bluuebunny/crossref_metadata_2025 huggingface dataset:
The development of a population-level clinical screening tool for self-harm repetition and suicide: the ReACT Self-Harm Rule
Authors: Steeg S. , Kapur N. , Webb R. , Applegate E. , Stewart S. L. K. , Hawton K. , Bergen H. , Waters K. , Cooper J.
Published: March 2012

Background

Self-harm is a common reason for Emergency Department (ED) attendance. We aimed to develop a clinical tool to help identify patients at higher risk of repeat self-harm, or suicide, within 6 months of an ED self-harm presentation.

Method

The tool, the ReACT Self-Harm Rule, was derived using multicentre data from a prospective cohort study. Binary recursive partitioning was applied to data from two centres, and data from a separate centre were used to test the tool. There were 29 571 self-harm presentations to five hospital EDs between January 2003 and June 2007, involving 18 680 adults aged ⩾16 years. We estimated sensitivity, specificity and positive and negative predictive values to measure the performance of the tool.

Results

A self-harm presentation was classified as higher risk if at least one of the following factors was present: recent self-harm (in the past year), living alone or homelessness, cutting as a method of harm and treatment for a current psychiatric disorder. The rule performed with 95% sensitivity [95% confidence interval (CI) 94–95] and 21% specificity (95% CI 21–22), and had a positive predictive value of 30% (95% CI 30–31) and a negative predictive value of 91% (95% CI 90–92) in the derivation centres; it identified 83/92 of all subsequent suicides.

Conclusions

The ReACT Self-Harm Rule might be used as a screening tool to inform the process of assessing self-harm presentations to ED. The four risk factors could also be used as an adjunct to in-depth psychosocial assessment to help guide risk formulation. The use of multicentre data helped to maximize the generalizability of the tool, but we need to further verify its external validity in other localities.
Initially fewer bloodstream infections for allogeneicvs. autologous stem-cell transplants in neutropenic patients
Authors: HIEKE S. , BERTZ H. , DETTENKOFER M. , SCHUMACHER M. , BEYERSMANN J.
Published: March 2012

Chemotherapy and/or radiotherapy used as conditioning regimens before autologous or allogeneic haematopoietic cell transplantations (HCTs) cause neutropenia, which is the main reason for bloodstream infections. Autologous HCTs are considered to be superior to allogeneic HCTs in terms of infection outcome. A previous analysis suggested that patients with allogeneic HCTs are exposed to a reduced infection hazard and that an unfavourable infection outcome of allogeneic HCTs may be mediated through prolonged neutropenia. Therefore, we investigated whether allogeneic HCTs initially lead to fewer infections. We evaluated data from a prospective non-randomized multi-centre cohort study, with a total of 1616 patients. Of these, 703 patients received autologous and 913 patients received allogeneic HCTs from January 2000 to June 2004. The retrospective analysis used simultaneous confidence bands for the cumulative infection probability in the presence of competing risks. Patients with allogeneic HCTs experienced fewer infections during the early phase of neutropenia. As patients with autologous HCTs are not necessarily subject to antibiotic prophylaxis, a future study should investigate this policy. A limitation of the analysis is that it did not find the effect of crossing cumulative infection probabilities to be significant.
ST22 and ST239 MRSA duopoly in Singaporean hospitals: 2006–2010
Authors: TEO J. , TAN T. Y. , HON P. Y. , LEE W. , KOH T. H. , KRISHNAN P. , HSU L. Y. ,   the Network for Antimicrobial Resistance Surveillance (Singapore)
Published: March 2012

Surveillance is integral for the monitoring and control of infectious diseases. We conducted prospective laboratory surveillance of methicillin-resistantStaphylococcus aureus(MRSA) in five Singaporean public-sector hospitals from 2006 to 2010, using WHONET 5.6 for data compilation and analysis. Molecular profiling using multilocus variable-number tandem-repeat analysis, staphylococcal cassette chromosomemecclassification and multilocus sequence typing was performed for a random selection of isolates. Our results showed overall stable rates of infection and bacteraemia, although there was significant variance among the individual hospitals, with MRSA rates increasing in two smaller hospitals and showing a trend towards decreasing in the two largest hospitals. The proportion of blood isolates that are EMRSA-15 (ST22-IV) continued to increase over time, slowly replacing the multi-resistant ST239-III. A new MRSA clone – ST45-IV – is now responsible for a small subset of hospital infections locally. More effort is required in Singaporean hospitals in order to reduce the rates of MRSA infection significantly.
Primary succession of lichen and bryophyte communities following glacial recession on Signy Island, South Orkney Islands, Maritime Antarctic
Authors: Favero-Longo Sergio E. , Worland M. Roger , Convey Peter , Lewis Smith Ronald I. , Piervittori Rosanna , Guglielmin Mauro , Cannone Nicoletta
Published: March 2012

