bluuebunny/crossref_metadata_2025 huggingface dataset:
Placebo mechanisms across different conditions: from the clinical setting to physical performance
Authors: Pollo Antonella , Carlino Elisa , Benedetti Fabrizio
Published: May 2011

Although the great increase in interest in the placebo phenomenon was spurred by the clinical implications of its use, the progressive elucidation of the neurobiological and pharmacological mechanisms underlying the placebo effect also helps cast new light on the relationship between mind (and brain) and body, a topic of foremost philosophical importance but also a major medical issue in light of the complex interactions between the brain on the one hand and body functions on the other. While the concept of placebo can be a general one, with a broad definition generally applicable to many different contexts, the description of the cerebral processes called into action in specific situations can vary widely. In this paper, examples will be given where physiological or pathological conditions are altered following the administration of an inert substance or verbal instructions tailored to induce expectation of a change, and explanations will be offered with details on neurotransmitter changes and neural pathways activated. As an instance of how placebo effects can extend beyond the clinical setting, data in the physical performance domain and implications for sport competitions will also be presented and discussed.
Placebo interventions, placebo effects and clinical practice
Authors: Linde Klaus , Fässler Margrit , Meissner Karin
Published: May 2011

This article reviews the role of placebo interventions and placebo effects in clinical practice. We first describe the relevance of different perspectives among scientists, physicians and patients on what is considered a placebo intervention in clinical practice. We then summarize how placebo effects have been investigated in randomized controlled trials under the questionable premise that such effects are produced by placebo interventions. We further discuss why a shift of focus from the placebo intervention to the overall therapeutic context is necessary and what research methods can be used for the clinical investigation of the relevance of context effects. In the last part of the manuscript, we discuss why placebo or contexteffectsare seen as positive in clinical practice when they are associated with active treatments, while placebointerventionspose major ethical and professional problems and have to be avoided.
The placebo response in clinical trials: more questions than answers
Authors: Enck Paul , Klosterhalfen Sibylle , Weimer Katja , Horing Björn , Zipfel Stephan
Published: May 2011

Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This ‘additive model’ is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in ‘comparator’ studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.
Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing
Authors: Kaptchuk Ted J.
Published: May 2011

Using a comparative analysis of Navajo healing ceremonials, acupuncture and biomedical treatment, this essay examines placebo studies and ritual theory as mutually interpenetrating disciplines. Healing rituals create a receptive person susceptible to the influences of authoritative culturally sanctioned ‘powers’. The healer provides the sufferer with imaginative, emotional, sensory, moral and aesthetic input derived from the palpable symbols and procedures of the ritual process—in the process fusing the sufferer's idiosyncratic narrative unto a universal cultural mythos. Healing rituals involve a drama ofevocation, enactment, embodiment and evaluationin a charged atmosphere of hope and uncertainty. Experimental research into placebo effects demonstrates that routine biomedical pharmacological and procedural interventions contain significant ritual dimensions. This research also suggests that ritual healing not only represents changes in affect, self-awareness and self-appraisal of behavioural capacities, but involves modulations of symptoms through neurobiological mechanisms. Recent scientific investigations into placebo acupuncture suggest several ways that observations from ritual studies can be verified experimentally. Placebo effects are often described as ‘non-specific’; the analysis presented here suggests that placebo effects are the ‘specific’ effects of healing rituals.
Spirituality: an overlooked predictor of placebo effects?
Authors: Kohls Nikola , Sauer Sebastian , Offenbächer Martin , Giordano James
Published: May 2011

Empirical findings have identified spirituality as a potential health resource. Whereas older research has associated such effects with the social component of religion, newer conceptualizations propose that spiritual experiences and the intrapersonal effects that are facilitated by regular spiritual practice might be pivotal to understanding potential salutogenesis. Ongoing studies suggest that spiritual experiences and practices involve a variety of neural systems that may facilitate neural ‘top-down’ effects that are comparable if not identical to those engaged in placebo responses. As meaningfulness seems to be both a hallmark of spirituality and placebo reactions, it may be regarded as an overarching psychological concept that is important to engaging and facilitating psychophysiological mechanisms that are involved in health-related effects. Empirical evidence suggests that spirituality may under certain conditions be a predictor of placebo response and effects. Assessment of patients' spirituality and making use of various resources to accommodate patients' spiritual needs reflect our most current understanding of the physiological, psychological and socio-cultural aspects of spirituality, and may also increase the likelihood of eliciting self-healing processes. We advocate the position that a research agenda addressing responses and effects of both placebo and spirituality could therefore be (i) synergistic, (ii) valuable to each phenomenon on its own, and (iii) contributory to an extended placebo paradigm that is centred around the concept of meaningfulness.
Motivation and placebos: do different mechanisms occur in different contexts?
Authors: Hyland Michael E.
Published: May 2011

