Central Panel Research Articles

Krisztus Szenvedései-ikontöredék Hajasdról. Az ikonográfia rekonstrukciójának kísérlete

In the ecclesiastic collection of the Ethnographic Museum there are carvings from churches of the Byzantine Rite including a Passion fragment from Hajasd (Volosianka, Ukraine), former Ung county. It was probably made in the third quarter of the 17th century on three contiguous vertical panels 180 cm in height each. The two outer panels of the three survive. They are predominated by ochre and brown hues with greyish blue, white and black pa tches. The forms are enclosed by thick black lines. Works of a similar character have survived in the area between Przemysl and Sanok. Despite the missing central panel and the destruction of nearly half of the right-hand panel, the iconographic program can be reconstructed. It is a conspicuous feature of the Hajasd scenes that they reiterate the composition of Flemish graphic series of the Passion. Apart from knowledge of the relatively fixed iconography of the Carpathian Passion series, the Flemish graphic cycles were most helpful to the reconstruction of the Hajasd Passion. It was the wealth of details in the Hajasd Passion that led to the discovery of its immediate source: the series of 51 sheets engraved by Adriaen Collaert after Marten de Vos's compositions and published in several editions in the early 17th century with the title “Vita, Passio et Resurrectio Iesu Christi…”, copies of which also travelled as far as Hungary and Poland. The scenes were arranged in six tiers, the central episode – the crucifixion – probably taking up three tiers of the central panel. The series of twenty scenes begins with the Transfiguration, which revives a local mediaeval tradition: the linking up of the Transfiguration and Easter also explicated in 17th century theological works. It was followed – in accordance with the liturgy of the Passion Week – by the resurrection of Lazarus (Lazarus Saturday), the entry into Jerusalem (Palm Sunday), the Last Supper, the washing of the apostles' feet (Holy Thursday), the scenes of Christ's trial, mocking and crucifixion (Good Friday). The sequence ends with the Deposition, Lamentation, Christ in Limbo and Resurrection scenes. The Hajasd Passion reveals the theological context of the redemption and resurrection in addition to the suffering of Christ. It is a peculiarity of the icon that its master elaborated on nearly the whole cycle of Collaert's works from no. 27 to no. 51, more or less adhering to the original order. The painter's individual abilities are proven by the adaptation of the compositions to the different format, the synthesizing ability and the addition of local narrative details (Pilate's ermine robe, wooden tub).

Σύνθετη εικόνα της αγίας Παρασκευής με σκηνές του βίου της στο Εκκλησιαστικό Μουσείο της Σιάτιστας

In the Ecclesiastical Museum of Siatista a «complex» icon is found withten scenes from the life of saint Paraskevi the Roman (fig. 1) in the centre ofwhich, after taking off the central panel, a more recent icon has been fitted inwith saint Paraskevi of Ikonio, in full length (fig. 2).Special interest appears in the fact that the added central icon and thatwith scenes from her life, depict a different saint Paraskevi. The palaeoslavonic inscriptions and the iconographic type of the saint in the central iconleave no doubt that it is about a depiction of saint Paraskevi of Ikonio. On thecontrary, the greek inscriptions and the particular incidents historiated on theframe of the older icon (although the artist doesn’t follow the historic narration faithfully) clearly indicate that it is about saint Paraskevi the Roman.There has been special reference in certain scenes of the frame, whichare scarce in the iconography of saint Paraskevi the Roman, such as the torture of the saint, which is hung by the hair, the apparition of Jesus Christ withthe angels in her prison, as well as her prayer before her decapitation. In fact,these scenes are attributed mainly to icons which are dated after the 17th century.Technical and stylistic elements indicate that the artist who painted theicon of the Ecclesiastical Museum of Siatista belongs to the north-greekschool of painting of the early 17th century. The added central icon with saintParaskevi of Ikonio nevertheless belongs to a Russian artist and is dated inthe 18th century

Ozone database in support of CMIP5 simulations: results and corresponding radiative forcing

