bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroscience findings are consistent with appraisal theories of emotion; but does the brain “respect” constructionism?
Authors: Scherer Klaus R.
Published: May 2012

I reject Lindquist et al.'s implicit claim that all emotion theories other than constructionist ones subscribe to a “brain locationist” approach. The neural mechanisms underlying relevance detection, reward, attention, conceptualization, or language use are consistent with many theories of emotion, in particular componential appraisal theories. I also question the authors' claim that the meta-analysis they report provides support for thespecificassumptions of constructionist theories.
BRAZILIAN HEALTH TECHNOLOGY ASSESSMENT BULLETIN: EDITORIAL PROCESS, DISSEMINATION STRATEGIES, CRITICAL APPRAISAL, AND INITIAL IMPACT
Authors: Silva Marcus Tolentino , de Almeida Rosimary Terezinha , Gava Cintia Maria , Galvão Taís Freire , da Silva Edina Mariko Koga , Santos Vania Cristina Canuto , Ronchini Misani Akiko Kanamota , de Mesquita Aline Monte , Elias Flávia Tavares Silva , d'Oliveira Alexandre Lemgruber Portugal , Atallah Álvaro Nagib
Published: May 2012

Objectives: This study reports on the Brazilian experience of developing a specialized bulletin, the Brazilian Health Technology Assessment Bulletin (BRATS), on health technology assessments (HTA).

Methods: The editorial process, format, and dissemination strategy of the publication are presented. A critical appraisal of the available issues was made using the checklist for HTA reports of the International Network of Agencies for Health Technology Assessment. The initial impact was estimated based on a retrospective observational measurement of the types of publications that cite the bulletin as a source of information. The publications citing BRATS were identified using Google Scholar.

Results: Since June 2008, fourteen issues of the bulletin have been produced. BRATS has not presented any significant limitation that would compromise generalizations of its results within the Brazilian context. The initial impact of the bulletin, however, has been small, which may be due to its exclusively electronic dissemination format and technical language. We found nine publications citing BRATS in Google Scholar.

Conclusions: It is hoped that the bulletin will promote the continuity of HTA actions among health-sector managers and professionals in Brazil.
The Good Prince: Transition, Texting and Moral Narrative in the Murals of Bonampak, Chiapas, Mexico
Authors: Houston Stephen
Published: May 2012

Nearly seventy years ago, a group of competitive explorers, few on good terms, reconnoitred the Maya ruins of Bonampak, Chiapas, Mexico. There, in what is now known as Structure 1, they found the most densely figured and compositionally ambitious paintings from Precolumbian America – the Bonampak murals, in a building dated by their final, painted notation to c. AD 791. The themes, events, dramatis personae, dynastic setting and execution of the murals find general consensus among scholars, if with some disagreement about detail and, in some respects, the overall thematic focus of the paintings. A key, under-used resource consists of some 125 texts or captions in hieroglyphic writing that identify, or studiously ignore, the serried warriors, dancers in feathered costumes, courtly ladies, foes in extremis, ambassadors, and lords in repose that crowd the murals. Brought to crisp view by infrared vidicon imaging in 1996, subsequently processed and here reported, the captions pose further questions about the decision to name people, past and present. The typology, positioning, relative weighting and onomastic contents of the captions at Bonampak clarify a veridical story, artfully positioned and cadenced, that stresses a tale of three youths. Likely brothers, they can be seen to enjoy a distinct centrality in the murals, more so than the ruler himself. The Bonampak paintings thus discharge several functions. They offer a specific account of a prince's career, assisted by two young peers, a primer for the skills and accomplishments of a suitable heir, a vertical account of generational interplay at times of transition, and a horizontal lesson, too, that a good prince both leads and relies on brothers, close kin and courtiers for collective success. Whether the path to the throne was completed remains an unresolved matter, insoluble without further evidence.
Bears and Meanings among Hunter-fisher-gatherers in Northern Fennoscandia 9000–2500 BC
Authors: Helskog Knut
Published: May 2012

An examination of meanings associated with bears among early hunter-gatherer-fisher populations in northern Fennoscandia, based on beliefs and ritual practices in the ethnohistoric record, indicates that they were an animal attributed multiple meanings in prehistoric as well as historic times. They were clan ancestors, spirit masters and symbols of power and reincarnation such as rebirth and the change of seasons. The evidence indicates a pattern of local variation and identities rather than a uniform regional pattern, and some large-scale differences from the coastal area of Norway in the west to Karelia in the east.
Introduction: Waiting for a Better World: Critical and Interdisciplinary Perspectives on Intercountry Adoption
Authors: Cuthbert Denise
Published: May 2012

Consider a social phenomenon which for over sixty years has seen the increasingly systematic and organised (but involuntary) expatriation, migration and resettlement of around one million children around the globe (Selman, 2012). In most cases, this expatriation entails the complete severance of ties with home countries, communities and families of origin; the provision of new families and citizenship; a legal change of identity that may include the issuing of new birth certificates; and, for many, a life among people from whom they remain visibly different just as they remain culturally and linguistically different from the communities in which they were born but from whom they are removed at an early age.
Stratospheric mean residence time and mean age on the tropopause: Connections and implications for observational constraints
Authors: Holzer Mark , Orbe Clara , Primeau François W.
Published: May 2012

