bluuebunny/crossref_metadata_2025 huggingface dataset:
Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial
Authors: Wells Samuel A. , Robinson Bruce G. , Gagel Robert F. , Dralle Henning , Fagin James A. , Santoro Massimo , Baudin Eric , Elisei Rossella , Jarzab Barbara , Vasselli James R. , Read Jessica , Langmuir Peter , Ryan Anderson J. , Schlumberger Martin J.
Published: October 2011

Purpose

There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC.

Patients and Methods

Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments.

Results

Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%).

Conclusion

Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).
First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors
Authors: Yap Timothy A. , Yan Li , Patnaik Amita , Fearen Ivy , Olmos David , Papadopoulos Kyriakos , Baird Richard D. , Delgado Liliana , Taylor Adekemi , Lupinacci Lisa , Riisnaes Ruth , Pope Lorna L. , Heaton Simon P. , Thomas George , Garrett Michelle D. , Sullivan Daniel M. , de Bono Johann S. , Tolcher Anthony W.
Published: October 2011

Purpose

AKT signaling is frequently deregulated in human cancers. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms with antitumor activity in preclinical models. A phase I study of MK-2206 was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy.

Patients and Methods

Patients with advanced solid tumors received MK-2206 on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated tumor and hair follicle analyses, and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog (PTEN) loss.

Results

Thirty-three patients received MK-2206 at 30, 60, 75, or 90 mg on alternate days. Dose-limiting toxicities included skin rash and stomatitis, establishing the MTD at 60 mg. Drug-related toxicities included skin rash (51.5%), nausea (36.4%), pruritus (24.2%), hyperglycemia (21.2%), and diarrhea (21.2%). PKs (area under the concentration-time curve from 0 to 48 hours and maximum measured plasma concentration) were dose proportional. Phosphorylated serine 473 AKT declined in all tumor biopsies assessed (P = .015), and phosphorylated threonine 246 proline-rich AKT substrate 40 was suppressed in hair follicles at 6 hours (P = .008), on days 7 (P = .028) and 15 (P = .025) with MK-2206; reversible hyperglycemia and increases in insulin c-peptide were also observed, confirming target modulation. A patient with pancreatic adenocarcinoma (PTEN loss; KRAS G12D mutation) treated at 60 mg on alternate days experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses.

Conclusion

MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.
Randomized Phase II Study of Erlotinib in Combination With Placebo or R1507, a Monoclonal Antibody to Insulin-Like Growth Factor-1 Receptor, for Advanced-Stage Non–Small-Cell Lung Cancer
Authors: Ramalingam Suresh S. , Spigel David R. , Chen David , Steins Martin B. , Engelman Jeffrey A. , Schneider Claus-Peter , Novello Silvia , Eberhardt Wilfried E.E. , Crino Lucio , Habben Kai , Liu Lian , Jänne Pasi A. , Brownstein Carrie M. , Reck Martin
Published: October 2011

Purpose

R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study.

Patients and Methods

Patients with advanced-stage non–small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate.

Results

In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo.

Conclusion

The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR.
Dpy19l1, a multi-transmembrane protein, regulates the radial migration of glutamatergic neurons in the developing cerebral cortex
Authors: Watanabe Keisuke , Takebayashi Hirohide , Bepari Asim K. , Esumi Shigeyuki , Yanagawa Yuchio , Tamamaki Nobuaki
Published: October 2011

During corticogenesis, the regulation of neuronal migration is crucial for the functional organization of the neocortex. Glutamatergic neurons are major excitatory components of the mammalian neocortex. In order to elucidate the specific molecular mechanisms underlying their development, we used single-cell microarray analysis to screen for mouse genes that are highly expressed in developing glutamatergic neurons. We identified dpy-19-like 1 (Dpy19l1), a homolog of C. elegans dpy-19, which encodes a putative multi-transmembrane protein shown to regulate directed migration of Q neuroblasts in C. elegans. At embryonic stages Dpy19l1 is highly expressed in glutamatergic neurons in the mouse cerebral cortex, whereas in the subpallium, where GABAergic neurons are generated, expression was below detectable levels. Downregulation of Dpy19l1 mediated by shRNA resulted in defective radial migration of glutamatergic neurons in vivo, which was restored by the expression of shRNA-insensitive Dpy19l1. Many Dpy19l1-knockdown cells were aberrantly arrested in the intermediate zone and the deep layer and, additionally, some extended single long processes towards the pial surface. Furthermore, we observed defective radial migration of bipolar cells in Dpy19l1-knockdown brains. Despite these migration defects, these cells correctly expressed Cux1, which is a marker for upper layer neurons, suggesting that Dpy19l1 knockdown results in migration defects but does not affect cell type specification. These results indicate that Dpy19l1 is required for the proper radial migration of glutamatergic neurons, and suggest an evolutionarily conserved role for the Dpy19 family in neuronal migration.
Apical migration of nuclei during G2 is a prerequisite for all nuclear motion in zebrafish neuroepithelia
Authors: Leung Louis , Klopper Abigail V. , Grill Stephan W. , Harris William A. , Norden Caren
Published: October 2011

