseline to 1.9±0.7 at 12-month follow-up (Pglaucoma surgeries were significantly associated with the failure of excisonal bleb revision. Excisional bleb revision could be considered as a relatively effective alternative option for management of inadequate IOP control after AGV implantation.

  18. Why have we failed to cure Alzheimer's disease? (United States)

    Korczyn, Amos D


    There is widespread recognition in the urgency to understand the causes and mechanisms of senile dementia. Attempts to find cures for Alzheimer's disease (AD) have, however, failed so far, in spite of enormous investments, intellectual and financial. We therefore have to reconsider the problem from new angles. AD is regarded as a disease because of its clinical manifestations and underlying pathology. However, this combination does not define a disease but rather a syndrome, just like hepatic cirrhosis in which liver pathology causes metabolic changes, but which can result from many different etiologies. It is unlikely that attacking a downstream phenomenon, like apoptosis or amyloid-β accumulation, can cure AD, or prevent the progression of the disease. It is probable that senile dementia is the result of a combination of several processes, working differently in each person. Epidemiological studies have identified many risk factors for "senile dementia of the Alzheimer type", some genetic but most environmental and therefore modifiable. Thus, a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age.

  19. Fail-fixed servovalve with positive fluid feedback (United States)

    Kast, Howard B. (Inventor)


    The servovalve includes a primary jet of fluid. A variable control signal is adapted to vary the angular position of the primary jet from its maximum recovery position. A first fluid path is adapted to supply fluid to a servopiston at a variable pressure determined at least in part by the control signal. A second fluid path is adapted to receive a predetermined portion of the primary jet fluid when the control signal reaches a predetermined value. The second fluid path terminates in the vicinity of the primary jet and is adapted to direct a secondary jet of fluid at the primary jet to deflect the primary jet toward the input orifice of the second fluid path. The resultant positive fluid feedback in the second fluid path causes the primary jet to latch in a first angular position relative to the maximum recovery position when the control signal reaches a predetermined value. The servovalve may further include a means to discharge the fluid and a means to block the first fluid path to the servopiston when the control signal falls below a second predetermined value. A method of operating a fail-fixed servovalve is also described.

  20. Sparse approximation problem: how rapid simulated annealing succeeds and fails (United States)

    Obuchi, Tomoyuki; Kabashima, Yoshiyuki


    Information processing techniques based on sparseness have been actively studied in several disciplines. Among them, a mathematical framework to approximately express a given dataset by a combination of a small number of basis vectors of an overcomplete basis is termed the sparse approximation. In this paper, we apply simulated annealing, a metaheuristic algorithm for general optimization problems, to sparse approximation in the situation where the given data have a planted sparse representation and noise is present. The result in the noiseless case shows that our simulated annealing works well in a reasonable parameter region: the planted solution is found fairly rapidly. This is true even in the case where a common relaxation of the sparse approximation problem, the G-relaxation, is ineffective. On the other hand, when the dimensionality of the data is close to the number of non-zero components, another metastable state emerges, and our algorithm fails to find the planted solution. This phenomenon is associated with a first-order phase transition. In the case of very strong noise, it is no longer meaningful to search for the planted solution. In this situation, our algorithm determines a solution with close-to-minimum distortion fairly quickly.

  1. Organism-level models: When mechanisms and statistics fail us (United States)

    Phillips, M. H.; Meyer, J.; Smith, W. P.; Rockhill, J. K.


    Purpose: To describe the unique characteristics of models that represent the entire course of radiation therapy at the organism level and to highlight the uses to which such models can be put. Methods: At the level of an organism, traditional model-building runs into severe difficulties. We do not have sufficient knowledge to devise a complete biochemistry-based model. Statistical model-building fails due to the vast number of variables and the inability to control many of them in any meaningful way. Finally, building surrogate models, such as animal-based models, can result in excluding some of the most critical variables. Bayesian probabilistic models (Bayesian networks) provide a useful alternative that have the advantages of being mathematically rigorous, incorporating the knowledge that we do have, and being practical. Results: Bayesian networks representing radiation therapy pathways for prostate cancer and head & neck cancer were used to highlight the important aspects of such models and some techniques of model-building. A more specific model representing the treatment of occult lymph nodes in head & neck cancer were provided as an example of how such a model can inform clinical decisions. A model of the possible role of PET imaging in brain cancer was used to illustrate the means by which clinical trials can be modelled in order to come up with a trial design that will have meaningful outcomes. Conclusions: Probabilistic models are currently the most useful approach to representing the entire therapy outcome process.

  2. Why Buildings Fail: Are We Learning From Our Mistakes?

    Directory of Open Access Journals (Sweden)

    M. Kevin Parfitt


    Full Text Available Most building professionals have investigated or performed remedial designs for at least one architectural or engineering system failure during their careers. Other practitioners, especially those who work for forensic consultants or firms specializing in disaster response and repair, are more familiar with the variety and extent of building failures as they assist their clients in restoring damaged or deficient buildings. The advent of social medial and twenty-four-hour news channels along with the general ease of finding more examples of failures in the Internet have made us realize that building failures in the broad sense are much more common than we may have realized.Relatively recent events leading to building failures such as the Christchurch, New Zealand earthquakes, the roof/parking deck of the Algo Centre mall in the northern Ontario, Canada city of Elliot Lake and the Indiana State Fairground stage collapse in the US are just a few reminders that much more work needs to be done on a variety of fronts to prevent building failures from a life safety standpoint. The need is compounded by economic concerns from what would be considered more mundane or common failures. Inspections by the author after Hurricane Katrina revealed a huge number of failures associated rain water alone as roofs, windows, flashing, mechanical penetrations etc. failed leading to interior water penetration often resulting in more damage from damp conditions and mold propagation than outright structural collapses.

  3. Diagnostic Profiles of Patients Differentially Failing Executive Functioning Measures. (United States)

    Hammers, Dustin; Ramirez, Gabriela; Persad, Carol; Heidebrink, Judith; Barbas, Nancy; Giordani, Bruno


    Limited research exists to explain differential executive functioning impairment in clinical populations, particularly between the Wisconsin Card Sorting Task (WCST) and the Trail Making Test (TMT). The distribution of clinical diagnoses was examined in patients failing none, one, or both tasks, and executive task performance was compared among dementia-related diagnoses. Two hundred and sixty-six participants received evaluations through an Alzheimer's Disease Research Center, which included executive tasks. Dementia-related diagnoses were established through consensus. Chi-square analyses indicated that TMT failure, with or without WCST failure, possessed higher associations with dementia diagnoses. Repeated measures analysis of variance similarly indicated that participants with dementia, especially mild and moderate severity, performed worse on TMT. Executive dysfunction was observed in dementia-related diagnoses, and TMT failure was implicated in dementia in higher proportions than WCST impairment. Trail Making Test appears more sensitive than WCST for assessing executive impairment across diagnoses, especially when time and resources are limited in screening and clinical settings. © The Author(s) 2015.

  4. FGF23 fails to inhibit uremic parathyroid glands. (United States)

    Canalejo, Rocío; Canalejo, Antonio; Martinez-Moreno, Julio Manuel; Rodriguez-Ortiz, M Encarnacion; Estepa, Jose C; Mendoza, Francisco Javier; Munoz-Castaneda, Juan Rafael; Shalhoub, Victoria; Almaden, Yolanda; Rodriguez, Mariano


    Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D(3). FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal-regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal-regulated kinase 1/2-mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition.

  5. Modified Mathieu repair for failed surgery for hypospadias ...

    African Journals Online (AJOL)

    Twenty patients presented with complete dehiscence after previous hypospadias repair, while a coronal fistula was present in 18. The meatal position was coronal in 22 patients and anterior penile in 16. Twenty-six patients underwent a single operation and 12 underwent multiple operations. The urethral plate was supple ...

  6. Experience with failed or damaged spent fuel and its impacts on handling

    International Nuclear Information System (INIS)

    Bailey, W.J.


    Spent fuel management planning needs to include consideration of failed or damaged spent light-water reactor (LWR) fuel. Described in this paper, which was prepared under the Commercial Spent Fuel Management (CSFM) Program that is sponsored by the US Department of Energy (DOE), are the following: the importance of fuel integrity and the behavior of failed fuel, the quantity and burnup of failed or damaged fuel in storage, types of defects, difficulties in evaluating data on failed or damaged fuel, experience with wet storage, experience with dry storage, handling of failed or damaged fuel, transporting of fuel, experience with higher burnup fuel, and conclusions. 15 refs

  7. Measuring mental disorders: The failed commensuration project of DSM-5. (United States)

    Whooley, Owen


    Commensuration - the comparison of entities according to a common quantitative metric - is a key process in efforts to rationalize medicine. The push toward evidence-based medicine and quantitative assessment has led to the proliferation of metrics in healthcare. While social scientific attention has revealed the effects of these metrics once institutionalized - on clinical practice, on medical expertise, on outcome assessment, on valuations of medical services, and on experiences of illness - less attention has been paid to the process of developing metrics. This article examines the attempt to create severity scales during the revision to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a case of failed commensuration. Using data from interviews with participants in the DSM-5 revision (n = 30), I reconstruct the problems that emerged in the DSM-5 Task Force's effort to develop viable psychometric instruments to measure severity. Framed as a part of a "paradigm shift" in psychiatry, the revision produced ad hoc, heterogeneous severity scales with divergent logics. I focus on two significant issues of metric construction in this case - diagnostic validity and clinical utility. Typically perceived as technical and conceptual challenges of design, I show how these issues were infused with, and undermined by, professional political dynamics, specifically tensions between medical researchers and clinicians. This case reveals that, despite its association with objectivity and transparency, commensuration encompasses more than identifying, operationalizing, and measuring an entity; it demands the negotiation of extra-scientific, non-empirical concerns that get written into medical metrics themselves. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Baseline series fragrance markers fail to predict contact allergy. (United States)

    Mann, Jack; McFadden, John P; White, Jonathan M L; White, Ian R; Banerjee, Piu


    Negative patch test results with fragrance allergy markers in the European baseline series do not always predict a negative reaction to individual fragrance substances. To determine the frequencies of positive test reactions to the 26 fragrance substances for which labelling is mandatory in the EU, and how effectively reactions to fragrance markers in the baseline series predict positive reactions to the fragrance substances that are labelled. The records of 1951 eczema patients, routinely tested with the labelled fragrance substances and with an extended European baseline series in 2011 and 2012, were retrospectively reviewed. Two hundred and eighty-one (14.4%) (71.2% females) reacted to one or more allergens from the labelled-fragrance substance series and/or a fragrance marker from the European baseline series. The allergens that were positive with the greatest frequencies were cinnamyl alcohol (48; 2.46%), Evernia furfuracea (44; 2.26%), and isoeugenol (40; 2.05%). Of the 203 patients who reacted to any of the 26 fragrances in the labelled-fragrance substance series, only 117 (57.6%) also reacted to a fragrance marker in the baseline series. One hundred and seven (52.7%) reacted to either fragrance mix I or fragrance mix II, 28 (13.8%) reacted to Myroxylon pereirae, and 13 (6.4%) reacted to hydroxyisohexyl 3-cyclohexene carboxaldehyde. These findings confirm that the standard fragrance markers fail to identify patients with contact allergies to the 26 fragrances. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Heart failure: when form fails to follow function. (United States)

    Katz, Arnold M; Rolett, Ellis L


    Cardiac performance is normally determined by architectural, cellular, and molecular structures that determine the heart's form, and by physiological and biochemical mechanisms that regulate the function of these structures. Impaired adaptation of form to function in failing hearts contributes to two syndromes initially called systolic heart failure (SHF) and diastolic heart failure (DHF). In SHF, characterized by high end-diastolic volume (EDV), the left ventricle (LV) cannot eject a normal stroke volume (SV); in DHF, with normal or low EDV, the LV cannot accept a normal venous return. These syndromes are now generally defined in terms of ejection fraction (EF): SHF became 'heart failure with reduced ejection fraction' (HFrEF) while DHF became 'heart failure with normal or preserved ejection fraction' (HFnEF or HFpEF). However, EF is a chimeric index because it is the ratio between SV--which measures function, and EDV--which measures form. In SHF the LV dilates when sarcomere addition in series increases cardiac myocyte length, whereas sarcomere addition in parallel can cause concentric hypertrophy in DHF by increasing myocyte thickness. Although dilatation in SHF allows the LV to accept a greater venous return, it increases the energy cost of ejection and initiates a vicious cycle that contributes to progressive dilatation. In contrast, concentric hypertrophy in DHF facilitates ejection but impairs filling and can cause heart muscle to deteriorate. Differences in the molecular signals that initiate dilatation and concentric hypertrophy can explain why many drugs that improve prognosis in SHF have little if any benefit in DHF. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email:

