bluuebunny/crossref_metadata_2025 huggingface dataset:
Tipping the Noxa/Mcl-1 Balance Overcomes ABT-737 Resistance in Chronic Lymphocytic Leukemia
Authors: Tromp Jacqueline M. , Geest Christian R. , Breij Esther C.W. , Elias Judith A. , van Laar Jacoline , Luijks Dieuwertje M. , Kater Arnon P. , Beaumont Tim , van Oers Marinus H.J. , Eldering Eric
Published: December 2011

Purpose: Chronic lymphocytic leukemia (CLL) cells in lymph nodes (LN), from which relapses are postulated to originate, display an antiapoptotic profile in contrast to CLL cells from peripheral blood (PB). The BH3 mimetic ABT-737 antagonizes the antiapoptotic proteins Bcl-XL and Bcl-2 but not Mcl-1 or Bfl-1. Previously, it was shown that CD40-stimulated CLL cells were resistant to ABT-737. We aimed to define which antiapoptotic proteins determine resistance to ABT-737 in CLL and whether combination of known antileukemia drugs and ABT-737 was able to induce apoptosis of CD40-stimulated CLL cells.

Experimental Design: To mimic the LN microenvironment, PB lymphocytes of CLL patients were cultured on feeder cells expressing CD40L and treated with ABT-737 with or without various drugs. In addition, we carried out overexpression or knockdown of pro- and antiapoptotic proteins in immortalized primary B cells.

Results: Upon CD40 stimulation patient-specific variations in ABT-737 sensitivity correlated with differences in levels of Mcl-1 and its antagonist Noxa. Knockdown of Noxa, as well as Mcl-1 overexpression, corroborated the importance of the Noxa/Mcl-1 ratio in determining the response to ABT-737. Inhibition of NF-κB resulted in increased Noxa levels and enhanced sensitivity to ABT-737. Interestingly, increasing the Noxa/Mcl-1 ratio, by decreasing Mcl-1 (dasatinib and roscovitine) or increasing Noxa levels (fludarabine and bortezomib), resulted in synergy with ABT-737.

Conclusions: Thus, the Noxa/Mcl-1 balance determines sensitivity to ABT-737 in CD40-stimulated CLL cells. These data provide a rationale to investigate the combination of drugs which enhance the Noxa/Mcl-1 balance with ABT-737 to eradicate CLL in chemoresistant niches. Clin Cancer Res; 18(2); 487–98. ©2011 AACR.
Spectral and Temporal Reduction as Stress Cues in Dutch
Authors: van Heuven Vincent J. , de Jonge Mirjam
Published: December 2011

Although much has been written on the relative importance of acoustic correlates of linguistic stress for the listener, the role of spectral expansion/reduction has been much understudied. The present article is the first to study the role of spectral expansion/reduction in a two- parameter study together with temporal structure exploiting systematic variation of both parameters in a 7 × 7 stimulus space. We used a single minimal stress pair in Dutch, a language in which all classic acoustic correlates of stress were shown earlier to be relevant in singleparameter studies, i.e. pitch movement, intensity (loudness), temporal organization and spectral expansion/reduction. The results of our study reconfirmed that temporal organization is a strong cue to stress perception when target words are presented out of focus (i.e. without a pitch accent on the target). Spectral expansion/reduction was a very weak stress cue; its effect was noticeable only when temporal structure was ambiguous between initial and final stress. These results suggest that spectral expansion/reduction is indeed the weakest of the four cues traditionally identified in the literature, at least in stress-accent languages such as English and Dutch.
Adenosine A2A-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders
Authors: Kulisevsky Jaime , Poyurovsky Michael
Published: December 2011

Parkinson’s disease and drug-induced movement disorders (DIMDs) have commonalities in etiology based on impaired dopamine-based neurotransmission. Adenosine A2A-receptor antagonism may provide a new mechanism through which these disorders can be managed. In the motor circuit, tonic output from the globus pallidus and substantia nigra regulates movement via opposing excitatory and inhibitory inputs to the cerebral cortex through the direct and indirect pathways. Increased activity of the direct pathway increases movement via an inhibitory effect on thalamocortical projection neurons; increased activity of the indirect pathway has the opposite effect. Regulation of these pathways is mediated primarily by reciprocal inhibitory interactions between dopamine and adenosine receptors on neurons of these pathways. Adenosine A2A receptors are colocalized with dopamine D2 receptors on the indirect pathway neurons, with A2A activation opposing the effect of D2 activation. The A2A receptors’ role in the pathophysiology of Parkinson’s disease and DIMDs is evidenced by the upregulation of A2A receptors in patients with Parkinson’s disease and patients receiving long-term administration of dopamine blockers. Further, A2A-receptor antagonists are effective in reversing parkinsonian motor deficits and extrapyramidal symptoms in animal models of Parkinson’s disease and DIMDs. Understanding the role of A2A-receptor antagonism in the pathophysiology of Parkinson’s disease and DIMD has therapeutic implications.
Correlation of Levels of Neuronal and Glial Markers with Radiological Measures of Infarct Volume in Ischaemic Stroke: A Systematic Review
Authors: Ahmad Omar , Wardlaw Joanna , Whiteley William N.
Published: December 2011