Nuclei in the proliferative pseudostratified epithelia of vastly different organisms exhibit a characteristic dynamics – the so-called interkinetic nuclear migration (IKNM). Although these movements are thought to be intimately tied to the cell cycle, little is known about the relationship between IKNM and distinct phases of the cell cycle and the role that this association plays in ensuring balanced proliferation and subsequent differentiation. Here, we perform a quantitative analysis of modes of nuclear migration during the cell cycle using a marker that enables the first unequivocal differentiation of all four phases in proliferating neuroepithelial cells in vivo. In zebrafish neuroepithelia, nuclei spend the majority of the cell cycle in S phase, less time in G1, with G2 and M being noticeably shorter still in comparison. Correlating cell cycle phases with nuclear movements shows that IKNM comprises rapid apical nuclear migration during G2 phase and stochastic nuclear motion during G1 and S phases. The rapid apical migration coincides with the onset of G2, during which we find basal actomyosin accumulation. Inhibiting the transition from G2 to M phase induces a complete stalling of nuclei, indicating that IKNM and cell cycle continuation cannot be uncoupled and that progression from G2 to M is a prerequisite for rapid apical migration. Taken together, these results suggest that IKNM involves an actomyosin-driven contraction of cytoplasm basal to the nucleus during G2, and that the stochastic nuclear movements observed in other phases arise passively due to apical migration in neighboring cells.
Nuclear trapping by GL3 controls intercellular transport and redistribution of TTG1 protein inArabidopsis
Authors: Balkunde Rachappa , Bouyer Daniel , Hülskamp Martin
Published: October 2011

Trichome patterning on Arabidopsis leaves is one of the best-studied model systems for two-dimensional de novo patterning. In addition to an activator-inhibitor-related mechanism, we previously proposed a depletion mechanism to operate during this process such that GLABRA3 (GL3) traps the trichome-promoting factor TRANSPARENT TESTA GLABRA1 (TTG1) in trichomes that, in turn, results in a depletion of TTG1 in trichome neighbouring cells. In this manuscript we analyze the molecular basis underlying this trapping mechanism. We demonstrate the ability of GL3 to regulate TTG1 mobility by expressing TTG1 and GL3 in different tissue layers in different combinations. We further show that TTG1 trapping by GL3 is based on direct interaction between both proteins and recruitment in the nucleus.
Notch/Delta signalling is not required for segment generation in the basally branching insectGryllus bimaculatus
Authors: Kainz Franz , Ewen-Campen Ben , Akam Michael , Extavour Cassandra G.
Published: October 2011

Arthropods and vertebrates display a segmental body organisation along all or part of the anterior-posterior axis. Whether this reflects a shared, ancestral developmental genetic mechanism for segmentation is uncertain. In vertebrates, segments are formed sequentially by a segmentation ‘clock’ of oscillating gene expression involving Notch pathway components. Recent studies in spiders and basal insects have suggested that segmentation in these arthropods also involves Notch-based signalling. These observations have been interpreted as evidence for a shared, ancestral gene network for insect, arthropod and bilaterian segmentation. However, because this pathway can play multiple roles in development, elucidating the specific requirements for Notch signalling is important for understanding the ancestry of segmentation. Here we show that Delta, a ligand of the Notch pathway, is not required for segment formation in the cricket Gryllus bimaculatus, which retains ancestral characteristics of arthropod embryogenesis. Segment patterning genes are expressed before Delta in abdominal segments, and Delta expression does not oscillate in the pre-segmental region or in formed segments. Instead, Delta is required for neuroectoderm and mesectoderm formation; embryos missing these tissues are developmentally delayed and show defects in segment morphology but normal segment number. Thus, what initially appear to be ‘segmentation phenotypes’ can in fact be due to developmental delays and cell specification errors. Our data do not support an essential or ancestral role of Notch signalling in segment generation across the arthropods, and show that the pleiotropy of the Notch pathway can confound speculation on possible segmentation mechanisms in the last common bilaterian ancestor.
Different roles for Aurora B in condensin targeting during mitosis and meiosis
Authors: Collette Karishma S. , Petty Emily L. , Golenberg Netta , Bembenek Joshua N. , Csankovszki Gyorgyi
Published: October 2011