  10. Obstetric Outcomes After Failed Hysteroscopic and Laparoscopic Sterilization Procedures. (United States)

    Brandi, Kristyn; Morgan, Jake R; Paasche-Orlow, Michael K; Perkins, Rebecca B; White, Katharine OʼConnell


    To compare obstetric outcomes after failed hysteroscopic and laparoscopic sterilization. This retrospective cohort study examined pregnancy outcomes including live birth, preterm birth, stillbirth, spontaneous abortion, therapeutic abortion, ectopic pregnancies, and gestational trophoblastic disease using a commercial claims administrative database for the years 2007-2013. We used a Z-test to compare pregnancy outcomes per 100 person-years based on type of sterilization. Cox proportional hazard models controlled for patient age, geographic region, urbanicity, comorbidities, and insurance type. We evaluated 997 pregnancy outcomes among 817 women from a total of 70,115 women with a history of either hysteroscopic sterilization (n=387 pregnancies/27,724 cases) or laparoscopic sterilization (n=610 pregnancies/42,391 cases). Women undergoing hysteroscopic sterilization were slightly older than, but otherwise similar to, women undergoing laparoscopic sterilization. The most common outcome was live birth, which was more likely after hysteroscopic sterilization compared with laparoscopic sterilization (adjusted hazard ratio 1.32, 95% CI 1.09-1.60). The rate of spontaneous abortion was not statistically significantly different between the two groups. Therapeutic abortion occurred more often after hysteroscopic sterilization (adjusted hazard ratio 1.49, 95% CI 1.10-2.01), whereas ectopic pregnancies occurred less often (adjusted hazard ratio 0.12, 95% CI 0.05-0.29) compared with laparoscopic sterilization. Hysteroscopic sterilization is associated with higher rates of live birth and lower rates of ectopic pregnancy compared with laparoscopic sterilization. Spontaneous abortion and preterm birth rates were similar in both groups. These data do not support an adverse effect of hysteroscopic sterilization on subsequent pregnancy outcomes.

  11. Failed surgery in primary hyperparathyroidism - what has changed with time. (United States)

    Wirowski, D; Goretzki, P E; Schwarz, K; Lammers, B J; Dotzenrath, C; Röher, H-D


    Advanced preoperative imaging of parathyroid adenomas and intraoperative parathyroid hormone determination optimized the results in the surgical treatment of primary hyperparathyroidism patients. We asked, whether reasons for failure have changed during the last 25 years.We retrospectively analyzed operations for persistent primary hyperparathyroidism in our department between 2001 and 2011 (n=67), and compared these results to our experience between 1986 and 2001 (n=80).From 2001 to 2011, 765 primary hyperparathyroidism patients were operated on at our department. All but 4 patients were cured (761/765, 99.5%). 67 operations were performed for persistent primary hyperparathyroidism. Main reasons for failure were a misdiagnosed sporadic multiple gland disease in our own patients (18/29, 62.1%), and an undetected solitary adenoma in patients referred to us after -initial operation in another hospital (22/38, 57.9%) (statistically significant). From 1986 to 2001 (1 105 primary hyperparathyroidism patients), main indications for re-operation due to persistent disease were an undiagnosed sporadic multiple gland disease in our own patients (15/24, 62.5%), and a missed solitary adenoma in patients being operated on primarily somewhere else (38/56, 67.9%) (statistically significant).Comparing our experience in 147 patients with persistent primary hyperparathyroidism being operated on between 2001-2011 and 1986-2001, not much has changed with the modern armamentarium of improved preoperative imaging or intraoperative biochemical control. Whereas sporadic multiple gland disease was the most common reason for unsuccessful surgery in experienced hands, other units mainly failed due to an undetected solitary adenoma. Re-operations for persistent primary hyperparathyroidism performed by us were successful in 93.8% (2001-2011) and 96.0% (1986-2001), respectively. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  12. Examination of a failed reactor coolant pump rotating assembly from Crystal River Unit 3

    International Nuclear Information System (INIS)

    Hayner, G.O.; Lubnow, T.; Clary, M.


    On January 18, 1989, the A reactor coolant pump rotating assembly at the Crystal River Unit 3 Nuclear Power Plant failed during operation. A rotating assembly from this pump had previously failed in 1986. The reactor coolant pump was fabricated by Byron Jackson Pump Division of Borg-Warner Ind. Products, Inc. from UNS S66286 superalloy (Alloy A286). A root cause failure analysis examination was performed on the pump shaft and other components. The failure analysis included shaft vibrational mode and stress analyses, pump clearance and alignment analyses, and detailed destructive examination of the shaft and hydrostatic bearing assemblies. Based on the detailed physical examination of the shaft it was concluded that cracks initiated in the pump shaft at two sites approximately 180 0 apart in a band of shallow, thermally induced fatigue cracks. The cracks initiated at the bottom edge of the motor end shrink fit pad under the shrink fit sleeve supporting the hydrostatic bearing journal. The band of thermally induced fatigue cracks was apparently caused by mixing of cold seal injection water and hot reactor coolant in gaps between the pump shaft and sleeve. The motor end shrink fit was apparently not effective in preventing introduction of the seal injection water to this area. Initial crack propagation occurred by fatigue due to lateral vibration; however, the majority of crack propagation occurred by abnormal torsional fatigue loading induced by contact and sticking between the rotating and stationary portions of the hydrostatic bearing. Final fracture of the shaft occurred by torsional overload. Metallurgical characteristics and mechanical properties of the shaft were within design specification and probably did not significantly influence the cracking process

  13. The MLH1 c.1852_1853delinsGC (p.K618A variant in colorectal cancer: genetic association study in 18,723 individuals.

    Directory of Open Access Journals (Sweden)

    Anna Abulí

    Full Text Available Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance", being the c.1852_1853delinsGC (p.K618A variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

  14. H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. (United States)

    Anandakrishnan, Ramu; Aguilar, Boris; Onufriev, Alexey V


    The accuracy of atomistic biomolecular modeling and simulation studies depend on the accuracy of the input structures. Preparing these structures for an atomistic modeling task, such as molecular dynamics (MD) simulation, can involve the use of a variety of different tools for: correcting errors, adding missing atoms, filling valences with hydrogens, predicting pK values for titratable amino acids, assigning predefined partial charges and radii to all atoms, and generating force field parameter/topology files for MD. Identifying, installing and effectively using the appropriate tools for each of these tasks can be difficult for novice and time-consuming for experienced users. H++ ( is a free open-source web server that automates the above key steps in the preparation of biomolecular structures for molecular modeling and simulations. H++ also performs extensive error and consistency checking, providing error/warning messages together with the suggested corrections. In addition to numerous minor improvements, the latest version of H++ includes several new capabilities and options: fix erroneous (flipped) side chain conformations for HIS, GLN and ASN, include a ligand in the input structure, process nucleic acid structures and generate a solvent box with specified number of common ions for explicit solvent MD.

  15. Protective effect of lanostane triterpenoids from the sclerotia of Poria cocos Wolf against cisplatin-induced apoptosis in LLC-PK1 cells. (United States)

    Lee, Dahae; Lee, Seulah; Shim, Sang Hee; Lee, Hae-Jeung; Choi, Youkyung; Jang, Tae Su; Kim, Ki Hyun; Kang, Ki Sung


    Cisplatin-induced nephrotoxicity is a serious adverse effect that limits the use of cisplatin in cancer patients. In the present study, we investigated the protective effect of lanostane triterpenoids (1-10) isolated from the ethanolic extract of Poria cocos Wolf against cisplatin-induced cell death in LLC-PK1 kidney tubular epithelial cells. Treatment of cisplatin induced significant cell death, which was suppressed by treatment with dehydroeburicoic acid monoacetate (1) and 3β-acetoxylanosta-7,9(11),24-trien-21-oic acid (9). Compound 1 exhibited the highest efficacy among the tested compounds and was thus subjected to further mechanistic studies. The increase in the percentage of apoptotic cells induced by cisplatin reduced by 4.3% after co-treatment of cells with compound 1 (50 and 100μM). Furthermore, phosphorylation of the mitogen-activated protein kinases JNK, ERK, and p38, and caspase-3, which characterize oxidative stress-mediated apoptosis, increased significantly after treatment with cisplatin, and decreased after treatment with compound 1. These results indicate that the renoprotective effects of compound 1 may be mediated by its anti-apoptotic activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Simple synthesis of carbon-11-labeled chromen-4-one derivatives as new potential PET agents for imaging of DNA-dependent protein kinase (DNA-PK) in cancer

    International Nuclear Information System (INIS)

    Gao, Mingzhang; Wang, Min; Miller, Kathy D.; Zheng, Qi-Huang


    Carbon-11-labeled chromen-4-one derivatives were synthesized as new potential PET agents for imaging of DNA repair enzyme DNA-dependent protein kinase (DNA-PK) in cancer. The target tracers, X-[ 11 C]methoxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; [ 11 C]4a–d), were prepared from their corresponding precursors, X-hydroxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; 5a–d), with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a C-18 Sep-Pak Plus cartridge. The radiochemical yields decay corrected to end of bombardment (EOB), from [ 11 C]CO 2 , were 40–60%. The specific activity at end of synthesis (EOS) was 185–370 GBq/μmol. - Highlights: ► New chromen-4-one derivatives were synthesized. ► New carbon-11-labeled chromen-4-one derivatives were synthesized. ► Simple solid-phase extraction (SPE) method was employed in radiosynthesis.

  17. 2 CFR 1.215 - Relationship to previous issuances. (United States)


    ... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false Relationship to previous issuances. 1.215 Section 1.215 Grants and Agreements ABOUT TITLE 2 OF THE CODE OF FEDERAL REGULATIONS AND SUBTITLE A Introduction toSubtitle A § 1.215 Relationship to previous issuances. Although some of the guidance was...

  18. 2 CFR 230.45 - Relationship to previous issuance. (United States)


    ... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false Relationship to previous issuance. 230.45 Section 230.45 Grants and Agreements OFFICE OF MANAGEMENT AND BUDGET CIRCULARS AND GUIDANCE Reserved COST PRINCIPLES FOR NON-PROFIT ORGANIZATIONS (OMB CIRCULAR A-122) § 230.45 Relationship to previous issuance. (a...

  19. Research Note Effects of previous cultivation on regeneration of ...

    African Journals Online (AJOL)

    Research Note Effects of previous cultivation on regeneration of Julbernadia globiflora and Brachystegia spiciformis in grazing areas of Mupfurudzi ... Plant attributes for Julbernadia globiflora and Brachystegia spiciformis were measured in previously cultivated and uncultivated sites making up rangelands of the scheme.

  20. 49 CFR 173.23 - Previously authorized packaging. (United States)


    ... 49 Transportation 2 2010-10-01 2010-10-01 false Previously authorized packaging. 173.23 Section... REQUIREMENTS FOR SHIPMENTS AND PACKAGINGS Preparation of Hazardous Materials for Transportation § 173.23 Previously authorized packaging. (a) When the regulations specify a packaging with a specification marking...




  2. Triple outlet right ventricle: a previously unknown cardiac malformation. (United States)

    Tingo, Jennifer E; Carroll, Sheila J; Crystal, Matthew A


    We present the case of an infant with three distinct outflow tracts from the right ventricle. Three outlets from the heart have been previously named the "Tritruncal Heart". We review the two previously reported cases of tritruncal hearts and describe the anatomy, diagnosis, surgical management, and outcome of our case. Embryologic implications are also discussed.