Background: A blood test that quantified the extent of brain damage following ischaemic stroke might be a useful surrogate outcome measure in trials of acute stroke treatments. Measures of neuronal and glial damage, such as neuron-specific enolase (NSE), glial fibrillary acidic protein, tau-protein, myelin-basic protein and S100-β are potential candidate biomarkers. Aim: We systematically reviewed the relevant literature to find studies that correlated blood levels of neuronal and glial damage markers with imaging measures of infarct volume. Methods: We identified studies with a comprehensive search of databases and the reference lists of relevant studies. We included studies that: (1) measured the highest level, or area under the curve (AUC) over time of markers of cerebral damage, (2) calculated infarct volume, and (3) correlated the two measures. Results: Seventeen studies met the criteria for the systematic review. There were sufficient data to provide summary estimates for S100-β and NSE. The peak level and AUC over time of both markers correlated with subacute infarct volume. Measurements of S100-β later than 24 h after stroke were better correlated with subacute infarct size than earlier measurements. However, scan times varied, and none was later than 8 days after stroke. Conclusion: Peak and AUC levels of NSE and S100-β levels correlated with subacute infarct volume. Correlations of S100-β with infarct volume were stronger when measured after 24 h than closer to admission. Exploratory studies within clinical trials are necessary before blood markers of cerebral tissue damage can be recommended as surrogate endpoints.
Hemodynamic Analysis of Intracranial Aneurysms with Daughter Blebs
Authors: Zhang Ying , Mu Shiqing , Chen Jialiang , Wang Shengzhang , Li Haiyun , Yu Hongyu , Jiang Fan , Yang Xinjian
Published: December 2011

Background and Purpose: Intracranial aneurysms with daughter blebs appear to have a higher risk of rupture. Whether hemodynamic factors are involved in this phenomenon is not clear. Methods: 54 patient-specific aneurysms harboring 69 daughter blebs were divided into ruptured and unruptured groups based on their clinical history. Realistic models were retrospectively constructed and analyzed by a computational fluid dynamic method. Results: There were no differences in the aspect ratio and morphology type of the aneurysms, the size of blebs or other common risk factors between the two groups. The wall shear stress (WSS) was significantly lower while the oscillatory shear index (OSI) was higher in the daughter blebs than in the primary aneurysms. Bleb-bearing aneurysms with a rupture history displayed significantly lower WSS in the daughter bleb. Of the daughter blebs, 73.9% were localized to the impingement region of the inflow jet. Conclusion: These observations indicate that low WSS and high OSI in the daughter blebs might be involved in increasing the risk of rupture. The localized striking force caused by inflow jets may contribute to the development of daughter blebs. However, a precise role of hemodynamics in predicting the future rupture of daughter blebs needs further study.
Impact of Age and Duration of Growth Hormone Therapy in Children with Turner Syndrome
Authors: Ross Judith , Lee Peter A. , Gut Robert , Germak John
Published: November 2011

Background/Aims: To assess height standard deviation scores (HSDS) in patients with Turner syndrome (TS) by age at treatment initiation and varying durations of treatment with growth hormone (GH). Methods: GH treatment-naïve patients with TS from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® Registry were analyzed at baseline, 4 months, and annually. Results: Three hundred and eighty-two patients with TS had a baseline mean (±SD) HSDS of –2.6 ± 0.9. Patients received short-term (1 year), long-term (<3 years), and extended GH treatment (≧3 years, mean = 4.54 years), resulting in 40.2% (n = 99/246), 60.5% (n = 69/114), and 62.3% (n = 86/138) of the patients achieving HSDS >–2. Patients starting GH at a younger age experienced better growth response, regardless of treatment duration. Change in HSDS from baseline (ΔHSDS) at 4 months correlated positively with ΔHSDS at 1 and 3 years, and ΔHSDS at 1 year with ΔHSDS at 3 years (p values from 0.0017 to<0.0001). Conclusions: Height gains in patients with TS during short-term treatment were found to be highly predictive of longer-term results. Continuation of GH treatment (≧3 years) resulted in 62.3% of the patients achieving an HSDS within the normal population range, indicating the clinical importance of early initiation and continuation of GH treatment in patients with TS.
VAP-1/SSAO Plasma Activity and Brain Expression in Human Hemorrhagic Stroke
Authors: Hernandez-Guillamon Mar , Solé Montse , Delgado Pilar , García-Bonilla Lidia , Giralt Dolors , Boada Cristina , Penalba Anna , García Sandra , Flores Alan , Ribó Marc , Alvarez-Sabin José , Ortega-Aznar Arantxa , Unzeta Mercedes , Montaner Joan
Published: December 2011