A directional primary succession with moderate species replacement was quantitatively characterized on Signy Island in zones of a glacial valley corresponding to their age since deglaciation. A continuous increase in diversity and abundance of lichens and bryophytes was observed between terrains deglaciated in the late 20th century, to areas where deglaciation followed the Little Ice Age, and others thought to be ice-free since soon after the Last Glacial Maximum. Classification (UPGMA) and ordination (principal co-ordinate analysis) of vegetation data identified three different stages of development: a) pioneer communities, which rapidly develop in a few decades, b) immature communities developing on three to four century old terrains, and c) a climax stage (Polytrichum strictum-Chorisodontium aciphyllum community) developing on the oldest terrains, but only where local-scale environmental features are more favourable. Multivariate analysis including environmental parameters (canonical correspondence analysis) indicated terrain age as being the dominant controlling factor, with other environmental factors also exhibiting significant conditional effects (duration of snow cover, surface stoniness). These findings not only quantitatively verify reports of the rapid colonization of Maritime Antarctic terrains following recent climate amelioration and associated decrease in glacial extent, but also show how local-scale environmental resistance may slow or even prevent vegetation succession from pioneer to more mature stages in future.
Aortic arch thrombectomy in a 2.8 kilogram neonate – a case report and review of the literature
Authors: Omeje Ikenna , Ram Awat , Kostolny Martin
Published: March 2012

Aortic arch thrombus is a rare occurrence in neonates. In the few described cases, this has mainly been associated with sepsis or early postnatal interventions, such as insertion of umbilical arterial line. We describe a case of occlusive aortic arch thrombus in a neonate who presented with signs of critical coarctation and successfully underwent surgical thrombectomy on deep hypothermic circulatory arrest. We also present a review of the most recently published cases of aortic arch thrombus in neonates and the treatment options employed.
LYING EPITAPHS:VANITY FAIR, WATERLOO, AND THE CULT OF THE DEAD
Authors: Heffernan Julian Jimenez
Published: March 2012

The significance of the Waterlooepisode inVanity Fairremains somewhat obscure. Early reviewers of the novel either ignored it or suggested its downright insignificance: “The battle of Waterloo, it is true, is introduced; but as far as regards the story, it brings about only one death, and one bankruptcy, which might either of them have happened in a hundred of other ways” (Rigby 79). Furthermore, when compared to Stendhal'sLa chartreuse de Parmeand Hugo'sLes misérables, two novels where a report of the battle is at least attempted,Vanity Fairlooks exceptional. The novel's mimetic elusiveness vis-à-vis the battle has been a source of puzzle and the object of some critical contention. In line with John Carey, who argued that “Vanity Fairis built round a thunderous void” (189), John Sutherland suggested that “Thackeray's battlefield reticence” impinged on the novel's “historical fabric” producing “gaping, but evidently carefully placed, holes” (15), the larger being (no pun intended) Waterloo. Some critics explained away this omission by invoking Thackeray's anti-heroic restraint, a position best expressed by Tolstoy: “For an historian considering the achievement of a certain aim, there are heroes; for the artist treating of man's relation to all sides of life there cannot and should not be heroes, but there should be men” (1309). Other readers blamed the silencing effect of an elegiac trauma – an “agony of glory,” in Coleridge's terms – not uncommonly affecting the winning side in a violent conflict. One could also adduce reasons of epistemological honesty, in line with Tolstoy's blunt assertion that “in every description of a battle there is a necessary lie” (1310).
WRITING FOR, YET APART: NINETEENTH-CENTURY BRITISH WOMEN'S CONTENTIOUS STATUS AS HYMN WRITERS AND EDITORS OF HYMNBOOKS FOR CHILDREN
Authors: Clapp-Itnyre Alisa
Published: March 2012

When Sandra Gilbert and Susan Gubarasked in 1979, “How then – since poets are priests – can women be poets?” (Madwoman in the Attic546), they opened up to debate the predominant ideological holdover from the Victorians that “the very nature of lyric poetry is inherently incompatible with the nature or essence of femaleness” (541). More than thirty years later, while women's poetic contributions are regularly considered by literary scholarship, I would now advocate for the woman hymn writer for children – she who, as hymn writer or editor, surely enacted the role of religious “priest” for countless generations of children during and after her lifetime, but who is all but forgotten today.
MEMSAHIBS AND THE “SUNNY EAST”: REPRESENTATIONS OF BRITISH INDIA BY MILLICENT DOUGLAS PILKINGTON AND BERYL WHITE
Authors: Dohmen Renate
Published: March 2012

Millicent Pilkington, the daughter of a Lancashire industrialist in her early twenties, arrived in India in December 1893 and returned to England December 1894. We know about her trip, or her Year's Frivol in the Sunny East as she calls it, from the sumptuous album orné or commonplace book she compiled filling it with water colour sketches, photographs, autographs, dinner invitations, newspaper clippings, etc. The material is carefully arranged over forty-five album pages, is often framed by elaborate, hand-painted decorative borders, many of them in an Indian style. We know of the album because it was deposited in the Centre for South Asian Studies at Cambridge University by a descendant.
ARTHUR MACHEN AND THE HORRORS OF DEEP HISTORY
Authors: Worth Aaron
Published: March 2012