  3. Implant breast reconstruction after salvage mastectomy in previously irradiated patients. (United States)

    Persichetti, Paolo; Cagli, Barbara; Simone, Pierfranco; Cogliandro, Annalisa; Fortunato, Lucio; Altomare, Vittorio; Trodella, Lucio


    The most common surgical approach in case of local tumor recurrence after quadrantectomy and radiotherapy is salvage mastectomy. Breast reconstruction is the subsequent phase of the treatment and the plastic surgeon has to operate on previously irradiated and manipulated tissues. The medical literature highlights that breast reconstruction with tissue expanders is not a pursuable option, considering previous radiotherapy a contraindication. The purpose of this retrospective study is to evaluate the influence of previous radiotherapy on 2-stage breast reconstruction (tissue expander/implant). Only patients with analogous timing of radiation therapy and the same demolitive and reconstructive procedures were recruited. The results of this study prove that, after salvage mastectomy in previously irradiated patients, implant reconstruction is still possible. Further comparative studies are, of course, advisable to draw any conclusion on the possibility to perform implant reconstruction in previously irradiated patients.

  4. No discrimination against previous mates in a sexually cannibalistic spider (United States)

    Fromhage, Lutz; Schneider, Jutta M.


    In several animal species, females discriminate against previous mates in subsequent mating decisions, increasing the potential for multiple paternity. In spiders, female choice may take the form of selective sexual cannibalism, which has been shown to bias paternity in favor of particular males. If cannibalistic attacks function to restrict a male's paternity, females may have little interest to remate with males having survived such an attack. We therefore studied the possibility of female discrimination against previous mates in sexually cannibalistic Argiope bruennichi, where females almost always attack their mate at the onset of copulation. We compared mating latency and copulation duration of males having experienced a previous copulation either with the same or with a different female, but found no evidence for discrimination against previous mates. However, males copulated significantly shorter when inserting into a used, compared to a previously unused, genital pore of the female.

  5. Mexico: a regional power or a failed State?

    Directory of Open Access Journals (Sweden)

    Karol Derwich


    Caribbean region for many years. This opinion has strong foundations. Territory, geographical location, economy, and political influence are the key factors that predestine this country to the role of a regional power. The democratic transition that has taken place in Mexico in last decades and economic cooperation with the United States also allow it to play a role of regional leader. However, Mexico has significant problems that make it difficult for the country to play the role of a real leader. The most important one is the development of narcobusiness. This phenomenon brings not only the growing activity of drug cartels but also the eruption of narcoviolence in Mexico. This gives rise to grave problems for the Mexican authorities. The development of narcobusiness is partially the result of weakness of some of its institutions. For example, police forces do not carry out their tasks and are closely related to the drug cartels. As a result, the Mexican state is incapable of assuring security to its citizens – one of the most important functions of every state. Is it able to control its territory? It definitely does not have a monopoly for the use of violence on its territory. Huge corruption enables different non-state actors to influence decision making processes. All these problems make substantiated theses that the Mexican state is dysfunctional in some areas. Some analysts go much further in their opinions and describe Mexico as a failed state. The aim of the paper is to analyze the present position of Mexico in Latin America and the Caribbean region. Are the contemporary problems so big that they can lead to the collapse of the Mexican state or does Mexico have a real potential to play the role of a local leader and regional power? The author would like to analyze the impact of the present day internal problems in Mexico’s geopolitical position.

  6. Preliminary findings of a previously unrecognized porcine primary immunodeficiency disorder. (United States)

    Ozuna, A G Cino; Rowland, R R R; Nietfeld, J C; Kerrigan, M A; Dekkers, J C M; Wyatt, C R


    Weaned pigs from a line bred for increased feed efficiency were enrolled in a study of the role of host genes in the response to infection with Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). Four of the pigs were euthanatized early in the study due to weight loss with illness and poor body condition; 2 pigs before PRRSV infection and the other 2 pigs approximately 2 weeks after virus inoculation. The 2 inoculated pigs failed to produce PRRSV-specific antibodies. Gross findings included pneumonia, absence of a detectable thymus, and small secondary lymphoid tissues. Histologically, lymph nodes, spleen, tonsils, and Peyer's patches were sparsely cellular with decreased to absent T and B lymphocytes.

  7. Addition of ash and PK with or without N on a peatland in southern Sweden. Effects on tree growth and needle element concentrate; Tillfoersel av aska och PK med eller utan N paa en torvmark i soedra Sverige. Effekter paa traedtillvaext och aemneshalter i barr

    Energy Technology Data Exchange (ETDEWEB)

    Sikstroem, Ulf (Forestry Research Inst. of Sweden, Uppsala (Sweden))


    In Sweden, about 1.3 million tonnes of ash are produced annually. Out of that amount, 150 000 - 300 000 tonnes have been estimated to originate from forest fuels, i.e. ashes that potentially can be brought back to the forest. Apart from being a compensatory measure after intensive forest harvest (e.g. including tops and branches), the ash may be used to increase the tree growth on peat soils (ash fertilization). On peat soils, tree growth is generally increased after addition of ash or phosphorous (P) and potassium (K) fertilizers. However, in some cases also nitrogen (N) addition is required. On sparsely stocked mires, fertilization may promote the regeneration as well as increase the growth of the trees. Sufficient drainage and supply of plant-available N are some prerequisites for increasing tree growth by PK-addition. In 1982, Skogforsk established a field experiment (168 Perstorp) located in the province of Scania in a sparsely stocked Pinus Sylvestris (L.) sapling stand on a ditched mire where different nutrient regimes were tested. The experiment had a randomized block design including four blocks and seven treatments. Ash and different dozes of P (raw phosphate) and K (potassium chloride), with or without simultaneous N addition, were included as well as un untreated control. The aim of the present study was to evaluate the effects on tree growth and needle elemental concentrations 26 years after treatment. The addition of similar dozes of P (approx. 40 kg P/ha), as ash (2.5 tonnes/ha) or as PK-fertilizer rendered similar growth responses. The increase in stem-wood growth was in the order of 1,6 - 1,9 m3/ha/yr during the 26-year period. The N-addition had no additional effect. On the control plots, the growth was more or less negligible (approx. 0,04 m3sk/ha/yr). On average, the high dozes of raw-phosphate and potassium chloride (40 kg P/ha and 80 kg K/ha) gave a higher growth increase than the low dozes (20 kg P/ha and 40 kg K/ha), although this effect was

  8. Adolescents previously involved in Satanism experiencing mental health problems

    Directory of Open Access Journals (Sweden)

    H Heathcote


    Full Text Available No research has previously been done regarding the phenomenon of adolescents who have previously been involved in Satanism and who experience obstacles in their strive for mental health. Adolescents previously involved in Satanism present behavioral problems like aggressive outbursts, depression, “ psychosis” or suicide attempts, that could lead to suicide. In the phenomenonanalysis semi-structured, phenomenological interviews were performed with the respondents and their parents. The respondents were requested to write a naïve sketch about their life. After completion of the data-control, guidelines for nursing staff were set.

  9. Influence of previous participation in physical activity on its ...

    African Journals Online (AJOL)

    ... participation can influence perceptions of PA among the students. Physical activity promotion programmes should consider the role of these factors which should be emphasised from childhood. Keywords: physical activity, students, perceived benefits, perceived barriers, previous participation, sedentary lifestyle, Rwanda

  10. Choice of contraception after previous operative delivery at a family ...

    African Journals Online (AJOL)

    Choice of contraception after previous operative delivery at a family planning clinic in Northern Nigeria. Amina Mohammed‑Durosinlorun, Joel Adze, Stephen Bature, Caleb Mohammed, Matthew Taingson, Amina Abubakar, Austin Ojabo, Lydia Airede ...

  11. Payload specialist Reinhard Furrer show evidence of previous blood sampling (United States)


    Payload specialist Reinhard Furrer shows evidence of previous blood sampling while Wubbo J. Ockels, Dutch payload specialist (only partially visible), extends his right arm after a sample has been taken. Both men show bruises on their arms.

  12. Delivery outcomes at term after one previous cesarean section. (United States)

    Yamani-Zamzami, Tarik Y


    To determine the maternal and perinatal outcomes at term in women with one previous cesarean delivery and with no history of vaginal birth. This is a case-control study conducted at King Abdul-Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia, between January 1, 1999 and December 31, 2002. One hundred sixty-two women with one previous cesarean delivery and with no previous vaginal birth were compared with 324 control women. The cesarean section rate was higher in the study group 40 (24.7%) versus 23 (7.1%) in the control group and was statistically significant (phistory of vaginal delivery are considered less favorable, the vaginal birth after cesarean section success rate may be even lower if the indication for previous primary cesarean delivery was failure to progress, and may be associated with increased risk of uterine rupture. Further study is required to confirm our findings.


    Seffah, J D; Adu-Bonsaffoh, K


    an inverse trend between the annual caesarean sections rates and the proportion of women with one previous CS scheduled for TOLAC. There was a statistically significant difference between women who had successful or failed VBAC regarding maternal age, parity, number of ANC visits, gestational age at delivery, birth weight, Apgar score at 1 min and Apgar score at 5 min. Birth weights of less than 1.5kg, and 3.5Kg or greater were associated significantly with higher incidence failed TOLAC and emergency repeat CS. However, birth weights ranging from 2.0 to 3.49kg were associated with significantly lower incidence of failed TOLAC and emergency repeat CS. Birth weight of 2.5-2.99kg was associated with the lowest incidence of failed TOLAC and repeat CS. . There is a significantly high vaginal birth after caesarian section (VBAC) success rate among carefully selected women undergoing trial of scar in Ghana although a decreasing trend towards trial of labor after caesarian section (TOLAC) and a rising CS rate were determined. TOLAC remains a viable option for child birth in low resource settings like West Africa even though there are specific clinical and management related challenges to overcome. Adequate patient education and counselling in addition to appropriate patient selection for TOLAC remains the cornerstone to achieving high VBAC success rate with minimal adverse outcomes in such settings.

  14. [Influence of previous abdominopelvic surgery on gynecological laparoscopic operation]. (United States)

    Jin, Haoran; Shi, Wei; Zhou, Yingfang; Wu, Beisheng; Peng, Chao


    To investigate the influence of previous abdominopelvic surgery on gynecological laparoscopic operation. A retrospective analysis of 3 283 cases of gynecological diseases by laparoscopic operation patients in Peking University First Hospital from 2007 January to 2012 December, among them, 719 (21.90%) patients with previous abdominopelvic surgery history (study Group), 2 564 (78.10%)patients have no history of abdominopelvic surgery (control group). Study group 719 patients, previous operation times: one time in 525 cases, 194 cases were multiple; previous operation: 185 cases of gynecological surgery, 305 cases of obstetric surgery, 108 cases of general surgery, and 121 complex surgery (include at least two kinds of surgery); previous operative approach: 650 cases laparotomy and 69 cases laparoscopy. Compared two groups of patients with abdominopelvic adhesion and the gynecologic laparoscopic operation situation, analyzed the influence of previous abdominopelvic surgery on abdominopelvic adhesion on and gynecological laparoscopic operation. The incidence of abdominopelvic adhesion in the patients with previous abdominopelvic surgery was 51.2% (368/719), which was significantly higher than that of 8.2% (211/2 564)in patients without previous abdominopelvic surgery (P surgery (23.1%, 166/719) was significantly higher than that in the control group (3.3% , 85/2 564;P laparotomy was 0.6% (4/719) significantly more than the control groups (0.1%, 2/2 564; P = 0.023). Compared with other groups, patients with gynecological or complex surgery or multiple operation history presented more severe abdominopelvic adhesion both in the score and degree (P laparotomy showed no statistical difference between the two groups (P > 0.05). The laparoscopic operation could be carried out successfully and safely in patients with a history of various abdominopelvic operations, but the conversion rate increases, for patients with a history of multiple operation because of pelvic adhesion

  15. Reforçament del ferm, millora del drenatge i condicionament de les zones urbanes a la GI-612, del PK 0+000 al 8+026. El Port de la Selva - Llançà


    Divins Rochés, Eduard


    L’objecte del present Projecte Constructiu és la millora de l’estat del paviment de la carretera GI-612 entre les poblacions de El Port de la Selva-Llançà (PK’s 0+000 al PK 8+026), determinant les possibles zones a sanejar i els gruixos de reforç a aplicar d’acord amb l’estudi de deflexions i la inspecció de camp realitzada.