Abstract. A continuous tropospheric and stratospheric vertically resolved ozone time series, from 1850 to 2099, has been generated to be used as forcing in global climate models that do not include interactive chemistry. A multiple linear regression analysis of SAGE I+II satellite observations and polar ozonesonde measurements is used for the stratospheric zonal mean dataset during the well-observed period from 1979 to 2009. In addition to terms describing the mean annual cycle, the regression includes terms representing equivalent effective stratospheric chlorine (EESC) and the 11-yr solar cycle variability. The EESC regression fit coefficients, together with pre-1979 EESC values, are used to extrapolate the stratospheric ozone time series backward to 1850. While a similar procedure could be used to extrapolate into the future, coupled chemistry climate model (CCM) simulations indicate that future stratospheric ozone abundances are likely to be significantly affected by climate change, and capturing such effects through a regression model approach is not feasible. Therefore, the stratospheric ozone dataset is extended into the future (merged in 2009) with multi-model mean projections from 13 CCMs that performed a simulation until 2099 under the SRES (Special Report on Emission Scenarios) A1B greenhouse gas scenario and the A1 adjusted halogen scenario in the second round of the Chemistry-Climate Model Validation (CCMVal-2) Activity. The stratospheric zonal mean ozone time series is merged with a three-dimensional tropospheric data set extracted from simulations of the past by two CCMs (CAM3.5 and GISS-PUCCINI) and of the future by one CCM (CAM3.5). The future tropospheric ozone time series continues the historical CAM3.5 simulation until 2099 following the four different Representative Concentration Pathways (RCPs). Generally good agreement is found between the historical segment of the ozone database and satellite observations, although it should be noted that total column ozone is overestimated in the southern polar latitudes during spring and tropospheric column ozone is slightly underestimated. Vertical profiles of tropospheric ozone are broadly consistent with ozonesondes and in-situ measurements, with some deviations in regions of biomass burning. The tropospheric ozone radiative forcing (RF) from the 1850s to the 2000s is 0.23 W m−2, lower than previous results. The lower value is mainly due to (i) a smaller increase in biomass burning emissions; (ii) a larger influence of stratospheric ozone depletion on upper tropospheric ozone at high southern latitudes; and possibly (iii) a larger influence of clouds (which act to reduce the net forcing) compared to previous radiative forcing calculations. Over the same period, decreases in stratospheric ozone, mainly at high latitudes, produce a RF of −0.08 W m−2, which is more negative than the central Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) value of −0.05 W m−2, but which is within the stated range of −0.15 to +0.05 W m−2. The more negative value is explained by the fact that the regression model simulates significant ozone depletion prior to 1979, in line with the increase in EESC and as confirmed by CCMs, while the AR4 assumed no change in stratospheric RF prior to 1979. A negative RF of similar magnitude persists into the future, although its location shifts from high latitudes to the tropics. This shift is due to increases in polar stratospheric ozone, but decreases in tropical lower stratospheric ozone, related to a strengthening of the Brewer-Dobson circulation, particularly through the latter half of the 21st century. Differences in trends in tropospheric ozone among the four RCPs are mainly driven by different methane concentrations, resulting in a range of tropospheric ozone RFs between 0.4 and 0.1 W m−2 by 2100. The ozone dataset described here has been released for the Coupled Model Intercomparison Project (CMIP5) model simulations in netCDF Climate and Forecast (CF) Metadata Convention at the PCMDI website (http://cmip-pcmdi.llnl.gov/).

Integrin activation as an alternative treatment approach for inflammatory diseases