Condensin complexes are essential for mitotic and meiotic chromosome segregation. Caenorhabditis elegans, like other metazoans, has two distinct mitotic and meiotic condensin complexes (I and II), which occupy distinct chromosomal domains and perform non-redundant functions. Despite the differences in mitotic and meiotic chromosome behavior, we uncovered several conserved aspects of condensin targeting during these processes. During both mitosis and meiosis, condensin II loads onto chromosomes in early prophase, and condensin I loads at entry into prometaphase. During both mitosis and meiosis, the localization of condensin I, but not condensin II, closely parallels the localization of the chromosomal passenger kinase Aurora B (AIR-2 in C. elegans). Interestingly, condensin I and AIR-2 also colocalize on the spindle midzone during anaphase of mitosis, and between separating chromosomes during anaphase of meiosis. Consistently, AIR-2 affects the targeting of condensin I but not condensin II. However, the role AIR-2 plays in condensin I targeting during these processes is different. In mitosis, AIR-2 activity is required for chromosomal association of condensin I. By contrast, during meiosis, AIR-2 is not required for condensin I chromosomal association, but it provides cues for correct spatial targeting of the complex.
Increased levels of the cytoplasmic domain of Crumbs repolarise developingDrosophilaphotoreceptors
Authors: Muschalik Nadine , Knust Elisabeth
Published: October 2011

Photoreceptor morphogenesis in Drosophila requires remodelling of apico-basal polarity and adherens junctions (AJs), and includes cell shape changes, as well as differentiation and expansion of the apical membrane. The evolutionarily conserved transmembrane protein Crumbs (Crb) organises an apical membrane-associated protein complex that controls photoreceptor morphogenesis. Expression of the small cytoplasmic domain of Crb in crb mutant photoreceptor cells (PRCs) rescues the crb mutant phenotype to the same extent as the full-length protein. Here, we show that overexpression of the membrane-tethered cytoplasmic domain of Crb in otherwise wild-type photoreceptor cells has major effects on polarity and morphogenesis. Whereas early expression causes severe abnormalities in apico-basal polarity and ommatidial integrity, expression at later stages affects the shape and positioning of AJs. This result supports the importance of Crb for junctional remodelling during morphogenetic changes. The most pronounced phenotype observed upon early expression is the formation of ectopic apical membrane domains, which often develop into a complete second apical pole, including ectopic AJs. Induction of this phenotype requires members of the Par protein network. These data point to a close integration of the Crb complex and Par proteins during photoreceptor morphogenesis and underscore the role of Crb as an apical determinant.
Hyperbolic Discounting and the Sustainability of Rotational Savings Arrangements
Authors: Basu Karna
Published: October 2011

People across the developing world join rotational savings and credit associations (roscas) to fund repeated purchases of nondivisible goods. When the scope for punishment is weak, there is a natural question about why agents not defect from roscas. This paper models roscas as commitment savings devices and derives conditions under which hyperbolic discounters will never defect, even in the absence of formal contracting, social punishment, and reputation. I show why, unlike with standard commitment devices, a hyperbolic discounter will not postpone entry into a rosca. Finally, this paper makes predictions about the relative survival of random and fixed roscas. (JEL D14, D91, O12)
Just Keep My Money! Supporting Tax-Time Savings with US Savings Bonds
Authors: Tufano Peter
Published: October 2011

This paper reports the results of a 2007 experiment testing whether specific process simplification can foster increased take-up rates for savings products, particularly by low-to-moderate income (LMI) households. Tax refund recipients at certain H&R Block tax preparation offices were given the option to purchase US Savings Bonds with their tax refunds, augmenting the tax-site savings options offered by H&R Block. Those who received the savings bond offer were substantially more likely to purchase a savings product on-site than those who didn't, even after controlling for client demographics. Much of this take-up was directed at intra-family gifting, or asset building on behalf of children. (JEL D14, H24)
A genomic integration method for the simultaneous visualization of endogenous mRNAs and their translation products in living yeast
Authors: Haim-Vilmovsky Liora , Gadir Noga , Herbst Rebecca H. , Gerst Jeffrey E.
Published: October 2011

