A phase I study of the Heat Shock Protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced, solid tumours.

PURPOSE: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). PATIENTS AND METHODS: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which = 1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. RESULTS: Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P

The factor structure of the revised Illness Perceptions Questionnaire in a population of oesophageal cancer survivors

Objectives
To determine whether the proposed 7-factor structure of the Illness Perception Questionnaire-Revised (Timeline Acute/Chronic, Timeline Cyclical, Consequences, Personal Control, Treatment Control, Illness Coherence and Emotional Representations) is appropriate among a population of oesophageal cancer survivors.
Methods
Everyone registered with the Oesophageal Patients’ Association in the UK (n=2185) was mailed a questionnaire booklet which included the Illness Perception Questionnaire-Revised. Responses from 587 oesophageal cancer survivors (27%) were subjected to a confirmatory factor analysis.
Results
The proposed 7 factor structure provided a reasonable fit of the data. Modification indices suggested that a significantly better fit could be provided if one of the items on the Timeline Acute/Chronic factor loaded on the Treatment Control factor and an error covariance was added between 2 other items on the Timeline Acute/Chronic factor.
Conclusions
The model fit for the 7 factor structure proposed by Moss-Morris et al. (2002) was found to be adequate in our study. However, the structure of the timeline acute/chronic factor needs to be considered, particularly when the IPQ-R is to be used among older people with a potentially life-threatening illness or those receiving palliative care.

Investigation into mercury bound to biothiols:structural identification using ESI-ion-trap MS and introduction of a method for their HPLC separation with simultaneous detection by ICP-MS and ESI-MS

Mercury in plants or animal tissue is supposed to occur in the form of complexes formed with biologically relevant thiols (biothiols), rather than as free cation. We describe a technique for the separation and molecular identification of mercury and methylmercury complexes derived from their reactions with cysteine (Cys) and glutathione (GS): Hg(Cys)(2), Hg(GS)(2), MeHgCys, MeHgGS. Complexes were characterised by electrospray mass spectrometry (MS) equipped with an ion trap and the fragmentation pattern of MeHgCys was explained by using MP2 and B3LYP calculations, showing the importance of mercury-amine interactions in the gas phase. Chromatographic baseline separation was performed within 10 min with formic acid as the mobile phase on a reversed-phase column. Detection was done by online simultaneous coupling of ES-MS and inductively coupled plasma MS. When the mercury complexes were spiked in real samples (plant extracts), no perturbation of the separation and detection conditions was observed, suggesting that this method is capable of detecting mercury biothiol complexes in plants.

Yersinia pseudotuberculosis and Yersinia pestis show increased outer membrane permeability to hydrophobic agents which correlates with lipopolysaccharide acyl-chain fluidity

The hydrophobic probe N-phenyl-1-naphthylamine accumulated less in non-pathogenic Yersinia spp. and non-pathogenic and pathogenic Yersinia enterocolitica than in Yersinia pseudotuberculosis or Yersinia pestis. This was largely due to differences in the activity of efflux systems, but also to differences in outer membrane permeability because uptake of the probe in KCN/arsenate-poisoned cells was slower in the former group than in Y. pseudotuberculosis and Y. pestis. The probe accumulation rate was higher in Y. pseudotuberculosis and Y. pestis grown at 37 degrees C than at 26 degrees C and was always highest in Y. pestis. These yersiniae had LPSs with shorter polysaccharides than Y. enterocolitica, particularly when grown at 37 degrees C. Gelliquid-crystalline phase transitions (Tc 28-31 degrees C) were observed in LPS aggregates of Y. enterocolitica grown at 26 and 37 degrees C, with no differences between non-pathogenic and pathogenic strains. Y. pseudotuberculosis and Y. pestis LPSs showed no phase transitions and, although the fluidity of LPSs of Y. pseudotuberculosis and Y. enterocolitica grown at 26 degrees C were close below the Tc of the latter, they were always in a more fluid state than Y. enterocolitica LPS. Comparison with previous studies of Salmonella choleraesuis subsp. choleraesuis serotype minnesota rough LPS showed that the increased fluidity and absence of transition of Y. pseudotuberculosis and Y. pestis LPSs cannot be explained by their shorter polysaccharides and suggested differences at the lipid A/core level. It is proposed that differences in LPS-LPS interactions and efflux activity explain the above observations and reflect the adaptation of Yersinia spp. to different habitats.

The Role of Personality Factors in the Reduction of Intergroup Anxiety and Amelioration of Outgroup Attitudes via Intergroup Contact

Two studies investigated the role of personality factors in the amelioration of outgroup attitudes via intergroup contact. In study 1, the effect of extraversion on outgroup attitude operated via an increase in cross-group friendship, whereas openness to experience and agreeableness had a direct effect on outgroup attitude. In study 2, we included intergroup anxiety as a mediator explaining these relationships, and we ruled out ingroup friendship as a potential confound. We found that the relationships between openness to experience and agreeableness on the one hand and outgroup attitude on the other were mediated by reduced intergroup anxiety. In addition, the effect of extraversion on outgroup attitude operated via an increase in cross-group friendship that was in turn associated with lower levels of intergroup anxiety. Across both studies, the friendship–attitude relationship was stronger among those low in agreeableness and extraversion. We discuss the importance of integrating personality and situational approaches to prejudice reduction in optimizing the impact of contact-based interventions. Copyright © 2013 John Wiley & Sons, Ltd.