Regulation of immune responses is a complex process that involves many signaling molecules in their specific interactions and interplays. For instance, the leukocytic integrin CD11b/CD18 plays a crucial role in leukocyte infiltration, which is commonly found in most inflammatory diseases. The highly abundant integrin CD11b/CD18 is a heterodimer of the αm (CD11b) and β2 (CD18) subunits. CD11b/CD18 is located in the cell surface of circulating leukocytes and can undergo active conformational change to mediate leukocyte adhesion, migration and accumulation at the sites of inflammation1. Current approaches for prevention of leukocyte infiltration focus on inhibiting the adhesion of leukocytic integrins to their respective ligands. For example, the specific integrin antibody M1/70 mAb blocks the binding of integrins to ligands found on the vascular wall, thereby reducing the infiltration of leukocytes into the inflamed tissues (Figure 1)2, 3. Despite the intensive research on identifying potent inhibitors for CD11b/CD18, such inhibitors had limited success in treating inflammatory diseases in humans. This may be because of the large intracellular pool of CD11b/CD18 that can be mobilized to leukocyte surface and hinder the complete blockade of CD11b/CD18 with specific antibodies4, or because it is crucial to have over 90% occupancy of active integrin receptors by inhibitors for suppression of leukocyte recruitment5. Moreover, unexpected adverse effects of antibodies against β2 integrins also prohibited the use of such blocking agent in clinical trials6. Recently, Maiguel and colleagues2 reported a new approach that involves the pharmacological activation, rather than blockade of CD11b/CD18 by small molecules, which has enlightened as promising treatment strategy for inflammatory diseases. Figure 1 Schematic showing integrin antagonists and agonists differ in their ability to reduce inflammatory disease. Integrin antagonists (central panel), such as blocking mAbs, prevent leukocyte adhesion to the inflamed endothelium, thereby reducing leukocyte ... Maiguel and colleagues2 successfully identified several potent small-molecule agonists (termed as leukadherins), which specifically target and enhance CD11b/CD18-dependent cell adhesion to fibrinogen or inflamed endothelium, leading to reduction of leukocyte migration and recruitment in both in vitro and in vivo models (Figure 1). Their data provide scientific insight that instead of identification of blocking agents for integrin, discovery of potent integrin CD11b/CD18 agonists could also be another effective strategy in reducing leukocyte infiltration and subsequent inflammation in humans. Through the high-throughput screening (HTS) of a chemical library (>100 000 small molecules), three leukadherin compounds were identified to target the ligand-binding αA domain and allosterically stabilize the active conformation of CD11b/CD18. In addition, leukadherins enhanced CD11b/CD18-dependent cell adhesion and reduced leukocyte motility, which led to a substantial reduction in leukocyte transendothelial migration and recruitment into inflamed tissues. Several clinically relevant diseases models such as thioglycolate-induced peritonitis mice model, arterial balloon injury rat model and zebra-fish tailfin injury model were adopted to demonstrate the physiologically relevant settings for anti-inflammatory effects of leukadherins, The results suggest that leukadherins are therapeutic lead compounds for future optimization. Most importantly, a comparison between M1/70 mAb, a well-characterized CD11b/CD18 antibody7, and one of these compounds revealed that leukadherin shows better efficacy and well preserves organ function upon inflammatory injury. Collectively, Maiguel's data suggested that integrin-specific, small-molecule agonists represent an effective pharmacological approach for the treatment of inflammatory and autoimmune diseases. The phenotype of reduced migration and recruitment of inflammatory cells and cellular adhesion due to the increase of constitutively active integrins was firstly demonstrated in knock-in mice expressing constitutively active mutants of the integrins8. However, it is not known whether the activation of wild-type integrin receptors in normal animals could have a similar phenotype in vivo and could reduce inflammation in physiologically relevant disease models. In this respect, Maiguel and colleagues highlighted the use of chemical-biological approach in demonstrating the endogenous, wild-type integrin protein perturbed by a specific small-molecule agonist, and provided an appropriate channel to analyze the effects of integrin activation on cellular functions in vivo. On the other hand, treatment of integrin agonists in vivo would increase adhesion of inflammatory cells to the vascular endothelium that may lead to vascular damage and leakage. Although Maiguel and colleagues found no systemic signs of vascular injury or leakage from the animals administrated with compounds for more than 3 months, the bio-markers for atherosclerosis can also be monitored in animals treated with integrin agonists for a longer treatment duration9. Now, the identification of potent anti-inflammatory compounds has become a hot topic in Chinese herbal drug research10, therefore, Chinese medicinal herbs may serve as a potential source for the identification of novel integrin agonists in the future.

The Third Transmembrane Segment of Orai1 Protein Modulates Ca2+ Release-activated Ca2+ (CRAC) Channel Gating and Permeation Properties

Orai1, the pore subunit of Ca(2+) release-activated Ca(2+) channels, has four transmembrane segments (TMs). The first segment, TMI, lines the pore and plays an important role in channel activation and ion permeation. TMIII, on the other hand, does not line the pore but still regulates channel gating and permeation properties. To understand the role of TMIII, we have mutated and characterized several residues in this domain. Mutation of Trp-176 to Cys (W176C) and Gly-183 to Ala (G183A) had dramatic effects. Unlike wild-type channels, which exhibit little outward current and are activated by STIM1, W176C mutant channels exhibited a large outward current at positive potentials and were constitutively active in the absence of STIM1. G183A mutant channels also exhibited substantial outward currents but were active only in the presence of 2-aminoethoxydiphenyl borate (2-APB), irrespective of STIM1. With W176C mutant channels inward, monovalent currents were blocked by Ca(2+) with a high affinity similar to the wild type, but the Ca(2+)-dependent blocking of outward currents differed in the two cases. Although a 50% block of the WT outward current required 250 μm Ca(2+), more than 6 mm was necessary to have the same effect on W176C mutant channels. In the presence of extracellular Ca(2+), W176C and G183A outward currents developed slowly in a voltage-dependent manner, whereas they developed almost instantaneously in the absence of Ca(2+). These changes in permeation and gating properties mimic the changes induced by mutations of Glu-190 in TMIII and Asp-110/Asp-112 in the TMI/TMII loop. On the basis of these data, we propose that TMIII maintains negatively charged residues at or near the selectivity filter in a conformation that facilitates Ca(2+) inward currents and prevents outward currents of monovalent cations. In addition, to controlling selectivity, TMIII may also stabilize channel gating in a closed state in the absence of STIM1 in a Trp-176-dependent manner.