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic–pituitary–adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.
Behavioural conditioning as the mediator of placebo responses in the immune system
Authors: Vits Sabine , Cesko Elvir , Enck Paul , Hillen Uwe , Schadendorf Dirk , Schedlowski Manfred
Published: May 2011

Current placebo research postulates that conditioning processes are one of the major mechanisms of the placebo response. Behaviourally conditioned changes in peripheral immune functions have been demonstrated in experimental animals, healthy subjects and patients. The physiological mechanisms responsible for this ‘learned immune response’ are not yet fully understood, but some relevant afferent and efferent pathways in the communication between the brain and the peripheral immune system have been identified. In addition, possible benefits and applicability in clinical settings have been demonstrated where behaviourally conditioned immunosuppression attenuated the exacerbation of autoimmune diseases, prolonged allograft survival and affected allergic responses. Here, we summarize data describing the mechanisms and the potential clinical benefit of behaviourally conditioned immune functions, with particular focus on learned placebo effects on allergic reactions.
Lessons learned from placebo groups in antidepressant trials
Authors: Mora Meike Shedden , Nestoriuc Yvonne , Rief Winfried
Published: May 2011

This comprehensive review provides an overview about placebo and nocebo phenomena in antidepressant trials. Improvements in the placebo groups may partly be explained through methodological issues such as natural course of depression and regression to the mean, but also fundamentally reflect investigators' and participants' expectations. A meta-analysis by our group of 96 randomized placebo-controlled trials showed large placebo responses to antidepressant medication. Moderator analyses revealed substantially larger placebo responses in observer ratings compared with self-report. Effect sizes in observer ratings showed strong increase with publication year while this effect was not found for patients' self-ratings. This reflects the strong influence of investigators' expectations. The analysis of ‘nocebo effects’, e.g. adverse effects in placebo groups of antidepressant trials also confirms the impact of expectations: nocebo symptoms reflected the typical side-effect patterns expected in the drug group, with higher symptoms rates in the placebo groups of tricyclic antidepressant trials compared with placebo groups of trials testing selective serotonin reuptake inhibitors. While the placebo response seems to be similar for women and men, gender differences were found for nocebo rates. In the conclusion, we discuss potential implications for clinical trial designs and argue for interventions aimed at optimizing positive expectations of treatment benefit while minimizing the impact of adverse effects.
How placebo responses are formed: a learning perspective
Authors: Colloca Luana , Miller Franklin G.
Published: May 2011

Despite growing scientific interest in the placebo effect and increasing understanding of neurobiological mechanisms, theoretical conceptualization of the placebo effect remains poorly developed. Substantial mechanistic research on this phenomenon has proceeded with little guidance by any systematic theoretical paradigm. This review seeks to present a theoretical perspective on the formation of placebo responses. We focus on information processing, and argue that different kinds of learning along with individuals' genetic make-up evolved as the proximate cause for triggering behavioural and neural mechanisms that enable the formation of individual expectations and placebo responses. Conceptualizing the placebo effect in terms of learning offers the opportunity for facilitating scientific investigation with a significant impact on medical care.
Harnessing the placebo effect: the need for translational research
Authors: Colloca Luana , Miller Franklin G.
Published: May 2011

Laboratory research recently has greatly enhanced the understanding of placebo and nocebo effects by identifying specific neuromodulators and brain areas associated with them. However, little progress has been made in translating this knowledge into improved patient care. Here, we discuss the limitations in our knowledge about placebo (and nocebo) effects and the need for translational research with the aim of guiding physicians in maximizing placebo effects and minimizing nocebo effects in their routine clinical practice. We suggest some strategies for how, when and why interventions to promote beneficial placebo responses might be administered in the clinical setting.
Placebo controls: historical, methodological and general aspects
Authors: Walach Harald
Published: May 2011

Control conditions were introduced through the trial of Mesmerism in Paris. Placebo controls became codified standard in 1946. Although seemingly unchallenged, there are various problems with this received view. The notion of a placebo is only defined from the negative. A positive notion proposed that placebo effects are effects owing to the meaning an intervention has for an individual. Thus, placebo effects are individualized, whereas standard research paradigms reveal only grossly averaged behaviour. Also, placebo effects are context sensitive, dependent on psychological factors such as expectancy, relief of stress and anxiety, and hence can generate strong and long-lasting treatment effects. These, however, are not predictable. Such a situation can lead to the efficacy paradox: sometimes, sham interventions can be more powerful than proved, evidence-based treatments. This situation has methodological consequences. Placebo-controlled randomized trials reveal only part of the answer, whether an intervention is effective. This is valuable information for regulators, but not necessarily also for patients and of limited value for providers. Hence, I have argued that we need to complement the hierarchical model of evidence by a circular one, in which various methods are employed on equal footing to answer different questions.
Patients' direct experiences as central elements of placebo analgesia
Authors: Vase Lene , Nørskov Kathrine Næsted , Petersen Gitte Laue , Price Donald D.
Published: May 2011

