Key issues in diagnosing and treating acute aortic syndromes: results from the metropolitan area of Bologna network

Background: Survival of patients with Acute Aortic Syndrome (AAS) may relate to the speed of diagnosis. Diagnostic delay is exacerbated by non classical presentations such as myocardial ischemia or acute heart failure (AHF). However little is known about clinical implications and pathophysiological mechanisms of Troponin T elevation and AHF in AAS. Methods and Results: Data were collected from a prospective metropolitan AAS registry (398 patients diagnosed between 2000 and 2013). Troponin T values (either standard or high sensitivity assay, HS) were available in 248 patients (60%) of the registry population; the overall frequency of troponin positivity was 28% (ranging from 16% to 54%, using standard or HS assay respectively, p = 0.001). Troponin positivity was associated with a twofold increased risk of long in-hospital diagnostic time (OR 1.92, 95% CI 1.05-3.52, p = 0.03), but not with in-hospital mortality. The combination of positive troponin and ACS-like ECG abnormalities resulted in a significantly increased risk of inappropriate therapy due to a misdiagnosis of ACS (OR 2.48, 95% CI 1.12-5.54, p = 0.02). Patients with AHF were identified by the presence of dyspnea as presentation symptom or radiological signs of pulmonary congestion or cardiogenic shock. The overall frequency of AHF was 28 % (32% type A vs. 20% type B AAS, p = 0.01). AHF was due to a variety of pathophysiological mechanisms including cardiac tamponade (26%), aortic regurgitation (25%), myocardial ischemia (17%), hypertensive crisis (10%). AHF was associated with increased surgical delay and with increased risk of in-hospital death (adjusted OR 1.97 95% CI1.13-3.37,p=0.01). Conclusions: Troponin positivity (particularly HS) was a frequent finding in AAS. Abnormal troponin values were strongly associated with ACS-like ECG findings, in-hospital diagnostic delay, and inappropriate therapy. AHF was associated with increased surgical delay and was an independent predictor of in-hospital mortality.

Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor

IgE antibodies bind the high-affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE-FcεRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE-FcεRI complexes that prime cells before allergen exposure dissociate extremely slowly and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms. Here we demonstrate that an engineered protein inhibitor, DARPin E2_79 (refs 9, 10, 11), acts through a non-classical inhibition mechanism, not only blocking IgE-FcεRI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79-IgE-Fc(3-4) complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE-FcεRI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE-FcεRI complexes can be actively dissociated to block the allergic response and suggest that protein-protein complexes may be more generally amenable to active disruption by macromolecular inhibitors.

Gothic Taste and Russian Culture of the 18th Century

This project was an experiment in widening the traditional borders of study in the field and looking at the phenomenon of Gothic taste in many genres and kinds of art. The Gothic taste was a major element in the cultural image of the Enlightenment both in western Europe and in Russia. It was an essential component in the world outlook of an educated person and without studying this phenomenon it is impossible to fully understand the thinking of artistic professionals, amateurs and users in Russian society in the 18th century. Mr. Khatchatourov first analysed the reasons for the importance of Gothic taste in the culture of the European Enlightenment and then studied its linguistic and lexicographic evolution in 18th century Russian culture. He sought to determine the semantic context which actively formed the human mind set in the Enlightenment, including potential users and producers of articles in the Gothic taste. He then looked at the process of absorption of this concept by those forms of art which express it most strongly, in particular architecture and the theatre. His study was based on a comprehensive historical and culturological study using a wide range of sources, a formal stylistic method approach considering the interaction of non-classical styles of the Enlightenment with the dominant classicism, and an iconographic approach which revealed the essential aspects in a new image synthesis of the culture of the Enlightenment.