Protein localization within cells can be achieved by the targeting and localized translation of mRNA. Yet, our understanding of the dynamics of mRNA targeting and protein localization, and of how general this phenomenon is, is not clear. Plasmid-based expression systems have been used to visualize exogenously expressed mRNAs and proteins; however, these methods typically produce them at levels greater than endogenous and can result in mislocalization. Hence, a method that allows for the simultaneous visualization of endogenous mRNAs and their translation products in living cells is needed. We previously developed a method (m-TAG) to localize endogenously expressed mRNAs in yeast by chromosomal insertion of the MS2 aptamer sequence between the open-reading frame (ORF) and 3′ UTR of any gene. Upon coexpression with the MS2 RNA-binding coat protein (MS2-CP) fused with GFP, the aptamer-tagged mRNAs bearing their 3′ UTRs are localized using fluorescence microscopy. Here we describe an advanced method (mp-TAG) that allows for the simultaneous visualization of both endogenously expressed mRNAs and their translation products in living yeast for the first time. Homologous recombination is used to insert the mCherry gene and MS2-CP binding sites downstream from any ORF, in order to localize protein and mRNA, respectively. As proof of the concept, we tagged ATP2 as a representative gene and demonstrated that endogenous ATP2 mRNA and protein localize to mitochondria, as shown previously. In addition, we demonstrate that tagged proteins like Hhf2, Vph1, and Yef3 localize to their expected subcellular location, while the localization of their mRNAs is revealed for the first time.
Grammatische Illusionen – Lokal wohlgeformt – global deviant
Authors: Haider Hubert
Published: October 2011

Grammatical illusions are linguistic equivalents of optical illusions in visual processing. A grammatical illusion amounts to an expression that is judged acceptable in spite of its grammatical deviance. It is the hitherto insufficiently appreciated fourth “aggregate state”, that completes the set of four logical pairings of the properties “(un-)grammatical” and “(un-)acceptable”.

A typical source of syntactic illusions is the mental processor's attempt to repair grammatical inconsistencies resulting from contradicting requirements of syntactic regularities. The resulting pseudo-solutions tend to be appraised as acceptable, although they remain patently ungrammatical.

The consequences of this phenomenon, when acknowledged, are evident: Acceptability turns out to be neither a necessary nor a sufficient property of a grammatical construction. The attempt of modeling any construction that is (introspectively) judged acceptable as grammatically well-formed is tantamount to the attempt of devising a grammatical derivation for constructions of arbitrary (un)grammaticality. Informant consultation results are contaminated and of limited value. Syntactic investigations (and semantic ones as well) deserve more reliable standards of data assessment than mere sampling of self-perception testimonies and corpus search.
Aspekt, Temporalität und Argumentstruktur bei attributiven Partizipien des Deutschen
Authors: Lübbe Anja , Rapp Irene
Published: October 2011

German has two participles, both of which occur in prenominal position. Traditionally, both participles are considered to be associated with particular semantic and syntactic features. The present participle (malend ‘painting’) is subject-oriented; it has imperfective aspect and indicates simultaneity of the participle event and the matrix clause event. The past participle (gemalt ‘painted’) is object-oriented; it has perfective aspect and indicates that the participle event precedes the event of the matrix clause. In this paper, we will first argue that aspect is indeed an inherent – hence invariant – feature of the participle morphology: The present participle always presents an event as ongoing, whereas the past participle presents it as completed. Secondly, we will show that participles – as non-finite verb forms – lack tense. Hence, their temporal properties vary according to lexical, syntactic and pragmatic factors. It will be demonstrated that the unmarked temporal readings of the participles are due to the maxim of relation. Finally, we will argue that the argument selection properties of both participles are grammatically determined; however, these properties can be altered if certain conditions are met.
Rietveld refinement of energy-dispersive synchrotron measurements
Authors: Apel Daniel , Klaus Manuela , Genzel Christoph , Balzar Davor
Published: October 2011

In the past two decades the energy-dispersive diffraction (EDD) method has become a powerful tool in many fields of materials research such as residual stress, texture, and crystal structure analysis, because of its favorable ratio of a comparatively low experimental effort in form of a simple and fixed instrumental setup to a high information content included in the measured diffraction patterns. However, mainly due to the rather poor instrumental resolution only little work has been done so far to apply the well-established methods of diffraction line profile analysis to the EDD data. In the paper, a Rietveld program is introduced that allows for particle size and strain broadening analysis by refining the whole EDD äpattern. With the examples of synchrotron measurements performed on the materials science beamline EDDI at BESSY II on instrumental standard as well as samples exhibiting size and/or strain broadened diffraction lines, it is demonstrated that the generalized Thompson, Cox & Hastings approach (TCH) using pseudo-Voigt functions for describing the diffraction line profiles yields sound and reliable results on the materials microstructure. For a first proof of the theoretical assumptions this Rietveld program is based on, the Pawley approach was used to extract the peak intensities obtained from powder samples affected by microstructural broadening. An excellent agreement with the results of the size-strain round robin was obtained. Future enhancements of the program code which aim at its application to full residual stress and microstructure analysis in the near surface zone and also in the material voläume of polycrystalline materials are discussed.
Treatment and screening of hypothyroidism in pregnancy: results of a European survey
Authors: Vaidya Bijay , Hubalewska-Dydejczyk Alicja , Laurberg Peter , Negro Roberto , Vermiglio Francesco , Poppe Kris
Published: October 2011