  16. Unveiling the Pathogenic Molecular Mechanisms of the Most Common Variant (p.K329E) in Medium-Chain Acyl-CoA Dehydrogenase Deficiency by in Vitro and in Silico Approaches. (United States)

    Bonito, Cátia A; Nunes, Joana; Leandro, João; Louro, Filipa; Leandro, Paula; Ventura, Fátima V; Guedes, Rita C


    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common genetic disorder affecting the mitochondrial fatty acid β-oxidation pathway. The mature and functional form of human MCAD (hMCAD) is a homotetramer assembled as a dimer of dimers (monomers A/B and C/D). Each monomer binds a FAD cofactor, necessary for the enzyme's activity. The most frequent mutation in MCADD results from the substitution of a lysine with a glutamate in position 304 of mature hMCAD (p.K329E in the precursor protein). Here, we combined in vitro and in silico approaches to assess the impact of the p.K329E mutation on the protein's structure and function. Our in silico results demonstrated for the first time that the p.K329E mutation, despite lying at the dimer-dimer interface and being deeply buried inside the tetrameric core, seems to affect the tetramer surface, especially the β-domain that forms part of the catalytic pocket wall. Additionally, the molecular dynamics data indicate a stronger impact of the mutation on the protein's motions in dimer A/B, while dimer C/D remains similar to the wild type. For dimer A/B, severe disruptions in the architecture of the pockets and in the FAD and octanoyl-CoA binding affinities were also observed. The presence of unaffected pockets (C/D) in the in silico studies may explain the decreased enzymatic activity determined for the variant protein (46% residual activity). Moreover, the in silico structural changes observed for the p.K329E variant protein provide an explanation for the structural instability observed experimentally, namely, the disturbed oligomeric profile, thermal stability, and conformational flexibility, with respect to the wild-type.

  17. In-core sipping method for the identification of failed fuel assemblies

    International Nuclear Information System (INIS)

    Wu Zhongwang; Zhang Yajun


    The failed fuel assembly identification system is an important safety system which ensures safe operations of reactor and immediate treatment of failed fuel rod cladding. The system uses an internationally recognized method to identify failed fuel assemblies in a reactor with fuel element cases. The in-core sipping method is customary used to identify failed fuel assemblies during refueling or after fuel rod cladding failure accidents. The test is usually performed after reactor shutdown by taking samples from each fuel element case while the cases are still in their original core positions. The sample activity is then measured to identify failed fuel assemblies. A failed fuel assembly identification system was designed for the NHR-200 based on the properties of the NHR-200 and national requirements. the design provides an internationally recognized level of safety to ensure the safety of NHR-200

  18. High-Dose Misoprostol as An Alternative Therapy After Failed Medical Abortion


    Li, Yiu-Tai; Hou, Guang-Qiong; Chen, Tien-Hui; Chu, Yi-Chih; Lin, Ta-Chin; Kuan, Long-Ching; Lin, Mau; Huang, Shu-Feng; Chen, Fu-Min; Kuo, Tsung-Cheng


    Objective: The aim of this study was to determine the complete abortion rate for the vaginal administration of high-dose misoprostol after a failed medical abortion. Materials and Methods: When their medical abortions failed after the conventional oral administration of mifepristone and misoprostol, participants then received 1,000 μg of misoprostol vaginally. The efficacy and side effects of this treatment were evaluated. Results: Twenty-seven women who failed to abort after the conven...

  19. Insights into failed lexical retrieval from network science. (United States)

    Vitevitch, Michael S; Chan, Kit Ying; Goldstein, Rutherford


    Previous network analyses of the phonological lexicon (Vitevitch, 2008) observed a web-like structure that exhibited assortative mixing by degree: words with dense phonological neighborhoods tend to have as neighbors words that also have dense phonological neighborhoods, and words with sparse phonological neighborhoods tend to have as neighbors words that also have sparse phonological neighborhoods. Given the role that assortative mixing by degree plays in network resilience, we examined instances of real and simulated lexical retrieval failures in computer simulations, analysis of a slips-of-the-ear corpus, and three psycholinguistic experiments for evidence of this network characteristic in human behavior. The results of the various analyses support the hypothesis that the structure of words in the mental lexicon influences lexical processing. The implications of network science for current models of spoken word recognition, language processing, and cognitive psychology more generally are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Secondary recurrent miscarriage is associated with previous male birth.

    LENUS (Irish Health Repository)

    Ooi, Poh Veh


    Secondary recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses after delivery of a viable infant. Previous reports suggest that a firstborn male child is associated with less favourable subsequent reproductive potential, possibly due to maternal immunisation against male-specific minor histocompatibility antigens. In a retrospective cohort study of 85 cases of secondary RM we aimed to determine if secondary RM was associated with (i) gender of previous child, maternal age, or duration of miscarriage history, and (ii) increased risk of pregnancy complications. Fifty-three women (62.0%; 53\\/85) gave birth to a male child prior to RM compared to 32 (38.0%; 32\\/85) who gave birth to a female child (p=0.002). The majority (91.7%; 78\\/85) had uncomplicated, term deliveries and normal birth weight neonates, with one quarter of the women previously delivered by Caesarean section. All had routine RM investigations and 19.0% (16\\/85) had an abnormal result. Fifty-seven women conceived again and 33.3% (19\\/57) miscarried, but there was no significant difference in failure rates between those with a previous male or female child (13\\/32 vs. 6\\/25, p=0.2). When patients with abnormal results were excluded, or when women with only one previous child were considered, there was still no difference in these rates. A previous male birth may be associated with an increased risk of secondary RM but numbers preclude concluding whether this increases recurrence risk. The suggested association with previous male birth provides a basis for further investigations at a molecular level.

  1. Secondary recurrent miscarriage is associated with previous male birth.

    LENUS (Irish Health Repository)

    Ooi, Poh Veh


    Secondary recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses after delivery of a viable infant. Previous reports suggest that a firstborn male child is associated with less favourable subsequent reproductive potential, possibly due to maternal immunisation against male-specific minor histocompatibility antigens. In a retrospective cohort study of 85 cases of secondary RM we aimed to determine if secondary RM was associated with (i) gender of previous child, maternal age, or duration of miscarriage history, and (ii) increased risk of pregnancy complications. Fifty-three women (62.0%; 53\\/85) gave birth to a male child prior to RM compared to 32 (38.0%; 32\\/85) who gave birth to a female child (p=0.002). The majority (91.7%; 78\\/85) had uncomplicated, term deliveries and normal birth weight neonates, with one quarter of the women previously delivered by Caesarean section. All had routine RM investigations and 19.0% (16\\/85) had an abnormal result. Fifty-seven women conceived again and 33.3% (19\\/57) miscarried, but there was no significant difference in failure rates between those with a previous male or female child (13\\/32 vs. 6\\/25, p=0.2). When patients with abnormal results were excluded, or when women with only one previous child were considered, there was still no difference in these rates. A previous male birth may be associated with an increased risk of secondary RM but numbers preclude concluding whether this increases recurrence risk. The suggested association with previous male birth provides a basis for further investigations at a molecular level.

  2. CT findings in ten patients with failed renal allografts: comparison with findings in functional grafts

    International Nuclear Information System (INIS)

    Gayer, Gabriela; Apter, Sara; Katz, Rama; Ben-David, Aharon; Katzir, Ze'ev; Hertz, Marjorie


    Our aim is to report the computed tomography (CT) features of the long-term failed renal allograft. Ten patients with failed renal transplants in whom the graft was left in situ underwent CT for various unrelated indications. The majority of the failed grafts showed marked shrinkage and coarse punctate diffuse parenchymal calcifications. Small cysts were seen in four grafts. A long-term failed renal transplant appeared on CT as a small rounded soft tissue mass. The graft was almost always heavily calcified. Lack of awareness of the nature of such a mass may mislead the radiologist in interpreting it as a space-occupying lesion

  3. First observation of γγ-> p$\\bar{p}$K+K- and search for exotic baryons in pK systems

    Energy Technology Data Exchange (ETDEWEB)

    Shen, C. P.; Yuan, C. Z.; Adachi, I.; Aihara, H.; Asner, David M.; Aulchenko, V.; Aushev, T.; Ayad, R.; Babu, V.; Badhrees, I.; Bakich, A. M.; Barberio, E.; Behera, P.; Bhardwaj, V.; Bhuyan, B.; Biswal, J.; Bobrov, A.; Bonvicini, Giovanni; Bozek, A.; Bracko, Marko; Browder, Thomas E.; Cervenkov, D.; Chang, P.; Chekelian, V.; Chen, A.; Cheon, B. G.; Chilikin, K.; Chistov, R.; Cho, K.; Chobanova, V.; Choi, S-K.; Choi, Y.; Cinabro, David A.; Dalseno, J.; Danilov, M.; Dash, N.; Dolezal, Z.; Drasal, Z.; Dutta, D.; Eidelman, S.; Fang, Wenzheng; Fast, James E.; Ferber, T.; Fulsom, Bryan G.; Gaur, Vipin; Gabyshev, N.; Garmash, A.; Gillard, R.; Glattauer, R.; Goldenzweig, P.; Grzymkowska, O.; Haba, J.; Hayasaka, K.; Hayashii, H.; Hou, W. S.; Iijima, T.; Inami, K.; Inguglia, G.; Ishikawa, A.; Itoh, R.; Iwasaki, Y.; Jaegle, Igal; Jeon, H. B.; Joo, K. K.; Julius, T.; Kang, K. H.; Kato, E.; Kiesling, C.; Kim, D. Y.; Kim, J. B.; Kim, K. T.; Kim, S. H.; Kim, Y. J.; Kodys, P.; Korpar, S.; Kotchetkov, Dmitri V.; Krizan, P.; Krokovny, Pavel; Kuzmin, A.; Kwon, Y. J.; Lange, J. S.; Li, C. H.; Li, H.; Li, Y.; Li Gioi, L.; Libby, J.; Liventsev, D.; Lubej, M.; Luo, T.; Masuda, M.; Matsuda, T.; Matvienko, D.; Miyabayashi, K.; Miyata, H.; Mizuk, R.; Mohanty, G. B.; Mohanty, Subhashree; Moll, A.; Moon, H K.; Mussa, R.; Nakano, E.; Nakao, M.; Nanut, T.; Nath, K.; Natkaniec, Z.; Nishida, S.; Ogawa, S.; Olsen, Stephen L.; Ostrowicz, W.; Pakhlov, P.; Pakhlova, G.; Pal, Bilas K.; Park, C. S.; Park, H.; Pesantez, L.; Pestotnik, R.; Petric, M.; Piilonen, Leo E.; Pulvermacher, C.; Rauch, J.; Ritter, M.; Sakai, Y.; Sandilya, Saurabh; Santelj, L.; Sanuki, T.; Savinov, Vladimir; Schluter, T.; Schneider, O.; Schnell, G.; Schwanda, C.; Seino, Y.; Semmler, D.; Senyo, K.; Seong, Ilsoo; Sevior, ME; Shibata, T. A.; Shiu, Jing-Ge; Shwartz, B.; Simon, F.; Sokolov, A.; Solovieva, E.; Stanic, S.; Staric, M.; Strube, Jan F.; Stypula, J.; Sumihama, M.; Sumiyoshi, T.; Takizawa, M.; Tamponi, Umberto; Tanida, K.; Tenchini, F.; Trabelsi, K.; Uchida, M.; Uehara, S.; Uglov, T.; Unno, Y.; Uno, S.; Urquijo, P.; Usov, Y.; Van Hulse, C.; Varner, G.; Wang, C. H.; Wang, M. Z.; Wang, P.; Watanabe, M.; Watanabe, Y.; Williams, K. M.; Won, E.; Yamaoka, Jared AK; Yelton, John; Yook, Youngmin; Yusa, Y.; Zhang, C. C.; Zhang, Z. P.; Zhilich, V.; Zhukova, V.; Zhulanov, V.; Zupanc, A.