Induction of EROD activity by 1-phenylimidazole and beta-naphthoflavone in rainbow trout cultured hepatocytes: a comparative study

The classical pathway for induction of cytochrome P4501A (CYP1A) by xenobiotics is ligand binding to the aryl hydrocarbon receptor (AhR). However, several studies with mammalian cell systems point out a range of xenobiotics including imidazole derivatives, which are able to activate CYP1A through non-classical mechanisms. The objective of the present work is to compare induction of CYP1A (determined at the catalytic level as 7-ethoxyresorufin-O-deethylase, EROD) in rainbow trout (Oncorhynchus mykiss) hepatocytes by the prototypic AhR ligand, beta-naphthoflavone (betaNF), and by the imidazole derivative, 1-phenylimidazole (PIM). PIM was able to induce EROD activity although its potency was clearly lower than that of betaNF. In order to assess the relative importance of classical AhR ligand binding and alternative signaling pathways in CYP1A induction by PIM, co-exposure experiments with the partial AhR antagonist alpha-naphthoflavone (alphaNF) or with inhibitors of protein kinase C (staurosporine) and tyrosine kinases (genistein, herbimicine) were performed. alphaNF and herbimicin provoked a decrease of EROD induction both by betaNF and PIM, whereas staurosporine and genistein remained without effect. The overall similarities in the response of betaNF and PIM to the various inhibitors suggest that both compounds, in apparent contrast to the behaviour of some other imidazole derivatives, induce CYP1A following similar mechanisms.

Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer

Rosette-forming glioneuronal tumor (RGNT) is a recently introduced, indolent neoplasm composed of diminutive circular aggregates of neurocytic-like cells on a noninfiltrative astrocytic background, typically located in the cerebellar midline The traded concept of RGNT being derived from site-specific periventricular precursors may be questioned in the face of extracerebellar examples as well as ones occurring in combination with other representatives of the glioneuronal family. We describe a hitherto not documented example of asymptomatic RGNT discovered during autopsy of a 74-year-old male. Located in the tuberal vermis, this lesion of 6 mm diameter consisted of several microscopic nests of what were felt to represent nascent stages of RGNT, all of them centered on the internal granular layer, and ranging from mucoid dehiscences thereof to fully evolved - if small - tumor foci. Molecular genetic analysis revealed a missense mutation in Exon 20 of the PIK3CA gene involving an A→G transition at Nucleotide 3140. On the other hand, neither codeletion of chromosomes 1p/19q nor pathogenic mutations of IDH1/2 were detected. By analogy with in situ paradigms in other organs, we propose that this tumor is likely to have arisen from the internal granular layer, rather than the plate of the 4th ventricle. A suggestive departure from the wholesale argument of "undifferentiated precursors", this finding also indirectly indicates that a subset of non-classical RGNTs - in particular extracerebellar examples, whose origin cannot be mechanistically accounted for by either of the above structures - may possibly reflect an instance of phenotypic convergence, rather than a lineage-restricted entity.

Exact Unification and Admissibility

A new hierarchy of "exact" unification types is introduced, motivated by the study of admissible rules for equational classes and non-classical logics. In this setting, unifiers of identities in an equational class are preordered, not by instantiation, but rather by inclusion over the corresponding sets of unified identities. Minimal complete sets of unifiers under this new preordering always have a smaller or equal cardinality than those provided by the standard instantiation preordering, and in significant cases a dramatic reduction may be observed. In particular, the classes of distributive lattices, idempotent semigroups, and MV-algebras, which all have nullary unification type, have unitary or finitary exact type. These results are obtained via an algebraic interpretation of exact unification, inspired by Ghilardi's algebraic approach to equational unification.