An Artificial Antigen-presenting Cell with Paracrine Delivery of IL-2 Impacts the Magnitude and Direction of the T Cell Response

Artificial antigen-presenting cells (aAPCs) are an emerging technology to induce therapeutic cellular immunity without the need for autologous antigen-presenting cells (APCs). To fully replace natural APCs, an optimized aAPC must present antigen (signal 1), provide costimulation (signal 2), and release cytokine (signal 3). Here we demonstrate that the spatial and temporal characteristics of paracrine release of IL-2 from biodegradable polymer aAPCs (now termed paAPCs) can significantly alter the balance in the activation and proliferation of CD8+ and CD4+ T cells. Paracrine delivery of IL-2 upon T cell contact with paAPCs induces significant IL-2 accumulation in the synaptic contact region. This accumulation increases CD25 (the inducible IL-2 Rα chain) on responding T cells and increases proliferation of CD8+ T cells in vitro to levels 10 times that observed with equivalent amounts of bulk IL-2. These CD8+ T cell responses critically depend upon close contact of T cells and the paAPCs and require sustained release of low levels of IL-2. The same conditions promote activation-induced cell death in CD4+ T cells. These findings provide insight into the response of T cell subsets to paracrine IL-2.

Notch sensitivity of ductile metallic foams: A computational study

The role of notches in the fracture strength of metal foams has been studied using a multiscale model based on a two-dimensional Voronoi representation of the cellular architecture. The effect of the crack length to the specimen width ratio on the net section strength of double edge notch (DEN) specimens and central crack panels (CCP) has been investigated in two ways: (i) by fixing the number of cells in the width and (ii) by fixing the number of cells in the ligament. Notch strengthening has been observed in DEN specimens in excellent agreement with experiments. Analysis of the strain fields suggests that in the DEN configuration, the constraint imposed on the rotation fields in the notch tip zones of the ligament enhances the net section strength. In CCP specimens, stress concentration and free-edge effects produced a small level of notch weakening. Our results show that both the ligament length as well as the notch length (normalized by the cell size) influence the notch behaviour in two-dimensional metal foams.

CmRBP50 Protein Phosphorylation Is Essential for Assembly of a Stable Phloem-mobile High-affinity Ribonucleoprotein Complex

RNA-binding proteins (RBPs) form ribonucleoprotein (RNP) complexes that play crucial roles in RNA processing for gene regulation. The angiosperm sieve tube system contains a unique population of transcripts, some of which function as long-distance signaling agents involved in regulating organ development. These phloem-mobile mRNAs are translocated as RNP complexes. One such complex is based on a phloem RBP named Cucurbita maxima RNA-binding protein 50 (CmRBP50), a member of the polypyrimidine track binding protein family. The core of this RNP complex contains six additional phloem proteins. Here, requirements for assembly of this CmRBP50 RNP complex are reported. Phosphorylation sites on CmRBP50 were mapped, and then coimmunoprecipitation and protein overlay studies established that the phosphoserine residues, located at the C terminus of CmRBP50, are critical for RNP complex assembly. In vitro pull-down experiments revealed that three phloem proteins, C. maxima phloem protein 16, C. maxima GTP-binding protein, and C. maxima phosphoinositide-specific phospholipase-like protein, bind directly with CmRBP50. This interaction required CmRBP50 phosphorylation. Gel mobility-shift assays demonstrated that assembly of the CmRBP50-based protein complex results in a system having enhanced binding affinity for phloem-mobile mRNAs carrying polypyrimidine track binding motifs. This property would be essential for effective long-distance translocation of bound mRNA to the target tissues.

DNA Binding Restricts the Intrinsic Conformational Flexibility of Methyl CpG Binding Protein 2 (MeCP2)

Mass spectrometry-based hydrogen/deuterium exchange (H/DX) has been used to define the polypeptide backbone dynamics of full-length methyl CpG binding protein 2 (MeCP2) when free in solution and when bound to unmethylated and methylated DNA. Essentially the entire MeCP2 polypeptide chain underwent H/DX at rates faster than could be measured (i.e. complete exchange in ≤10 s), with the exception of the methyl DNA binding domain (MBD). Even the H/DX of the MBD was rapid compared with that of a typical globular protein. Thus, there is no single tertiary structure of MeCP2. Rather, the full-length protein rapidly samples many different conformations when free in solution. When MeCP2 binds to unmethylated DNA, H/DX is slowed several orders of magnitude throughout the MBD. Binding of MeCP2 to methylated DNA led to additional minor H/DX protection, and only locally within the N-terminal portion of the MBD. H/DX also was used to examine the structural dynamics of the isolated MBD carrying three frequent mutations associated with Rett syndrome. The effects of the mutations ranged from very little (R106W) to a substantial increase in conformational sampling (F155S). Our H/DX results have yielded fine resolution mapping of the structure of full-length MeCP2 in the absence and presence of DNA, provided a biochemical basis for understanding MeCP2 function in normal cells, and predicted potential approaches for the treatment of a subset of RTT cases caused by point mutations that destabilize the MBD.