Placebo analgesic effects appear to be related to patients' perception of the therapeutic intervention. In this paper, we review quantitative findings of how the relationship with the physician and the verbal suggestions given for relief may influence patients' perception of a treatment and how patients' expectations and emotional feelings may affect treatment outcome. We also present qualitative data from interviews with patients who have experienced pain relief following a placebo or an active treatment. A special focus is given to the temporal development of placebo analgesia at psychological and neurophysiological levels. Finally, we discuss the extent to which the quantitative and qualitative findings supplement or contrast with each other, and we touch upon possible implications of patients' direct experience as central for placebo analgesia.
The placebo effect and the autonomic nervous system: evidence for an intimate relationship
Authors: Meissner Karin
Published: May 2011

For many subjectively experienced outcomes, such as pain and depression, rather large placebo effects have been reported. However, there is increasing evidence that placebo interventions also affect end-organ functions regulated by the autonomic nervous system (ANS). After discussing three psychological models for autonomic placebo effects, this article provides an anatomical framework of the autonomic system and then critically reviews the relevant placebo studies in the field, thereby focusing on gastrointestinal, cardiovascular and pulmonary functions. The findings indicate that several autonomic organ functions can indeed be altered by verbal suggestions delivered during placebo and nocebo interventions. In addition, three experimental studies provide evidence for organ-specific effects, in agreement with the current knowledge on the central control of the ANS. It is suggested that the placebo effects on autonomic organ functions are best explained by the model of ‘implicit affordance’, which assumes that placebo effects are dependent on ‘lived experience’ rather than on the conscious representation of expected outcomes. Nevertheless, more studies will be needed to further elucidate psychological and neurobiological pathways involved in autonomic placebo effects.
Reframing placebo in research and practice
Authors: Jonas Wayne B.
Published: May 2011

The terms ‘placebo’ and ‘placebo effects’ cause confusion among patients, practitioners and scientists. This confusion results in both the adoption of practices that have no evidence of specificity yet considerable risk (such as surgery for low back pain) or the elimination of clinical practices proven to facilitate healing because they are not ‘better than placebo’ (such as acupuncture for low back pain). In this article, I discuss these issues and introduce the concept of optimal healing environment as a framework for disentangling what is useful from placebo research for adopting into clinical practice in a manner that is ethical and evidence-based.
The relation of emotions to placebo responses
Authors: Flaten Magne Arve , Aslaksen Per M. , Lyby Peter S. , Bjørkedal Espen
Published: May 2011

The hypothesis put forth is that expectations of treatment effects reduce negative emotions and thereby reduce symptoms, e.g. pain. Negative emotions increase pain, and it is hypothesized that placebos reduce pain by reducing negative emotions, i.e. feelings of nervousness, fear and anxiety. Placebo analgesia has been shown to be mediated via opioid activity, and relaxation increases opioid activity. The placebo acquires its relaxing effect due to verbal information that pain will be reduced, or due to associations between the placebo and the reduction in pain after effective treatment. Thus, the placebo signals that unpleasantness will be less after administration of the placebo. This involves negative reinforcement which is due to activation of a dopaminergic system that has been found to be activated during placebo analgesia and is involved in positive emotions. The nocebo effect of increased pain is, consistent with this model, because of increased fear and anxiety. The new aspect of the presented model is the hypothesis that expectations reduce negative emotions, and that negative reinforcement that involves the dopaminergic reinforcement system should be a contributor to placebo responses.
Introduction to placebo effects in medicine: mechanisms and clinical implications
Authors: Meissner Karin , Kohls Niko , Colloca Luana
Published: May 2011

The field of placebo research has made considerable progress in the last years and it has become a major focus of interest. We know now that the placebo effect is a real neurobiological phenomenon and that the brain's ‘inner pharmacy’ is a critical determinant for the occurrence of psychobiological and behavioural changes relevant to healing processes and well-being. However, harnessing the advantages of placebo effects in healthcare is still a challenge. The first part of the theme issue summarizes and discusses the various kinds of placebo mechanisms across medical fields, thereby not only focusing on two main explanatory models—expectation and conditioning theory—but also taking into account empathy and social learning, emotion and motivation, spirituality and the healing ritual. The second part of the issue focuses on questions related to transferring knowledge from placebo research into clinical practice and discusses implications for the design and interpretation of clinical trials, for the therapeutic settings in daily patient care, and for future translational placebo research.
Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress
Authors: Zaugg Kathrin , Yao Yi , Reilly Patrick T. , Kannan Karuppiah , Kiarash Reza , Mason Jacqueline , Huang Ping , Sawyer Suzanne K. , Fuerth Benjamin , Faubert Brandon , Kalliomäki Tuula , Elia Andrew , Luo Xunyi , Nadeem Vincent , Bungard David , Yalavarthi Sireesha , Growney Joseph D. , Wakeham Andrew , Moolani Yasmin , Silvester Jennifer , Ten Annick You , Bakker Walbert , Tsuchihara Katsuya , Berger Shelley L. , Hill Richard P. , Jones Russell G. , Tsao Ming , Robinson Murray O. , Thompson Craig B. , Pan Guohua , Mak Tak W.
Published: May 2011