In what is surely his best-known“shocker” of the 1890s, Arthur Machen has one of his ubiquitous bachelor heroes (Clarke by name) try to warn another off his pursuit of the truth about a preternaturally dangerous femme fatale figure, a woman responsible for the hideous deaths of a number of English gentlemen. “I am,” he writes to his friend, “like a traveller who has peered over an abyss, and has drawn back in terror. What I know is strange enough and horrible enough, but beyond my knowledge there are depths and horrors more frightful still” (“Pan” 89). But to what “depths,” exactly, does the fearful Clarke refer? What “horrors”? And why, here as elsewhere in this text, do depth and horror seem so intimately interconnected? The tale in question, “The Great God Pan” (1890), bristles with multifarious horrors, to be sure. In the novella's opening episode, a mad scientist figure performs experimental brain surgery on a young woman (“a slight lesion in the grey matter, that is all,” he says to an over-scrupulous chum), causing her to “see the god Pan,” and reducing her to idiocy and death (“Pan” 62, 68). The bulk of the subsequent narrative concerns a sequence of seemingly unrelated tragedies – the mysterious death of one gentleman in London, a rash of particularly horrid suicides by a number of others, the demise of an English artist in Buenos Aires – which prove all to be connected to a single figure of monstrous evil, a woman who goes by the name of Helen Vaughn (among others). She is, it turns out, the offspring of the subject of the surgical experiment and Pan himself, and her own (forced) suicide at the end of the story leads to a gruesome tableau of bodily dissolution reminiscent of Poe's M. Valdemar (or, to update the reference, the gooey, B-movie slime Slavoj Žižek seems to have claimed in the name of the Lacanian Real).
A woman of consequence: Pandora in Hesiod'sWorks and Days
Authors: Fraser Lilah-Grace
Published: March 2012

The Pandora myth as told in Hesiod'sWorks and Days(59–105) has been criticised since antiquity as internally inconsistent. In the nineteenth and most of the twentieth century this led editors to propose radical atheteses and emendations to resolve the inconsistencies. Although in recent decades the impetus has swung more towards conservative editing, and seemingly endless work has been done on the myth, the passage still has not been fully understood in terms of its purpose within the Hesiodic corpus. In this paper I argue that the ‘suspect’ lines are perfectly consistent when understood in terms of the intertextual relationship between Hesiod'sWorks and Daysand hisTheogony, a relationship which has been established by scholars such as Jean-Pierre Vernant (1980), Glenn Most (1993) and Jenny Strauss Clay (2003). I argue that, in representing Pandora inWorks and Days, Hesiod is engaged in a project of expansion which had its roots in hisTheogony. Pandora is of more importance to the Iron AgeWorks and Daysthan to the divineTheogony; so she is described in greater detail and becomes more of a prominent figure in her own right. Furthermore, I argue that Hesiod does not stop there, but enacts an expansion of the expansion withinWorks and Daysitself, from Zeus' commands to the gods for Pandora's creation atOp.60–68, to the execution of those commands at 70–80.
Black Sea variations: Arrian'sPeriplus
Authors: Rood Tim
Published: March 2012

Comme tous les Grecs, il n'a pas pu ne pas embellir ce qu'il a touché. On retrouve en lui cet éminent esprit d'une race privilégiée qui dans les sujets les plus arides fait pénétrer l'art et même la poésie. … même en quittant … le Périple d'Arrien, nous pouvons dire comme Fuséli en quittant les marbres du Parthénon: ‘Ah! les Grecs, les Grecs, c'étaient des dieux.’ H. Chotard,Le Périple de la Mer Noire par Arrien

Arrian'sPeriplus maris Euxini (Circumnavigation of the Euxine)is an ambitious and unusual work. Written in the 130s AD in the form of a letter to the emperor Hadrian, who had himself visited the Black Sea a few years earlier, it was a literary complement to a report Arrian made in Latin, as governor of Cappadocia, on Rome's military position in the Black Sea. It is also unusual in its form: unlike mostperiploi, which are marked by continuity of movement and by a highly repetitive style, it is discontinuous both in its spatial movement and in its narrative style.
DEBATE: Should the obligations of states and armed groups under international humanitarian law really be equal?
Authors: Sassòli Marco , Shany Yuval
Published: March 2012

By introducing a new ‘debate’ section, theReviewhopes to contribute to the reflection on current ethical, legal, or practical controversies around humanitarian issues. This section will expose readers to the key arguments concerning a particular contemporary question of humanitarian law or humanitarian action.

For this first debate, theReviewasked two members of its Editorial Board,Professor Marco SassòliandProfessor Yuval Shany, to debate on the topic of equality of states and armed groups under international humanitarian law.Professor René Provostcomments on this debate, adding a third dimension to the discussion.

The crucial question is whether it is realistic to apply the current legal regime to non-state armed groups. How can armed groups, with sometimes very limited means and low levels of organization, meet the same obligations as states? What are the incentives for armed groups to respect rules that their opponents have enacted? Why should they respect any rules when the very fact of taking arms against the state already makes them ‘outlaws’?

All participants in this discussion share an aspiration to ensure better legal protection for all those affected by armed conflicts. Professors Sassòli and Shany have agreed to present two ‘radically’ opposed stances, Professor Sassòli maintaining that equality should be reconsidered and replaced by a sliding scale of obligations, and Professor Shany rebutting this assertion. Professor Provost then reflects on the stances put forward by the two debaters and invites us to revisit the very notion of equality of belligerents.