Clinical Validation of the Cervista HPV HR and 16/18 Genotyping Tests for Use in Women With ASC-US Cytology

Abstract Objective High-risk (HR) human papillomavirus (HPV) testing is important in cervical cancer screening for triage to colposcopy. This study evaluated the clinical performance of the Cervista® HPV HR and 16/18 genotyping tests for detection of HPV in cervical cytology specimens. Methods The tests were prospectively evaluated in a multicenter clinical study. DNA was extracted from approximately 4000 residual liquid-based cytology specimens collected during routine liquid-based Papanicolaou tests at standard of care visits and was assessed for the presence of HR HPV and/or HPV types 16 and 18. All women with cytology results of atypical squamous cells of undetermined significance (ASC-US) or greater underwent colposcopic examination and biopsies were collected. Test results were compared with local colposcopy and histology results from a central pathology review panel. Results There were 1347 subjects with complete data sets of cytology, HR HPV, colposcopy, and histology included in the analysis of the HPV HR test. Sensitivity of the HPV HR test for detection of cervical intraepithelial neoplasia (CIN) 2+ among women with ASC-US cytology was 92.8% (95% confidence interval [CI]: 84.1–96.9) and the negative predictive value (NPV) was 99.1% (95% CI: 98.1–99.6). Sensitivity for detection of ≥CIN 3 in women with ASC-US was 100% (95% CI: 85.1–100) and the NPV was 100% (95% CI: 99.4–100). The specificity of the test for detection of ≥CIN 2 and ≥CIN 3 was 44.2% (95% CI: 41.5–46.9) and 43% (95% CI: 40.3–45.7), respectively. The HPV 16/18 genotyping test also performed as expected in women with ASC-US cytology who were positive for HR HPV. Conclusion The Cervista® HPV HR test can be clinically used for detecting HR HPV types in conjunction with cervical cytology for use in triage of women with ASC-US cytology during routine cervical cancer screening.

Early chemotherapy intensification with BEACOPP in advanced‐stage Hodgkin lymphoma patients with a interim‐PET positive after two ABVD courses

Interim 2-[18F]Fluoro-2-deoxy-D-glucose Positron Emission Tomography performed after two chemotherapy cycles (PET-2) is the most reliable predictor of treatment outcome in ABVD-treated Hodgkin Lymphoma (HL) patients. We retrospectively analysed the treatment outcome of a therapeutic strategy based on PET-2 results: positive patients switched to BEACOPP, while negative patients continued with ABVD. Between January 2006 and December 2007, 219 newly diagnosed HL patients admitted to nine centres were enrolled; 54 patients, unfit to receive this treatment were excluded from the analysis. PET-2 scans were reviewed by a central panel of nuclear medicine experts, according to the Deauville score (Meignan, 2009). After a median follow up of 34 months (12-52) the 2-year failure free survival (FFS) and overall survival for the entire cohort of 165 patients were 88% and 98%; the FFS was 65% for PET-2 positive and 92% for PET-2 negative patients. For 154 patients in which treatment was correctly given according to PET-2 review, the 2-year FFS was 91%: 62% for PET-2 positive and 95% for PET-2 negative patients. this strategy, with BEACOPP intensification only in PET-2 positive patients, showed better results than ABVD-treated historic controls, sparing BEACOPP toxicity to the majority of patients.

Making it not too obvious: the effect of ambient light feedback on space heating energy consumption

Earlier research investigating persuasive technology—technology designed to influence human behavior or attitude—indicates that persuasive technology can stimulate energy-efficient behavior. However, most applications of persuasive technology need people’s focal attention to be successful, and people may often not have these cognitive resources available. The current research investigates a form of persuasive technology that is less obvious and easier to process: ambient lighting as persuasive technology. In an experimental study, participants could conserve energy while setting temperatures on a central heating panel and receive feedback about their energy consumption in each task. We tested the effect of feedback through a lamp that gradually changed color dependent on energy consumption and compared these effects to more widely used factual feedback. Half of the participants received lighting feedback, and half of the participants received numerical feedback. To investigate whether ambient feedback is easier to process than numerical feedback, half of the participants performed a cognitive load task in addition to the focal task. Results indicated that feedback through lighting has stronger persuasive effects than numerical feedback. Furthermore, ambient lighting feedback seemed easier to process than numerical feedback because cognitive load interfered with processing numerical feedback, but not with processing lighting feedback. Implications for theory and design of energy consumption feedback systems, persuasive lighting, and (ambient) persuasive technology are discussed.