Stratospheric mean residence time
and mean age on the tropopause ΓΩ are shown to measure physically distinct aspects of stratospheric transport. Both ΓΩ and
are mean transit times through the stratosphere of air that enters through tropopause region Ωi and exits through region Ωf, but they represent averages over different populations of fluid elements. The averaging for ΓΩ is based on the population of fluid elements exiting the stratosphere, while
is based on the population of Ωi → Ωf fluid elements residing in the stratosphere. Thus, ΓΩ is the mean age on exit, while
is the expected mean residence time in the interior of the stratosphere. The physical basis for defining and robustly computing both timescales is the one‐way stratosphere‐to‐troposphere flux of air labeled with the boundary‐propagator Green function,
. By re‐expressing the boundary‐value problem for
in terms of first‐order loss in a tropopause layer with a timescaleτc in the limit τc → 0, we show that both
and ΓΩ can be obtained as ratios of moments of
extrapolated to the tropopause. One obtains
= ΓΩ + 2Δ2/ΓΩ, where Δ quantifies the width of the transit‐time distribution. Because the moments of
can be estimated from the mixing ratio of transient trace gases, it is in principle possible to estimate
from measurements of two independent transient tracers. The distinctness of
and ΓΩ is elucidated using idealized models.
Prolonged Gaseous Hypothermia Prevents the Upregulation of Phagocytosis-Specific Protein Annexin 1 and Causes Low-Amplitude EEG Activity in the Aged Rat Brain after Cerebral Ischemia
Authors: Joseph Christy , Buga Ana-Maria , Vintilescu Raluca , Balseanu Adrian Tudor , Moldovan Mihai , Junker Heike , Walker Lary , Lotze Martin , Popa-Wagner Aurel
Published: May 2012

In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. In animal studies of focal ischemia, short-term hypothermia often reduces infarct size. Nevertheless, efficient neuroprotection requires long-term, regulated lowering of whole-body temperature. Previously, we reported that post-stroke exposure to hydrogen sulfide (H2S) effectively lowers whole-body temperature and confers neuroprotection in aged animals. In the present study using magnetic resonance imaging, electroencephalogram recording, DNA arrays, reverse transcriptase polymerase chain reaction, western blotting and immunofluorescence, we characterized the central nervous system response to H2S-induced hypothermia and report, for the first time, that annexin A1, a major pro-inflammatory protein that is upregulated after stroke, was consistently downregulated in polymorphonuclear cells in the peri-lesional cortex of post-ischemic, aged rat brain after 48 hours of hypothermia induced by exposure to H2S. Our data suggest that long-term hypothermia may be a viable clinical approach to protecting the aged brain from cerebral injury. Our findings further suggest that, in contrast to monotherapies that have thus far uniformly failed in clinical practice, hypothermia has pleiotropic effects on brain physiology that may be necessary for effective protection of the brain after stroke.
Aspartoacylase Supports Oxidative Energy Metabolism during Myelination
Authors: Francis Jeremy S , Strande Louise , Markov Vladamir , Leone Paola
Published: May 2012

The inherited leukodystrophy Canavan disease arises due to a loss of the ability to catabolize N-acetylaspartic acid (NAA) in the brain and constitutes a major point of focus for efforts to define NAA function. Accumulation of noncatabolized NAA is diagnostic for Canavan disease, but contrasts with the abnormally low NAA associated with compromised neuronal integrity in a broad spectrum of other clinical conditions. Experimental evidence for NAA function supports a role in white matter lipid synthesis, but does not explain how both elevated and lowered NAA can be associated with pathology in the brain. We have undertaken a systematic analysis of postnatal development in a mouse model of Canavan disease that delineates development and pathology by identifying markers of oxidative stress preceding oligodendrocyte loss and dysmyelination. These data suggest a role for NAA in the maintenance of metabolic integrity in oligodendrocytes that may be of relevance to the strong association between NAA and neuronal viability. N-acetylaspartic acid is proposed here to support lipid synthesis and energy metabolism via the provision of substrate for both cellular processes during early postnatal development.
Positional cloning and characterization reveal the molecular basis for soybean maturity locus
E1
that regulates photoperiodic flowering
Authors: Xia Zhengjun , Watanabe Satoshi , Yamada Tetsuya , Tsubokura Yasutaka , Nakashima Hiroko , Zhai Hong , Anai Toyoaki , Sato Shusei , Yamazaki Toshimasa , Lü Shixiang , Wu Hongyan , Tabata Satoshi , Harada Kyuya
Published: May 2012

