Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma

Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma.

The quality of primary care in a country with universal health care coverage

Standard indicators of quality of care have been developed in the United States. Limited information exists about quality of care in countries with universal health care coverage.

Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat

Tubulo-interstitial fibrosis is a constant feature of chronic renal failure and it is suspected to contribute importantly to the deterioration of renal function. In the fibrotic kidney there exists, besides normal fibroblasts, a large population of myofibroblasts, which are supposedly responsible for the increased production of intercellular matrix. It has been proposed that myofibroblasts in chronic renal failure originate from the transformation of tubular cells via epithelial-mesenchymal transition (EMT) or from infiltration by bone marrow-derived precursors. Little attention has been paid to the possibility of a transformation of resident fibroblasts into myofibroblasts in renal fibrosis. Therefore we examined the fate of resident fibroblasts in the initial phase of renal fibrosis in the classical model of unilateral ureter obstruction (UUO) in the rat. Rats were perfusion-fixed on days 1, 2, 3 and 4 after ligature of the right ureter. Starting from 1 day of UUO an increasing expression of alpha-smooth muscle actin (alphaSMA) in resident fibroblasts was revealed by immunofluorescence and confirmed by the observation of bundles of microfilaments and webs of intermediate filaments in the electron microscope. Inversely, there was a decreased expression of 5'-nucleotidase (5'NT), a marker of renal cortical fibroblasts. The RER became more voluminous, suggesting an increased synthesis of matrix. Intercellular junctions, a characteristic feature of myofibroblasts, became more frequent. The mitotic activity in fibroblasts was strongly increased. Renal tubules underwent severe regressive changes but the cells retained their epithelial characteristics and there was no sign of EMT. In conclusion, after ureter ligature, resident peritubular fibroblasts proliferated and they showed progressive alterations, suggesting a transformation in myofibroblasts. Thus the resident fibroblasts likely play a central role in fibrosis in that model.

Approximating method of frames

In this paper, the well-known method of frames approach to the signal decomposition problem is reformulated as a certain bilevel goal-attainment linear least squares problem. As a consequence, a numerically robust variant of the method, named approximating method of frames, is proposed on the basis of a certain minimal Euclidean norm approximating splitting pseudo-iteration-wise method.

3D volumetric intensity reconsturction from 2D x-ray images using partial least squares regression

Reconstruction of shape and intensity from 2D x-ray images has drawn more and more attentions. Previously introduced work suffers from the long computing time due to its iterative optimization characteristics and the requirement of generating digitally reconstructed radiographs within each iteration. In this paper, we propose a novel method which uses a patient-specific 3D surface model reconstructed from 2D x-ray images as a surrogate to get a patient-specific volumetric intensity reconstruction via partial least squares regression. No DRR generation is needed. The method was validated on 20 cadaveric proximal femurs by performing a leave-one-out study. Qualitative and quantitative results demonstrated the efficacy of the present method. Compared to the existing work, the present method has the advantage of much shorter computing time and can be applied to both DXA images as well as conventional x-ray images, which may hold the potentials to be applied to clinical routine task such as total hip arthroplasty (THA).

Expectation Conditional Maximization-Based Deformable Shape Registration

This paper addresses the issue of matching statistical and non-rigid shapes, and introduces an Expectation Conditional Maximization-based deformable shape registration (ECM-DSR) algorithm. Similar to previous works, we cast the statistical and non-rigid shape registration problem into a missing data framework and handle the unknown correspondences with Gaussian Mixture Models (GMM). The registration problem is then solved by fitting the GMM centroids to the data. But unlike previous works where equal isotropic covariances are used, our new algorithm uses heteroscedastic covariances whose values are iteratively estimated from the data. A previously introduced virtual observation concept is adopted here to simplify the estimation of the registration parameters. Based on this concept, we derive closed-form solutions to estimate parameters for statistical or non-rigid shape registrations in each iteration. Our experiments conducted on synthesized and real data demonstrate that the ECM-DSR algorithm has various advantages over existing algorithms.

„Offene Grenzen“ oder „freiwillige Ghetttoisierung“? Aktuelle Kontroversen um die Sicherung der Kontinuität des Judentums