Intra-Reader Variability In Identifying Centroblast Cells From Digital Follicular Lymphoma Cases

AbstractAbstract 5097 MethodThe goal of this research is to assess intra-reader variability in identifying centroblast (CB) cells from digitized H&E-stained Follicular Lymphoma (FL) cases. We have enrolled three board-certified hematopathologists experienced in FL grading to complete two reading sessions on 51 High Power Field (HPF: 40 × magnification) images. These images were selected randomly from a database of five hundred HPF images collected from 17 different patients. The dataset is comprised of lymphoma cases with different grades FL and all grades (1, 2, and 3) are represented. Each pathologist was asked to grade the same set of images (51 images, 3 per patient) on different days (with a minimum of two month intervals). In the second reading the order of the images were also randomized. In each reading session, the pathologists examined digital images and recorded the spatial coordinates of CBs using in-house built marking software that allowed pathologists to mark CB cells using only their computer mouse. Experimental ResultsThe results from each reading session were analyzed in terms of FL grade which was determined by averaging the centroblast counts across the three images for a patient and assigning grade using the standard WHO guidelines: Grade I = 0–5, Grade II = 6–15, Grade III = > 15 centroblasts/image. Two different kappa statistics were used to measure agreement. First, we used a weighted kappa in order to measure intra-reader agreement on the three level grade and then we computed a simple kappa measuring agreement on a two level diagnosis: Grade I or II (no chemoprevention assigned) versus Grade III (chemoprevention assigned).Weighted Kappa for Three Level GradePathologistKappap-value10.42950.082420.46880.0515310.0015Mean0.6328 DiscussionTable 1 provides the weighted kappa statistics based on the three level grading system. There was statistically significant agreement for each pathologist with pathologist 3 exhibiting nearly perfect agreement in grade while pathologists 1 and 2 exhibited moderate agreement. However, when we examined agreement based on the clinically significant diagnosis (Grade I or II versus III) (see table 2), the kappa statistics for pathologists for 1 and 2 were not significantly different from zero suggesting that there is not significant agreement in their diagnoses. Pathologist 3, on the other hand, exhibited perfect agreement in the two level diagnosis across readings. ConclusionIn this study, we have examined intra-reader variability in grading follicular lymphoma in digital images. Although similar studies have been conducted to measure the variability at the slide level [2], this is the first time we are reviewing the variability in CB detection. A larger data set will be considered in the near future to generalize the results. Reference1. J. R. Landis and G. G. Koch (1977) “The measurement of observer agreement for categorical data” in Biometrics, 1977, vol. 33, pp. 159–1742. G. E. Metter, B.N. Nathwani, J.S. Burke, et al, “Morphological subclassification of follicular lymphoma: variability of diagnoses among hematopathologists, a collaborative study between the Repository Center and Pathology Panel for Lymphoma Clinical Studies”, J. Clin Oncol. 1985: 3(1): 25–38. Disclosures:No relevant conflicts of interest to declare.

Geodynamics of the France Southeast Basin

AbstractWe investigate the geodynamics of the Southeast Basin with the help of maps of the basement and of major sedimentary horizons based on available seismic reflection profiles and drill holes. We also present a study of the seismicity along the Middle Durance fault. The present seismic activity of the SE Basin cannot be attributed to the Africa/Eurasia shortening since spatial geodesy demonstrates that there is no significant motion of Corsica-Sardinia with respect to Eurasia and since gravitational collapse of the Alps has characterized the last few millions years. Our study demonstrates that the basement of this 140 by 200 km Triassic basin has been essentially undeformed since its formation, most probably because of the hardening of the cooling lithosphere after its 50% thinning during the Triassic distension. The regional geodynamics are thus dominated by the interaction of this rigid unit with the surrounding zones of active deformation. The 12 km thick Mesozoic sediment cover includes at its base an up to 4 km thick mostly evaporitic Triassic layer that is hot and consequently highly fluid. The sedimentary cover is thus decoupled from the basement. As a result, the sedimentary cover does not have enough strength to produce reliefs exceeding about 500 to 750 m. That the deformation and seismicity affecting the basin are the results of cover tectonics is confirmed by the fact that seismic activity in the basin only affects the sedimentary cover. Based on our mapping of the structure of the basin, we propose a simple mechanism accounting for the Neogene deformation of the sedimentary cover. The formation of the higher Alps has first resulted to the north in the shortening of the Diois-Baronnies sedimentary cover that elevated the top of Jurassic horizons by about 4 km with respect to surrounding areas to the south and west. There was thus passage from a brittle-ductile basement decollement within the higher Alps to an evaporitic decollement within the Diois-Baronnies. This shortening and consequent elevation finally induced the southward motion of the basin cover south of the Lure mountain during and after the Middle Miocene. This southward motion was absorbed by the formation of the Luberon and Trévaresse mountains to the south. To the east of the Durance fault, there is no large sediment cover. The seismicity there, is related to the absorption of the Alps collapse within the basement itself. To the west of the Salon-Cavaillon fault, on the other hand, gravity induces a NNE motion of the sedimentary cover with extension to the south and shortening to the north near Mont Ventoux. When considering the seismicity of this area, it is thus important to distinguish between the western Basin panel, west of the Salon-Cavaillon fault affected by very slow NNE gliding of the sedimentary cover, with extension to the south and shortening to the north; the central Basin panel west of the Durance fault with S gliding of the sedimentary cover and increasing shortening to the south; and finally the basement panel east of the Durance fault with intrabasement absorption of the Alps collapse through strike-slip and thrust faults.