The complex and coordinated regulation of flowering has high ecological and agricultural significance. The maturity locus
E1
has a large impact on flowering time in soybean, but the molecular basis for the
E1
locus is largely unknown. Through positional cloning, we delimited the
E1
locus to a 17.4-kb region containing an intron-free gene (
E1
). The E1 protein contains a putative bipartite nuclear localization signal and a region distantly related to B3 domain. In the recessive allele, a nonsynonymous substitution occurred in the putative nuclear localization signal, leading to the loss of localization specificity of the E1 protein and earlier flowering. The early-flowering phenotype was consistently observed in three ethylmethanesulfonate-induced mutants and two natural mutations that harbored a premature stop codon or a deletion of the entire
E1
gene.
E1
expression was significantly suppressed under short-day conditions and showed a bimodal diurnal pattern under long-day conditions, suggesting its response to photoperiod and its dominant effect induced by long day length. When a functional
E1
gene was transformed into the early-flowering cultivar Kariyutaka with low
E1
expression, transgenic plants carrying exogenous
E1
displayed late flowering. Furthermore, the transcript abundance of
E1
was negatively correlated with that of
GmFT2a
and
GmFT5a
, homologues of
FLOWERING LOCUS T
that promote flowering. These findings demonstrated the key role of
E1
in repressing flowering and delaying maturity in soybean. The molecular identification of the maturity locus
E1
will contribute to our understanding of the molecular mechanisms by which a short-day plant regulates flowering time and maturity.
Spike timing plays a key role in synapse elimination at the neuromuscular junction
Authors: Favero Morgana , Busetto Giuseppe , Cangiano Alberto
Published: May 2012

Nerve impulse activity produces both developmental and adult plastic changes in neural networks. For development, however, its precise role and the mechanisms involved remain elusive. Using the classic model of synapse competition and elimination at newly formed neuromuscular junctions, we asked whether spike timing is the instructive signal at inputs competing for synaptic space. Using a rat strain whose soleus muscle is innervated by two nerves, we chronically evoked different temporal spike patterns in the two nerves during synapse formation in the adult. We found that asynchronous activity imposed upon the two nerves promotes synapse elimination, provided that their relative spikes are separated by 25 ms or more; remarkably, this elimination occurs even though an equal number of spikes were evoked in the competing axons. On the other hand, when spikes are separated by 20 ms or less, activity is perceived as synchronous, and elimination is prevented. Thus, in development, as in adult plasticity, precise spike timing plays an instructive role in synaptic modification.
Apolipoprotein A-IV improves glucose homeostasis by enhancing insulin secretion
Authors: Wang Fei , Kohan Alison B. , Kindel Tammy L. , Corbin Kathryn L. , Nunemaker Craig S. , Obici Silvana , Woods Stephen C. , Davidson W. Sean , Tso Patrick
Published: May 2012

Apolipoprotein A-IV (apoA-IV) is secreted by the small intestine in response to fat absorption. Here we demonstrate a potential role for apoA-IV in regulating glucose homeostasis. ApoA-IV–treated isolated pancreatic islets had enhanced insulin secretion under conditions of high glucose but not of low glucose, suggesting a direct effect of apoA-IV to enhance glucose-stimulated insulin release. This enhancement involves cAMP at a level distal to Ca
2+
influx into the β cells. Knockout of apoA-IV results in compromised insulin secretion and impaired glucose tolerance compared with WT mice. Challenging apoA-IV
−/−
mice with a high-fat diet led to fasting hyperglycemia and more severe glucose intolerance associated with defective insulin secretion than occurred in WT mice. Administration of exogenous apoA-IV to apoA-IV
−/−
mice improved glucose tolerance by enhancing insulin secretion in mice fed either chow or a high-fat diet. Finally, we demonstrate that exogenous apoA-IV injection decreases blood glucose levels and stimulates a transient increase in insulin secretion in KKAy diabetic mice. These results suggest that apoA-IV may provide a therapeutic target for the regulation of glucose-stimulated insulin secretion and treatment of diabetes.
Spontaneous transmitter release recruits postsynaptic mechanisms of long-term and intermediate-term facilitation in
Aplysia
Authors: Jin Iksung , Udo Hiroshi , Rayman Joseph B. , Puthanveettil Sathya , Kandel Eric R. , Hawkins Robert D.
Published: May 2012

Whereas short-term (minutes) facilitation at
Aplysia
sensory–motor neuron synapses is presynaptic, long-term (days) facilitation involves synaptic growth, which requires both presynaptic and postsynaptic mechanisms. How are the postsynaptic mechanisms recruited, and when does that process begin? We have been investigating the possible role of spontaneous transmitter release from the presynaptic neuron. In the previous paper, we found that spontaneous release is critical for the induction of long-term facilitation, and this process begins during an intermediate-term stage of facilitation that is the first stage to involve postsynaptic as well as presynaptic mechanisms. We now report that increased spontaneous release during the short-term stage acts as an orthograde signal to recruit postsynaptic mechanisms of intermediate-term facilitation including increased IP3, Ca
2+
, and membrane insertion and recruitment of clusters of AMPA-like receptors, which may be first steps in synaptic growth during long-term facilitation. These results suggest that the different stages of facilitation involve a cascade of pre- and postsynaptic mechanisms, which is initiated by spontaneous release and may culminate in synaptic growth.
Specificity and independence of the literary game
Authors: Lahire Bernard
Published: May 2012