    The process γγ→p$\\bar{p}$K+K- and its intermediate processes are measured for the first time using a 980 fb-1 data sample collected with the Belle detector at the KEKB asymmetric-energy e+e- collider. The production of p$\\bar{p}$K+K- and a Λ(1520)0 ($\\bar{Λ}$(1520)0) signal in the pK- ($\\bar{p}$K+) invariant mass spectrum are clearly observed. However, no evidence for an exotic baryon near 1540 MeV/c2, denoted as Θ(1540)0 ($\\bar{Θ}$(1540)0) or Θ(1540)++ (Θ(1540)--), is seen in the pK- ($\\bar{p}$K+) or pK+ ($\\bar{p}$K-) invariant mass spectra. Cross sections for γγ→p$\\bar{p}$K+K-, Λ(1520)0$\\bar{p}$K++c.c. and the products σ(γγ→Θ(1540)0$\\bar{p}$K++c.c.)B(Θ(1540)0→pK-) and σ(γγ→Θ(1540)++$\\bar{p}$K-+c.c.)B(Θ(1540)++→pK+) are measured. We also determine upper limits on the products of the χc0 and χc2 two-photon decay widths and their branching fractions to p$\\bar{p}$K+K- at the 90% credibility level.

  4. Simultaneous determination of four furostanol glycosides in rat plasma by UPLC-MS/MS and its application to PK study after oral administration of Dioscorea nipponica extracts. (United States)

    Liao, Min; Dai, Cong; Liu, Mengping; Chen, Jiefeng; Chen, Zuanguang; Xie, Zhiyong; Yao, Meicun


    A novel, sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method for simultaneous quantification of four furostanol glycosides in rat plasma was established and validated. Ginsenoside Rb1 was used as an internal standard. Plasma samples were pretreated by liquid-liquid extraction with n-butanol and chromatographed on a C18 column (2.1×50 mm i.d., 2.6 μm) using a gradient elution program consisting of acetonitrile and water (containing 0.03% formic acid and 0.1 mM lithium acetate) at a flow rate of 0.4 mL/min. Lithium adduct ions were employed to enhance the response of the analytes in electrospray positive ionization mode and multiple reaction monitoring transitions were performed for detection. All calibration curves exhibited good linearity (r>0.999) over the range of 10-20,000 ng/mL for protodioscin and 2-4000 ng/mL for protogracillin, pseudoprotodioscin and pseudoprotogracillin. The recoveries of the whole analytes were more than 80.3% and exhibited no severe matrix effect. Meanwhile, the intra- and inter-day precisions were all less than 10.7% and accuracies were within the range of -8.1-12.9%. The four saponins showed rapid excretion and relative high plasma concentrations when the validated method was applied to the PK study of Dioscorea nipponica extracts by intragastric administration at low, medium and high dose to rats. Moreover, the T(1/2) and AUC(0-t) of each compound turned out to behave in a dose-dependent pattern by comparing them at different dose levels. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Preservation of peripheral benzodiazepine receptors: differential effects of freezing on [3H]Ro 5-4864 and [3H]PK 11195 binding

    International Nuclear Information System (INIS)

    Basile, A.S.; Ostrowski, N.L.; Skolnick, P.


    A statistically significant decrease in the density of peripheral benzodiazepine receptors was observed in renal membranes of rats beginning 2 weeks after adrenalectomy when compared with sham-operated controls. This decrease in peripheral benzodiazepine receptor density was manifest as a decrease in the Bmax of two ligands [ 3 H]Ro 5-4864 and [ 3 H]PK 11195, without accompanying changes in their apparent affinity (Kd) for this site. Similar changes were not seen in another aldosterone-sensitive organ, the submandibular salivary gland. The decrease in peripheral benzodiazepine receptor density in observed in adrenalectomized rat renal membranes was restored to control levels after 1 week of aldosterone administration using a dose (12.5 micrograms/kg/day) that had no effect on peripheral benzodiazepine receptor density in sham-operated animals. In contrast, dexamethasone administration (50 micrograms/kg/day, 1 week) had no effect on renal peripheral benzodiazepine receptor density when administered to either adrenalectomized or sham-operated rats. Further, adrenal demedullation had no effect on renal peripheral benzodiazepine receptor density or affinity. The decrease in peripheral benzodiazepine receptor density was localized to the renal cortex and the outer stripe of the medulla by gross dissection of renal slices and renal tissue section autoradiography. The specific effect of adrenalectomy on renal peripheral benzodiazepine receptor density, the lack of direct effect of aldosterone on [ 3 H]Ro 5-4864 binding, and the localization of the change in peripheral benzodiazepine receptor density to the renal cortex and outer stripe suggests that these changes may reflect an adaptation of the renal nephron (possibly the distal convoluted tubule, intermediate tubule and/or the collecting duct) to the loss of mineralocorticoid hormones

  6. Feasibility of a tubularised incised-plate urethroplasty with double de-epithelised dartos flaps in a failed hypospadias repair: A preliminary report

    Directory of Open Access Journals (Sweden)

    Abdullah Yildiz


    Full Text Available Background: Reoperation for failed hypospadias has been considered to be seriously problematic. The dense fibrotic tissue causes difficulties in wound healing and increases the rate of complications. The tubularised incised-plate urethroplasty (TIPU method has become a preferred method for all varieties of hypospadias in the past decade. However, fistulas are still one of the most common complications of this technique. The aim of this paper was to present the preliminary results of TIPU procedure with double de-epithelised dartos flaps in failed hypospadias repair. Materials and Methods: All patients were treated between January 2009 and August 2010 by the same procedure, utilising TIPU with double de-epithelised dartos flaps. Vascularised ventral dartos flaps harvested from each side of the penis with their vascular supply were transposed to cover the suture line by wrapping them from either side of the penis. Results: There were 21 boys with failed hypospadias: 20 had previously undergone TIPU, and one Koyanagi repair. Patients presented with very large fistulas in four and dehiscence in 17. Repair of the failed hypospadias using TIPU with double de-epithelised dartos flaps was quite successful, with no fistula recurrence or dehiscence observed. Conclusion: The preliminary results showed that TIPU with double de-epithelised dartos flaps is a useful method of successfully repairing failed hypospadias.

  7. FSHD myoblasts fail to downregulate intermediate filament protein vimentin during myogenic differentiation.

    Directory of Open Access Journals (Sweden)

    Lipinski M.


    Full Text Available Facioscapulohumeral muscular dystrophy (FSHD is an autosomal dominant hereditary neuromuscular disorder. The clinical features of FSHD include weakness of the facial and shoulder girdle muscles followed by wasting of skeletal muscles of the pelvic girdle and lower extremities. Although FSHD myoblasts grown in vitro can be induced to differentiate into myotubes by serum starvation, the resulting FSHD myotubes have been shown previously to be morphologically abnormal. Aim. In order to find the cause of morphological anomalies of FSHD myotubes we compared in vitro myogenic differentiation of normal and FSHD myoblasts at the protein level. Methods. We induced myogenic differentiation of normal and FSHD myoblasts by serum starvation. We then compared protein extracts from proliferating myoblasts and differentiated myotubes using SDS-PAGE followed by mass spectrometry identification of differentially expressed proteins. Results. We demonstrated that the expression of vimentin was elevated at the protein and mRNA levels in FSHD myotubes as compared to normal myotubes. Conclusions. We demonstrate for the first time that in contrast to normal myoblasts, FSHD myoblasts fail to downregulate vimentin after induction of in vitro myogenic differentiation. We suggest that vimentin could be an easily detectable marker of FSHD myotubes

  8. Active Fail-Safe Micro-Array Flow Control for Advanced Embedded Propulsion Systems (United States)

    Anderson, Bernhard H.; Mace, James L.; Mani, Mori


    The primary objective of this research effort was to develop and analytically demonstrate enhanced first generation active "fail-safe" hybrid flow-control techniques to simultaneously manage the boundary layer on the vehicle fore-body and to control the secondary flow generated within modern serpentine or embedded inlet S-duct configurations. The enhanced first-generation technique focused on both micro-vanes and micro-ramps highly-integrated with micro -jets to provide nonlinear augmentation for the "strength' or effectiveness of highly-integrated flow control systems. The study focused on the micro -jet mass flow ratio (Wjet/Waip) range from 0.10 to 0.30 percent and jet total pressure ratios (Pjet/Po) from 1.0 to 3.0. The engine bleed airflow range under study represents about a 10 fold decrease in micro -jet airflow than previously required. Therefore, by pre-conditioning, or injecting a very small amount of high-pressure jet flow into the vortex generated by the micro-vane and/or micro-ramp, active flow control is achieved and substantial augmentation of the controlling flow is realized.

  9. Experimental immunologically mediated aplastic anemia (AA) in mice: cyclosporin A fails to protect against AA

    International Nuclear Information System (INIS)

    Knospe, W.H.; Steinberg, D.; Gratwohl, A.; Speck, B.


    Immunologically mediated aplastic anemia (AA) in mice was induced by the i.v. injection of 10(7) lymph node cells (LNC) from H-2k identical but Mls mismatched CBA/J donor mice into previously irradiated (600 rad total body gamma) C3H/HeJ mice. Cyclosporin A (CsA), 25 mg/kg, was administered subcutaneously from day -1 to day 30. Control mice included C3H/HeJ mice which received 600 rad alone, C3H/HeJ mice which received 600 rad plus CsA as above, and C3H/HeJ mice which received 600 rad total body irradiation followed by 10(7) LNC from CBA/J donors. CsA failed to prevent lethal AA. These results suggest that the pathogenetic mechanisms operating in immunologically mediated AA differ from the mechanisms operating in rodents transplanted with allogeneically mismatched marrow or spleen cells which develop graft-versus-host disease. The results are consistent with a non-T cell-dependent mechanism causing the AA

  10. Fission-product-release signatures for LWR fuel rods failed during PCM and RIA transients

    International Nuclear Information System (INIS)

    Osetek, D.J.; King, J.J.; Croucher, D.W.


    This paper discusses fission product release from light-water-reactor-type fuel rods to the coolant loop during design basis accident tests. One of the tests was a power-cooling-mismatch test in which a single fuel rod was operated in film boiling beyond failure. Other tests discussed include reactivity initiated accident (RIA) tests, in which the fuel rods failed as a result of power bursts that produced radial-average peak fuel enthalpies ranging from 250 to 350 cal/g. One of the RIA tests used two previously irradiated fuel rods. On-line gamma spectroscopic measurements of short-lived fission products, and important aspects of fission product behavior observed during the tests, are discussed. Time-dependent release fractions for short-lived fission products are compared with release fractions suggested by: the Reactor Safety Study; NRC Regulatory Guides; and measurements from the Three Mile Island accident. Iodine behavior observed during the tests is discussed, and fuel powdering is identified as a source of particulate fission product activity, the latter of which is neglected for most accident analyses

  11. Role of laparohysteroscopy in women with normal pelvic imaging and failed ovulation stimulation with intrauterine insemination

    Directory of Open Access Journals (Sweden)

    K Jayakrishnan


    Full Text Available Context: Women with primary infertility and no obvious pelvic pathology on clinical evaluation and imaging are either treated empirically or further investigated by laparoscopy. Aims: The role of diagnostic laparoscopy in women who fail to conceive after empirical treatment with ovulation induction and intrauterine insemination was evaluated. Settings and Design: Retrospective study at a private infertility center. Materials and Methods: A study of patients who underwent diagnostic laparoscopy between 1 st January 2001 and 31 st December 2008 was performed. Those patients who had no detectable pathology based on history, physical examination, and ultrasound and had treatment for three or more cycles in the form of ovulation induction and IUI were included in the study. Moderate and severe male factor infertility and history of any previous surgery were exclusion criteria. Statistical Analysis Used: Data were statistically analyzed using Statistics Package for Social Sciences (ver. 16.0; SPSS Inc., Chicago. Results: Of the 127 women who underwent diagnostic laparoscopy and hysteroscopy, 87.4% ( n= 111 of patients had positive findings. Significant pelvic pathology (moderate endometriosis, pelvic inflammatory disease, and tubal pathology was seen in 26.8% of cases. Conclusion: One in four women had significant pelvic pathology where treatment could possibly improve future fertility. Diagnostic laparoscopy has a role in infertile women with no obvious abnormality before they proceed to more aggressive treatments.

  12. WDR-PK-AK-018

    Energy Technology Data Exchange (ETDEWEB)

    Hollister, R


    Method - CES SOP-HW-P556 'Field and Bulk Gamma Analysis'. Detector - High-purity germanium, 40% relative efficiency. Calibration - The detector was calibrated on February 8, 2006 using a NIST-traceable sealed source, and the calibration was verified using an independent sealed source. Count Time and Geometry - The sample was counted for 20 minutes at 72 inches from the detector. A lead collimator was used to limit the field-of-view to the region of the sample. The drum was rotated 180 degrees halfway through the count time. Date and Location of Scans - June 1,2006 in Building 235 Room 1136. Spectral Analysis Spectra were analyzed with ORTEC GammaVision software. Matrix and geometry corrections were calculated using OR TEC Isotopic software. A background spectrum was measured at the counting location. No man-made radioactivity was observed in the background. Results were determined from the sample spectra without background subtraction. Minimum detectable activities were calculated by the Nureg 4.16 method. Results - Detected Pu-238, Pu-239, Am-241 and Am-243.