Direct analysis of the central panel of the so‐called Wyts triptych after Jan van Eyck

AbstractThe applicability of mobile, non‐destructive techniques such as energy dispersive X‐ray fluorescence spectroscopy, which reveals the elemental composition, and fibre‐coupled Raman spectroscopy, offering molecular information, is applied to the central panel of the Wyts triptych, after Jan van Eyck. Using a combination of these direct techniques, vermilion (HgS), lead white (2PbCO3·Pb(OH)2), anatase (TiO2), massicot (PbO), zinc white (ZnO) and lead‐tin yellow type I (Pb2SnO4) could be identified. X‐ray fluorescence spectroscopy (XRF) measurements also confirmed the presence of cobalt. Also, copper was detected in different blue and green areas. For the brown and red colour, iron oxides were used. Apart from identifying pigments, the combination of these analytical techniques also gave information about restored parts and the layered structure of the panel. XRF maps of three different areas of the panel painting were recorded to get an idea of the changes the painting underwent during its past history. This research confirms the results of the visual analysis that the painting is a heavily restored copy of a lost original by Jan van Eyck. Copyright © 2010 John Wiley & Sons, Ltd.

Response to Letter by Quinn et al

HomeStrokeVol. 41, No. 12Response to Letter by Quinn et al Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter by Quinn et al Jeffrey L. Saver, MD, Bogdan Filip, MD, Scott Hamilton, PhD, Anna Yanes, RN, Sharon Craig, RN, Michelle Cho, BS, Robin Conwit, MD and Sidney Starkman, MD Jeffrey L. SaverJeffrey L. Saver For the FAST-MAG Investigators and Coordinators Search for more papers by this author , Bogdan FilipBogdan Filip For the FAST-MAG Investigators and Coordinators Search for more papers by this author , Scott HamiltonScott Hamilton For the FAST-MAG Investigators and Coordinators Search for more papers by this author , Anna YanesAnna Yanes For the FAST-MAG Investigators and Coordinators Search for more papers by this author , Sharon CraigSharon Craig For the FAST-MAG Investigators and Coordinators Search for more papers by this author , Michelle ChoMichelle Cho For the FAST-MAG Investigators and Coordinators Search for more papers by this author , Robin ConwitRobin Conwit For the FAST-MAG Investigators and Coordinators Search for more papers by this author and Sidney StarkmanSidney Starkman For the FAST-MAG Investigators and Coordinators Search for more papers by this author Originally published28 Oct 2010https://doi.org/10.1161/STROKEAHA.110.591214Stroke. 2010;41:e603Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 28, 2010: Previous Version 1 Response:We are grateful for the interest of Dr Quinn et al1 in our work and are pleased that none of the criticisms advanced in their letter apply to the Rankin focused assessment (RFA) that was the subject of our report.The RFA does not seek to reduce the time spent in deriving a Rankin score. By requiring formal assessment of several domains of function, the RFA actually precludes overly rapid, snap judgments that can occur with holistic assessments.The RFA is not inflexibly reductionist, although it is operationalized. For many patients, use of the RFA forces a multi-domain assessment that structurally counteracts overly reductionist tendencies that can occur in less ordered encounters.The design of the RFA recognizes that patients may occasionally struggle to answer a categorical question regarding their capacities and activities. In such instances, the RFA takes the approach recommended by Quinn et al,1 explicitly directing raters to obtain information from all available sources, including other informants and the medical record, to arrive at a final assessment regarding each line item.We concur with Quinn et al1 that additional studies comparing the RFA against traditional and alternative Rankin assessment techniques would be most welcome. We also agree that additional benefits may be gained by combining a focused assessment with central adjudicator panel scoring, but we emphasize the importance of making available to the central review committee not only the video of an interview with a single patient informant but also all other available salient data, including physician, nursing, and rehabilitation therapist assessments in the medical record, the concurrent neurological examination, and interviews with family and caretakers.DisclosureNone.1 Quinn TJ, McArthur K, Dawson J, Walters MR, Lees KR. Reliability of structured modified Rankin scale assessment. Stroke. 2010; 41: e602.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails December 2010Vol 41, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.110.591214 Originally publishedOctober 28, 2010 PDF download Advertisement

This Month in Gastroenterology

This Month in Gastroenterology

Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for hodgkin disease in children and adolescents: Report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies

To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long-term survivors of pediatric Hodgkin disease (HD). The study cohort comprised 1,132 survivors of HD who received treatment before 18 years of age in consecutive trials between 1978 and 1995. They had maintained remission without secondary malignancy for 3.1-29.4 years. The cumulative doxorubicin dose was uniformly 160 mg/m(2), the mediastinal radiation dose (MedRD) was 36, 30, 25, 20, or 0 Gy. Follow-up questionnaires complemented by additional contacts served to collect information on late effects from patients and physicians. A central expert panel reviewed all reported cardiac abnormalities. By October 2008, cardiac diseases (CD) had been diagnosed in 50 of 1,132 patients aged 15.0-41.7 (median 32.2) years. The interval since HD therapy was 3.0-28.2 (median 19.5) years. Valvular defects were diagnosed most frequently, followed by coronary artery diseases, cardiomyopathies, conduction disorders, and pericardial abnormalities. The cumulative incidence of CD after 25 years was highest in the MedRD-36 group (21%) decreasing to 10%, 6%, 5%, and 3% in the lower MedRD groups (P < 0.001). Multivariate Cox analysis of several putative risk factors showed MedRD to be the only significant variable predicting for CD-free survival (P = 0.0025). Our results indicate that lower MedRDs are less cardiotoxic. Consequently, reduction of cardiac late effects may be expected with the lower radiation doses used in current HD protocols. Longer follow-up is needed to confirm the present results.

Na+-dependent HCO3− Import by the slc4a10 Gene Product Involves Cl− Export

The slc4a10 gene encodes an electroneutral Na(+)-dependent HCO(3)(-) importer for which the precise mode of action remains unsettled. To resolve this issue, intracellular pH (pH(i)) recordings were performed upon acidification in the presence of CO(2)/HCO(3)(-) by 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) fluorometry of stably slc4a10-transfected NIH-3T3 fibroblasts. slc4a10 expression induced a significant Na(+)-dependent pH(i) recovery, which was accompanied by an increase in the intracellular Na(+) concentration evaluated by use of the Na(+)-sensitive fluorophore CoroNa Green. The estimated Na(+):HCO(3)(-) stoichiometry was 1:2. Cl(-) is most likely the counterion maintaining electroneutrality because (i) Na(+)-dependent pH(i) recovery was eliminated in Cl(-)-depleted cells; (ii) acute extracellular Cl(-) removal led to a larger alkalization in slc4a10-transfected cells than in control cells; and (iii) the 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS)-sensitive and Na(+)- and HCO(3)(-)-dependent (36)Cl(-)-efflux during pH(i) recovery was significantly greater in acidified slc4a10-transfected cells than in control cells. Charged amino acids specific to slc4a gene family members that transport Na(+) and are expected to move more HCO(3)(-) molecules/turnover were targeted by site-directed mutagenesis. Na(+)-dependent pH(i) recovery was reduced in each of the single amino acid mutated cell lines (E890A, E892A, H976L, and H980G) compared with wild type slc4a10-transfected cells and completely eliminated in quadruple mutant cells. In conclusion, the data suggest that slc4a10 expressed in mammalian cells encodes a Na(+)-dependent Cl(-)/HCO(3)(-) exchanger in which four specific charged amino acids seem necessary for ion transport.

The Caenorhabditis elegansbus-2 Mutant Reveals a New Class of O-Glycans Affecting Bacterial Resistance

Microbacterium nematophilum causes a deleterious infection of the C. elegans hindgut initiated by adhesion to rectal and anal cuticle. C. elegans bus-2 mutants, which are resistant to M. nematophilum and also to the formation of surface biofilms by Yersinia sp., carry genetic lesions in a putative glycosyltransferase containing conserved domains of core-1 beta1,3-galactosyltransferases. bus-2 is predicted to act in the synthesis of core-1 type O-glycans. This observation implies that the infection requires the presence of host core-1 O-glycoconjugates and is therefore carbohydrate-dependent. Chemical analysis reported here reveals that bus-2 is indeed deficient in core-1 O-glycans. These mutants also exhibit a new subclass of O-glycans whose structures were determined by high performance tandem mass spectrometry; these are highly fucosylated and have a novel core that contains internally linked GlcA. Lectin studies showed that core-1 glycans and this novel class of O-glycans are both expressed in the tissue that is infected in the wild type worms. In worms having the bus-2 genetic background, core-1 glycans are decreased, whereas the novel fucosyl O-glycans are increased in abundance in this region. Expression analysis using a red fluorescent protein marker showed that bus-2 is expressed in the posterior gut, cuticle seam cells, and spermatheca, the first two of which are likely to be involved in secreting the carbohydrate-rich surface coat of the cuticle. Therefore, in the bus-2 background of reduced core-1 O-glycans, the novel fucosyl glycans likely replace or mask remaining core-1 ligands, leading to the resistance phenotype. There are more than 35 Microbacterium species, some of which are pathogenic in man. This study is the first to analyze the biochemistry of adhesion to a host tissue by a Microbacterium species.