In developing his theory of the “literary field,” Pierre Bourdieu essentially had in mind the case of France from the second half of the nineteenth century, the use of which as a case undoubtedly contributed to his marginalizing numerous aspects of the national microcosm. Among its unstated and unrecognized particular qualities, France is mono-national (rather than multinational) and monolingual (rather than multilingual), and occupies the dominant position in the international Francophone world (much as Germany is at the heart of the German-speaking world). A state, a nation, a language, a territory, a literature — all of these make one unit and prevent one from considering situations more complex or tangled, such as those of many minority literatures. These allow the tackling of issues — among others, problems of their “autonomy” in relation to realities outside of literature such as the political, religious, linguistic, and economic. Rather than imposing constraints on a research agenda, the study of minority literatures allows one to shed light on the complex and contradictory relations between the political (the national, the communal, and sometimes the state), the market, and the literary game.
Languages, politics and field theory — the question of the autonomy of small literatures
Authors: Scalbert-Yücel Clémence
Published: May 2012

InImagined Communities: Reflections on the Origin and Spread of Nationalism, Benedict Anderson stressed the role that literature, and particularly the development of the novel,actuallyplayed in building a nation as an “imagined community.” Others have emphasized how building a national literature has often gone hand in hand with the creation of a national identity (e.g. Thiesse; Jusdanis). All have underlined the strong relationship between nationalism and literature: literature is a concrete tool that builds the nation as a community; literature also serves to build and spread a national identity.
High-throughput analysis of epistasis in genome-wide association studies with BiForce
Authors: Gyenesei Attila , Moody Jonathan , Semple Colin A.M. , Haley Chris S. , Wei Wen-Hua
Published: May 2012

Motivation: Gene–gene interactions (epistasis) are thought to be important in shaping complex traits, but they have been under-explored in genome-wide association studies (GWAS) due to the computational challenge of enumerating billions of single nucleotide polymorphism (SNP) combinations. Fast screening tools are needed to make epistasis analysis routinely available in GWAS.

Results: We present BiForce to support high-throughput analysis of epistasis in GWAS for either quantitative or binary disease (case–control) traits. BiForce achieves great computational efficiency by using memory efficient data structures, Boolean bitwise operations and multithreaded parallelization. It performs a full pair-wise genome scan to detect interactions involving SNPs with or without significant marginal effects using appropriate Bonferroni-corrected significance thresholds. We show that BiForce is more powerful and significantly faster than published tools for both binary and quantitative traits in a series of performance tests on simulated and real datasets. We demonstrate BiForce in analysing eight metabolic traits in a GWAS cohort (323 697 SNPs, >4500 individuals) and two disease traits in another (>340 000 SNPs, >1750 cases and 1500 controls) on a 32-node computing cluster. BiForce completed analyses of the eight metabolic traits within 1 day, identified nine epistatic pairs of SNPs in five metabolic traits and 18 SNP pairs in two disease traits. BiForce can make the analysis of epistasis a routine exercise in GWAS and thus improve our understanding of the role of epistasis in the genetic regulation of complex traits.

Availability and implementation: The software is free and can be downloaded from http://bioinfo.utu.fi/BiForce/.

Contact:  wenhua.wei@igmm.ed.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Paraneoplastic Isaacs' Syndrome
Authors: Rana Sandeep S. , Ramanathan Ramnath Santosh , Small George , Adamovich Brenda
Published: May 2012

Objective:

Isaacs' syndrome is a rare disease resulting from hyperexcitability of peripheral nerves causing continuous muscle fiber activity characterized by muscle twitching and stiffness at rest and delayed muscle relaxation after voluntary contraction. Our objective was to discuss the relationship of Isaacs' syndrome to paraneoplastic syndromes as reported in the available literature and in 3 patients evaluated at our academic medical center.

Methods:

We review the literature on Isaacs' syndrome and describe 3 patients in whom Isaacs' syndrome heralded underlying malignancy or benign neoplasm, including their presenting symptoms, electrophysiologic findings, and laboratory and pathology results.

Results:

In all 3 cases, clinical and electrodiagnostic testing was suggestive of Isaacs' syndrome. Two patients tested positive, and one was negative for voltage-gated potassium channel antibodies. Two of the patients developed malignant tumors, that is, one was diagnosed with metastatic thymoma and one with lymphoplasmacytic lymphoma, ranging from 6 months to 1 year after the diagnosis of Isaacs' syndrome. One patient was diagnosed with a spinal cord hemangioblastoma 5 years after he was diagnosed with Isaacs' syndrome.