A European Culture War in the Twentieth Century? Antic-Catholicism and Anti-Bolshevism between Moscow, Berlin, and the Vatican 1922 to 1933

The term “culture war” has become a generic expression for secular-catholic conflicts across nineteenth-century Europe. Yet, if measured by acts of violence, anticlericalism peaked in the years between 1927 and 1939, when thousands of Catholic priests and believers were imprisoned or executed and hundreds of churches razed in Mexico, Spain and Russia. This essay argues that not only in these three countries, but indeed across Europe a culture war raged in the interwar period. It takes, as a case study, the interaction of communist and Catholic actors located in the Vatican, the Soviet Union, and Germany in the period between the beginning of the Pontificate of Pius XI in 1922 and Hitler’s appointment as chancellor of Germany in 1933. Using correspondence and reports from the Vatican archives, this essay shows how Papal officials and communist leaders each sought to mobilize the German populace to achieve their own diplomatic ends. German Catholics and communists gladly responded to the call to arms that sounded from Rome and Moscow in 1930, but they did so also to further their own domestic goals. The case study shows how national contexts inflected the transnational dynamics of radical anti-Catholicism in interwar Europe. In the end, agitation against “godlessness” did not lead to the return of a “Christian State” desired by many conservative Christians. Instead, the culture war further destabilized the republic and added a religious dimension to a landscape well suited to National Socialist efforts to reach a Christian population otherwise mistrustful of its völkisch and anticlerical elements.

Metaphor and Matter(s) Arising: Gongorine Metaphor and the Cultivation of the Imagination

This article focuses on the concept of metaphor as metaphorai, as varied means of transfer and transport, specifically on Góngora's innovative development of the metaphor as a vehicle for experiential transformation and epistemological exploration; ultimately emphasizing a hitherto neglected valorization of affect in the liberation of the imagination. Although Góngora's use of metaphor became a major source of controversy in the debate unleashed by the Polifemo and Soledades during his lifetime, the Generation of 1927 looked to Gongorine metaphor as model and inspiration for their cultivation of imaginary worlds through poetry. By examining the models and concepts that nourished Góngora's innovative engagement with metaphor, shaped readers' responses to the poet's imaginary worlds of metaphor, triggered the recovery and reframing of Gongorine metaphor as springboard for the poetic imagination in the twentieth century, and sheds light on the power of Góngora's metaphor to transform and transmute the world through the exercise of the imagination.

Designing Bare Essentials: Aldi, Lidle and the architectures of cheapness

They’re cheap. They’re in every settlement of significance in Britain, Ireland and elsewhere. We all use them but perhaps do not always admit to it. Especially, if we are architects.
Over the past decades Aldi/Lidl low cost supermarkets have escaped from middle Europe to take over large tracts of the English speaking world remaking them according to a formula of mass-produced sheds, buff-coloured cobble-lock car parks, logos in primary colours, bare-shelves and eclectic special offers. Response within architectural discourse to this phenomenon has been largely one of indifference and such places remain, perhaps reiterating Pevsner’s controversial insights into the bicycle shed, on the peripheries of what we might term architecture. This paper seeks to explore the spatial complexities of the discount supermarket and in doing so open up a discussion on the architecture of cheapness. As a road-map, it takes former managing director Dieter Brandes’ treatise on the Aldi formula, Bare Essentials: the Aldi Way to Retailing, and investigates the strategies through which economic exigencies manifest themselves in a series of spatial tactics which involve building. Central to this is the idea of architecture as system rather than form and, in Aldi/Lidl’s case, the result of a spatial network of flows. To understand the architecture of the supermarket, then, it is necessary to measure the times and spaces of supply across the scales of intersection between global and local.
Evaluating the energy, economy and precision of such systems challenges the liminal position of the commercial, the placeless and especially the cheap within architectural discourse. As is well known, architectures of mass-production and prefabrication and their origins exercised modernist thinkers such as Sigfried Giedion and Walter Gropius in the early twentieth century and has undergone a resurgence in recent times. Meanwhile, the mapping of the hitherto overlooked forms and iconography of commerce in Learning from Las Vegas (1971) was extended by Rem Koolhaas et al into an investigation of the technologies, systems and precedents of retail in the Harvard Design School Guide to Shopping, thirty years later in 2001. While obviously always a criteria for building, to find writings on architecture which explicitly celebrate cheapness as a design virtue or, indeed, even iterate the word cheap is more difficult. Walter Gropius’ essay ‘How can we build cheaper, better, more attractive houses?’ (1927), however, situates the cheap within the discussions – articulated, amongst others, by Karl Teige and Bruno Taut – surrounding the minimal dwelling and the moral benefits of absence of the 1920s and 30s.
In our contemporary age of heightened consumption, it is perhaps fitting that an architecture of bare essentials is defined in retail rather than in housing, a commercial existenzminimum where the Miesian paradox of ‘less is more’ is resold as a paradigm of ‘more for less’ in the ubiquitous yet overlooked architectures of the discount supermarket.