Background: Vascular adhesion protein-1 (VAP-1) is a cell surface and circulating enzyme that belongs to the semicarbazide-sensitive amine oxidase (SSAO) family, which oxidatively deaminates primary amines and is implicated in leukocyte extravasation. Our aim was to investigate the alteration of soluble VAP-1/SSAO activity in plasma samples after acute intracerebral hemorrhage (ICH) and its presence in human ICH brain tissue. Methods: VAP-1/SSAO activity was determined in plasma of 66 ICH patients and 58 healthy controls. In addition, we assessed the expression of VAP-1/SSAO in postmortem brain tissue from hemorrhagic stroke patients by Western blot and immunohistochemistry. Results: We observed significantly higher levels of plasma VAP-1/SSAO activity in patients with ICH compared to matched elderly controls (p = 0.001). Plasma VAP-1/SSAO activity <2.7 pmol/min·mg and baseline ICH volume <17 ml were independent predictors of neurological improvement after 48 h (OR 6.8, 95% CI 1.14–41.67, p = 0.035, and OR 10.64, 95% CI 1.1–100, p = 0.041, respectively), after adjustment for baseline stroke severity. We also found that membrane-bound VAP-1/SSAO levels were lower in the perihematoma region than in the corresponding contralateral brain areas of patients deceased due to ICH (p = 0.024). Conclusions: Our data demonstrate that plasma VAP-1/SSAO activity is increased in ICH and predicts neurological outcome, suggesting a possible contribution of the soluble protein in secondary brain damage. Furthermore, anti-VAP-1/SSAO strategies might be a promising approach to prevent neurological worsening following ICH.
Etiology, Risk Factors and Sex Differences in Ischemic Stroke in the Ludwigshafen Stroke Study, a Population-Based Stroke Registry
Authors: Palm F. , Urbanek C. , Wolf J. , Buggle F. , Kleemann T. , Hennerici M.G. , Inselmann G. , Hagar M. , Safer A. , Becher H. , Grau A.J.
Published: December 2011

Background: Stroke etiology in ischemic stroke guides preventive measures and etiological stroke subgroups may show considerable differences between both sexes. In a population-based stroke registry we analyzed etiological subgroups of ischemic stroke and calculated sex-specific incidence and mortality rates. Methods: The Ludwigshafen Stroke Study is a prospective ongoing population-based stroke registry. Multiple overlapping methods of case ascertainment were used to identify all patients with incident stroke or transient ischemic attack. Modified TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria were applied for subgroup analysis in ischemic stroke. Results: Out of 626 patients with first-ever ischemic stroke in 2006 and 2007, women (n = 327) were older (73.5 ± 12.6 years) than men (n = 299; 69.7 ± 11.5 years; p < 0.001). The age-adjusted incidence rate of ischemic stroke was significantly higher in men (1.37; 95% CI 1.20–1.56) than in women (1.12; 95% CI 0.97–1.29; p = 0.04). Cardioembolism (n = 219; 35.0%), small-artery occlusion (n = 164; 26.2%), large-artery atherosclerosis (n = 98; 15.7%) and ‘probable atherothrombotic stroke’ (n = 84; 13.4%) were common subgroups of ischemic stroke. Stroke due to large-artery atherosclerosis (p = 0.025), current smoking (p = 0.008), history of smoking (p < 0.001), coronary artery disease (p = 0.0015) and peripheral artery disease (p = 0.024) was significantly more common in men than in women. Overall, 1-year survival was not different between both sexes; however, a significant age-sex interaction with higher mortality in elderly women (>85 years) was detected. Conclusions: Cardioembolism is the main source for ischemic stroke in our population. Etiology of ischemic stroke differs between sexes, with large-artery atherosclerotic stroke and associated diseases (coronary artery disease and peripheral artery disease) being more common in men.
Long-Term Efficacy and Safety of Two Doses of Growth Hormone in Short Japanese Children Born Small for Gestational Age
Authors: Tanaka Toshiaki , Yokoya Susumu , Seino Yoshiki , Togari Hajime , Mishina Jun , Kappelgaard Anne-Marie , Fujieda Kenji
Published: November 2011

Background/Aims: To investigate the long-term efficacy and safety of two doses (33 and 67 µg/kg/day) of growth hormone (GH) in short Japanese children born small for gestational age (SGA). Methods: 96 children born SGA (age 3 to <8 years) were randomized to GH at 33 or 67 µg/kg/day for 104 weeks, or to an untreated control (UC) group for 52 weeks. After 52 weeks, the UC group was randomized to GH at a dose of 33 or 67 µg/kg/day for a 156-week extension study. Initial treatment groups continued unchanged for the extension phase. Efficacy was evaluated by change in height SDS for chronological age from baseline to 208/260 weeks. Results: After 208 weeks, change in height SDS from baseline (least square (LS) means (SE)) was 1.01 (0.47) and 1.99 (0.67) in the UC 33 and UC 67 µg/kg/day groups, respectively. After 260 weeks, change in height SDS from baseline was 1.22 (0.51) and 2.01 (0.64) in the 33 and 67 µg/kg/day groups, respectively. Insulin-like growth factor-1 levels were significantly higher in the groups receiving 67 µg/kg/day but largely remained within normal limits (–2 to +2 SDS). Conclusion: Long-term continuous GH treatment was well tolerated and effective in improving height SDS. Improvements were dose-dependent and significantly higher at 67 than 33 µg/kg/day.
Selective Use of Endoscopic Ultrasound in the Evaluation of Carcinomas of the Pancreatic Head
Authors: Morris-Stiff Gareth , Escofet Xavier , Barry John D. , Lewis Wyn G. , Puntis Malcolm C.A. , Roberts S. Ashley
Published: December 2011