Conclusions:

Our case series highlights the association of Isaacs' syndrome with a variety of neoplasms both malignant and benign. Our report also underscores the fact that Isaacs' syndrome may be diagnosed several years before a neoplasm is discovered. In our cases, Isaacs' syndrome overlapped with other neuromuscular disorders, that is, myasthenia gravis in a patient with thymoma and chronic inflammatory demyelinating polyneuropathy in a patient with lymphoplasmacytic lymphoma with paraproteinemia. To our knowledge, this is the first report of an association between Isaacs' syndrome with lymphoplasmacytic lymphoma and a spinal cord hemangioblastoma.
What's in the Literature?
Authors: El-Dokla Ahmed , Lacomis David
Published: May 2012

Over the past 3 months, there was an explosion of articles describing the clinical, imaging, and pathological features of familial amyotrophic lateral sclerosis and frontotemporal dementia associated with the C9ORF72 hexanucleotide repeat expansion. A proposal for amyotrophic lateral sclerosis staging and an overview of changing utilization of noninvasive ventilation in the United Kingdom are also reviewed. There was also an interesting series of articles on generalized myasthenia gravis that is seronegative for acetylcholine receptor and muscle-specific kinase antibodies but harbors antibodies against the low-density lipoprotein receptor–related protein 4, which binds agrin on the postsynaptic cleft and seems to play a pathogenic role in myasthenia gravis. The clinically important disorder, small fiber neuropathy (SFN), is also reviewed including an important discovery of sodium channel Nav1.7 mutations in patients with previously idiopathic SFN and a treatment approach for SFN using a Nav1.7 channel blocker. Another important article expands the phenotypes of anoctamin 5 autosomal recessive limb–girdle muscular dystrophy. Presentations were variable with adult-onset sometimes asymmetric weakness with proximal and sometimes calf involvement and high creatine kinase. Females were less severely affected and often had exercise induced myalgia without weakness.
Fitness conferred by replaced amino acids declines with time
Authors: Naumenko Sergey A. , Kondrashov Alexey S. , Bazykin Georgii A.
Published: May 2012

The fitness landscape of a locus, the array of fitnesses conferred by its alleles, can be affected by allele replacements at other loci, in the presence of epistatic interactions between loci. In a pair of diverging homologous proteins, the initially high probability that an amino acid replacement in one of them will make it more similar to the other declines with time, implying that the fitness landscapes of homologous sites diverge. Here, we use data on within-population non-synonymous polymorphisms and on amino acid replacements between species to study the dynamics, after an amino acid replacement, of the fitness of the ancestral amino acid, and show that selection against its restoration increases with time. This effect can be owing to increase of fitness conferred by the new amino acid occupying the site, and/or to decline of fitness conferred by the replaced amino acid. We show that the fitness conferred by the replaced amino acid rapidly declines, reaching a new lower steady-state level after approximately 20 per cent of amino acids in the protein get replaced. Therefore, amino acid replacements in evolving proteins are routinely involved in negative epistatic interactions with currently absent amino acids, and chisel off the unused parts of the fitness landscape.
Post-secretion processing influences spider silk performance
Authors: Blamires Sean J. , Wu Chung-Lin , Blackledge Todd A. , Tso I-Min
Published: May 2012

Phenotypic variation facilitates adaptations to novel environments. Silk is an example of a highly variable biomaterial. The two-spidroin (MaSp) model suggests that spider major ampullate (MA) silk is composed of two proteins—MaSp1 predominately contains alanine and glycine and forms strength enhancing β-sheet crystals, while MaSp2 contains proline and forms elastic spirals. Nonetheless, mechanical properties can vary in spider silks without congruent amino acid compositional changes. We predicted that post-secretion processing causes variation in the mechanical performance of wild MA silk independent of protein composition or spinning speed across 10 species of spider. We used supercontraction to remove post-secretion effects and compared the mechanics of silk in this ‘ground state’ with wild native silks. Native silk mechanics varied less among species compared with ‘ground state’ silks. Variability in the mechanics of ‘ground state’ silks was associated with proline composition. However, variability in native silks did not. We attribute interspecific similarities in the mechanical properties of native silks, regardless of amino acid compositions, to glandular processes altering molecular alignment of the proteins prior to extrusion. Such post-secretion processing may enable MA silk to maintain functionality across environments, facilitating its function as a component of an insect-catching web.
Nanoscale mechanisms of surface stress and morphology evolution in FCC metals under noble-gas ion bombardments
Authors: Kim Sang-Pil , Chew Huck Beng , Chason Eric , Shenoy Vivek B. , Kim Kyung-Suk
Published: May 2012

Here, we uncover three new nanoplasticity mechanisms, operating in highly stressed interstitial-rich regions in face-centred-cubic (FCC) metals, which are particularly important in understanding evolution of surface stress and morphology of a FCC metal under low-energy noble-gas ion bombardments. The first mechanism is the configurational motion of self-interstitials in subsonic scattering during ion bombardments. We have derived a stability criterion of self-interstitial scattering during ion embedding, which consistently predicts the possibility of vacancy- and interstitial-rich double-layer formation for various ion bombardments. The second mechanism is the growth by gliding of prismatic dislocation loops (PDLs) in a highly stressed interstitial-rich zone. This mechanism allows certain prismatic dislocations with their Burgers vectors parallel to the surface to grow in subway-glide mode (SGM) during ion bombardment. The SGM growth creates a large population of nanometre-sized prismatic dislocations beneath the surface. The third mechanism is the Burgers vector switching of a PDL that leads to unstable eruption of adatom islands during certain ion bombardments of FCC metals. We have also derived the driving force and kinetics for the growth by gliding of prismatic dislocations in an interstitial-rich environment as well as the criterion for Burgers vector switching, which consistently clarifies previously unexplainable experimental observations.
An exact solution describing slow axonal transport of cytoskeletal elements: the effect of a finite half-life
Authors: Kuznetsov A. V.
Published: May 2012