  13. Chickadees fail standardized operant tests for octave equivalence. (United States)

    Hoeschele, Marisa; Weisman, Ronald G; Guillette, Lauren M; Hahn, Allison H; Sturdy, Christopher B


    Octave equivalence occurs when an observer judges notes separated by a doubling in frequency perceptually similar. The octave appears to form the basis of pitch change in all human cultures and thus may be of biological origin. Previously, we developed a nonverbal operant conditioning test of octave generalization and transfer in humans. The results of this testing showed that humans with and without musical training perceive the octave relationship between pitches. Our goal in the current study was to determine whether black-capped chickadees, a North American songbird, perceive octave equivalence. We chose these chickadees because of their reliance on pitch in assessing conspecific vocalizations, our strong background knowledge on their pitch height perception (log-linear perception of frequency), and the phylogenetic disparity between them and humans. Compared to humans, songbirds are highly skilled at using pitch height perception to classify pitches into ranges, independent of the octave. Our results suggest that chickadees used that skill, rather than octave equivalence, to transfer the note-range discrimination from one octave to the next. In contrast, there is evidence that at least some mammals, including humans, do perceive octave equivalence.

  14. Social Misdirection Fails to Enhance a Magic Illusion (United States)

    Cui, Jie; Otero-Millan, Jorge; Macknik, Stephen L.; King, Mac; Martinez-Conde, Susana


    Visual, multisensory and cognitive illusions in magic performances provide new windows into the psychological and neural principles of perception, attention, and cognition. We investigated a magic effect consisting of a coin “vanish” (i.e., the perceptual disappearance of a coin after a simulated toss from hand to hand). Previous research has shown that magicians can use joint attention cues such as their own gaze direction to strengthen the observers’ perception of magic. Here we presented naïve observers with videos including real and simulated coin tosses to determine if joint attention might enhance the illusory perception of simulated coin tosses. The observers’ eye positions were measured, and their perceptual responses simultaneously recorded via button press. To control for the magician’s use of joint attention cues, we occluded his head in half of the trials. We found that subjects did not direct their gaze at the magician’s face at the time of the coin toss, whether the face was visible or occluded, and that the presence of the magician’s face did not enhance the illusion. Thus, our results show that joint attention is not necessary for the perception of this effect. We conclude that social misdirection is redundant and possibly detracting to this very robust sleight-of-hand illusion. We further determined that subjects required multiple trials to effectively distinguish real from simulated tosses; thus the illusion was resilient to repeated viewing. PMID:22046155

  15. Left ventricular assist device effects on metabolic substrates in the failing heart.

    Directory of Open Access Journals (Sweden)

    Lindsay B Weitzel

    Full Text Available Heart failure patients have inadequate nutritional intake and alterations in metabolism contributing to an overall energy depleted state. Left ventricular assist device (LVAD support is a common and successful intervention in patients with end-stage heart failure. LVAD support leads to alterations in cardiac output, functional status, neurohormonal activity and transcriptional profiles but the effects of LVADs on myocardial metabolism are unknown. This study set out to measure cardiac metabolites in non-failing hearts, failing hearts, and hearts post-LVAD support.The study population consisted of 8 non-ischemic failing (at LVAD implant and 8 post-LVAD hearts, plus 8 non-failing hearts obtained from the tissue bank at the University of Colorado. NMR spectroscopy was utilized to evaluate differences in myocardial energy substrates. Paired and non-paired t-tests were used to determine differences between the appropriate groups.Glucose and lactate values both decreased from non-failing to failing hearts and increased again significantly in the (paired post-LVAD hearts. Glutamine, alanine, and aromatic amino acids decreased from non-failing to failing hearts and did not change significantly post-LVAD. Total creatine and succinate decreased from non-failing to failing hearts and did not change significantly post-LVAD.Measured metabolites related to glucose metabolism are diminished in failing hearts, but recovered their values post-LVAD. This differed from the amino acid levels, which decreased in heart failure but did not recover following LVAD. Creatine and the citric acid cycle intermediate succinate followed a similar pattern as the amino acid levels.

  16. Disks around Failed Stars - a Question of Age (United States)


    First Ground-Based Mid-Infrared Observations of Brown Dwarfs [1] Summary A team of European astronomers [2] have observed eight Brown Dwarfs, i.e., small and faint objects also known as "failed stars", with the TIMMI2 infrared sensitive instrument at the ESO 3.6-m telescope on La Silla. From two of these, mid-infrared radiation is detected - for the first time ever from such objects with a ground-based telescope . While the younger Brown Dwarf, aged a few million years, is found to be surrounded by a dusty disk, no warm dust is present around the older ones. The new observations support the following formation hypothesis for Brown Dwarfs: they are born in the same way as "real" stars, by contraction in interstellar clouds of gas and dust . During the later stages of this process, the infalling material is transferred onto the star via a gas and dust disk . This disk - in which planets may possibly form - then disperses with time. PR Photo 17a/02 : Image of Brown Dwarf LP 944-20 PR Photo 17b/02 : Models of the disk around Brown Dwarf Cha HA 2 Brown Dwarfs are faint and cool objects Astronomical objects known as "Brown Dwarfs" are "failed stars" . Their comparatively small mass, less than about 7% of that of our Sun (or about 75 times the mass of planet Jupiter), is too small to achieve sufficiently high pressure and temperature at their centre to ignite energy-producing nuclear processes. Some astronomers also refer to Brown Dwarfs as a "missing link" between planets and stars, being neither one nor the other, yet with similarities to both. They do not burn hydrogen to helium as "real" stars do, but continue to emit faint light as they slowly contract and cool during millions of years. They end their inglorious life with a whimper and finally fade into eternal insignificance. Although Brown Dwarfs were theoretically predicted already in 1963, astronomers had to wait until 1995 for the first one to be discovered. This was mainly due to their extreme faintness as

  17. 2 CFR 225.45 - Relationship to previous issuance. (United States)


    ... 2 Grants and Agreements 1 2010-01-01 2010-01-01 false Relationship to previous issuance. 225.45 Section 225.45 Grants and Agreements OFFICE OF MANAGEMENT AND BUDGET CIRCULARS AND GUIDANCE Reserved COST PRINCIPLES FOR STATE, LOCAL, AND INDIAN TRIBAL GOVERNMENTS (OMB CIRCULAR A-87) § 225.45 Relationship to...

  18. Cryptococcal meningitis in a previously healthy child | Chimowa ...

    African Journals Online (AJOL)

    An 8-year-old previously healthy female presented with a 3 weeks history of headache, neck stiffness, deafness, fever and vomiting and was diagnosed with cryptococcal meningitis. She had documented hearing loss and was referred to tertiary-level care after treatment with fluconazole did not improve her neurological ...

  19. Rapid fish stock depletion in previously unexploited seamounts: the ...

    African Journals Online (AJOL)

    Rapid fish stock depletion in previously unexploited seamounts: the case of Beryx splendens from the Sierra Leone Rise (Gulf of Guinea) ... A spectral analysis and red-noise spectra procedure (REDFIT) algorithm was used to identify the red-noise spectrum from the gaps in the observed time-series of catch per unit effort by ...

  20. Obstructive pulmonary disease in patients with previous tuberculosis ...

    African Journals Online (AJOL)

    Obstructive pulmonary disease in patients with previous tuberculosis: Pathophysiology of a community-based cohort. B.W. Allwood, R Gillespie, M Galperin-Aizenberg, M Bateman, H Olckers, L Taborda-Barata, G.L. Calligaro, Q Said-Hartley, R van Zyl-Smit, C.B. Cooper, E van Rikxoort, J Goldin, N Beyers, E.D. Bateman ...

  1. Balance and bilateral skills of selected previously disadvantaged ...

    African Journals Online (AJOL)

    Balance and bilateral skills of selected previously disadvantaged children aged 9 to 12 years. Eileen K Africa, Karel J Van Deventer. Abstract. The main aim of the study was to design an appropriate motor skills development programme that could be implemented in any primary school to improve the fundamental motor ...

  2. Outcome Of Pregnancy Following A Previous Lower Segment ...

    African Journals Online (AJOL)

    Background: A previous ceasarean section is an important variable that influences patient management in subsequent pregnancies. A trial of vaginal delivery in such patients is a feasible alternative to a secondary section, thus aiding to reduce the ceasarean section rate and its associated co-morbidities. Objective: To ...

  3. Suburethral sling procedures after previous surgery for urinary ...

    African Journals Online (AJOL)

    Objective. To compare the outcome of suburethral sling procedures (tension-free vaginal tape (TVT), obturator tape (Ob-tape)) for stress urinary incontinence (SUI) in women with previous surgery for SUI or pelvic organ prolapse (POP). Methods. A comparative, descriptive, retrospective study was done using information ...

  4. 5 CFR 532.405 - Use of highest previous rate. (United States)


    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Use of highest previous rate. 532.405 Section 532.405 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS... rate may be based upon a rate of pay received during a temporary promotion, so long as the temporary...

  5. 24 CFR 1710.552 - Previously accepted state filings. (United States)


    ... of Substantially Equivalent State Law § 1710.552 Previously accepted state filings. (a) Materials... and contracts or agreements contain notice of purchaser's revocation rights. In addition see § 1715.15..., unless the developer is obligated to do so in the contract. (b) If any such filing becomes inactive or...

  6. 5 CFR 9701.352 - Use of highest previous rate. (United States)


    ... HUMAN RESOURCES MANAGEMENT SYSTEM Pay and Pay Administration Pay Administration § 9701.352 Use of... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Use of highest previous rate. 9701.352 Section 9701.352 Administrative Personnel DEPARTMENT OF HOMELAND SECURITY HUMAN RESOURCES MANAGEMENT...

  7. Bilateral orbital infarction and retinal detachment in a previously ...

    African Journals Online (AJOL)

    In this report, we present a case of an 11‑year‑old previously undiagnosed sickle cell disease Nigerian girl with severe acute bilateral orbital infarction and retinal detachment to highlight that hemoglobinopathy induced orbital infarction should be considered in African children with acute onset proptosis with or without ...

  8. Response to health insurance by previously uninsured rural children. (United States)

    Tilford, J M; Robbins, J M; Shema, S J; Farmer, F L


    To examine the healthcare utilization and costs of previously uninsured rural children. Four years of claims data from a school-based health insurance program located in the Mississippi Delta. All children who were not Medicaid-eligible or were uninsured, were eligible for limited benefits under the program. The 1987 National Medical Expenditure Survey (NMES) was used to compare utilization of services. The study represents a natural experiment in the provision of insurance benefits to a previously uninsured population. Premiums for the claims cost were set with little or no information on expected use of services. Claims from the insurer were used to form a panel data set. Mixed model logistic and linear regressions were estimated to determine the response to insurance for several categories of health services. The use of services increased over time and approached the level of utilization in the NMES. Conditional medical expenditures also increased over time. Actuarial estimates of claims cost greatly exceeded actual claims cost. The provision of a limited medical, dental, and optical benefit package cost approximately $20-$24 per member per month in claims paid. An important uncertainty in providing health insurance to previously uninsured populations is whether a pent-up demand exists for health services. Evidence of a pent-up demand for medical services was not supported in this study of rural school-age children. States considering partnerships with private insurers to implement the State Children's Health Insurance Program could lower premium costs by assembling basic data on previously uninsured children.

  9. The effect of previous traumatic injury on homicide risk. (United States)

    Griffin, Russell L; Davis, Gregory G; Levitan, Emily B; MacLennan, Paul A; Redden, David T; McGwin, Gerald


    Research has reported that a strong risk factor for traumatic injury is having a previous injury (i.e., recidivism). To date, the only study examining the relationship between recidivism and homicide reported strong associations, but was limited by possible selection bias. The current matched case-control study utilized coroner's data from 2004 to 2008. Subjects were linked to trauma registry data to determine whether the person had a previous traumatic injury. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between homicide and recidivism. Homicide risk was increased for those having a previous traumatic injury (OR 1.81, 95% CI 1.09-2.99) or a previous intentional injury (OR 2.53, 95% CI 1.24-5.17). These results suggest an association between homicide and injury recidivism, and that trauma centers may be an effective setting for screening individuals for secondary prevention efforts of homicide through violence prevention programs. © 2014 American Academy of Forensic Sciences.