Background: The aims of this study were to assess the role of endoscopic ultrasound (EUS) in the evaluation of adenocarcinoma of the head of the pancreas in cases of diagnostic dilemma and to determine the strength of agreement between perceived pre-operative stage as determined by computerised tomography (CT) and EUS and histopathological stage. Methods: Patients undergoing pancreatic EUS were identified from a computerised radiology database. The strengths of agreement between the radiological and histopathological stages were determined by the weighted kappa (Kw) statistic. Results: Fifty-eight patients were identified. Of 37 patients with a pancreatic head mass on prior imaging, 32 had a diagnosis of adenocarcinoma confirmed by EUS, as did 11 of 21 patients with suspicious pancreatic head lesions. Twenty-five of 43 patients were deemed to have resectable carcinomas, and 2 patients had resectable mucinous lesions. In comparing CT and EUS in the 25 patients undergoing resection, the Kw for T and N stages was 0.250 (p = 0.05) and –0.080 (p = 0.288), respectively, for CT, compared with 0.738 (p = 0.0001) and 0.606 (p = 0.0001), respectively, for EUS. Conclusions: EUS was effective in assessing the resectability of pancreatic head adenocarcinomas. Furthermore, EUS held a significant 3-fold advantage over CT with regard to T stage and an even higher significant advantage with regard to N stage.
The Tragedy of the Margins: Land Rights and Marginal Lands in Vietnam (c. 1800-1945)
Authors: Kleinen John
Published: November 2011

Abstract

This article deals with aspects of official land registers in pre-colonial and colonial Vietnam and their relationship with marginal lands since the eleventh century and especially since the beginning of the nineteenth century. The changing pattern of land ownership and control is studied in detail in one specific village in the Red River Delta of northern Vietnam. Several practices of land use and land distribution are discussed, as are various efforts in parts of Vietnam to expand agricultural land, in particular near rivers and coasts, especially as a result of land reclamation. The study of marginal lands is focused on alluvial lands, which were seen originally as empty or waste lands but gradually developed into safety nets for the poor. The traditional social function of these communal waste lands, managed by village elites, was eroded and became a tool for manipulation in the hands of state and village authorities.
Land Rights and the Environment in the Indonesian Archipelago, 800-1950
Authors: Boomgaard Peter
Published: November 2011

Abstract

This article has two basic aims. First, I discuss several notions regarding long-term changes in land-tenure arrangements, mainly in what is now Indonesia. I argue that the character of these changes is often badly understood, partly because the older literature has been misrepresented, partly because the older literature was wrong, and partly because many scholars implicitly or explicitly appear to believe in “stages theories” (best known among scholars under the German term Stufentheorie), which posit fairly uniform and unidirectional stages of land-tenure development across the board. Second, this article deals with environmental causes and effects of long-term land-tenure developments in the Indonesian Archipelago.

Land tenure and conservation are hotly debated at present, but the historical substance in such debates is meagre, usually going back no further than the 1950s or 60s. Nor does there seem to be much interest in the environmental roots of land-tenure arrangements, perhaps because the participants in the land-tenure-and-the-environment debate are mainly anthropologists and environmentalists, who might find such topics of antiquarian importance only. As an historian I cannot share this view.
Survival, Conversion and Restoration: Reflections on the Redaction History of the Book of Zephaniah
Authors: Hadjiev Tchavdar S.
Published: November 2011

Abstract

Understanding the redaction history of a biblical book helps us to see how the community of faith received, applied and reinterpreted the prophetic words. There are a number of places in the book of Zephaniah that can be recognized as secondary in their present literary context. Analysis of their style and content shows that they are the result of three subsequent reworkings of the prophetic scroll: a ‘restoration of the remnant’ redaction (2:7, 9b-10 and 3:11-13 plus the phrase ‘all the humble of the earth who do his justice’ in 2:3); a ‘salvation of the nations’ redaction (2:11 and 3:9-10) and a ‘salvation of Judah’ redaction (3:14-20). These redactions focused exclusively on the issue of salvation beyond judgment but gave very different answers to the questions ‘who is going to be saved?’ (the remnant, all the nations, Judah) as well as ‘what ushers the age of salvation?’ (repentance or the grace of Yahweh).
St. Augustine on Time, Time Numbers, and Enduring Objects
Authors: Carter Jason W.
Published: November 2011

Abstract

Throughout his works, St. Augustine offers at least nine distinct views on the nature of time, at least three of which have remained almost unnoticed in the secondary literature. I first examine each these nine descriptions of time and attempt to diffuse common misinterpretations, especially of the views which seek to identify Augustinian time as consisting of an un-extended point or a distentio animi. Second, I argue that Augustine’s primary understanding of time, like that of later medieval scholastics, is that of an accident connected to the changes of created substances. Finally, I show how this interpretation has the benefit of rendering intelligible Augustine’s contention that, at the resurrection, motion will still be able to occur, but not time.
The Authority of Early Hebrew Scripture Texts
Authors: Tov Emanuel
Published: November 2011