This paper presents an exact solution for a two kinetic state model of slow axonal transport that is based on the stop-and-go hypothesis. The model accounts for two populations of cytoskeletal elements (CEs): pausing and running. The model also accounts for a finite half-life of CEs involved in slow axonal transport. It is assumed that initially CEs are injected into the axon such that their concentration forms a rectangular pulse; initially all CEs are assumed to be in the pausing state. Kinetic processes quickly redistribute CEs between the pausing and running states. After less than a minute, equilibrium is established, forming two pulses, representing concentrations of pausing and running CEs, respectively. As these pulses propagate, their shape changes and they turn to bell-shaped waves. The amplitude of the waves decreases, and the waves spread out as they propagate down the axon. The rate of the amplitude decrease is larger for CEs with a shorter half-life, but even if CE half-life is infinitely long, some decrease of the waves' amplitudes is observed. The velocity of the waves' propagation is found to be independent of the CE half-life and is in good agreement with published experimental data for slow axonal transport of neurofilaments.
Work conjugacy error in commercial finite-element codes: its magnitude and how to compensate for it
Authors: Bažant Zdeněk P. , Gattu Mahendra , Vorel Jan
Published: May 2012

Most commercial finite-element programs use the Jaumann (or co-rotational) rate of Cauchy stress in their incremental (Riks) updated Lagrangian loading procedure. This rate was shown long ago not to be work-conjugate with the Hencky (logarithmic) finite strain tensor used in these programs, nor with any other finite strain tensor. The lack of work-conjugacy has been either overlooked or believed to cause only negligible errors. Presented are examples of indentation of a naval-type sandwich plate with a polymeric foam core, in which the error can reach 28.8 per cent in the load and 15.3 per cent in the work of load (relative to uncorrected results). Generally, similar errors must be expected for all highly compressible materials, such as metallic and ceramic foams, honeycomb, loess, silt, organic soils, pumice, tuff, osteoporotic bone, light wood, carton and various biological tissues. It is shown that a previously derived equation relating the tangential moduli tensors associated with the Jaumann rates of Cauchy and Kirchhoff stresses can be used in the user’s material subroutine of a black-box commercial program to cancel the error due to the lack of work-conjugacy and make the program perform exactly as if the Jaumann rate of Kirchhoff stress, which is work-conjugate, were used.
The ciprofloxacin target AUC : MIC ratio is not reached in hospitalized patients with the recommended dosing regimens
Authors: Haeseker Michiel , Stolk Leo , Nieman Fred , Hoebe Christian , Neef Cees , Bruggeman Cathrien , Verbon Annelies
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The efficacy target of AUC : MIC > 125 is based on the study of Forrest et al. in 1993.

• Recent studies have shown that in ICU patients the ciprofloxacin efficacy target of AUC : MIC > 125 is often not reached.

WHAT THIS STUDY ADDS

• The efficacy targets of ciprofloxacin in patients in general wards are often not reached. Most patients have low AUC with current i.v. dosing regimens. We suggest increasing the standard dose of ciprofloxacin to 1200 mg intravenously 24 h–1.

• Patients in general wards have high interindividual variability of pharmacokinetic parameters and therapeutic drug monitoring could be useful to support dosing.

AIM The aim of this study was to determine the ciprofloxacin serum concentrations in hospitalized patients and to determine which percentage reached the efficacy target of AUC : MIC > 125. Additionally, the influence of demographic anthropomorphic and clinical parameters on the pharmacokinetics and pharmacodynamics of ciprofloxacin were investigated.

METHODS In serum of 80 hospitalized patients ciprofloxacin concentrations were measured with reverse phase high performance liquid chromatography with fluorescence detection. The ciprofloxacin dose was 400–1200 mg day−1 i.v. in two or three doses depending on renal function and causative bacteria. Pharmacokinetic parameters were calculated with maximum a posteriori Bayesian estimation (MW\PHARM 3.60). A two compartment open model was used.

RESULTS Mean (± SD) age was 66 (± 17) years, the mean clearance corrected for bodyweight was 0.24 l h−1 kg−1 and the mean AUC was 49 mg l−1 h. Ciprofloxacin clearance and thus AUC were associated with both age and serum creatinine. Of all patients, 21% and 75% of the patients, did not reach the proposed ciprofloxacin AUC : MIC > 125 target with MICs of 0.25 and 0.5 mg l−1, respectively. A computer simulated increase in the daily dose from 800 mg to 1200 mg, decreased these percentages to 1% and 37%, respectively.

CONCLUSION A substantial proportion of the hospitalized patients did not reach the target ciprofloxacin AUC : MIC and are suboptimally dosed with recommended doses. Taking into account the increasing resistance to ciprofloxacin worldwide, a ciprofloxacin dose of 1200 mg i.v. daily in patients with normal renal function is necessary to reach the targeted AUC : MIC > 125.
A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ‐secretase inhibitor avagacestat
Authors: Tong Gary , Wang Jun‐Sheng , Sverdlov Oleksandr , Huang Shu‐Pang , Slemmon Randy , Croop Robert , Castaneda Lorna , Gu Huidong , Wong Oi , Li Hewei , Berman Robert M. , Smith Christina , Albright Charles F. , Dockens Randy
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Under homeostatic conditions, sequential cleavage of amyloid precursor protein by β‐site cleaving enzyme and γ‐secretase forms the common Aβ isoforms, Aβ1–38, Aβ1–40, and Aβ1–42.