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.
CpG islands and the regulation of transcription
Authors: Deaton Aimée M. , Bird Adrian
Published: May 2011

Vertebrate CpG islands (CGIs) are short interspersed DNA sequences that deviate significantly from the average genomic pattern by being GC-rich, CpG-rich, and predominantly nonmethylated. Most, perhaps all, CGIs are sites of transcription initiation, including thousands that are remote from currently annotated promoters. Shared DNA sequence features adapt CGIs for promoter function by destabilizing nucleosomes and attracting proteins that create a transcriptionally permissive chromatin state. Silencing of CGI promoters is achieved through dense CpG methylation or polycomb recruitment, again using their distinctive DNA sequence composition. CGIs are therefore generically equipped to influence local chromatin structure and simplify regulation of gene activity.
De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state
Authors: Pawlak Mathias , Jaenisch Rudolf
Published: May 2011

Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the transduction of defined transcription factors, and this process involves dynamic changes in DNA methylation. While the reprogramming of somatic cells is accompanied by demethylation of pluripotency genes, the functional importance of de novo DNA methylation has not been clarified. Here, using loss-of-function studies, we generated iPSCs from fibroblasts that were deficient in de novo DNA methylation mediated by Dnmt3a and Dnmt3b. These iPSCs reactivated pluripotency genes, underwent self-renewal, and showed restricted developmental potential that was rescued upon reintroduction of Dnmt3a and Dnmt3b. We conclude that de novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells.
The Dbp5 cycle at the nuclear pore complex during mRNA export II: nucleotide cycling and mRNP remodeling by Dbp5 are controlled by Nup159 and Gle1
Authors: Noble Kristen N. , Tran Elizabeth J. , Alcázar-Román Abel R. , Hodge Christine A. , Cole Charles N. , Wente Susan R.
Published: May 2011

Essential messenger RNA (mRNA) export factors execute critical steps to mediate directional transport through nuclear pore complexes (NPCs). At cytoplasmic NPC filaments, the ATPase activity of DEAD-box protein Dbp5 is activated by inositol hexakisphosphate (IP6)-bound Gle1 to mediate remodeling of mRNA–protein (mRNP) complexes. Whether a single Dbp5 executes multiple remodeling events and how Dbp5 is recycled are unknown. Evidence suggests that Dbp5 binding to Nup159 is required for controlling interactions with Gle1 and the mRNP. Using in vitro reconstitution assays, we found here that Nup159 is specifically required for ADP release from Dbp5. Moreover, Gle1-IP6 stimulates ATP binding, thus priming Dbp5 for RNA loading. In vivo, a dbp5-R256D/R259D mutant with reduced ADP binding bypasses the need for Nup159 interaction. However, NPC spatial control is important, as a dbp5-R256D/R259D nup42Δ double mutant is temperature-sensitive for mRNA export. Further analysis reveals that remodeling requires a conformational shift to the Dbp5–ADP form. ADP release factors for DEAD-box proteins have not been reported previously and reflect a new paradigm for regulation. We propose a model wherein Nup159 and Gle1-IP6 regulate Dbp5 cycles by controlling its nucleotide-bound state, allowing multiple cycles of mRNP remodeling by a single Dbp5 at the NPC.
The Dbp5 cycle at the nuclear pore complex during mRNA export I: dbp5 mutants with defects in RNA binding and ATP hydrolysis define key steps for Nup159 and Gle1
Authors: Hodge Christine A. , Tran Elizabeth J. , Noble Kristen N. , Alcazar-Roman Abel R. , Ben-Yishay Rakefet , Scarcelli John J. , Folkmann Andrew W. , Shav-Tal Yaron , Wente Susan R. , Cole Charles N.
Published: May 2011

Nuclear export of messenger RNA (mRNA) occurs by translocation of mRNA/protein complexes (mRNPs) through nuclear pore complexes (NPCs). The DEAD-box protein Dbp5 mediates export by triggering removal of mRNP proteins in a spatially controlled manner. This requires Dbp5 interaction with Nup159 in NPC cytoplasmic filaments and activation of Dbp5's ATPase activity by Gle1 bound to inositol hexakisphosphate (IP6). However, the precise sequence of events within this mechanism has not been fully defined. Here we analyze dbp5 mutants that alter ATP binding, ATP hydrolysis, or RNA binding. We found that ATP binding and hydrolysis are required for efficient Dbp5 association with NPCs. Interestingly, mutants defective for RNA binding are dominant-negative (DN) for mRNA export in yeast and human cells. We show that the DN phenotype stems from competition with wild-type Dbp5 for Gle1 at NPCs. The Dbp5–Gle1 interaction is limiting for export and, importantly, can be independent of Nup159. Fluorescence recovery after photobleaching experiments in yeast show a very dynamic association between Dbp5 and NPCs, averaging <1 sec, similar to reported NPC translocation rates for mRNPs. This work reveals critical steps in the Gle1-IP6/Dbp5/Nup159 cycle, and suggests that the number of remodeling events mediated by a single Dbp5 is limited.
Light-regulated interactions with SPA proteins underlie cryptochrome-mediated gene expression: Figure 1.
Authors: Fankhauser Christian , Ulm Roman
Published: May 2011