The debaters have simplified their complex legal reasoning for the sake of clarity and brevity. Readers of theReviewshould bear in mind that the debaters actual legal positions are more nuanced than they may appear in this debate.
Developmental programming: impact of prenatal testosterone treatment and postnatal obesity on ovarian follicular dynamics
Authors: Padmanabhan V. , Smith P. , Veiga-Lopez A.
Published: March 2012

Prenatal testosterone (T) excess leads to reproductive dysfunctions in sheep with obesity exaggerating such defects. Developmental studies found ovarian reserve is similar in control and prenatal T sheep at fetal day 140, with prenatal T females showing increased follicular recruitment and persistence at 10 months of age (postpubertal). This study tested whether prenatal T sheep show accelerated depletion prepubertally and whether depletion of ovarian reserve would explain loss of cyclicity in prenatal T females and its amplification by postnatal obesity. Stereological examinations were performed at 5 (prepubertal, control and prenatal T) and 21 months of age (control, prenatal T and prenatal T obese, following estrus synchronization). Obesity was induced by overfeeding from weaning. At 5 months, prenatal T females had 46% less primordial follicles than controls (P < 0.01), supportive of increased follicular depletion. Depletion rate was slower and a higher percentage of growing follicles was present in 21-month compared with 5-month-old prenatal T females (P < 0.01). Postnatal obesity did not exaggerate the impact of prenatal T on follicular recruitment indicating that compounding effects of obesity on loss of cyclicity females is not due to depletion of ovarian reserve. Assessment of follicular dynamics across several time points during the reproductive lifespan (this and earlier study combined) provides evidence supportive of a shift in follicular dynamics in prenatal T females from one of accelerated follicular depletion initiated before puberty to stockpiling of growing follicles after puberty, a time point critical in the development of the polycystic ovary syndrome phenotype.
On the need for automated multiobjective optimization and uncertainty estimation of glacier mass balance models
Authors: Rye Cameron J. , Willis Ian C. , Arnold Neil S. , Kohler Jack
Published: March 2012

Physically based models are valuable tools for exploring the detailed spatial and temporal responses of glaciers and ice sheets to climate forcing. However, while the last two decades have seen considerable progress in the development of increasingly sophisticated numerical descriptions, very little attention has been given to simulation uncertainty. In particular, glaciological models have traditionally been calibrated (or “tuned”) in order to identify a single set of parameters (e.g., snow density, surface albedo, temperature lapse rate) such that the model's behavior closely matches real‐world observations. The present study disputes this classical approach by demonstrating that it is often difficult (if not impossible) to find a single “best” solution. Instead, multiple equally plausible parameter sets will usually exist. To address this limitation, we present a novel application of a calibration technique previously not used in glacial modeling – multiobjective optimization – designed to identify multiple optimal parameter sets that fit different characteristics of available observations, thereby enabling an assessment of the uncertainty associated with predictions. The strength and applicability of our approach is illustrated through the implementation of a surface mass balance model for two glaciers in Svalbard: Midre Lovénbreen and Kongsvegen. The model is forced using the ERA‐40 reanalysis and calibrated against available mass balance measurements. The overall uncertainty range in modeled cumulative annual surface mass balance is −7.84 to −14.02 m w.e. for Midre Lovénbreen (over the period 1968–2001) and −0.91 to +9.80 m w.e. for Kongsvegen (over the period 1987–2001). The calibrated model is used to extend the mass balance records of the two glaciers back to the beginning of the ERA‐40 reanalysis, giving a cumulative loss of loss of 13.2 ± 3.3 m w.e. for Midre Lovénbreen and a cumulative gain of 5.3 ± 3.4 m w.e. for Kongsvegen over the period 1958–2001. The multiobjective optimization results also indicate that current mass balance models may contain structural inadequacies relating to how the mass balance gradient is simulated.
Direct correlation of Chinese speleothem δ18O and South China Sea planktonic δ18O: Transferring a speleothem chronology to the benthic marine chronology
Authors: Caballero‐Gill Rocio P. , Clemens Steve C. , Prell Warren L.
Published: March 2012

Orbital tuning of benthic δ18O is a common approach for assigning ages to ocean sediment records. Similar environmental forcing of the northern South China Sea and the southeast Asian cave regions allows for transfer of the speleothem δ18O radiometric chronology to the planktonic and benthic δ18O records from Ocean Drilling Program Site 1146, yielding a new chronology with 41 radiometrically calibrated datums, spanning the past 350 kyr. This approach also provides for an independent assessment of the accuracy of the orbitally tuned benthic δ18O chronology for the last 350 kyr. The largest differences relative to the latest chronology occur in marine isotope stages (MIS) 5.4, 5.5, 6, 7, and 9.3. Prominent suborbital‐scale structure believed to be global in nature is identified within MIS 5.4 and MIS 7.2. On the basis of the radiometrically calibrated chronology, the time constant of the ice sheet is found to be 5.4 kyr at the precession band (light δ18O lags precession minima by −55.4°) and 10.4 kyr at the obliquity band (light δ18O lags obliquity maxima by 57.4°). These values are significantly shorter than the single 17 kyr time constant originally estimated by Imbrie et al. (1984), based primarily on the timing of terminations I and II and the 15 kyr time constant used by Lisiecki and Raymo (2005).
Exploring the relationship between changes in climate and floods using a model‐based analysis
Authors: Hundecha Yeshewatesfa , Merz Bruno
Published: March 2012

A model‐based approach is implemented to attribute changes in the seasonal extreme river flows to meteorological drivers. A semidistributed model that simulates daily runoff from daily series of meteorological variables was employed together with a multisite, multivariable weather generator. Ensembles of synthetic meteorological variables were synthesized using the weather generator and were used to drive the hydrological model. In order to systematically assess the relative importance of each of the meteorological variables in explaining the detected changes in the flood behavior, the variables were generated by accounting for the year to year variability of the distribution of one of the variables at a time while keeping the distributions of the others temporally stationary. The approach was tested on eight case study catchments from different parts of Germany. The results show the ability of the approach in identifying the meteorological variable that is associated with the detected change in the extreme flow. Changes in precipitation were found to be the major meteorological drivers of the trends detected in the seasonal extreme flows in most of the investigated catchments. Temperature was found to be less important in explaining any of the changes in all catchments.
Summer thermal structure and anticyclonic circulation of Lake Erie
Authors: Beletsky Dmitry , Hawley Nathan , Rao Yerubandi R. , Vanderploeg Henry A. , Beletsky Raisa , Schwab David J. , Ruberg Steven A.
Published: March 2012