• However, in the pathological Alzheimer's disease (AD) state, Aβ clearance is decreased nearly 30%. As such, γ‐secretase is a promising drug target for AD therapy, as a decrease in its enzymatic activity has the potential to reduce Aβ levels and modify disease.

• In contrast, current treatments for AD provide only short term symptomatic relief.

WHAT THIS STUDY ADDS

• Unique among previous studies of γ‐secretase inhibitors (GSIs), such as semagacestat and begacestat, our results showed that avagacestat, an oral GSI in clinical development for the disease‐modifying treatment of AD, decreased Aβ1–40 plasma concentrations and was well‐tolerated in both young and elderly subjects, with adverse events being predominantly mild to moderate in severity.

AIM To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ‐secretase inhibitor BMS‐708163 (avagacestat) in young and elderly men and women.

METHODS All subjects received double‐blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid‐β (Aβ)1–40 concentratios and exploration of Notch biomarkers.

RESULTS Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median tmax between 1 and 2 h post dose and an average half‐life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aβ1–40 serum concentrations showed a pattern of decreasing concentrations over the first 4–6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly.

CONCLUSIONS The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease.
Illumination properties and imaging promises of blended, multiple‐scattering seismic data: a tutorial
Authors: Berkhout A.J. , Verschuur D.J. , Blacquière G.
Published: May 2012

In traditional seismic surveys the firing time between shots is such that the shot records do not interfere in time. In the concept of blended acquisition, however, shot records do overlap, allowing denser source sampling and wider azimuths in an economic way. A denser shot sampling and wider azimuths make that each subsurface gridpoint is illuminated from a larger number of angles and will therefore improve the image quality in terms of signal‐to‐noise ratio and spatial resolution. In this tutorial, we show that, even with very simple blending parameters like time delays, the incident wavefield at a specific subsurface gridpoint represents a dispersed time series with a complex code. For shot record migration purposes, this time series should be designed such that it facilitates a stable inversion process. In a next step, we explain how the illumination property of the incident wavefield can be further improved by utilizing the surface‐related multiples. This means that these multiples can be exploited to improve the incident wavefield by filling angle gaps in the illumination and/or by extending the range of angles (‘natural blending’). In this way the energy contained in the multiples now contributes to the image, rather than decreasing its quality. One remarkable consequence of this property is that the benefits to be obtained from the improved illumination depend on the detector locations in acquisition geometries as well. We explain how to quantify the contribution of the blended surface multiples to the incident wavefield for a blended source configuration. In addition, we explain how blended measurements can be directly used in an angle‐dependent migration process with a bifocal, least‐squares imaging condition. The result is a densely sampled reflectivity function in the ray parameter domain, also improving the capability of velocity estimation. We will show examples to illustrate the theory.
Cartilage restoration in haemophilia: advanced therapies
Authors: LIRAS A. , GABAN A. S. , RODRIGUEZ‐MERCHAN E. C.
Published: May 2012

Summary.  Current treatment of joint cartilage lesions is based either on conventional techniques (bone marrow stimulation, osteochondral autograft or allograft transplantation) or on newly developed techniques (chondrocyte implantation and those based on cell therapy that use bioreactors, growth factors, mesenchymal stem cells [MSCs] and genetically modified cells). The aim of this article is to review the therapeutic strategies above mentioned and to determine whether the chondral damage seen in haemophilia could benefit from any of them. The different conventional techniques have shown similar results whereas autologous chondrocyte implantation, which is in common use at the present time, has not been shown to produce any conclusive results or to lead to the formation of hyaline cartilage. MSCs hold promise for the repair of joint cartilage given their differentiation capacity and the therapeutic effect. The use of bioreactors and growth factors, which stimulate cartilage formation, may optimize such strategies in the context of reimplantation of chondrocytes, differentiated MSCs and cartilage progenitor cells. The aim of cell therapy is restoration of function through the repair of damaged tissue or the stimulation of growth factor synthesis. Implantation of autologous chondrocytes or MSCs was up to now able to address only highly localized chondral lesions. Adequate control of the differentiation process as well as the use of growth factors and appropriate bioreactors could transform cell‐based therapies into a more efficient and longer term treatment even for patients with haemophilia. Nevertheless, raising false expectations in these patients should be avoided. There are a number of approaches to cartilage restoration in haemophilic arthropathy, which are currently being explored for other joint related degenerative disorders. If it can be proven to be effective for the disorders in which clinical trials are ongoing and costs could be limited, it might be an useful palliative approach to haemophilic arthropathy. However, we still have a long way to go for use in haemophilic arthropathy.
Parenting under Pressure: a grounded theory of parenting young children with life‐threatening congenital heart disease
Authors: Rempel Gwen R. , Ravindran Vinitha , Rogers Laura G. , Magill‐Evans Joyce
Published: May 2012

rempel g.r., ravindran v., rogers l.g. & magill‐evans j. (2013) Parenting under pressure: a grounded theory of parenting young children with life‐threatening congenital heart disease. Journal of Advanced Nursing69(3), 619–630. doi: 10.1111/j.1365‐2648.2012.06044.x

Aim.  To report a grounded theory study to describe the process of parenting young children who have survived hypoplastic left heart syndrome to inform parent‐focused interventions.