Abstract

Our investigation begins with an analysis of the abstract and tangible aspects of Scriptural authority after the first century ce, thus laying the foundation for a discussion of this topic in earlier times. It is much more difficult to define authority at that early stage than in later periods, because Scripture was still in the making. We avoid an analysis of canonization, focusing on ancient scrolls, but realize that scrolls were only copied after a book had obtained an authoritative status. Among the textual witnesses of Scripture, we assume textual plurality, which is particularly noticeable at Qumran, across the board, while the proto-rabbinic movement adhered only to the proto-MT texts, and the Samaritans only to their own Torah. We describe different kinds of Scripture scrolls, assuming that Scripture-like scrolls such as liturgical, excerpted and partial scrolls had no authoritative status, while all other scrolls did. These scrolls were authoritative throughout ancient Israel in spite of the differences between them, although it is unclear which source other than tradition granted that authority. We provide some tentative criteria for assuming an authoritative status.
A Narratological Approach to Witchcraft Trial: A Scottish Case
Authors: Willumsen Liv Helene
Published: November 2011

Abstract

This article is a microstudy of a Scottish witchcraft document from 1662, focusing of the case of a woman accused of witchcraft in Bute. It emphasizes the various “voices” that are possible to “hear” in the material—for example, the voice of the scribe, the witnesses, or the accused person. It argues on linguistic grounds that the way the story was told by the scribe influences the interpretation of this document, since the scribe had the authority over the contents of the text. This narratological analysis is finally put in a broader historical context, adding factual information about the woman accused of witchcraft and her final fate. Methodologically, this article crosses the border between literature and history, working in a new way with regard to interpretation of historical documents and is an empirical example of the fruitfulness of cross-cultural studies.
The Relevance of Economic and Political Conditions for Protection under Investment Treaties
Authors: Kriebaum Ursula
Published: November 2011

Abstract

Some treaty standards for the protection of investments, like national treatment and MFN, are variable. They depend upon standards granted to the host State's nationals or to investors from third States. By contrast, standards like fair and equitable treatment and full protection and security provide fixed reference points. The question arises whether these reference points are the same for all states regardless of their level of development and their economic, social and political circumstances at the time of the investment.

Some arbitral tribunals have been prepared to consider the social, economic and political situation prevailing in the host country when assessing the threshold for the violation of investment protection standards or the level of compensation required by BITs. This article addresses the question whether and how tribunals have made use of the flexibility in the legal standards in investment law to take account of the different economic and political conditions across nations. It concludes by considering what the implications of this flexibility might be and how far it should go.
The Reform of the United Nations Administration of Justice System: The United Nations Appeals Tribunal after One Year
Authors: Otis Louise , Reiter Eric H.
Published: November 2011

Abstract

This article surveys some emerging issues in the jurisprudence of the new United Nations Appeals Tribunal. Through an analysis of both procedural and substantive questions that the tribunal has faced in its first year (for example specific performance, production of documents, and whistleblower protection), the article offers an assessment of the implementation of the reform of the formal justice system of the United Nations. The developing jurisprudence of the tribunal will be an important indicator of the success or failure of the implementation of an independent system of justice within the United Nations.
Developments at the International Criminal Court
Authors: McCausland Julieta Solano , Rojo Enrique Carnero
Published: November 2011

Abstract

This column covers the activity of the International Criminal Court during the second third of 2010. The Court has continued investigating situations in five countries (the Democratic Republic of the Congo, Uganda, Sudan, the Central African Republic and Kenya) and has started one new case. The judicial activity of the Court has remained stable, with three accused persons undergoing trial and one more waiting for his trial to start. Several Chambers have continued to develop the rules applicable to pre-trial and trial proceedings, confirming their previous decisions, including on the issue of victim participation during the trial. Moreover, the Court has adopted its first decision charging a suspect with allegations of genocide and has ruled on the admissibility of the third of its cases to proceed to trial. All in all, during the period of time covered in this column, the Court has continued the conduct of its investigations and trials.
The right to education of Roma children in Romania: European policies and Romanian practices
Authors: Moisa Florin , Roth Maria
Published: December 2011

After a long history of living in Europe, latterly in democracies governed with reference to human, and children's, rights, Roma children still have a very low education status and very low school participation rates. The aims of this article are to review the current state of participation of Roma children in education in European countries, with a special focus on Romania, and to discuss some issues about how the right to education is, or is not, respected in the region. Data accumulated in the last decade are revisited and educational policies are analyzed. Particular attention is given to issues of segregation in education, scrutinized through the lens of Romanian and international education practices. The article recommends a number of policy responses, including the value of added cash transfers, as well as action to ensure quality standards in all education settings frequented by Roma children.
A love couple revealed, Jacob Adriaensz Backer's so called David en Bathsheba identified as Isaac and Rebecca
Authors: Kok Erna
Published: November 2011

Jacob Backer signed and dated (1640) a history piece that until now was entitled David and Bathsheba and is located in Tokyo. The image however, lacks the traditional iconographical motifs from which we can recognize this old biblical story.