In most thermally stratified lakes, the summer thermocline has the shape of a “dome”, with a shallower depth offshore than nearshore. This configuration is accompanied by a lake‐wide cyclonic circulation. Lake‐wide observations of subsurface temperature in central Lake Erie revealed an atypical “depressed” or “bowl‐shaped” thermocline in late summer, with a deeper thermocline in the middle of the lake and a shallower thermocline nearshore. Currents measured in the central basin when the bowl‐shaped thermocline was observed were anticyclonic, forming a single basin‐wide gyre. It is suggested that the unusual bowl‐shaped thermocline is the result of Ekman pumping driven by anticyclonic vorticity in surface winds. The bowl‐shaped thermocline can lead to greater hypoxia in bottom waters and negative effects on biota by reducing the hypolimnetic volume.
Are megaquakes clustered?
Authors: Daub Eric G. , Ben‐Naim Eli , Guyer Robert A. , Johnson Paul A.
Published: March 2012

We study statistical properties of the number of large earthquakes over the past century. We analyze the cumulative distribution of the number of earthquakes with magnitude larger than thresholdMin time intervalT, and quantify the statistical significance of these results by simulating a large number of synthetic random catalogs. We find that in general, the earthquake record cannot be distinguished from a process that is random in time. This conclusion holds whether aftershocks are removed or not, except at magnitudes belowM = 7.3. At long time intervals (T= 2–5 years), we find that statistically significant clustering is present in the catalog for lower magnitude thresholds (M= 7–7.2). However, this clustering is due to a large number of earthquakes on record in the early part of the 20th century, when magnitudes are less certain.
TIMED/SABER observations of lower mesospheric inversion layers at low and middle latitudes
Authors: Gan Quan , Zhang Shao Dong , Yi Fan
Published: March 2012

We present the global distribution, seasonal, and interannual variations of the lower mesospheric inversion layers (MILs) using SABER (Sounding of the Atmosphere using Broadband Emission Radiometry) temperature data. We show that both the characteristics and the formation mechanisms of large spatiotemporal‐scale lower MILs are latitude dependent. At low latitudes, the monthly zonal mean amplitude of the lower MILs exhibits a semi‐annual cycle and reaches a maximum of ∼40 K in spring and a secondary maximum of ∼30 K in autumn. On the equator, the semi‐annual oscillations in the background and diurnal‐migrating‐tide temperatures could contribute more than 12 and 25 K, respectively, suggesting they are the key causes of large spatiotemporal‐scale lower MILs at low latitudes. At middle latitudes, the monthly zonal mean amplitude of the lower MILs exhibits an annual cycle with its maximum in the range 24–33 K in winter. In addition, their longitudinal distribution and daily variation in winter are closely correlated with the transient structure of a composite wave composed of stationary and westward‐propagating quasi‐16‐day planetary waves with zonal wave number 1. The correlation coefficient between the lower MILs and the composite wave can sometimes reach unity. The composite planetary wave could contribute temperature enhancements of at least 15–20 K to the lower MILs. Thus, we believe that the transient structure of planetary waves is also an important cause of the large spatiotemporal‐scale lower MILs in winter at middle latitudes, in addition to previously proposed mechanisms.
How the Discovery of Brain Correlates of Consciousness Supports Non-Reductive Physicalism
Authors: Pereira Alfredo
Published: March 2012

In this work I attempt to justify the claim that the discovery of statistically relevant brain correlates of consciousness supports Non-Reductive Physicalism. First I distinguish the main varieties of Reductive and Non-Reductive Physicalism, selecting the right one that is benefited by progress in brain sciences. Second, I discuss epistemological problems in the search of brain correlates of consciousness, focusing on the simultaneous occurrence of conscious activity, known by means of subjective report, and the corresponding brain activity, registered with the help of technology. Finally, I argue – using Salmon´s concept of Statistical Explanation - that statistics affords a distinction of causal (physical) from casual (illusory) correlations.
B Lymphocytes in Human Subcutaneous Adipose Crown‐Like Structures
Authors: McDonnell Marie E. , Ganley‐Leal Lisa M. , Mehta Ankeeta , Bigornia Sherman J. , Mott Melanie , Rehman Qasim , Farb Melissa G. , Hess Donald T. , Joseph Lija , Gokce Noyan , Apovian Caroline M.
Published: March 2012