Transcriptional upregulation of the p21Cip1 promoter by STAT3 and nuclear ErbB2

Over-expression of the receptor tyrosine kinase ErbB2 is prevalent in approximately 30% of human breast carcinomas and confers Taxol resistance. In breast cancer cells, Taxol induces tubulin polymerization and hyperstable microtubule formation. This in turn prematurely activates Cdc2 kinase allowing early entry into the G2/M phase of the cell cycle resultant in mitotic catastrophe followed by apoptosis. Over-expression of ErbB2 upregulates p21Cip1, which inhibits Cdc2 activation, and leads to Taxol resistance in patients. However, the mechanism of ErbB2-mediated p21 Cip1 upregulation is unclear. Here in this study, we investigated the mechanism of ErbB2 downstream signaling events leading to upregulation. The CDKN1A (p21Cip1) gene promoter contains numerous cis-elements including a Signal transducer and activator of transcription (STAT) Inducable Element (SIE) located at -679 kb. Our studies showed ErbB2 overexpressing cells had increased activated levels of STAT3, and therefore we hypothesized that STAT3 is responsible for the upregulation of the p21Cip1 promoter by ErbB2. EMSA and ChIP assays confirmed the binding of STAT3 to the p21Cip1 promoter and luciferase assays showed higher p21 Cip1 promoter activity in ErbB2 over-expressing transfectants when compared to parental cells, in a STAT3 binding site dependant manner. Additionally, reduced level of STAT3 led to reduced p21Cip1 protein expression and promoter activity indicating that both the STAT3 binding site and STAT3 protein are required for ErbB2-mediated p21Cip1 upregulation. Further investigation of ErbB2 downstream signaling showed increased Src kinase activity in ErbB2 over-expressing cells which was required for ErbB2-mediated STAT3 activation and p21Cip1 increase. Treatment of ErbB2 over-expressing resistant cells with STAT3 inhibitor peptides sensitized the cells to Taxol. In addition to classical signal transduction pathways, I identified a novel ErbB2 mediated regulatory mechanism of p21Cip1. I found that a nuclear ErbB2 and STAT3 complex binds directly to the p21Cip1 promoter offering a non-classical mechanism of p21Cip1 promoter regulation. These data suggest that ErbB2 over-expression can confer Taxol resistance of breast cancer cells by transcriptional upregulation of p21 Cip1 via activation of STAT3 by Src kinase and also by cooperation with nuclear ErbB2. The data suggest a potential clinical mechanism for STAT3 inhibitors in sensitizing ErbB2 over-expressing breast cancers to Taxol. ^

Effects of asbestos and silica on superoxide anion production in the guinea pig alveolar macrophage

Asbestos and silica are important industrial hazards. Exposure to these dusts can result in pulmonary fibrosis and, in the case of asbestos, cancer. Although the hazards of asbestos and silica exposure have long been known, the pathogenesis of dust-related disease is not well understood. Both silica and asbestos are thought to alter the function of the alveolar macrophage, but the nature of the biochemical alteration is unknown. Therefore, this study examined the effect of asbestos and silica on the activation pathway of the guinea pig alveolar macrophage. Activation of macrophages by physiological agents results in stimulation of phospholipase C causing phosphatidyl inositol turnover and intracellular calcium mobilization. Phosphatidyl inositol turnover produces diacylglycerol which activates protein kinase C causing superoxide anion production.^ Chrysotile stimulated alveolar macrophages to produce superoxide anion. This stimulation proceeded via phospholipase C, since chrysotile stimulated phosphatidyl inositol turnover and intracellular calcium mobilization. The possible involvement of a coupling protein was evaluated by pretreating cells with pertussis toxin. Pertussis toxin pretreatment partially inhibited chrysotile stimulation, suggesting that chrysotile activates a coupling protein in an non-classical manner. Potential binding sites for chrysotile stimulation were examined using a series of nine lectins. Chrysotile-stimulated superoxide anion production was blocked by pretreatment with lectins which bound to N-acetylglucosamine, but not by lectins which bound to mannose, fucose, or N-acetylgalactosamine. In addition, incubation with the N-acetylglucosamine polymer, chitin, inhibited chrysotile-stimulated superoxide anion production, suggesting that chrysotile stimulated superoxide anion production by binding to N-acetylglucosamine residues.^ On the other hand, silica did not stimulate superoxide anion production. The effect of silica on agonist stimulation of this pathway was examined using two stimulants of superoxide anion production, N-formyl-nle-leu-phe (FNLP, which stimulates through phospholipase C) and phorbol-12,13-dibutyrate (which directly activates protein kinase C). Sublethal doses of silica inhibited FNLP-stimulated superoxide anion production, but did not affect phorbol-12,13-dibutyrate-stimulated superoxide anion production, suggesting that the site of inhibition precedes protein kinase C. This inhibition was not due to cell membrane damage, since cell permeability to calcium-45 and rubidium-86 was not increased. It is concluded that chrysotile binds to N-acetylglucosamine residues on macrophage surface glycoproteins to stimulate the physiological pathway resulting in superoxide anion production. In contrast, silica does not stimulate superoxide anion production, but it did inhibit FNLP-stimulated superoxide anion production. ^

