The complex clinical picture of side effects to biologicals

Biologicals are proteins used as drugs. Biologicals target clearly defined molecular structures, being part of established pathogenetic pathways. Therefore, their focused mode of action seems to render them superior to classic small molecular drugs regarding "off-target" adverse drug reactions (ADR). Nevertheless, the increasing use of biologicals for the treatment of different diseases has revealed partially unexpected adverse reactions. The often direct interaction of a biological with the immune system provides a clue to most side effects, which have consequently been subclassified, based on pathogenetic principles, into 5 subtypes named alpha, beta, gamma, delta, and epsilon, reflecting overstimulation (high cytokine values, type alpha), hypersensitivity (type beta), immune deviation (including immunodeficiency, type gamma), cross-reactivity (type delta), and nonimmune mediated side effects (type epsilon). This article presents typical clinical manifestations of these subtypes of ADR to biologicals, proposes general rules for treating them, and provides a scheme for a thorough allergological workup. This approach should help in future handling of these often very efficient drugs.

Adverse side-effects to biological agents

Biological agents-like cytokines, monoclonal antibodies and fusion proteins are widely used in anti-inflammatory and tumour therapy. They are highly efficient in certain diseases, but can cause a great variety of adverse side-effects. Based on the peculiar features of biological agents a new classification of these adverse side-effects of biological agents is proposed - related but clearly distinct from the classification of side-effects observed with chemicals and drugs. This classification differentiates five distinct types, namely clinical reactions because of high cytokine levels (type alpha), hypersensitivity because of an immune reaction against the biological agent (beta), immune or cytokine imbalance syndromes (gamma), symptoms because of cross-reactivity (delta) and symptoms not directly affecting the immune system (epsilon). This classification could help to better deal with the clinical features of these side-effects, to identify possible individual and general risk factors and to direct research in this novel area of medicine.

Automated end-to-side anastomosis to the middle cerebral artery: a feasibility study

The treatment of complex cerebrovascular or skull base pathological conditions necessitates a microsurgical blood flow preservation or augmentative revascularization procedure as either an adjunctive safety measure or a definitive treatment. The brain is susceptible to ischemia, and procedure-related risks can be minimized by the reduction of occlusion time or the use of a nonocclusive technique. The authors therefore analyzed the feasibility of an automatic device (C-Port xA, Cardica) designed for constructing an end-to-side anastomosis with or without flow interruption for a middle cerebral artery (MCA) bypass in a human cadaveric model and in an in vivo craniotomy simulation model.

Transfer of spatial knowledge from a virtual environment to reality: Impact of route complexity and subject’s strategy on the exploration mode

The use of virtual reality as tool in the area of spatial cognition raises the question of the quality of learning transfer from a virtual to a real environment. It is first necessary to determine with healthy subjects, the cognitive aids that improve the quality of transfer and the conditions required, especially since virtual reality can be used as effective tool in cognitive rehabilitation. The purpose of this study was to investigate the influence of the exploration mode of virtual environment (Passive vs. Active) according to Route complexity (Simple vs. Complex) on the quality of spatial knowledge transfer in three spatial tasks. Ninety subjects (45 men and 45 women) participated. Spatial learning was evaluated by Wayfinding, sketch-mapping and picture classification tasks in the context of the Bordeaux district. In the Wayfinding task, results indicated that active learning in a Virtual Environment (VE) increased the performances compared to the passive learning condition, irrespective of the route complexity factor. In the Sketch-mapping task, active learning in a VE helped the subjects to transfer their spatial knowledge from the VE to reality, but only when the route was complex. In the Picture classification task, active learning in a VE when the route was complex did not help the subjects to transfer their spatial knowledge. These results are explained in terms of knowledge levels and frame/strategy of reference [SW75, PL81, TH82].

The heparan sulfate proteoglycan agrin contributes to barrier properties of mouse brain endothelial cells by stabilizing adherens junctions

Barrier characteristics of brain endothelial cells forming the blood-brain barrier (BBB) are tightly regulated by cellular and acellular components of the neurovascular unit. During embryogenesis, the accumulation of the heparan sulfate proteoglycan agrin in the basement membranes ensheathing brain vessels correlates with BBB maturation. In contrast, loss of agrin deposition in the vasculature of brain tumors is accompanied by the loss of endothelial junctional proteins. We therefore wondered whether agrin had a direct effect on the barrier characteristics of brain endothelial cells. Agrin increased junctional localization of vascular endothelial (VE)-cadherin, β-catenin, and zonula occludens-1 (ZO-1) but not of claudin-5 and occludin in the brain endothelioma cell line bEnd5 without affecting the expression levels of these proteins. This was accompanied by an agrin-induced reduction of the paracellular permeability of bEnd5 monolayers. In vivo, the lack of agrin also led to reduced junctional localization of VE-cadherin in brain microvascular endothelial cells. Taken together, our data support the notion that agrin contributes to barrier characteristics of brain endothelium by stabilizing the adherens junction proteins VE-cadherin and β-catenin and the junctional protein ZO-1 to brain endothelial junctions.