Background.  Technological advances in paediatric cardiology worldwide have improved the survival rates for young children with hypoplastic left heart syndrome who undergo staged surgical palliation. These children, however, are at risk for life‐threatening complications and parents are charged with the responsibility to monitor their children at home with minimal support and guidance from healthcare professionals once home.

Design.  A constructivist grounded theory study.

Method.  The study was conducted in 2006–2008. Participants were 25 parents (15 mothers, 10 fathers) and 28 grandparents (17 grandmothers, 11 grandfathers) of 15 young children (6 months–4·5 years) who had undergone the Sano surgical approach for hypoplastic left heart syndrome. The 53 interviews were digitally recorded, transcribed and analysed using open and focused coding, constant comparative analysis and memoing.

Findings.  A process of Parenting under Pressure emerged that was characterized by four overlapping and re‐emerging phases: (1) realizing and adjusting to the inconceivable; (2) growing increasingly attached; (3) watching for and accommodating the unexpected; and (4) encountering new challenges.

Conclusions.  In‐depth understanding of the phases of Parenting under Pressure provides direction for nurses to support parents of children who survive hypoplastic left heart syndrome. Interventions that help carers of children with complex health conditions move through the phases of our Parenting under Pressure process may help them safeguard the survival of their children, and their own survival as parents as they manage multiple demands.
Relationship Between the Neuroprotective Effects of Insulin‐Like Growth Factor‐1 and 17β‐Oestradiol in Human Neuroblasts
Authors: Luciani P. , Deledda C. , Benvenuti S. , Cellai I. , Modi G. , Fibbi B. , Danza G. , Vannelli G. B. , Peri A.
Published: May 2012

Insulin‐like growth factor‐1 (IGF‐1) and oestrogens interact with each other as neuroprotective factors. We have previously demonstrated that 17β‐oestradiol protects against β‐amyloid and oxidative stress toxicity and increases the amount of cell cholesterol in human foetal neuroblasts (FNC). The present study aimed: (i) to assess the protective effects of IGF‐1 in FNC cells; (ii) to investigate the relationship between IGF‐1 and 17β‐oestradiol; and (iii) to determine whether cholesterol was a major mediator of the effects of IGF‐1, similarly to 17β‐oestradiol. We found that IGF‐1 effectively exerts neuroprotective effects in FNC cells. We also demonstrated that the IGF‐1 receptor (IGF‐1R) pathway is needed to maintain oestrogen‐mediated neuroprotection. Finally, we found that, opposite to 17β‐oestradiol, IGF‐1 did not cause a significant increase in cell cholesterol. These findings indicate that a cross‐talk between IGF‐1 and 17β‐oestradiol occurs in FNC cells. In particular, the activation of the IGF‐1R cascade appears to be fundamental to warrant 17β‐oestradiol‐mediated neuroprotection, even though cell cholesterol does not play a major role as an effector of this pathway.
Pharmacokinetics of florfenicol and its metabolite, florfenicol amine, in rice field eel (Monopterus albus) after a single‐dose intramuscular or oral administration
Authors: XIE L.‐L. , WU Z.‐X. , CHEN X.‐X. , LI Q. , YUAN J. , LIU H. , YANG Y.
Published: May 2012

The pharmacokinetics of florfenicol (FF) and its metabolite, florfenicol amine (FFA), were studied in rice field eel (Monopterus albus) after a single dose (20 mg/kg) by intramuscular (i.m.) or oral gavage (p.o.) dose at 25 °C. The elimination half‐lives (t1/2β), peak concentration of FF (Cmax), and time to reach FF peak concentration (Tmax) in plasma were estimated as 18.39 h, 10.83 μg/mL, and 7.00 h, respectively, after i.m. injection and 13.46 h, 8.37 μg/mL, and 5 h, respectively, after p.o. administration. The Tmax values of FF in tissues (i.e., kidney, muscle, and liver) were larger for i.m. injection compared with those for p.o. administration. The t1/2β had the following order kidney > muscle > liver for i.m. administrated and kidney > liver > muscle for p.o. administrated. The largest area under the concentration–time curve (AUC) was calculated to be 384.29 mg · h/kg after i.m. dosing, and the mean residence time (MRT) was 42.46 h by oral administration in kidney. FFA was also found in all tissues with a lower concentration than FF for both i.m. and p.o. administrations throughout the study. The elimination of FFA was slow with a t1/2β between 18.19 and 47.80 h in plasma and tissues. The mean metabolic rate of FFA for i.m. and p.o. administrations was >23.30%.