In this article I propose that the painting is a portrait historié of the wealthy Amsterdam couple Marinus Lowysse and Eva Ment represented as Isaac and Rebecca. Backer modelled his biblical love couple after Rafael's fresco Isaac and Rebecca spied upon by Abemelich in the Vatican. Backer must have known that image from Sisto Badalocchio's print of 1607 in Historia del Testamento Vecchio - this collection of fifty prints was reprinted in Amsterdam in 1638.

The identification as Isaac and Rebecca does not show at first sight in the present painting. Therefore, we have to take in consideration that the current image is heavily over painted and the canvas is reduced by almost 65 %. Fortunately a drawing in Braunschweig – that was convincingly attributed by Peter van den Brink as a modello by Backer - offers a clear idea of the monumental standing format of the original painting and it's explicit erotic content. This is particular notable in the slung-leg motif that contemporaries undoubtedly would have recognized as the act of making love. The erotic allusions, the rare subject, and the unusual huge standing format are indicative of a commission.

The identification of the commissioners derives from the striking likeness, in features and clothing, that the man in the Tokyo painting shows with the portrait of Marinus Lowysse, that he – as we know - commissioned from Backer in the same year of 1640, a Portrait historié of Marinus Lowysse en Eva Ment, with their children, presenting the history of Christ and the Canaanite Woman, now in Middelburg. Recently an unknown painting of Backer turned up at the art market, which is very likely another portrait of Marinus Lowysse; apparently he was an important client of Backer.
From Promise to Practice? The Legal Significance of the Responsibility to Protect Concept
Authors: Orford Anne
Published: December 2011

According to UN Secretary-General Ban Ki-Moon, the challenge facing the international community is to transform the responsibility to protect concept from 'promise to practice' or from 'words into deeds'. This article argues that the legal significance of the concept lies not in its capacity to transform promise into practice, but rather in its capacity to do the reverse – that is, to transform practice into promise, or deeds into words. The responsibility to protect concept offers a coherent normative framework for the practices of international executive rule that have developed to maintain order and protect life in the decolonised world since the 1950s. In that sense, the appeal to 'responsibility' does not function to impose new duties and obligations upon legal subjects or international actors. Rather, the language of 'responsibility' serves a different normative function – it works to allocate jurisdiction, confer power of a public nature and provide international officials with legal authorisation for certain kinds of activities. This article concludes by suggesting why it is useful to think about the responsibility to protect concept in these terms.
Reconsidering Theory: Power, the Learning Body, and Cultural Change during Early American Colonization
Authors: Spady James O'Neil
Published: November 2011

This essay participates in recent calls for more direct engagement with theory in research and teaching within History and Early American Studies. Over the last decade voices have gathered for a reconsideration of fundamental theoretical concepts in the historiography of culture. This essay reconsiders theory on semiotics, learning, and the body to reopen a conceptual problem in early American cultural historiography: the relationships between organized power and individual agency. I suggest an approach to power and agency specifically tuned to the conditions of early America colonization, which was more intimate and diverse while possessing fewer institutions and less communications-saturation than a focus on myth, ideology, or discursive formations might assume. Reconsidering semiotics as embodied allows a conception of the body as a learning entity creatively mediating discourses and social constructions and thereby generating new historical identities and relations of power. The argument draws on studies on gender/sexuality, Native Americans, and the enslaved and takes cues from the work of Gyatri Spivak, Ann Laura Stoler, Michel Foucault, Lev Vygotsky, and Charles Sanders Peirce.
Christian Cypriot perceptions of Muslim Cypriots, 1878-1931: an interpretation of the sources
Authors: Pophaides Irene
Published: November 2011

Christian Cypriot perceptions of Muslim Cypriots went through several transformations in the period 1878-1931. This procedure, located in the context of the development of the Greek Cypriot nationalist movement, the political activity of the British administrators and the Church of Cyprus, the attempts of the Greek state to communicate the notion of the Megali Idea in the island, the shift in the allegiances of the Muslim Cypriot community as well as of international events the ramifications of which were experienced in Cyprus, can be vividly revealed through the sources. In exposing it, this article will suggest another interpretative tool which can enlighten the complex evolution of Greek Cypriot nationalism in the island.
Reflective Knowledge and Intellectual Assurance
Authors: Fumerton Richard
Published: November 2011

In this discussion of Sosa's second volume on reflective knowledge, I focus on the question of whether Sosa's account of knowledge is flawed for failing to capture a connection between possessing knowledge and gaining assurance of truth. In particular, I worry that if there is no more to reflective knowledge than apt belief about apt belief, where the understanding of aptness is the same at both the first and the second level, Sosa hasn't given us a way of gaining philosophically satisfying knowledge.
Epistemic Circularity: Vicious, Virtuous and Benign
Authors: Greco John
Published: November 2011