Background

Maternal hypothyroidism in pregnancy is associated with several adverse outcomes. The Endocrine Society Guidelines for the management of thyroid diseases in pregnancy were published in 2007; however, impact of the guidelines in routine clinical practice is unknown. Therefore, we have carried out a survey of members of the European Thyroid Association (ETA) to study current practices relating to the management of hypothyroidism in pregnancy.

Subjects and methods

In December 2010, we emailed an electronic questionnaire survey based on clinical case scenarios to 605 members of the ETA. Responses from 190 clinician members (from 28 European countries) were analyzed.

Results

For a pregnant woman with newly diagnosed overt hypothyroidism, most responders initiated a full dose of l-thyroxine (l-T4). For a woman with hypothyroidism planning pregnancy, 50% recommended increasing the dose of l-T4 as soon as pregnancy is confirmed, whilst 43% favored testing thyroid function before adjusting the dose. Responders used diverse combinations of tests to monitor the dose of l-T4. The target of thyroid function tests that responders aimed to achieve with l-T4 was also inconsistent. Forty-two percent responders or their institutions screened all pregnant women for thyroid dysfunction, 43% performed targeted screening of only the high-risk group, whilst 17% did not carry out systemic screening. Timing of the screening, tests used, and criteria for starting treatment and monitoring were variable.

Conclusions

There is wide variation in the clinical practice relating to the treatment and screening of hypothyroidism during pregnancy in Europe.
Extrapolation of Adult Data and Other Data in Pediatric Drug-Development Programs
Authors: Dunne Julia , Rodriguez William J. , Murphy M. Dianne , Beasley B. Nhi , Burckart Gilbert J. , Filie Jane D. , Lewis Linda L. , Sachs Hari C. , Sheridan Philip H. , Starke Peter , Yao Lynne P.
Published: October 2011

OBJECTIVES:

In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time.

METHODS:

We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling.

RESULTS:

Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation.

CONCLUSIONS:

Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.
Disability 3, 12, and 24 Months After Traumatic Brain Injury Among Children and Adolescents
Authors: Rivara Frederick P. , Koepsell Thomas D. , Wang Jin , Temkin Nancy , Dorsch Andrea , Vavilala Monica S. , Durbin Dennis , Jaffe Kenneth M.
Published: October 2011

OBJECTIVE:

To examine disability in children and adolescents after traumatic brain injury (TBI) across the spectrum of injury severity.

METHODS:

This was a prospective cohort study of children younger than 18 years treated for a TBI (n = 729) or an arm injury (n = 197) between March 1, 2007, and September 30, 2008. The main outcome measures were disability in health-related quality of life, adaptive skills, and participation in social and community activities 3, 12, and 24 months after injury compared with preinjury functioning.

RESULTS:

The health-related quality of life for children with moderate or severe TBI was lower at all follow-up times compared with baseline, but there was some improvement during the first 2 years after injury. Three months after injury, there was a substantial decrease in the level of activities in which children with moderate and severe TBI were able to participate; these activities improved at 12 and 24 months but were still significantly impaired. Communication and self-care abilities in children with moderate and severe TBI were lower at 3 months than at baseline and did not improve by 24 months. Children who met the definition of mild TBI but had an intracranial hemorrhage had lower quality-of-life scores at 3 months.

CONCLUSIONS:

Children with moderate or severe TBI and children with mild TBI who had intracranial hemorrhage had substantial long-term reduction in their quality of life, participation in activities with others, and ability to communicate and care for themselves.
Biomimetic Polymer Nanoparticles Embedding Quantum Dots
Authors: Ishihara Kazuhiko , Goto Yusuke , Matsuno Ryosuke
Published: October 2011