Accumulation of macrophages and T cells within crown‐like structures (CLS) in subcutaneous adipose tissue predicts disease severity in obesity‐related insulin resistance (OIR). Although rodent data suggest the B cell is an important feature of these lesions, B cells have not been described within the human CLS. In order to identify B cells in the human subcutaneous CLS (sCLS) in obese subjects and determine whether the presence of B cells predict insulin resistance, we examined archived samples of subcutaneous and omental fat from 32 obese men and women and related findings to clinical parameters. Using immunohistochemistry, we identified B (CD19+) and T cells (CD3 +) within the sCLS and perivascular space. The presence and density of B cells (B cells per high‐power field (pHPF), T cells pHPF, and B cell:T cell (B:T) ratio) were compared with measures of insulin resistance (homeostasis model assessment (HOMA)) and other variables. In 16 of 32 subjects (50%) CD19+ B cells were localized within sCLS and were relatively more numerous than T cells. HOMA was not different between subjects with CD19+ vs. CD19− sCLS (5.5 vs. 5.3, P = 0.88). After controlling for diabetes and glycemia (hemoglobin A1c (HbA1c)), the B:T ratio correlated with current metformin treatment (r = 0.89, P = 0.001). These results indicate that in human OIR, B cells are an integral component of organized inflammation in subcutaneous fat, and defining their role will lead to a better understanding of OIR pathogenesis and potentially impact treatment.
Targeting Lyn tyrosine kinase through protein fusions encompassing motifs of Cbp (Csk-binding protein) and the SOCS box of SOCS1
Authors: Whiting Rhiannon J. , Payne Christine J. , Satiaputra Jiulia , Kucera Nicole , Qiu Theresa W. , Irtegun Sevgi , Gunn Natalie J. , Lavova-Azmanova Neli S. , Mulhern Terrence D. , Ingley Evan
Published: March 2012

The tyrosine kinase Lyn is involved in oncogenic signalling in several leukaemias and solid tumours, and we have previously identified a pathway centred on Cbp [Csk (C-terminal Src kinase)-binding protein] that mediates both enzymatic inactivation, as well as proteasomal degradation of Lyn via phosphorylation-dependent recruitment of Csk (responsible for phosphorylating the inhibitory C-terminal tyrosine of Lyn) and SOCS1 (suppressor of cytokine signalling 1; an E3 ubiquitin ligase). In the present study we show that fusing specific functional motifs of Cbp and domains of SOCS1 together generates a novel molecule capable of directing the proteasomal degradation of Lyn. We have characterized the binding of pY (phospho-tyrosine) motifs of Cbp to SFK (Src-family kinase) SH2 (Src homology 2) domains, identifying those with high affinity and specificity for the SH2 domain of Lyn and that are preferred substrates of active Lyn. We then fused them to the SB (SOCS box) of SOCS1 to facilitate interaction with the ubiquitination-promoting elongin B/C complex. As an eGFP (enhanced green fluorescent protein) fusion, these proteins can direct the polyubiquitination and proteasomal degradation of active Lyn. Expressing this fusion protein in DU145 cancer cells (but not LNCaP or MCF-7 cells), that require Lyn signalling for survival, promotes loss of Lyn, loss of caspase 3, appearance of an apoptotic morphology and failure to survive/expand. These findings show how functional domains of Cbp and SOCS1 can be fused together to generate molecules capable of inhibiting the growth of cancer cells that express high levels of active Lyn.
Kinetics of Torpedo californica acetylcholinesterase inhibition by bisnorcymserine and crystal structure of the complex with its leaving group
Authors: Bartolucci Cecilia , Stojan Jure , Yu Qian-sheng , Greig Nigel H. , Lamba Doriano
Published: March 2012

Natural and synthetic carbamates act as pseudo-irreversible inhibitors of AChE (acetylcholinesterase) as well as BChE (butyrylcholinesterase), two enzymes involved in neuronal function as well as in the development and progression of AD (Alzheimer's disease). The AChE mode of action is characterized by a rapid carbamoylation of the active-site Ser200 with release of a leaving group followed by a slow regeneration of enzyme action due to subsequent decarbamoylation. The experimental AD therapeutic bisnorcymserine, a synthetic carbamate, shows an interesting activity and selectivity for BChE, and its clinical development is currently being pursued. We undertook detailed kinetic studies on the activity of the carbamate bisnorcymserine with Tc (Torpedo californica) AChE and, on the basis of the results, crystallized the complex between TcAChE and bisnorcymserine. The X-ray crystal structure showed only the leaving group, bisnoreseroline, trapped at the bottom of the aromatic enzyme gorge. Specifically, bisnoreseroline interacts in a non-covalent way with Ser200 and His440, disrupting the existing interactions within the catalytic triad, and it stacks with Trp84 at the bottom of the gorge, giving rise to an unprecedented hydrogen-bonding contact. These interactions point to a dominant reversible inhibition mechanism attributable to the leaving group, bisnoreseroline, as revealed by kinetic analysis.
Crystal and Molecular Structure of 7-Diethylamino-[1′,3′,3′-trimethyl-4-((1,3,3-trimethyl-1,3-dihydro-2H-indole-2-ylidene)methyl)-1′,3,3′,4-tetrahydrospiro[chromene-2,2′-indole]]: A Dicondensation Product From the Reaction of 4-Diethylaminosalicylaldehyde with Fischer's Base
Authors: Ashraf Mohamed , Gainsford Graeme J. , Kay Andrew J.
Published: March 2012

The novel molecule, 7-diethylamino-[1′,3′,3′-trimethyl-4-((1,3,3-trimethyl-1,3-dihydro-2H-indole-2-ylidene)methyl)-1′,3,3′,4-tetrahydrospiro[chromene-2,2′-indole]], was isolated as the product from the condensation of diethylaminosalicylaldehyde with two equivalents of Fischer’s base and its crystal structure determined, initially using MoKα radiation. The diffraction data at higher theta angles (d < 0.9 Å) was notably weak so a further dataset was collected using CuKα to determine the cause. Although a different crystal batch and larger crystal was used and a better dataset obtained (with significantly improved atomic resolution) the comparison shows that the essential molecular features and weak intermolecular binding are duplicated in the refinement with the latter data. Comparison is made with a closely related structure. Consistent with observations for this related structure it is proposed that the product is formed through the interception of an intermediate carbinol by Fischer’s base.
Undernutrition during early follicle development has irreversible effects on ovulation rate and embryos
Authors: Chen T. Y. , Stott P. , Athorn R. Z. , Bouwman E. G. , Langendijk P.
Published: March 2012