Die jüdische Gemeinschaft gilt generell als Musterbeispiel einer gut integrierten, religiösen Minderheit. Tatsächlich jedoch bewirken gerade die jüngsten gesellschaftlichen Entwicklungen − verstärkte Säkularisierung und Individualisierung verbunden mit steigenden Mischehenraten und einer Neudefinitionder Geschlechterrollen − eine Infragestellung der Kontinuität europäisch-jüdischer Existenz.Seit den 70iger Jahren des 20. Jahrhunderts bewegt sich die Mischehenrate fast überall in der Diaspora bei über 50%. Da die Weitergabe des Judentums religionsgesetzlich nur über die Mutter erfolgt,stellt der Umgang mit nichtjüdischen Familienmitgliedern einen hochsensiblen Bereich für die Gemeinschaft dar. Die soziale und religiöse Integration von nichtjüdischen Ehefrauen und vaterjüdischenKindern ist auf Grund einer nicht selten willkürlich erscheinenden Aufnahmepraxis ein häufig tabuisierter Aspekt des Gemeindelebens, der zu permanenten Spannungen führt. Konflikte bezüglich der Zugehörigkeitskriterien aber auch der religiösen Rolle der Frau führen zu Polarisierungs- und Pluralisierungstendenzen. Im Rahmen eines Projektes des NFP 58 wurden aktuelle innerjüdische Grenzziehungsdebatten im Kontext des Schweizer Judentums auch mit Methoden der Oral History festgehalten und analysiert. Die Auseinandersetzungen innerhalb der schweizerisch-jüdischen Gemeinschaft wurden zudem mit Entwicklungen in anderen Ländern der Diaspora und in Israel verglichen. Es ergab sich das Bild einer dynamischen und zugleich jedoch tief gespaltenen Religionsgemeinschaft, innerhalb der sich die verschiedenen Richtungen („liberal“ bis „ultra-orthodox“) die Verantwortung für eine zunehmende Schwächung und Spaltung des jüdischen Volkes zuweisen. Bibliographie Benbassa, Esther u. Jean-Christophe Attias. 2001. Les Juifs ont-t-ils un avenir? Paris. Lattés. Gerson, Daniel.2012. Ausbreitung und Bedeutung des Judentums in der Schweiz.in : Religionen in der Schweiz. Bulletin Schweizerische Akademie der Geistes- und Sozialwissenschaften, Nr 2.Bern. Gerson, Daniel.2011. Partizipation ohne Konversion? Grenzziehungsdebatten in neuen jüdischen Gemeinschaften der Schweiz,in: Chilufim. Zeitschrift für Jüdische Kulturgeschichte, Nr.11.Wien. Phoibos. Gerson, Daniel.2010. Gemeinschaftsbildung und «demokratischer» Antisemitismus: Das Entstehen eines Schweizer Judentums im Spannungsverhältnis von Akkulturation, Einwanderung und Ausgrenzung, in: Wyrwa, Ulrich (Hrsg.): Einspruch und Abwehr. Die Reaktion des europäischen Judentums und die Entstehung des Antisemitismus in Europa. Frankfurt am Main. Campus. Lambert, Nick.2008. Jews and Europe in the Twenty-First Century. London. Vallentine Mitchell. Picard, Jacques.2007. Judentum in der Schweiz: zwischen religiöser, kultureller und politischer Identität,in: Baumann, Martin u. Jörg Stolz (Hrsg.); Eine Schweiz - viele Religionen. Bielefeld. transcript. Wasserstein, Bernard.1996. Vanishing Diaspora. The Jews in Europa since 1945. New York.Harvard University Press.

Impact of a 4th generation iterative reconstruction technique on image quality in low-dose computed tomography of the chest in immunocompromised patients

PURPOSE To determine the image quality of an iterative reconstruction (IR) technique in low-dose MDCT (LDCT) of the chest of immunocompromised patients in an intraindividual comparison to filtered back projection (FBP) and to evaluate the dose reduction capability. MATERIALS AND METHODS 30 chest LDCT scans were performed in immunocompromised patients (Brilliance iCT; 20-40 mAs; mean CTDIvol: 1.7 mGy). The raw data were reconstructed using FBP and the IR technique (iDose4™, Philips, Best, The Netherlands) set to seven iteration levels. 30 routine-dose MDCT (RDCT) reconstructed with FBP served as controls (mean exposure: 116 mAs; mean CDTIvol: 7.6 mGy). Three blinded radiologists scored subjective image quality and lesion conspicuity. Quantitative parameters including CT attenuation and objective image noise (OIN) were determined. RESULTS In LDCT high iDose4™ levels lead to a significant decrease in OIN (FBP vs. iDose7: subscapular muscle 139.4 vs. 40.6 HU). The high iDose4™ levels provided significant improvements in image quality and artifact and noise reduction compared to LDCT FBP images. The conspicuity of subtle lesions was limited in LDCT FBP images. It significantly improved with high iDose4™ levels (> iDose4). LDCT with iDose4™ level 6 was determined to be of equivalent image quality as RDCT with FBP. CONCLUSION iDose4™ substantially improves image quality and lesion conspicuity and reduces noise in low-dose chest CT. Compared to RDCT, high iDose4™ levels provide equivalent image quality in LDCT, hence suggesting a potential dose reduction of almost 80%.