To develop new functional fluorescence probe based on semiconductor nanoparticles, such as quantum dots (QD)s, we investigated polymer particle embedding QDs and covered with artificial cell membrane-biointerface. These nanoparticles were prepared by assembling 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer as a platform and biomolecules immobilized on the surface of the nanoparticles. The fluorescence property of QDs remained after embedding in the polymer nanoparticles. The MPC polymer surface showed high resistance to non-specific cellular uptake due to the phosphorylcholine groups in the side chain. On the other hand, when cell-penetration oligopeptide, octaarginine was immobilized on the surface, they could permeate the membrane of cells effectively and good fluorescence based on QDs could be observed. Cytotoxicity and inflammation reaction was not produced by these nanoparticles even after immobilization of octapeptide. In conclusion, we could obtain stable fluorescence polymer nanoparticles covered with artificial cell membrane, which are useful as an excellent bioimaging probe and as a novel evaluation tool for biomolecular function in the target cells.
Statin Therapy for the Prevention of Atrial Fibrillation: A Meta‐analysis of Randomized Controlled Trials
Authors: Wang Zhongsu , Zhang Yong , Gao Mei , Wang Jiangrong , Wang Qing , Wang Xiaojun , Su Lequn , Hou Yinglong
Published: October 2011

Study Objectives. To assess the efficacy of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) for primary and secondary prevention of atrial fibrillation, and to evaluate the efficacy of individual statins and their dosages.

Design. Meta‐analysis of 20 randomized controlled trials.

Patients. A total of 32,311 patients who received either a statin (16,203 patients) or a placebo or active control regimen (16,108 patients) for either primary or secondary prevention of atrial fibrillation as part of a research study.

Measurements and Main Results. A systemic literature search of MEDLINE, EMBASE, and the Cochrane Controlled Trials Register was performed to identify randomized controlled trials involving the prevention of atrial fibrillation with statin therapy. Effect size was expressed as odds ratio (OR) with 95% confidence interval (CI). Subgroup analysis was performed to explore the reasons for heterogeneity. Of the 20 trials, atorvastatin was studied in 11, pravastatin in five, rosuvastatin in three, and simvastatin in one. Overall, among the 32,311 patients in these trials, the risk of atrial fibrillation was significantly reduced by statins (OR 0.59, 95% CI 0.45‐0.76), and the drugs were effective for both primary prevention (OR 0.67, 95% CI 0.51‐0.88) and secondary prevention (OR 0.40, 95% CI 0.20‐0.83). Secondary prevention was not superior to primary prevention, however. A significant benefit was observed in the atorvastatin‐treated subgroup (OR 0.43, 95% CI 0.27‐0.66), especially in the dose range of 10–40 mg/day (OR 0.29, 95% CI 0.19‐0.45). No protective effect was observed in the pravastatin subgroup (OR 1.03, 95% CI 0.77‐1.37).

Conclusion. This meta‐analysis suggests that statin therapy is useful for the prevention of atrial fibrillation. The benefit of statins in secondary prevention was significant but not superior to primary prevention. Atorvastatin was more effective than pravastatin, and its effects were dose related, with lower doses being more effective. The number of trials focusing on individual drugs is still insufficient, and more randomized controlled trials are necessary to further support these conclusions.
Blood Pressure Level Attainment Among Patients with Coronary Artery Disease and Uncontrolled Blood Pressure
Authors: McConnell Karen J. , Morris Jessica L. , Delate Thomas , Cymbala Alicia A. , Hornak Roseanne , Kauffman Amy B. , McGinnis Brandy D. ,   Clinical Pharmacy Cardiac Risk Service Study Group
Published: October 2011

Study Objectives. To determine the proportion of patients with coronary artery disease (CAD) and uncontrolled blood pressure who attained a blood pressure of less than 130/80 mm Hg, and to compare patient‐ and health system—specific characteristics and identify factors independently associated with attaining this blood pressure level.

Design. Retrospective, longitudinal, cohort study.

Setting. Health maintenance organization.

Patients. A cohort of 1380 patients (14%) who had uncontrolled blood pressure out of 9785 adults with established CAD enrolled in the Clinical Pharmacy Cardiac Risk Service.

Measurements and Main Results. Uncontrolled hypertension was defined as a mean of two consecutive blood pressure readings of 140/90 mm Hg or higher in 2006 or 2007, most proximal to December 31, 2007 (baseline). The cohort was followed from January 1, 2008–June 30, 2009 (follow‐up). The follow‐up blood pressure level was the mean of the last two consecutive blood pressure readings most proximal to June 30, 2009. Of the 1380 patients, 34.9% (482 patients), 34.0% (469), and 31.1% (429) attained a blood pressure below 130/80, 130/80–139/89, and 140/90 mm Hg or higher, respectively, at follow‐up. Significantly more patients in the less than 130/80 mm Hg group were male, had Medicare insurance, had lower baseline systolic and/or diastolic blood pressures, and had a higher Chronic Disease Score compared with the other groups. For every additional clinic visit, there was a 3% increased likelihood of attaining a blood pressure below 130/80 mm Hg (adjusted odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01‐1.04). Patients experiencing a cardiac event during the follow‐up period were approximately twice as likely to attain a blood pressure below 130/80mm Hg (OR 1.97, 95% CI 1.04‐3.77) compared with those who did not have a subsequent event.