This study assessed carry-over effects of energy level during the early antral phase and subsequent follicular phase on follicle recruitment and ovulation rate. Gilts (n = 45) were fed a standard diet to a low (L, ~1.2 kg day–1) or high (H, ~2.7 kg day–1) level during the early antral (luteal) phase, and subsequently fed a H or L feed level during the follicular phase, resulting in four treatment groups (HH, HL, LH and LL). Follicle size at the end of the luteal phase was greater for gilts fed a high feed level previously (3.3 vs 3.0 mm; P < 0.05). During the follicular phase, high feeding increased follicle size at Day 5 (6.9 vs 6.2 mm; P < 0.005) and plasma oestradiol concentration (P < 0.05). Nevertheless, a low feed level during the luteal phase reduced ovulation rate (14.4 vs 13.2; P < 0.05) and embryo number (12.6 vs 10.5; P < 0.05), and this was not counteracted by feed level during the follicular phase. Plasma progesterone concentration after ovulation was lower for LL gilts than for other treatments (P < 0.05). These results indicate that undernutrition during early antral follicle development may have a residual effect on follicle recruitment and quality.
Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery
Authors: Li Hairi , Zhou Hongyan , Wang Dong , Qiu Jinsong , Zhou Yu , Li Xiangqiang , Rosenfeld Michael G. , Ding Sheng , Fu Xiang-Dong
Published: March 2012

The advent of powerful genomics technologies has uncovered many fundamental aspects of biology, including the mechanisms of cancer; however, it has not been appropriately matched by the development of global approaches to discover new medicines against human diseases. Here we describe a unique high-throughput
s
creening strategy by high-throughput sequencing, referred to as HTS
2
, to meet this challenge. This technology enables large-scale and quantitative analysis of gene matrices associated with specific disease phenotypes, therefore allowing screening for small molecules that can specifically intervene with disease-linked gene-expression events. By initially applying this multitarget strategy to the pressing problem of hormone-refractory prostate cancer, which tends to be accelerated by the current antiandrogen therapy, we identify Peruvoside, a cardiac glycoside, which can potently inhibit both androgen-sensitive and -resistant prostate cancer cells without triggering severe cytotoxicity. We further show that, despite transcriptional reprogramming in prostate cancer cells at different disease stages, the compound can effectively block androgen receptor-dependent gene expression by inducing rapid androgen receptor degradation via the proteasome pathway. These findings establish a genomics-based phenotypic screening approach capable of quickly connecting pathways of phenotypic response to the molecular mechanism of drug action, thus offering a unique pathway-centric strategy for drug discovery.
The mevalonate pathway regulates microRNA activity in
Caenorhabditis elegans
Authors: Shi Zhen , Ruvkun Gary
Published: March 2012

The mevalonate pathway is highly conserved and mediates the production of isoprenoids, which feed into biosynthetic pathways for sterols, dolichol, ubiquinone, heme, isopentenyl adenine, and prenylated proteins. We found that in
Caenorhabditis elegans
, the nonsterol biosynthetic outputs of the mevalonate pathway are required for the activity of microRNAs (miRNAs) in silencing their target mRNAs. Inactivation of genes that mediate multiple steps of the mevalonate pathway causes derepression of several miRNA target genes, with no disruption of the miRNA levels, suggesting a role in miRNA-induced silencing complex activity. Dolichol phosphate, synthesized from the mevalonate pathway, functions as a lipid carrier of the oligosaccharide moiety destined for protein
N
-linked glycosylation. Inhibition of the dolichol pathway of protein
N
-glycosylation also causes derepression of miRNA target mRNAs. The proteins that mediate miRNA repression are therefore likely to be regulated by
N
-glycosylation. Conversely, drugs such as statins, which inhibit the mevalonate pathway, may compromise miRNA repression as well as the more commonly considered cholesterol biosynthesis.
Reflectometry-based plasma position feedback control demonstration at ASDEX Upgrade
Authors: Santos J. , Guimarãis L. , Zilker M. , Treutterer W. , Manso M.
Published: March 2012

In fusion experiments, real-time feedback control of the plasma position plays a vital role for machine protection and disruption avoidance. This control task is presently performed using magnetic measurements that, in future long pulse tokamak devices of the ITER class, may be affected by drifting integrators or radiation induced voltages in the magnetic pickup coils. These effects could have an impact on the magnetic equilibrium reconstruction, causing potential losses of position control and, consequently, leading to premature discharge termination or plasma-facing component damage. Frequency modulated continuous wave O-mode reflectometry, a non-magnetic dependent technique used to measure the density profile, was proposed to backup or complement the standard magnetic-based control in such devices. This new control scheme has just been successfully demonstrated for the first time on the ASDEX Upgrade (AUG) tokamak. The location of the plasma boundary, used in the control of the plasma column position, was tracked in real-time (RT) using dedicated algorithms and a new approach that combines the reflectometry edge profile and a scaled line integrated density measurement from interferometry. Although feasibility studies on the viability of this method had been previously conducted at AUG, the capabilities required to produce this on-line demonstration were only incorporated in the diagnostic after a recent upgrade of its data acquisition and processing hardware. The results herein presented show the first successful demonstration of the reflectometry plasma position application as proposed for ITER.
ELM pacing using modulated non-axisymmetric magnetic fields on DIII-D
Authors: Solomon W.M. , Burrell K.H. , Garofalo A.M. , Groebner R.J. , Lasnier C.J. , Makowski M.A. , Osborne T.H. , Reimerdes H. , deGrassie J.S. , Doyle E.J. , Evans T.E. , Fenstermacher M.E. , Jackson G.L. , Schaffer M.J.
Published: March 2012