Comparación de un nuevo método de aceleración de análisis dinámicos con métodos de reducción de modelos

La dinámica estructural estudia la respuesta de una estructura ante cargas o fenómenos variables en el tiempo. En muchos casos, estos fenómenos requieren realizar análisis paramétricos de la estructura considerando una gran cantidad de configuraciones de diseño o modificaciones de la estructura. Estos cambios, ya sean en fases iniciales de diseño o en fases posteriores de rediseño, alteran las propiedades físicas de la estructura y por tanto del modelo empleado para su análisis, cuyo comportamiento dinámico se modifica en consecuencia. Un caso de estudio de este tipo de modificaciones es la supervisión de la integridad estructural, que trata de identificar la presencia de daño estructural y prever el comportamiento de la estructura tras ese daño, como puede ser la variación del comportamiento dinámico de la estructura debida a una delaminación, la aparición o crecimiento de grieta, la debida a la pérdida de pala sufrida por el motor de un avión en vuelo, o la respuesta dinámica de construcciones civiles como puentes o edificios frente a cargas sísmicas. Si a la complejidad de los análisis dinámicos requeridos en el caso de grandes estructuras se añade la variación de determinados parámetros en busca de una respuesta dinámica determinada o para simular la presencia de daños, resulta necesario la búsqueda de medios de simplificación o aceleración del conjunto de análisis que de otra forma parecen inabordables tanto desde el punto de vista del tiempo de computación, como de la capacidad requerida de almacenamiento y manejo de grandes volúmenes de archivos de datos. En la presente tesis doctoral se han revisado los métodos de reducción de elementos .nitos más habituales para análisis dinámicos de grandes estructuras. Se han comparado los resultados de casos de estudio de los métodos más aptos, para el tipo de estructuras y modificaciones descritas, con los resultados de aplicación de un método de reducción reciente. Entre los primeros están el método de condensación estática de Guyan extendido al caso con amortiguamiento no proporcional y posteriores implementaciones de condensaciones dinámicas en diferentes espacios vectoriales. El método de reducción recientemente presentado se denomina en esta tesis DACMAM (Dynamic Analysis in Complex Modal space Acceleration Method), y consiste en el análisis simplificado que proporciona una solución para la respuesta dinámica de una estructura, calculada en el espacio modal complejo y que admite modificaciones estructurales. El método DACMAM permite seleccionar un número reducido de grados de libertad significativos para la dinámica del fenómeno que se quiere estudiar como son los puntos de aplicación de la carga, localizaciones de los cambios estructurales o puntos donde se quiera conocer la respuesta, de forma que al implementar las modificaciones estructurales, se ejecutan los análisis necesarios sólo de dichos grados de libertad sin pérdida de precisión. El método permite considerar alteraciones de masa, rigidez, amortiguamiento y la adición de nuevos grados de libertad. Teniendo en cuenta la dimensión del conjunto de ecuaciones a resolver, la parametrización de los análisis no sólo resulta posible, sino que es también manejable y controlable gracias a la sencilla implementación del procedimiento para los códigos habituales de cálculo mediante elementos .nitos. En el presente trabajo se muestra la bondad y eficiencia del método en comparación con algunos de los métodos de reducción de grandes modelos estructurales, verificando las diferencias entre sí de los resultados obtenidos y respecto a la respuesta real de la estructura, y comprobando los medios empleados en ellos tanto en tiempo de ejecución como en tamaño de ficheros electrónicos. La influencia de los diversos factores que se tienen en cuenta permite identificar los límites y capacidades de aplicación del método y su exhaustiva comparación con los otros procedimientos. ABSTRACT Structural dynamics studies the response of a structure under loads or phenomena which vary over time. In many cases, these phenomena require the use of parametric analyses taking into consideration several design configurations or modifications of the structure. This is a typical need in an engineering o¢ ce, no matter the structural design is in early or final stages. These changes modify the physical properties of the structure, and therefore, the finite element model to analyse it. A case study, that exempli.es this circumstance, is the structural health monitoring to predict the variation of the dynamical behaviour after damage, such as a delaminated structure, a crack onset or growth, an aircraft that suffers a blade loss event or civil structures (buildings or bridges) under seismic loads. Not only large structures require complex analyses to appropriately acquire an accurate solution, but also the variation of certain parameters. There is a need to simplify the analytical process, in order to bring CPU time, data .les, management of solutions to a reasonable size. In the current doctoral thesis, the most common finite element reduction methods for large structures are reviewed. Results of case studies are compared between a recently proposed method, herein named DACMAM (Dynamic Analysis in Complex Modal space Acceleration Method), and different condensation methods, namely static or Guyan condensation and dynamic condensation in different vectorial spaces. All these methods are suitable for considering non-classical damping. The reduction method DACMAM consist of a structural modification in the complex modal domain which provides a dynamic response solution for the reduced models. This process allows the selection of a few degrees of freedom that are relevant for the dynamic response of the system. These d.o.f. are the load application points, relevant structural points or points in which it is important to know the response. Consequently, an analysis with structural modifications implies only the calculation of the dynamic response of the selected degrees of freedom added, but with no loss of information. Therefore, mass, stiffness or damping modifications are easily considered as well as new degrees of freedom. Taking into account the size of the equations to be solved, the parameterization of the dynamic solutions is not only possible, but also manageable and controllable due to the easy implementation of the procedure in the standard finite element solvers. In this thesis, the proposed reduction method for large structural models is compared with other published model order reduction methods. The comparison shows and underlines the efficiency of the new method, and veri.es the differences in the response when compared with the response of the full model. The CPU time, the data files and the scope of the parameterization are also addressed.