Conclusion. Despite systematic and aggressive treatment of blood pressure in patients with CAD and uncontrolled blood pressure, a minority of patients attained a blood pressure of less than 130/80 mm Hg. Considering that higher utilization of the health care system was associated with reaching this blood pressure level and that a similar number of therapeutic interventions in the groups resulted in variable success for blood pressure lowering, attaining a blood pressure level of less than 130/80 mm Hg may be difficult for some patients with CAD.
Generic Maintenance Immunosuppression in Solid Organ Transplant Recipients
Authors: Ensor Christopher R. , Trofe‐Clark Jennifer , Gabardi Steven , McDevitt‐Potter Lisa M. , Shullo Michael A.
Published: October 2011

Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immuno‐suppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.
Spring temperature responses of oaks are synchronous with North Atlantic conditions during the last deglaciation
Authors: Voelker Steven L. , Noirot-Cosson Paul-Emile , Stambaugh Michael C. , McMurry Erin R. , Meinzer Frederick C. , Lachenbruch Barbara , Guyette Richard P.
Published: October 2011

Paleoclimate proxies based on the measurement of xylem cell anatomy have rarely been developed across the temperature range of a species or applied to wood predating the most recent millennium. Here we describe wood anatomy‐based proxies for spring temperatures in central North America from modern bur oaks (Quercus macrocarpa Michx.). The strong coherence of temperature signals across the species range supports the use of these proxies across thousands of years of climatic change. We also used 79 subfossil oak log cross sections from northern Missouri, 14C‐dated to 9.9–13.63 ka (ka is 1000 cal yr BP), to assess the frequency of oak deposition into alluvial sediments and a subset of these oaks for a wood anatomy‐based reconstruction of spring paleotemperatures. Temperatures during the Younger Dryas cold period (YD) were up to 3.5°C lower than modern temperatures for that region, equivalent to or lower than those experienced at the northern edge of the modern species range. Compared to extant oaks growing at much higher [CO2], subfossil oaks had greater vessel frequencies. Besides very low theoretical (or estimated) xylem conductivity near the beginning of the oak record near 13.6 ka, vessel frequencies greater than modern trees compensated for reduced vessel dimensions so that theoretical xylem conductivity was consistently above that of modern trees at the cold northern sites. Significant correlations were found between the frequency of 14C‐dated oaks and either δ18O from the NGRIP (North Greenland Ice Core Project) ice core or from the Cariaco grayscale marine‐sediment record from the southern Caribbean sea. Oak deposition into alluvial sediments during the YD was significantly lower than expected given the average sample depth of oaks from 9.9 to 13.6 ka. Reduced oak deposition during the YD suggests that an abrupt shift in climate reduced oak populations across the region and/or changed the rates of channel movement across drainages.
Air demand in gated tunnels – a Bayesian approach to merge various predictions
Authors: Najafi Mohammad Reza , Kavianpour Zahra , Najafi Banafsheh , Kavianpour Mohammad Reza , Moradkhani Hamid
Published: October 2011

High flowrate through gated tunnels may cause critical flow conditions, especially downstream of the regulating gates. Aeration is found to be the most effective and efficient way to prevent cavitation attack. Several experimental equations are presented to predict air demand in gated tunnels; however, they are restricted to particular model geometries and flow conditions and often provide differing results. In this study the current relationships are first evaluated, and then other approaches for air discharge estimation are investigated. Three machine learning techniques are compared based on the flow measurements of eight physical models, with scales ranging from 1:12–1:20, including the fuzzy inference system (FIS), the genetic fuzzy system (GFS), and the adaptive network-based fuzzy inference system (ANFIS). The Bayesian Model Average (BMA) method is then proposed as a tool to merge the simulations from all models. The BMA provides the weighted average of the predictions, by assigning weights to each model in a probabilistic approach. The application of the BMA is found to be useful for improving the design of hydraulic structures by combining different models and experimental equations.
Fouling with aerobic granule membrane bioreactor
Authors: Juang Yu-Chuan , Su Ay , Fang Li-Hsing , Lee Duu-Jong , Lai Juin-Yih
Published: October 2011