  10. Control of feed intake as affected by previous treatment | Pienaar ...

    African Journals Online (AJOL)

    An experiment was conducted with eighteen rumen cannulated sheep fed on a chopped lucerne diet. Previous level of intake significantly influenced the level at which sheep initially established voluntary feed intake. This difference had disappeared after three weeks on an ad lib. intake. Perturbation analysis of the results ...

  11. "Battered Women" and Previous Victimization: Is the Question Relevant? (United States)

    Gudim, Laurie, Comp.; And Others

    This report discusses battered women and the role of their previous victimization. After a literature review on family violence in general, these topics are discussed: (1) family violence and the patriarchy; (2) the historical background of family violence; (3) intergenerational cycle of violence; and (4) psychological literature's four ways…

  12. Choice of contraception after previous operative delivery at a family ...

    African Journals Online (AJOL)

    Age, education, religion, parity, prior contraception, and interval from the last delivery were significantly associated with the current choice of contraception (P 0.05). Overall, when comparing the pattern among those with a previous operative delivery and those without, ...

  13. Process cells dismantling of EUREX pant: previous activities

    International Nuclear Information System (INIS)

    Gili, M.


    In the '98-'99 period some process cells of the EUREX pant will be dismantled, in order to place there the liquid wastes conditioning plant 'CORA'. This report resumes the previous activities (plant rinsing campaigns and inactive Cell 014 dismantling), run in the past three years and the drawn experience [it

  14. The job satisfaction of principals of previously disadvantaged schools

    African Journals Online (AJOL)

    The aim of this study was to identify influences on the job satisfaction of previously disadvantaged school principals in North-West Province. Evans's theory of job satisfaction, morale and motivation was useful as a conceptual framework. A mixedmethods explanatory research design was important in discovering issues with ...

  15. Previous utilization of service does not improve timely booking in ...

    African Journals Online (AJOL)

    Previous utilization of service does not improve timely booking in antenatal care: Cross sectional study on timing of antenatal care booking at public health facilities in ... Methods: A cross sectional study was conducted to collect data from 630 pregnant women who were attending antenatal care service at 10 governmental ...

  16. Research Note Effects of previous cultivation on regeneration of ...

    African Journals Online (AJOL)

    We investigated the effects of previous cultivation on regeneration potential under miombo woodlands in a resettlement area, a spatial product of Zimbabwe's land reforms. We predicted that cultivation would affect population structure, regeneration, recruitment and potential grazing capacity of rangelands. Plant attributes ...

  17. Mondor's Disease of the Breast in a Nigerian Woman Previously ...

    African Journals Online (AJOL)


    Sep 14, 2017 ... Case Report. How to cite this article: Olarinoye-Akorede SA, Silas BT. Mondor's disease of the breast in a Nigerian woman previously treated for invasive ductal carcinoma in the ... and the new creations are licensed under the identical terms. For reprints .... malignancy. Financial support and sponsorship.

  18. 44 CFR 402.5 - Forwarding commodities previously shipped. (United States)


    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Forwarding commodities... commodities previously shipped. Order T-1 applies to transportation on or discharge from ships documented... ship or aircraft, before the issuance of Order T-1, had transported restricted commodities manifested...

  19. Reoperative sentinel lymph node biopsy after previous mastectomy. (United States)

    Karam, Amer; Stempel, Michelle; Cody, Hiram S; Port, Elisa R


    Sentinel lymph node (SLN) biopsy is the standard of care for axillary staging in breast cancer, but many clinical scenarios questioning the validity of SLN biopsy remain. Here we describe our experience with reoperative-SLN (re-SLN) biopsy after previous mastectomy. Review of the SLN database from September 1996 to December 2007 yielded 20 procedures done in the setting of previous mastectomy. SLN biopsy was performed using radioisotope with or without blue dye injection superior to the mastectomy incision, in the skin flap in all patients. In 17 of 20 patients (85%), re-SLN biopsy was performed for local or regional recurrence after mastectomy. Re-SLN biopsy was successful in 13 of 20 patients (65%) after previous mastectomy. Of the 13 patients, 2 had positive re-SLN, and completion axillary dissection was performed, with 1 having additional positive nodes. In the 11 patients with negative re-SLN, 2 patients underwent completion axillary dissection demonstrating additional negative nodes. One patient with a negative re-SLN experienced chest wall recurrence combined with axillary recurrence 11 months after re-SLN biopsy. All others remained free of local or axillary recurrence. Re-SLN biopsy was unsuccessful in 7 of 20 patients (35%). In three of seven patients, axillary dissection was performed, yielding positive nodes in two of the three. The remaining four of seven patients all had previous modified radical mastectomy, so underwent no additional axillary surgery. In this small series, re-SLN was successful after previous mastectomy, and this procedure may play some role when axillary staging is warranted after mastectomy.

  20. Methodology of failed section location in case of leaks in PGN-200M sectional steam generator

    International Nuclear Information System (INIS)

    Kuznetsov, A.A.; Govorov, P.P.; Nosov, Yu.V.; Karavaev, A.P.


    The article considers a way of the failed section location when indications of water-sodium reaction emerge in PGN-200M sectional steam generator of the BN-600 power unit. The selection of diagnostic parameters used to locate the failed section is justified. Various alternative locations of leaks have been simulated [ru

  1. Somalia: An Anti-Thesis of the Western Conception of Failed States ...

    African Journals Online (AJOL)

    This paper reviews the concept of failed states and its supposed results of anarchy, conflict and safe-haven for terrorists. Using the US policy towards Somalia as a case study, it points out the flaws in the concept of “Failed States” and argues that these flaws when not fully dealt with, may affect any meaningful global effort to ...

  2. The Role of Tertiary Education in Fixing Failed States: Globalization and Public Goods (United States)

    Tierney, William G.


    The plight of nations labeled as "failed" is well-documented, as are suggested strategies to fix them. One area that receives a great deal of focus in the extant literature is education. How can education contribute to the rebuilding of a failed State? Most often the responses to this question focus on the importance of reestablishing primary and…

  3. 45 CFR 261.50 - What happens if a State fails to meet the participation rates? (United States)


    ... Requirements? § 261.50 What happens if a State fails to meet the participation rates? (a) If we determine that... 45 Public Welfare 2 2010-10-01 2010-10-01 false What happens if a State fails to meet the participation rates? 261.50 Section 261.50 Public Welfare Regulations Relating to Public Welfare OFFICE OF...

  4. Failure to Fail in a Final Pre-Service Teaching Practicum (United States)

    Danyluk, Patricia J.; Luhanga, Florence; Gwekwerere, Yovita N.; MacEwan, Leigh; Larocque, Sylvie


    This article presents a Canadian perspective on the issue of failure to fail in Bachelor of Education programs. The issue of failure to fail in Bachelor of Education programs is one that had not been explored in any great detail. What literature does exist focuses on the strain that a teacher experiences when s/he mentors a student teacher…

  5. Understanding "Failed" Markets: Conflicting Logics and Dissonance in Attempts to Price the Priceless Child

    NARCIS (Netherlands)

    Vermeulen, P.A.M.; Ansari, S.; Lounsbury, M.; Gehman, J.; Lounsbury, M.; Greenwood, R.


    While scholars have developed increasingly well-developed accounts of institutional change, little attention has been paid to how change is resisted and, in particular, how efforts to marketize fail. We draw on the institutional logics perspective to guide analysis of an empirical case of the failed

  6. The Value of Failing in Career Development: A Chaos Theory Perspective (United States)

    Pryor, Robert G. L.; Bright, James E. H.


    Failing is a neglected topic in career development theory and counselling practice. Most theories see failing as simply the opposite of success and something to be avoided. It is contended that the Chaos Theory of Careers with its emphasis on complexity, uncertainty and consequent human imitations, provides a conceptually coherent account of…

  7. Turning the Question Around: Do Colleges Fail to Meet Students' Expectations? (United States)

    Rosenbaum, James E.; Becker, Kelly Iwanaga; Cepa, Kennan A.; Zapata-Gietl, Claudia E.


    Research often focuses on how students fail to meet college expectations, but it rarely asks how colleges fail to meet students' expectations. This study examines students' expectations of college and their institutional confidence--their level of certainty that college will meet their expectations. Drawing on 65 pilot interviews and a survey of…

  8. Contribution of targeted saliva screening for congenital CMV-related hearing loss in newborns who fail hearing screening. (United States)

    Ari-Even Roth, Daphne; Lubin, Daniel; Kuint, Jacob; Teperberg-Oikawa, Michal; Mendelson, Ella; Strauss, Tzipora; Barkai, Galia


    We previously reported a 2.2% rate of infants born with sensorineural hearing loss (SNHL) due to congenital cytomegalovirus (cCMV) infection identified by universal neonatal screen for cCMV using saliva. To evaluate the contribution of targeted saliva screening for cCMV to the detection of infants born with cCMV-related SNHL who failed universal newborn hearing screening (UNHS). We retrospectively reviewed the audiological and medical records of infants who failed UNHS and were tested for cCMV using saliva sample prior to discharge at Sheba Medical Center between 2014 and 2015. Positive cases were confirmed by urine sample. Two hundred (1%) of the 19 830 infants tested during the study period failed in-hospital hearing screening. A saliva specimen was obtained prior to discharge in 187 infants (93.5% of those who failed UNHS). In 178 infants saliva testing was performed at ≤21 days of chronological age and yielded results. cCMV infection was identified in 4/178 tested infants (2.25%, 95% CI 0.8% to 5.3%), of whom three were diagnosed with SNHL (1.7%, 95% CI 0.5% to 4.4%) and offered antiviral treatment. Two of the tested infants (1.12%, 95% CI 0.2% to 3.6%) were diagnosed with cCMV solely due to failure in UNHS. Occult central nervous system (CNS) symptoms of cCMV infection were detected in 2/4 infants following targeted investigation. Targeted cCMV screening in newborns who failed UNHS contributed to the early detection of infants born with cCMV-related isolated SNHL or with occult CNS symptoms who could potentially benefit from antiviral treatment. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. The Rockall Trough, NE Atlantic: An Extinct Young Ocean Basin or a Failed Breakup Basin? (United States)

    Roberts, Alan; Kusznir, Nick; Alvey, Andy


    We investigate the crustal structure and composition of the Rockall Trough which is located in the NE Atlantic to the west of Ireland and the UK. The Rockall Trough is a large extensional basin formed in the Early Cretaceous and has dimensions of approximately 250 km in width and 1000 km in length. It is one of several basins formed during the complex Mesozoic northward propagation of rifting, continental breakup and sea-floor spreading initiation of the North Atlantic; other adjacent basins formed at this time include the Porcupine Trough to its east and the East and West Orphan Basins on the Canadian conjugate margin. To investigate the crustal structure of the Rockall Trough we have used three independent analyses of available 2D and 3D data: 1. 3D gravity inversion, using public-domain gravity and sediment-thickness information, has produced maps of (i) depth to Moho, (ii) crustal thickness (figure 1) and (iii) stretching/thinning factor across both margins. 2. Gravity inversion as above, but using public-domain gravity data combined with new proprietary 2D sediment-thickness information, has produced a series of cross-sections which show (i) depth to Moho, (ii) crustal thickness and (iii) stretching/thinning factor across both margins 3. Geodynamic modelling, comprising 2D flexural backstripping and forward modelling, has been used to produce (i) estimates of stretching/thinning factor, (ii) whole-crustal cross-sections and (iii) predictions of palaeobathymetry through time along a series of project-specific transects. Our analysis of the Rockall Trough shows a rapid shallowing of crustal basement thicknesses on the flanks of the basin with central values of crustal thickness typically 8-10 km consistent with previously published seismic estimates. An important question is whether this thin crust is hyper-extended continental crust or proto-oceanic crust. Locally isolated patches of crustal thicknesses as low as 3km are observed which are consistent with the