Cryptochromes are a class of photosensory receptors that control important processes in animals and plants primarily by regulating gene expression. How photon absorption by cryptochromes leads to changes in gene expression has remained largely elusive. Three recent studies, including Lian and colleagues (pp. 1023–1028) and Liu and colleagues (pp. 1029–1034) in this issue of Genes & Development, demonstrate that the interaction of light-activated Arabidopsis cryptochromes with a class of regulatory components of E3 ubiquitin ligase complexes leads to environmentally controlled abundance of transcriptional regulators.
Polycomb-mediated repression during terminal differentiation: what don't you want to be when you grow up?: Figure 1.
Authors: Conerly Melissa L. , MacQuarrie Kyle L. , Fong Abraham P. , Yao Zizhen , Tapscott Stephen J.
Published: May 2011

Chromatin-modifying enzymes are known to be critical components for the correct differentiation of embryonic stem cells into specific lineages, such as neurons. Recently, the role of Polycomb group proteins has been studied in the specification and differentiation of muscle stem cells. In this perspective, we review a recent study by Juan and colleagues (pp. 789–794) in Genes & Development of the role of the polycomb group protein Ezh2 in muscle stem cells, and discuss the implications for general lineage restriction.
CIFXML: a schema and toolkit for managing CIFs in XML
Authors: Day Nick E. , Murray-Rust Peter , Tyrrell Simon M.
Published: May 2011

CIFXML applies the XML strategies and technologies to create a general interface for processing CIF documents that conform to the CIF syntax and DDL1. Both a DTD and an XML schema for CIFs are presented. CIFs can be read, edited, validated syntactically, sorted, normalized, filtered, stored as an XML document object model, transformed and output.CIFXOMprovides an easy way of converting CIFs to XML andvice versausing Java.
Triclinic and monoclinic structures of SrLaCuNbO6and SrLaCuTaO6double perovskites
Authors: West D. Vincent , Davies Peter K.
Published: May 2011

SrLaCuNbO6and SrLaCuTaO6are Jahn–Teller distorted double perovskites with completeB-site ordering. The crystal structure of SrLaCuTaO6has been solved by refinement of neutron powder diffraction data at 323 (triclinic), 573 (monoclinic) and 923 K (body-centered monoclinic). Synchrotron X-ray and electron diffraction reveal local-scale features similar to those seen in ferroelectric perovskites, and also inA-site ordered perovskites exhibiting nanoscale periodicities. The crystal structure of SrLaCuNbO6was solved by refinement of synchrotron X-ray powder diffraction data at 673 and 1273 K. Because of the high resolution of the synchrotron, adjustments to these structure models were necessary in order to account for profile irregularities resulting from the local-scale behavior.
A uniaxial tensile stage with tracking capabilities for micro X-ray diffraction applications
Authors: Lynch P. A. , Parry D. , Liang D. , Kirkham R. , Davey P. , Stevenson A. W. , Bettles C. J. , Gibson M. A. , Tomus D.
Published: May 2011

First results are presented for a uniaxial tensile stage designed to operate on a scanning micro X-ray diffraction synchrotron beamline. The new tensile stage allows experiments at typical loading cycles used in standard engineering stress–strain tests. Several key features have been implemented to supportin situloading experiments at the intragranular length scale. The physical size and weight of the load cell were minimized to maintain the correct working distance for the X-ray focusing optics and to avoid overloading the high-resolution raster scan translation stages. A high-magnification optical microscope and image correlation code were implemented to enable automated online tracking capabilities during macroscopic elongation of the sample. Preliminaryin situtensile loading experiments conducted on beamline 12.3.2 at the Advanced Light Source using a polycrystalline commercial-purity Ti test piece showed that the elastic–plastic response of individual grains could be measured with submicrometre spatial resolution. The experiments highlight the unique instrumentation capabilities of the tensile stage for direct measurement of deviatoric strain and observation of dislocation patterning on an intragranular length scale as a function of applied load.
Inhomogeneous dynamic nuclear polarization of protons in a lamella-forming diblock copolymer investigated by a small-angle neutron scattering method
Authors: Noda Yohei , Kumada Takayuki , Hashimoto Takeji , Koizumi Satoshi
Published: May 2011