An alternative pathway for rod signals in the rodent retina: Rod photoreceptors, cone bipolar cells, and the localization of glutamate receptors

In the mammalian retina, extensive processing of spatiotemporal and chromatic information occurs. One key principle in signal transfer through the retina is parallel processing. Two of these parallel pathways are the ON- and OFF-channels transmitting light and dark signals. This dual system is created in the outer plexiform layer, the first relay station in retinal signal transfer. Photoreceptors release glutamate onto ON- and OFF-type bipolar cells, which are functionally distinguished by their postsynaptic expression of different types of glutamate receptors, namely ionotropic and metabotropic glutamate receptors. In the current concept, rod photoreceptors connect only to rod bipolar cells (ON-type) and cone photoreceptors connect only to cone bipolar cells (ON- and OFF-type). We have studied the distribution of (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunits at the synapses in the outer plexiform layer of the rodent retina by immunoelectron microscopy and serial section reconstruction. We report a non-classical synaptic contact and an alternative pathway for rod signals in the retina. Rod photoreceptors made synaptic contact with putative OFF-cone bipolar cells that expressed the AMPA glutamate receptor subunits GluR1 and GluR2 on their dendrites. Thus, in the retina of mouse and rat, an alternative pathway for rod signals exists, where rod photoreceptors bypass the rod bipolar cell and directly excite OFF-cone bipolar cells through an ionotropic sign-conserving AMPA glutamate receptor.

The Finite Embeddability Property for some noncommutative knotted varieties of RL and DRL.

Residuated lattices, although originally considered in the realm of algebra providing a general setting for studying ideals in ring theory, were later shown to form algebraic models for substructural logics. The latter are non-classical logics that include intuitionistic, relevance, many-valued, and linear logic, among others. Most of the important examples of substructural logics are obtained by adding structural rules to the basic logical calculus

The philosophical significance of Cox's theorem

Cox's theorem states that, under certain assumptions, any measure of belief is isomorphic to a probability measure. This theorem, although intended as a justification of the subjectivist interpretation of probability theory, is sometimes presented as an argument for more controversial theses. Of particular interest is the thesis that the only coherent means of representing uncertainty is via the probability calculus. In this paper I examine the logical assumptions of Cox's theorem and I show how these impinge on the philosophical conclusions thought to be supported by the theorem. I show that the more controversial thesis is not supported by Cox's theorem. (C) 2003 Elsevier Inc. All rights reserved.