Sosa's work on epistemic circularity has significance beyond his own brand of virtue epistemology, with its characteristic distinction between animal and reflective knowledge. On the contrary, it demonstrates the necessity of embracing foundationalism and externalism in epistemology, while at the same time answering various charges (some perennial) against epistemology in general. This paper distinguishes six kinds of epistemic circularity that are discussed in Sosa's work: two virtuous, two vicious, and two benign. This framework is used to reconstruct Sosa's responses to various problems involving charges of epistemic circularity. In particular, we look at Sosa's response to e Problem of the Criterion.
Boghossian's Refutation of Relativism
Authors: Amini Majid , Caldwell Christopher M.
Published: November 2011

In Fear of Knowledge, Paul Boghossian presents a series of arguments against epistemic relativism and constructivism, doctrines that he considers to have exerted an overly unjustified influence over the human and social sciences in the past two decades. In the presentation of his arguments, Boghossian charts out a terrain that closely identifies relativism with skepticism. Yet, the relationship between the two does not seem to be a simple matter of entailment or implication. The purpose of this paper is to clarify the landscape surrounding relativism and skepticism and thereby to highlight their difference(s). The implications of such a clarification will include illustrating (1) that some arguments thought to be against relativism are actually against skepticism, (2) that there are very different ways of understanding the relationship between relativism and skepticism, and (3) that a commitment to either relativism or skepticism does not entail commitment to the other. The overall objective is to show that Boghossian's conception of the terrain is incorrect and to offer an explanation for this pervasive misconception about the connection between relativism and skepticism.
Pyrrhonian Skepticism and Two Kinds of Knowledge
Authors: Williams Michael
Published: November 2011

In his Reflective Knowledge, Ernest Sosa offers a theory of knowledge, broadly virtue-theoretic in character, that is meant to transcend simple ways of contrasting "internalist" with "externalist" or "foundationalist" with "coherentist" approaches to knowledge and justification. Getting beyond such simplifications, Sosa thinks, is the key to finding an exit from "the Pyrrhonian Problematic": the ancient and profound skeptical problem concerning the apparent impossibility of validating the reliability of our basic epistemic faculties and procedures in a way that escapes vicious circularity. Central to Sosa's anti-skeptical strategy is the claim that there are two kinds of knowledge. His thought is that animal knowledge, which can be understood in purely reliabilist terms, can ground justified trust in the reliability of our basic cognitive faculties, thus elevating us (without vicious circularity) to the level of reflective knowledge. I offer a sketch of an alternative approach, linking knowledge and justification with epistemic accountability and responsible belief-management, which casts doubt on the idea that "animal" knowledge is knowledge properly so-called. However, it turns out that this approach is (perhaps surprisingly) close in spirit to Sosa's. I suggest that the differences between us may rest on a disagreement over the possibility of providing a direct answer to the Pyrrhonian challenge.
Replies to Richard Fumerton, John Greco, and Michael Williams
Authors: Sosa Ernest
Published: November 2011

is is my response to three commentators—Richard Fumerton, John Greco, and Michael Williams—for a symposium on my book, Reflective Knowledge.
Global Business, Global Responsibilities
Authors: van den Heuvel Gijs , Soeters Joseph , Gössling Tobias
Published: December 2011

This study examines the effects of culture, gender, and function on orientation toward corporate social responsibility (CSR) among 416 employees of an international financial service organization. The main objective of the study is to investigate the variation of corporate social responsibility orientation (CSRO) across national cultures. The authors draw on a theory of cultural value orientations to identify three culturally distinct transnational clusters: West Europe, the English speaking countries, and South Asia. These clusters coincide with the business units (BUs) and markets of the organization under investigation. By employing a framework of CSRO, the study reveals substantial differences across clusters within one single internationally operating organization. The English-speaking and the South Asia clusters were found to be most concerned with legal regulations and economic performance. In contrast, the West Europe continental cluster was found to be more concerned about business conforming to ethical norms than achieving high levels of economic performance or conforming to legal regulations. Furthermore, the study reveals gender differences in CSRO and differences among random employees and employees who are professionally active in the area of CSR. This article concludes by discussing implications of these findings for internationally operating organizations in the light of the recent global financial crisis.
Fatigue and Voluntary Utilization of Automation in Simulated Driving
Authors: Neubauer Catherine , Matthews Gerald , Langheim Lisa , Saxby Dyani
Published: December 2011

Objective:

A driving simulator was used to assess the impact on fatigue, stress, and workload of full vehicle automation that was initiated by the driver.

Background:

Previous studies have shown that mandatory use of full automation induces a state of “passive fatigue” associated with loss of alertness. By contrast, voluntary use of automation may enhance the driver’s perceptions of control and ability to manage fatigue.

Method:

Participants were assigned to one of two experimental conditions, automation optional (AO) and nonautomation (NA), and then performed a 35-min, monotonous simulated drive. In the last 5 min, automation was unavailable and drivers were required to respond to an emergency event. Subjective state and workload were evaluated before and after the drive.

Results:

Making automation available to the driver failed to alleviate fatigue and stress states induced by driving in monotonous conditions. Drivers who were fatigued prior to the drive were more likely to choose to use automation, but automation use increased distress, especially in fatigue-prone drivers. Drivers in the AO condition were slower to initiate steering responses to the emergency event, suggesting optional automation may be distracting.