Driving and dementia: a clinical decision pathway

OBJECTIVE This study aimed to develop a pathway to bring together current UK legislation, good clinical practice and appropriate management strategies that could be applied across a range of healthcare settings. METHODS The pathway was constructed by a multidisciplinary clinical team based in a busy Memory Assessment Service. A process of successive iteration was used to develop the pathway, with input and refinement provided via survey and small group meetings with individuals from a wide range of regional clinical networks and diverse clinical backgrounds as well as discussion with mobility centres and Forum of Mobility Centres, UK. RESULTS We present a succinct clinical pathway for patients with dementia, which provides a decision-making framework for how health professionals across a range of disciplines deal with patients with dementia who drive. CONCLUSIONS By integrating the latest guidance from diverse roles within older people's health services and key experts in the field, the resulting pathway reflects up-to-date policy and encompasses differing perspectives and good practice. It is potentially a generalisable pathway that can be easily adaptable for use internationally, by replacing UK legislation for local regulations. A limitation of this pathway is that it does not address the concern of mild cognitive impairment and how this condition relates to driving safety. © 2014 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.

Analyzing diffuse scattering with supercomputers

Two new approaches to quantitatively analyze diffuse diffraction intensities from faulted layer stacking are reported. The parameters of a probability-based growth model are determined with two iterative global optimization methods: a genetic algorithm (GA) and particle swarm optimization (PSO). The results are compared with those from a third global optimization method, a differential evolution (DE) algorithm [Storn & Price (1997). J. Global Optim. 11, 341–359]. The algorithm efficiencies in the early and late stages of iteration are compared. The accuracy of the optimized parameters improves with increasing size of the simulated crystal volume. The wall clock time for computing quite large crystal volumes can be kept within reasonable limits by the parallel calculation of many crystals (clones) generated for each model parameter set on a super- or grid computer. The faulted layer stacking in single crystals of trigonal three-pointedstar- shaped tris(bicylco[2.1.1]hexeno)benzene molecules serves as an example for the numerical computations. Based on numerical values of seven model parameters (reference parameters), nearly noise-free reference intensities of 14 diffuse streaks were simulated from 1280 clones, each consisting of 96 000 layers (reference crystal). The parameters derived from the reference intensities with GA, PSO and DE were compared with the original reference parameters as a function of the simulated total crystal volume. The statistical distribution of structural motifs in the simulated crystals is in good agreement with that in the reference crystal. The results found with the growth model for layer stacking disorder are applicable to other disorder types and modeling techniques, Monte Carlo in particular.

Fast parallel kriging-based stepwise uncertainty reduction with application to the identification of an excursion set

Stepwise uncertainty reduction (SUR) strategies aim at constructing a sequence of points for evaluating a function  f in such a way that the residual uncertainty about a quantity of interest progressively decreases to zero. Using such strategies in the framework of Gaussian process modeling has been shown to be efficient for estimating the volume of excursion of f above a fixed threshold. However, SUR strategies remain cumbersome to use in practice because of their high computational complexity, and the fact that they deliver a single point at each iteration. In this article we introduce several multipoint sampling criteria, allowing the selection of batches of points at which f can be evaluated in parallel. Such criteria are of particular interest when f is costly to evaluate and several CPUs are simultaneously available. We also manage to drastically reduce the computational cost of these strategies through the use of closed form formulas. We illustrate their performances in various numerical experiments, including a nuclear safety test case. Basic notions about kriging, auxiliary problems, complexity calculations, R code, and data are available online as supplementary materials.

From hierarchies to well-foundedness

We highlight that the connection of well-foundedness and recursive definitions is more than just convenience. While the consequences of making well-foundedness a sufficient condition for the existence of hierarchies (of various complexity) have been extensively studied, we point out that (if parameters are allowed) well-foundedness is a necessary condition for the existence of hierarchies e.g. that even in an intuitionistic setting (Π01−CA0)α⊢wf(α)where(Π01−CA0)α stands for the iteration of Π01 comprehension (with parameters) along some ordinal α and wf(α) stands for the well-foundedness of α.

Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression

The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.

Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses.

Segmented filamentous bacterium (SFB) is a symbiont that drives postnatal maturation of gut adaptive immune responses. In contrast to nonpathogenic E. coli, SFB stimulated vigorous development of Peyer's patches germinal centers but paradoxically induced only a low frequency of specific immunoglobulin A (IgA)-secreting cells with delayed accumulation of somatic mutations. Moreover, blocking Peyer's patch development abolished IgA responses to E. coli, but not to SFB. Indeed, SFB stimulated the postnatal development of isolated lymphoid follicles and tertiary lymphoid tissue, which substituted for Peyer's patches as inductive sites for intestinal IgA and SFB-specific T helper 17 (Th17) cell responses. Strikingly, in mice depleted of gut organized lymphoid tissue, SFB still induced a substantial but nonspecific intestinal Th17 cell response. These results demonstrate that SFB has the remarkable capacity to induce and stimulate multiple types of intestinal lymphoid tissues that cooperate to generate potent IgA and Th17 cell responses displaying only limited target specificity.