By combining two methods of selective doping of paramagnetic species into a microdomain and small-angle neutron scattering (SANS), thespatially inhomogeneous proton polarizationcreated by dynamic nuclear polarization (DNP) has been precisely evaluated. A lamella-forming diblock copolymer composed of polystyrene (PS) and polyisoprene (PI) block chains (PS-b-PI) was employed, the SANS profile of which clearly shows scattering peaks up to the third order due to interlamellar interference. As a source of electron spin for DNP, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was doped into one or other of the microdomains; samples with PS or PI microdomains selectively doped with TEMPO are designated PS.-b-PI and PS-b-PI., respectively. The SANS intensity at the first- and third-order peaks is well reproduced by assuming that the proton polarization is homogeneous throughout the sample, but that at the second-order peak cannot be explained by this assumption. This anomaly regarding the second-order peak was successfully explained by a model postulating that proton polarization in a doped microdomain decreases with increasing distance from the interface with a neighbouring doped microdomain. The decrease in proton polarization at the centre of a doped microdomain was estimated to be 0.07 (2) for PS-b-PI.and 0.05 (1) for PS.-b-PI, relative to constant proton polarization in a doped microdomain. The inhomogeneous proton polarization results from two competing dynamic processes,i.e.spin diffusion from doped to undoped microdomains, and spin lattice relaxation occurring on the pathway of proton spin diffusion.
Theory of X-ray reflection broadening for textures with double-axis averaging: from semicrystalline polymers exhibiting twisted lamellar growth to discotic liquid crystals
Authors: Luchnikov Valeriy , Anokhin Denis , Cheng Stephen Z. D. , Wang Chien-Lung , Bar Georg , Ivanov Dimitri A.
Published: May 2011

It is shown that textures with double-axis averaging similar to thea-texture, or Keller–Machin Type I texture, are not specific to semicrystalline polymers exhibiting twisted lamellar growth. In this work, such texture is observed in extruded fibers of a typical discotic molecule,trans-diC60-Zn porphyrin. Experimentally, these textures can be detected from the characteristic `comma'-like azimuthal profiles of the non-equatorial diffraction peaks in two-dimensional X-ray patterns. Analytical expressions for the azimuthal intensity distribution are developed, which are in good agreement with the experiment. In the proposed generalized coordinates, the diffraction peak shape becomes universal. This provides a simple means of checking the closeness of the sample morphology to thea-texture from just one two-dimensional pattern, without constructing the whole X-ray pole figure.
Microstructural changes in porous hematite nanoparticles upon calcination
Authors: Johnsen Rune E. , Knudsen Kenneth D. , Molenbroek Alfons M.
Published: May 2011

This combined study using small-angle neutron scattering (SANS), X-ray powder diffraction (XRPD), transmission electron microscopy (TEM) and adsorption isotherm techniques demonstrates radical changes in the microstructure of porous hematite (α-Fe2O3) nanoparticles upon calcination in air. TEM images of the as-synthesized hematite sample show that it consists of subrounded nanoparticles [50 (8)–61 (11) nm in average minimum and maximum diameters] with an apparent porous structure of nanosized pores/channels or cracks. SANS data confirm the presence of two characteristic sizes, one originating from the particle size and the other from the pore/void structure. Furthermore, the TEM images show that the particle sizes are nearly unaffected by calcination at 623 K, whereas their pore/void structure changes radically to an apparently pitted or spongy microstructure with cavities or/and voids. The change in microstructure also causes a reduction in the surface area as calculated by gaseous adsorption. The XRPD and SANS data show that the crystallite and SANS particle sizes are virtually unchanged by calcination at 623 K. Calcination at 973 K induces a significant alteration of the sample. The XRPD data reveal that the crystallite size increases significantly, and the SANS and adsorption isotherm studies suggest that the specific surface area decreases by a factor of ∼5–6. The TEM images show that the particles are sintered into larger agglomerates, but they also show that parts of the porous microstructure observed in the sample calcined at 623 K are retained in the sample calcined at 973 K.
A narrow microbeam is more effective for tumor growth suppression than a wide microbeam: anin vivostudy using implanted human glioma cells
Authors: Uyama Atsushi , Kondoh Takeshi , Nariyama Nobuteru , Umetani Keiji , Fukumoto Manabu , Shinohara Kunio , Kohmura Eiji
Published: May 2011

The tumoricidal mechanisms of microbeam radiation therapy, and the more recently proposed minibeam radiation therapy, for the treatment of brain tumors are as yet unclear. Moreover, from among the various parameters of beam geometry the impact of changing the beam width is unknown. In this study, suppression of tumor growth in human glioma cells implanted in mice was evaluated experimentally using microbeams of two different widths: a conventional narrow beam (20 µm width, 100 µm center-to-center distance) and a wide beam (100 µm width, 500 µm center-to-center distance). The tumor growth ratio was compared and acute cell death was studied histologically. With cross-planar irradiation, tumor growth was significantly suppressed between days 4 and 28 after 20 µm microbeam irradiation, whereas tumor growth was suppressed, and not significantly so, only between days 4 and 18 after 100 µm microbeam irradiation. Immunohistochemistry using TUNEL staining showed no increase in TUNEL-positive cells with either microbeam at 24 and 72 h post-irradiation. The 20 µm microbeam was found to be more tumoricidal than the 100 µm microbeam, and the effect was not related to apoptotic cell death. The underlying mechanism may be functional tissue deterioration rather than direct cellular damage in the beam path.
Fast X-ray powder diffraction on I11 at Diamond
Authors: Thompson Stephen P. , Parker Julia E. , Marchal Julien , Potter Jonathan , Birt Adrian , Yuan Fajin , Fearn Richard D. , Lennie Alistair R. , Street Steven R. , Tang Chiu C.
Published: May 2011