Conclusion:

Optional, driver-controlled automation appears to pose the same dangers to task engagement and alertness as externally initiated automation.

Application:

Drivers of automated vehicles may be vulnerable to fatigue that persists when normal vehicle control is restored. It is important to evaluate automated systems’ impact on driver fatigue, to seek design solutions to the issue of maintaining driver engagement, and to address the vulnerabilities of fatigue-prone drivers.
Having to be: The possessive constitution of organization
Authors: Bencherki Nicolas , Cooren François
Published: December 2011

How does an organization act? Can it be considered an actor on its own or does it need organizational members who act on its behalf? We would like to suggest our own take on the issue by suggesting a genuinely communicative approach to the issue of organizational action. Using the narratology of AJ Greimas to make apparent in talk some of process philosophy’s tenets, we show how organizations act by being attributed actions. The detailed study of meetings from a community organization serves as our empirical grounding. We suggest that through the imbrication of mandates and programs of action in a logic of appropriation/attribution, the organization can effectively act while always relying on others to do so. Far from ‘just talk,’ we contend that in doing so, participants reconfigure their organization and make it do things. There is no need to resort to an essentialist ontology of organization to state that it acts ‘itself.’ We therefore reconcile the two most common views of organizational action – that of an organization acting by itself and that of agents acting on its behalf.
Ovulation‐Inhibiting Effects of Dienogest in a Randomized, Dose‐Controlled Pharmacodynamic Trial of Healthy Women
Authors: Klipping Christine , Duijkers Ingrid , Remmers Ageeth , Faustmann Thomas , Zurth Christian , Klein Stefan , Schuett Barbara
Published: December 2011

Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation‐inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.5, 1, 2, or 3 mg daily for up to 72 days to women aged 18 to 35 years (n = 102). Ovarian activity was assessed pretreatment and during 2 treatment periods (days 0–36 and days 37–72) by the Hoogland score, based on follicle size and serum estradiol and progesterone levels. Additional hormonal parameters and endometrial thickness were assessed. Hoogland scoring indicated ovulation in all women pretreatment, decreasing to 3 of 21, 1 of 23, 0 of 20, and 0 of 23 women in the 0.5‐, 1‐, 2‐, and 3‐mg groups, respectively (per‐protocol set). Maximum serum estradiol concentrations were similar to pretreatment levels in the 0.5‐ or 1‐mg group and decreased moderately (within physiologic levels) in the 2‐ or 3‐mg group. Endometrial thickness was reduced by all dienogest doses. Hormonal changes during follow‐up indicated resumption of ovulation in most women, shortly after treatment cessation. Dienogest ≥2 mg daily provides moderate suppression of estradiol production and reliable ovulation inhibition, which reverses rapidly after treatment cessation.
Predicting the proficiency level of language learners using lexical indices
Authors: Crossley Scott A. , Salsbury Tom , McNamara Danielle S.
Published: December 2011

This study explores how second language (L2) texts written by learners at various proficiency levels can be classified using computational indices that characterize lexical competence. For this study, 100 writing samples taken from 100 L2 learners were analyzed using lexical indices reported by the computational tool Coh-Metrix. The L2 writing samples were categorized into beginning, intermediate, and advanced groupings based on the TOEFL and ACT ESL Compass scores of the writer. A discriminant function analysis was used to predict the level categorization of the texts using lexical indices related to breadth of lexical knowledge (word frequency, lexical diversity), depth of lexical knowledge (hypernymy, polysemy, semantic co-referentiality, and word meaningfulness), and access to core lexical items (word concreteness, familiarity, and imagability). The strongest predictors of an individual’s proficiency level were word imagability, word frequency, lexical diversity, and word familiarity. In total, the indices correctly classified 70% of the texts based on proficiency level in both a training and a test set. The authors argue for the applicability of a statistical model as a method to investigate lexical competence across language levels, as a method to assess L2 lexical development, and as a method to classify L2 proficiency.
Management of community-owned facilities post-acquisition
Authors: Skerratt Sarah , Hall Clare
Published: November 2011

The drive within (development) policy and practice in the UK is towards ownership of local facilities by local communities, with the surrounding rhetoric focusing on community empowerment, inclusion and sustainable development. Coupled with this is a normative presumption of unproblematic ownership by community. This article seeks to question the uncritical nature of these developments by reference to empirical data from Scotland, gathered through a postal survey of 347 rural village hall committees, six in-depth case studies and interviews with funders and fund distributors whose remit covers village halls. Findings are presented with reference to the Community Capitals Framework, focusing particularly on human, social and political capitals. The evidence shows that village hall committees identify a need for support for human and social capacity-building through training to enable them to move beyond short-term ‘fire-fighting’ and operational challenges towards strategic thinking and sustained community engagement. Funders identify key requirements for communities to enhance the sustainability of village halls, including the need to have a strategic rather than operational mindset and to engage in ongoing community-level capacity-building. With the increasing push towards public sector asset transfer to communities, the article argues that much greater cognisance must be made of the complexities and capacity challenges that exist once an asset has been acquired by a community. More effective brokerage and sharing of resources is a critical component in ensuring that community assets do not become liabilities over time.