  10. Ab Interno Trabeculectomy With the Trabectome as a Valuable Therapeutic Option for Failed Filtering Blebs. (United States)

    Wecker, Thomas; Neuburger, Matthias; Bryniok, Laura; Bruder, Kathrin; Luebke, Jan; Anton, Alexandra; Jordan, Jens F


    Uncontrolled intraocular pressure (IOP) after glaucoma filtration surgery is a challenging problem in the management of glaucoma patients. The Trabectome is a device for selective electroablation of the trabecular meshwork through a clear cornea incision without affecting the conjunctiva. Minimally invasive glaucoma surgery using the Trabectome is safe and effective as primary glaucoma surgery. Here we investigate the results of ab interno trabeculectomy with the Trabectome for IOP control in patients with a failed filtering bleb. A total of 60 eyes of 60 consecutive patients with primary open-angle glaucoma (POAG) or pseudoexfoliative glaucoma (PXG) were enrolled in this single center observational study. Trabectome surgery was performed alone or in combination with phacoemulsification by 2 experienced surgeons. IOP readings and number of IOP lowering medication as primary outcome parameters were taken by an independent examiner. Intraoperative and postoperative medication were recorded systematically. Mean IOP before surgery was 24.5±3.5 mm Hg and decreased to 15.7±3.4 (-36%) after mean follow-up of 415 days. The number of necessary IOP lowering medication dropped from 2.1±1.3 to 1.8±1.2 (14% reduction from baseline). A total of 25% (n=15) of cases reported here needed additional surgery after 517 days (range: 6 to 1563 d). No major complications were observed. After mean follow-up, we found a qualified success rate for PXG of 87% and 50% for POAG as revealed by the Kaplan-Meier analysis according to the definitions for success in advanced glaucoma cases according to the World Glaucoma Association (40% reduction from baseline IOP and maximum IOP of 15 mm Hg). Trabectome surgery for uncontrolled IOP after trabeculectomy is safe and effective especially in PXG patients. Given the demanding subgroup of patients studied here, it is not surprising that success rates are lower compared with previous studies investigating the Trabectome for primary glaucoma surgery

  11. Clinical predictors of failing one dose of methotrexate for ectopic pregnancy after in vitro fertilization. (United States)

    Brady, Paula C; Missmer, Stacey A; Farland, Leslie V; Ginsburg, Elizabeth S


    The aim of this study is to investigate the clinical predictors of failure of a single dose of methotrexate (MTX) for management of ectopic pregnancy after in vitro fertilization (IVF). A retrospective cohort study was performed of women who conceived ectopic pregnancies following fresh or frozen IVF cycles at an academic infertility clinic between 2007 and 2014, and received intramuscular MTX (50 mg/m 2 ). Successful single-dose MTX treatment was defined as a serum beta-human chorionic gonadotropin (hCG) decline ≥15% between days 4 and 7 post-treatment. Logistic regression models adjusted for oocyte age, number of embryos transferred, and prior ectopic pregnancy were used to estimate the adjusted odds ratio (OR) (95% confidence interval [CI]) of failing one dose of MTX. Sixty-four patients with ectopic pregnancies after IVF were included. Forty required only one dose of MTX (62.5%), while 15 required additional MTX alone (up to four total doses, 23.4%), and 9 required surgery (14.1%). By multivariable logistic regression, the highest tertiles of serum hCG at peak (≥499 IU/L, OR = 9.73, CI 1.88-50.25) and at first MTX administration (≥342 IU/L, OR = 4.74, CI 1.11-20.26), fewer embryos transferred (OR = 0.37 per each additional embryo transferred, CI 0.19-0.74), and adnexal mass by ultrasound (OR = 3.65, CI 1.10-12.11) were each correlated with greater odds of requiring additional MTX and/or surgery. This is the first study to report that in women with ectopic pregnancies after IVF, higher hCG-though well below treatment failure thresholds previously described in spontaneous pregnancies-fewer embryos transferred, and adnexal masses are associated with greater odds of failing one dose of MTX. These findings can be used to counsel IVF patients regarding the likelihood of success with single-dose MTX.

  12. Previously unreported abnormalities in Wolfram Syndrome Type 2. (United States)

    Akturk, Halis Kaan; Yasa, Seda


    Wolfram syndrome (WFS) is a rare autosomal recessive disease with non-autoimmune childhood onset insulin dependent diabetes and optic atrophy. WFS type 2 (WFS2) differs from WFS type 1 (WFS1) with upper intestinal ulcers, bleeding tendency and the lack ofdiabetes insipidus. Li-fespan is short due to related comorbidities. Only a few familieshave been reported with this syndrome with the CISD2 mutation. Here we report two siblings with a clinical diagnosis of WFS2, previously misdiagnosed with type 1 diabetes mellitus and diabetic retinopathy-related blindness. We report possible additional clinical and laboratory findings that have not been pre-viously reported, such as asymptomatic hypoparathyroidism, osteomalacia, growth hormone (GH) deficiency and hepatomegaly. Even though not a requirement for the diagnosis of WFS2 currently, our case series confirm hypogonadotropic hypogonadism to be also a feature of this syndrome, as reported before. © Polish Society for Pediatric Endocrinology and Diabetology.

  13. Nicotine Elicits Methamphetamine-Seeking in Rats Previously Administered Nicotine


    Neugebauer, N. M.; Harrod, S. B.; Bardo, M. T.


    Research has indicated a high correlation between psychostimulant use and tobacco cigarette smoking in human substance abusers. The objective of the current study was to examine the effects of acute and repeated nicotine administration on responding for intravenous methamphetamine (0.03 mg/kg/infusion) in a rodent model of self-administration, as well as the potential of nicotine to induce reinstatement of previously extinguished drug-taking behavior in male Sprague-Dawley rats. In addition, ...

  14. Influence of previous knowledge in Torrance tests of creative thinking


    Aranguren, María; Consejo Nacional de Investigaciones Científicas y Técnicas CONICET


    The aim of this work is to analyze the influence of study field, expertise and recreational activities participation in Torrance Tests of Creative Thinking (TTCT, 1974) performance. Several hypotheses were postulated to explore the possible effects of previous knowledge in TTCT verbal and TTCT figural university students’ outcomes. Participants in this study included 418 students from five study fields: Psychology;Philosophy and Literature, Music; Engineering; and Journalism and Advertisin...

  15. Previous climatic alterations are caused by the sun

    International Nuclear Information System (INIS)

    Groenaas, Sigbjoern


    The article surveys the scientific results of previous research into the contribution of the sun to climatic alterations. The author concludes that there is evidence of eight cold periods after the last ice age and that the alterations largely were due to climate effects from the sun. However, these effects are only causing a fraction of the registered global warming. It is assumed that the human activities are contributing to the rest of the greenhouse effect

  16. Event Sequence Variability in Healthy Swallowing: Building on Previous Findings


    Molfenter, Sonja M.; Leigh, Chelsea; Steele, Catriona M.


    This study builds on previous work by Kendall, Leonard and McKenzie, which investigated event sequence variability for 12 paired-events during swallowing by healthy volunteers. They identified four event pairs, which always occurred in a stereotyped order as well as a most-common occurring overall order of events during swallowing. In the current study, we investigate overall event sequencing and the same four paired-events in a sample of swallows by healthy, young (under 45 years old) volunt...

  17. Prevalence and significance of previously undiagnosed rheumatic diseases in pregnancy. (United States)

    Spinillo, Arsenio; Beneventi, Fausta; Ramoni, Véronique; Caporali, Roberto; Locatelli, Elena; Simonetta, Margherita; Cavagnoli, Chiara; Alpini, Claudia; Albonico, Giulia; Prisco, Elena; Montecucco, Carlomaurizio


    The objective of this study was to evaluate the rates of previously undiagnosed rheumatic diseases during the first trimester of pregnancy and their impact on the pregnancy outcome. Pregnant women in their first trimester were screened using a two-step approach using a self-administered 10-item questionnaire and subsequent testing for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies and lupus anticoagulant) and evaluation by a rheumatologist. Overall, the complications of pregnancy evaluated included fetal loss, pre-eclampsia, gestational diabetes, fetal growth restriction, delivery at less than 34 weeks, neonatal resuscitation and admission to the neonatal intensive care unit. Out of the 2458 women screened, the authors identified 62 (2.5%) women with previously undiagnosed undifferentiated connective tissue disease (UCTD) and 24 (0.98%) women with previously undiagnosed definite systemic rheumatic disease. The prevalences were seven (0.28%) for systemic lupus erythematosus and Sjogren's syndrome, six (0.24%) for rheumatoid arthritis, three (0.12%) for antiphospholipid syndrome and one (0.04%) for systemic sclerosis. In multiple exact logistic regression, after adjustment for potential confounders, the OR of overall complications of pregnancy were 2.81 (95% CI 1.29 to 6.18) in women with UCTD and 4.57 (95% CI 1.57 to 13.57) in those with definite diseases, respectively, compared with asymptomatic controls. In our population approximately 2.5% and 1% of first trimester pregnant women had a previously undiagnosed UCTD and definite systemic rheumatic disease, respectively. These conditions were associated with significant negative effects on the outcome of pregnancy.

  18. Previously infertile couples and the newborn intensive care unit. (United States)

    Lind, R F; Pruitt, R L; Greenfeld, D


    Having a newborn child admitted to a newborn intensive care unit can be a traumatic experience for parents; however, parents who previously have been infertile face unique problems in coping with this situation. The authors discuss the difficulties parents must overcome in resolving their crises and in developing a good relationship with their child, or, in some cases, coming to terms with the child's death or ongoing disability. In addition, the authors offer suggestions for effective social work intervention.

  19. Antenatal diagnosis of Patau syndrome with previous anomalous baby


    Keerthi Kocherla; Vasantha Kocherla


    Patau syndrome is the least common and most severe of the viable autosomal trisomies with median survival of fewer than 3 days was first identified as a cytogenetic syndrome in 1960. Patau syndrome is caused by an extra copy of chromosome 13. In this case report, we present antenatal imaging findings and gross foetal specimen correlation of foetus with Patau syndrome confirmed by karyotyping in third gravida who had significant previous obstetric history of gastrochisis in monochorionic and...

  20. Genomic reconstruction of Shewanella oneidensis MR-1 metabolism reveals previously uncharacterized machinery for lactate utilization

    Energy Technology Data Exchange (ETDEWEB)

    Pinchuk, Grigoriy E.; Rodionov, Dmitry A.; Yang, Chen; Li, Xiaoqing; Osterman, Andrei L.; Dervyn, Etienne; Geydebrekht, Oleg V.; Reed, Samantha B.; Romine, Margaret F.; Collart, Frank R.; Scott, J.; Fredrickson, Jim K.; Beliaev, Alex S.


    The ability to utilize lactate as a sole source of carbon and energy is one of the key metabolic signatures of Shewanellae, a diverse group of dissimilatory metal reducing bacteria commonly found in aquatic and sedimentary environments. Nonetheless, homology searches failed to recognize orthologs of previously described bacterial D- or L-lactate oxidizing enzymes (Escherichia coli genes dld and lldD) in any of the 13 analyzed genomes of Shewanella spp. Using comparative genomic techniques, we identified a conserved chromosomal gene cluster in Shewanella oneidensis MR-1 (locus tag: SO1522-SO1518) containing lactate permease and candidate genes for both D- and L-lactate dehydrogenase enzymes. The predicted D-LDH gene (dldD, SO1521) is a distant homolog of FAD-dependent lactate dehydrogenase from yeast, whereas the predicted L-LDH is encoded by three genes with previously unknown functions (lldEGF, SO1520-19-18). Through a combination of genetic and biochemical techniques, we experimentally confirmed the predicted physiological role of these novel genes in S. oneidensis MR-1 and carried out successful functional validation studies in Escherichia coli and Bacillus subtilis. We conclusively showed that dldD and lldEFG encode fully functional D-and L-LDH enzymes, which catalyze the oxidation of the respective lactate stereoisomers to pyruvate. Notably, the S. oneidensis MR-1 LldEFG enzyme is the first described example of a multi-subunit lactate oxidase. Comparative analysis of >400 bacterial species revealed the presence of LldEFG and Dld in a broad range of diverse species accentuating the potential importance of these previously unknown proteins in microbial metabolism.