The commissioning and performance characterization of a position-sensitive detector designed for fast X-ray powder diffraction experiments on beamline I11 at Diamond Light Source are described. The detecting elements comprise 18 detector-readout modules of MYTHEN-II silicon strip technology tiled to provide 90° coverage in 2θ. The modules are located in a rigid housing custom designed at Diamond with control of the device fully integrated into the beamline data acquisition environment. The detector is mounted on the I11 three-circle powder diffractometer to provide an intrinsic resolution of Δ2θ ≃ 0.004°. The results of commissioning and performance measurements using reference samples (Si and AgI) are presented, along with new results from scientific experiments selected to demonstrate the suitability of this facility for powder diffraction experiments where conventional angle scanning is too slow to capture rapid structural changes. The real-time dehydrogenation of MgH2, a potential hydrogen storage compound, is investigated along with ultrafast high-throughput measurements to determine the crystallite quality of different samples of the metastable carbonate phase vaterite (CaCO3) precipitated and stabilized in the presence of amino acid molecules in a biomimetic synthesis process.
Fine‐scale spatial and temporal variations in diets of the pipefish Stigmatopora nigra within seagrass patches
Authors: Smith T. M. , Hindell J. S. , Jenkins G. P. , Connolly R. M. , Keough M. J.
Published: May 2011

Diets of the pipefish Stigmatopora nigra were analysed to determine if food availability was causing S. nigra to distribute according to habitat edge effects. Gut analysis found little difference in the diets of S. nigra at the edge and interior of seagrass patches, regardless of time of day or season. Fish diets did, however, vary with seagrass density: S. nigra in denser seagrass consumed more harpacticoid copepods and fewer planktonic copepods. The lack of difference in prey eaten by S. nigra at the edge and interior of patches suggests either that food was not determining S. nigra distribution patterns within patches or that differences in fish densities across patches meant that relative fish–prey densities were similar at edge and interior positions. Alternatively, any edge effects in diet might be masked by gradients in seagrass structure.
Iodine 125‐labeled mesenchymal–epithelial transition factor binding peptide‐click‐cRGDyk heterodimer for glioma imaging
Authors: Kim Eun‐Mi , Jeong Min‐Hee , Kim Dong Wook , Jeong Hwan‐Jeong , Lim Seok Tae , Sohn Myung‐Hee
Published: May 2011

In our previous study, mesenchymal–epithelial transition factor (c‐Met)‐binding peptides (cMBP) had been readily radiolabeled with radioactive iodide for glioma imaging because of five histidine amino acids. However, iodinated cMBP showed relatively unfavorable in vivo kinetics. For this reason, we tried to design dual peptide ligands that would be advantageous in recognizing both c‐Met receptor and integrin αvβ3. A cMBP‐click‐cRGDyk (cyclic Arg‐Gly‐Asp‐Tyr‐Lys) heterodimer was synthesized from mini polyethylene glycol‐conjugated cMBP‐3 glycine (GGG)‐a single name of amino acids (SC) (Ser‐Cys) and cRGDyk through a click (1 + 3 cycloaddition), and then labeled with iodine 125 (I‐125) via histidine in the cMBP and tyrosine in the cRGDyk. The receptor‐binding characteristics and tumor‐targeting efficacy of cMBP‐click‐cRGDyk were tested in vitro and in vivo. A cMBP‐click‐cRGDyk had comparable integrin αvβ3‐binding affinity with cRGDyk. The results of the biodistribution of 125I‐cMBP‐click‐cRGDyk at 4 h showed higher tumor‐to‐blood, tumor‐to‐liver, and tumor‐to‐muscle ratios: 10.07, 6.76, and 11.12, compared to 2.34, 1.99, and 5.18 of 125I‐cMBP‐GGG‐SC, respectively. U87MG tumor xenografts could be visualized by single photon emission computed tomography (SPECT)/CT using 125I‐cMBP‐click‐cRGDyk and also image contrast and overall quality were improved compared to 125I‐cMBP‐GGG‐SC. As the results of in vivo inhibition using free cRGDyk or cMBP‐GGG‐SC indicated, the tumoral uptake of 125I‐cMBP‐click‐cRGDyk decreased. This finding means that 125I‐cMBP‐click‐cRGDyk was specifically uptaken by integrin αvβ3 and the c‐Met receptor. Although imaging quality was improved, additional experiments are needed to acquire significant image‐quality improvement. (Cancer Sci 2011; 102: 1516–1521)
Validation analysis of Japanese histological classification of breast cancer using the National Summary of Hospital Cancer Registry 2007, Japan
Authors: Teramoto Norihiro , Tanimizu Masahito
Published: May 2011