Edge localized mode (ELM) pacing using modulated n = 3 non-axisymmetric fields has been demonstrated on DIII-D over a wide range of conditions, including significant variations in temperature, βN, density and shape. At low collisionality, the pacing results in a clear reduction in the ELM size and peak heat flux to the divertor, up to a factor of 5–6 for short time windows, although only a factor of two for sustained periods with the present hardware capability. At higher collisionality, although similar increases in the ELM frequency have been demonstrated, no meaningful reduction in the heat flux is typically observed as a direct result of the pacing. However, it appears that the ELM size may be reduced indirectly via changes in the L–H power threshold as a result of density pumpout associated with the application of non-axisymmetric fields. At this stage, it remains unclear whether the failure to reduce the ELM size with modulated fields is a limitation associated with high collisionality, high density, or relative proximity to the L–H power threshold.
PDK1 in apical signaling endosomes participates in the rescue of the polarity complex atypical PKC by intermediate filaments in intestinal epithelia
Authors: Mashukova Anastasia , Forteza Radia , Wald Flavia A. , Salas Pedro J.
Published: March 2012

Phosphorylation of the activation domain of protein kinase C (PKC) isoforms is essential to start a conformational change that results in an active catalytic domain. This activation is necessary not only for newly synthesized molecules, but also for kinase molecules that become dephosphorylated and need to be refolded and rephosphorylated. This “rescue” mechanism is responsible for the maintenance of the steady-state levels of atypical PKC (aPKC [PKCι/λ and ζ]) and is blocked in inflammation. Although there is consensus that phosphoinositide-dependent protein kinase 1 (PDK1) is the activating kinase for newly synthesized molecules, it is unclear what kinase performs that function during the rescue and where the rescue takes place. To identify the activating kinase during the rescue mechanism, we inhibited protein synthesis and analyzed the stability of the remaining aPKC pool. PDK1 knockdown and two different PDK1 inhibitors—BX-912 and a specific pseudosubstrate peptide—destabilized PKCι. PDK1 coimmunoprecipitated with PKCι in cells without protein synthesis, confirming that the interaction is direct. In addition, we showed that PDK1 aids the rescue of aPKC in in vitro rephosphorylation assays using immunodepletion and rescue with recombinant protein. Surprisingly, we found that in Caco-2 epithelial cells and intestinal crypt enterocytes PDK1 distributes to an apical membrane compartment comprising plasma membrane and apical endosomes, which, in turn, are in close contact with intermediate filaments. PDK1 comigrated with the Rab11 compartment and, to some extent, with the transferrin compartment in sucrose gradients. PDK1, pT555-aPKC, and pAkt were dependent on dynamin activity. These results highlight a novel signaling function of apical endosomes in polarized cells.
GENI-DB: a database of global events for epidemic intelligence
Authors: Collier Nigel , Doan Son
Published: March 2012

Summary: We present a novel public health database (GENI-DB) in which news events on the topic of over 176 infectious diseases and chemicals affecting human and animal health are compiled from surveillance of the global online news media in 10 languages. News event frequency data were gathered systematically through the BioCaster public health surveillance system from July 2009 to the present and is available to download by the research community for purposes of analyzing trends in the global burden of infectious diseases. Database search can be conducted by year, country, disease and language.

Availability: The GENI-DB is freely available via a web portal at http://born.nii.ac.jp/

Contact:  collier@nii.ac.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
The Childhood Immunisation Programme
Authors: Paul Siba Prosad , Almashta Zaid , Wallace Ann
Published: March 2012

Availability of safe drinking water and immunisation have been the most cost effective public health measures. It is estimated that worldwide 2–3 million deaths are prevented annually due to immunisation. Herd immunity extends protection to the whole community but immunisation uptake needs to be high. This article aims to clarify the immunisation programme in the UK and to discuss the challenges GPs may face. Illustrative examples will demonstrate the challenges that practitioners may come across in their routine practice.
A GP inside the WHO
Authors: Irving Greg
Published: March 2012

Over the last year, I have been fortunate enough to work at the World Health Organization (WHO) headquarters in Geneva. My work there involved developing strategies to help low- and middle-income countries address health inequalities, defined as the systematic and potentially remediable differences in one or more aspects of health across populations. I was fascinated to see that policy attempts to reduce health inequalities had been prioritized into two key areas: Primary Health Care and the Social Determinants of Health, areas of great relevance to general practice. The WHO has made two significant contributions to both these policy areas — the Commission on the Social Determinants of Health and the 2008 World Health Report on Primary Health Care. As a GP, I found myself reflecting on how these two policy areas relate to one another, and importantly how we, as GPs, can take action on the social determinants of health to strengthen primary health care.