Aerobic granulation (AG) and membrane bioreactor (MBR) are two promising, novel environmental biotechnological processes that draw interest of researchers working in the area of biological wastewater treatment. Membrane fouling in the combined aerobic granular membrane bioreactor (AGMBR) process and the conventional MBR process was investigated in this work. The irreversible fouling on hollow-fibre membranes in both reactors were observed with the multiple staining and confocal laser scanning microscope technique. Following physical and chemical washing, the external fouling layers were mostly removed. However, the biofilms built up in the interior surface of membrane remained and contributed to the irreversible fouling resistance. AGMBR retained most cells with granules, thereby reducing their penetration through membrane and thus the chance to form internal fouling layer. The internal biofilm layer was principally composed of live cells embedded in a matrix of proteins and polysaccharides, with that on AGMBR denser and thicker than that on MBR. Prevention of development of internal biofilm is essential to reduce irreversible fouling of AGMBR and MBR membranes.
Butanol and ethanol production from tapioca starch wastewater by Clostridium spp.
Authors: Ouephanit Chanika , Virunanon Chompunuch , Burapatana Vorakan , Chulalaksananukul Warawut
Published: October 2011

Total (TWW) and tapioca starch wash wastewater (TSWW) from a cassava processing plant in Thailand were analyzed for their composition with a view to evaluate their potential as substrates for solvent production by ABE fermentation with Clostridium spp. Starch was detected at a 1.63-fold higher level in the TWW than that in the TSWW (24.4% and 15.0% (w/w), respectively). The chemical oxygen demand (COD) was broadly similar (20,093 and 20,433 mg/L), but the biological oxygen demand (BOD) was 1.84-fold higher (18,000 and 9,750 mg/L) in the TWW than that in the TSWW. Thus, the TSWW was selected as a substrate to evaluate its potential for butanol and ethanol production by two Clostridium spp. The combined ethanol plus butanol production in the TSWW at pH 6.5 was higher than that at pH 4.5, being around 27.8- and 3.4-fold higher in C. butyricum TISTR 1032 and C. acetobutylicum ATCC 824, respectively. In both strains, the butanol (and combined butanol plus ethanol) production level was improved at pH 5.5. The addition of yeast extract increased the bacterial cell production, but did not significantly improve solvent productivity in C. acetobutylicum, and even decreased butanol production by C. butyricum.
Effect of film thickness and filler properties on sulphuric acid permeation in various commercially available epoxy mortar coatings
Authors: Valix M. , Mineyama H. , Chen C. , Cheung W. H. , Shi J. , Bustamante H.
Published: October 2011

The performance of various commercially available epoxy mortar coatings was compared by measuring their sulphuric acid diffusivity. Apparent diffusivities, which were measured gravimetrically, were found to be dependent on coating tortuosity. In composite materials like epoxy mortars, the tortuosity was determined by filler properties and polymer alignment. Tortuosity was found to depend on the filler size, their dispersion, filler aspect ratio and concentration. The order and greater alignment of polymer aggregates, which characterises thinner coatings effects higher tortuosity and thus lower permeabilities. The result is that sulphuric acid diffusivities were observed to increase with coating thickness, which challenges the notion that greater coating thicknesses provide greater protection or environmental barrier. The effect of film thickness and filler properties observed in this study has significant implications to the current selection of coatings and sewer protection.
Robustness of an aerobic metabolically vinyl chloride degrading bacterial enrichment culture
Authors: Zhao He-Ping , Schmidt Kathrin R. , Lohner Svenja , Tiehm Andreas
Published: October 2011

Degradation of the lower chlorinated ethenes is crucial to the application of natural attenuation or in situ bioremediation on chlorinated ethene contaminated sites. Recently, within mixtures of several chloroethenes as they can occur in contaminated groundwater inhibiting effects on aerobic chloroethene degradation have been shown. The current study demonstrated that metabolic vinyl chloride (VC) degradation by an enrichment culture originating from groundwater was not affected by an equimolar concentration (50 μM) of cis-1,2-dichloroethene (cDCE). Only cDCE concentrations at a ratio of 2.4:1 (initial cDCE to VC concentration) caused minor inhibition of VC degradation. Furthermore, the degradation of VC was not affected by the presence of trans-1,2-dichloroethene (tDCE), 1,1-dichloroethene (1,1-DCE), trichloroethene (TCE), and tetrachloroethene (PCE) in equimolar concentrations (50 μM). Only cDCE and tDCE were cometabolically degraded in small amounts. The VC-degrading culture demonstrated a broad pH tolerance from 5 to 9 with an optimum between 6 and 7. Results also showed that the culture could degrade VC concentrations up to 1,800 μM (110 mg/L).