Using the National Summary of Hospital Cancer Registry 2007, Japan, (HCRJ) from 219 local core cancer hospitals (LCCH) that had registered more than 29 breast cancers, we validated the Japanese classification of breast cancer (JCBC). In JCBC, most invasive ductal carcinomas (IDC) are subclassified as papillotubular carcinoma (coded as 850031 in the HCRJ) or scirrhous carcinoma (850033). Because of the confusing criterion that IDC with substantial ductal carcinoma in situ (DCIS) is papillotubular carcinoma, pathological T (pT)1 might be overestimated as pT2–3 by measuring the tumor size to include DCIS at LCCH where papillotubular carcinoma is diagnosed correctly. The LCCH were divided based on the difference between the proportion of papillotubular carcinoma to scirrhous carcinoma (PPS), that is, the proportion of 850031 cases to the sum of 850031 and 850033 cases at each LCCH (mean: 45.6%), and the PPS of the LCCH whose in‐house histological classification was the origin of JCBC (standard PPS [StPPS]: 42.3%), into G5 (PPS within StPPS ± 5%), L5 (PPS < StPPS–5%), HL (StPPS + 15% ≥ PPS > StPPS + 5%), and HH (PPS > StPPS + 15%). On pT2–3, the proportion of N1–3 cases to N0 in G5 and HL was significantly lower than that in L5. The averages of the proportion at each LCCH of G5 and HL were also significantly lower than that of L5. Meanwhile, on pT1, the proportions and averages were not significantly different among the groups. The frequent overestimation of pT in G5 and HL explains their lower frequency of lymph nodal metastasis on pT2–3, leaving the frequency on pT1 unchanged. The JCBC has spoiled the accuracy of pTNM. (Cancer Sci 2011; 102: 1597–1601)
Comparison of the i‐gel and the LMA‐Unique laryngeal mask airway in patients with mild to moderate obesity during elective short‐term surgery
Authors: Weber U. , Oguz R. , Potura L. A. , Kimberger O. , Kober A. , Tschernko E.
Published: May 2011

The aim of our study was to compare leakage pressure, ease and time of insertion of the i‐gel and the LMA‐Unique laryngeal mask airway in patients with mild to moderate obesity during elective short‐term surgery. In this prospective, randomised crossover trial, we included patients with a body mass index (BMI) > 25 and < 35 kg.m−2, and , age > 18 years, undergoing elective surgery in the supine position with an expected duration of surgery < 2 h. Leakage pressures, insertion difficulty, time and number of insertion attempts were evaluated. We included 50 patients consisting of 29 mildly (BMI > 25 and < 30 kg.mg−2) and 21 moderately (BMI > 30 and < 35 kg.mg−2) obese patients. Mean (SD) leakage pressures were 23.7 (9.2) cmH2O (i‐gel) and 17.4 (7.0) cmH2O (LMA‐Unique) (p < 0.01). Subgroup analyses showed leakage pressures of 22.2 (9.4) cmH2O (i‐gel) and 17.5 (7.5) cmH2O (LMA‐Unique) (p = 0.013) in the mild subgroup, and 25.7 (8.6) cmH2O (i‐gel) and 17.0 (6.2) cmH2O (LMA‐Unique) (p < 0.01), in the moderate subgroup. Insertion of the i‐gel was associated with significantly higher leakage pressures compared with the LMA‐Unique in mildly and moderately obese patients.
A national survey of prevention of infection in obstetric central neuraxial blockade in the UK
Authors: McKenzie A. G. , Darragh K.
Published: May 2011

We conducted a postal survey of all consultant‐led UK obstetric anaesthetic units in August 2009, to assess the standard of aseptic technique used for neuraxial blocks. One hundred and sixty‐four units responded giving a response rate of 76%; 93% of units (149/160) follow recommended precautions and attach a bacterial micropore filter to the epidural catheter. Epidural top‐ups are provided by 72% (116/162) of units, with about two thirds using premixed solutions (of local anaesthetic with opioid) in a variety of ways: 51% (57/111) via a continuous infusion pump; 47% (52/111) by a prefilled syringe; and 23% (25/111) by multiple use of a premixed bag of solution. For spinals, 91% of units (149/164) add diamorphine: of these 85% (126/149) draw the diamorphine from non‐sterile‐wrapped ampoules. If required to draw opioid from a non‐sterile‐wrapped ampoule, 86% (119/138) of units use a micropore filter and 21% (29/138) wipe the ampoule neck with an alcohol swab. Although sepsis secondary to neuraxial block in obstetric practice is uncommon (declared by 8.5% of units over an unspecified period of time), there is scope for further improvement.