E-comparisons: A new approach to round robin tests for environmental noise assessment in transport infrastructures

The increasing importance of pollutant noise has led to the creation of many new noise testing laboratories in recent years. For this reason and due to the legal implications that noise reporting may have, it is necessary to create procedures intended to guarantee the quality of the testing and its results. For instance, the ISO/IEC standard 17025:2005 specifies general requirements for the competence of testing laboratories. In this standard, interlaboratory comparisons are one of the main measures that must be applied to guarantee the quality of laboratories when applying specific methodologies for testing. In the specific case of environmental noise, round robin tests are usually difficult to design, as it is difficult to find scenarios that can be available and controlled while the participants carry out the measurements. Monitoring and controlling the factors that can influence the measurements (source emissions, propagation, background noise…) is not usually affordable, so the most extended solution is to create very effortless scenarios, where most of the factors that can have an influence on the results are excluded (sampling, processing of results, background noise, source detection…) The new approach described in this paper only requires the organizer to make actual measurements (or prepare virtual ones). Applying and interpreting a common reference document (standard, regulation…), the participants must analyze these input data independently to provide the results, which will be compared among the participants. The measurement costs are severely reduced for the participants, there is no need to monitor the scenario conditions, and almost any relevant factor can be included in this methodology

Contribution of the noise radiated by a single vehicle to the road traffic noise

El ruido del tráfico rodado supone aproximadamente la mitad del ruido global ambiental. Las técnicas de control de ruido habitual en emisión (límites de emisión de vehículos) e inmisión (barreras acústicas, doble acristalamiento) no han sido suficientes para disminuir significativamente las molestias por el tráfico rodado en las últimas tres décadas. El efecto positivo de estas técnicas de control ha sido contrarrestado por el aumento de la densidad del tráfico. Por otra parte, la molestia del ruido del tráfico está altamente correlacionada con los niveles máximos de ruido (MNL), producidos por lo general por conductores agresivos. Sin embargo, los sistemas actuales de medición de ruido de tráfico se basan en una valoración global, por lo que no son capaces de discriminar entre los conductores silenciosos y ruidosos. Por lo tanto, en esta tesis se propone un sistema de medida de ruido en el campo cercano, que es capaz de medir la contribución de cada vehículo individual al ruido del tráfico rodado, permitiendo la detección de los conductores ruidosos. Este trabajo describe también una combinación de investigaciones analíticas y experimentales para la identificación de los conductores responsables de la generación de niveles máximos de ruido. El sistema se basa en dos micrófonos embarcados, uno para el ruido del motor y otro para el ruido de rodadura. Con el fin de relacionar estas mediciones de campo cercano con el ruido de los vehículos radiado al campo lejano, se desarrolla un procedimiento completo para la extrapolación del ruido medido por los micrófonos de campo próximo a las posiciones de campo lejano, usando una combinación de predicción analítica y mediciones experimentales. Las correcciones para los niveles extrapolados se deben a factores atmosféricos, al término de divergencia esférica y a las condiciones de absorción de la superficie de propagación. Para el micrófono situado próximo al motor, es necesario también caracterizar las propiedades acústicas del capó del motor. Ambos niveles de ruido se extrapolan de forma independiente a la posición de campo lejano, donde se realiza una comparación entre la predicción y mediciones para confirmar que la metodología es fiable para estimar el impacto a distancia del ruido de tráfico

Assessment of a simplified experimental procedure to evaluate impact sound reduction of floor coverings

The impact noise reduction provided by floor coverings is usually obtained in laboratory, using the methodology described in the standard EN ISO 140-8, which requires the use of standard acoustic chambers. The construction of such chambers, following the requirements described in the EN ISO 140-1, implies a significant investment, and therefore only a limited number exists in each country. Alternatives to these standard methodologies, that allow a sufficiently accurate evaluation and require lower resources, have been interesting many researchers and manufacturers. In this paper, one such strategy is discussed, where a reduced sized slab is used to determine the noise reduction provided by floor coverings, following the procedure described in the ISO/CD 16251-1 technical document. Several resilient coverings, floating floors and floating slabs are tested and the results are compared with those obtained using the procedures described in the standards EN ISO 140-8 and EN ISO 717-2.

The adaptive response of humans to exercise: Impact of exercise intensity, fibre-type specific responses and molecular patterns of response

In an attempt to improve the current understanding of the adaptive response to exercise in humans, this dissertation performed a series of studies designed to examine the impact of training intensity and mode on aerobic capacity and performance, fibre-type specific adaptations to training, and individual patterns of response across molecular, morphological and genetic factors. Project #1 determined that training intensity, session dose, baseline VO2max and total training volume do not influence the magnitude of change in VO2max by performing a meta-regression, and meta-analysis of 28 different studies. The intensity of training had no effect on the magnitude of increase in maximal oxygen uptake in young healthy participants, but similar adaptations were achieved with lower training doses following high intensity training. Project # 2 determined the acute molecular response, and training-induced adaptations in aerobic performance, aerobic capacity and muscle phenotype following high-intensity interval training (HIT) or endurance exercise (END). The acute molecular response (fibre recruitment and signal activation) and training-induced adaptations in aerobic capacity, aerobic performance, and muscle phenotype were similar following HIT and END. Project # 3 examined the impact of baseline muscle morphology and molecular characteristics on the training response, and if muscle adaptations are coordinated. The muscle phenotype of individuals who experience the largest improvements (high responders) were lower before training for some muscle characteristics and molecular adaptations were coordinated within individual participants. Project # 4 examined the impact of 2 different intensities of HIT on the expression of nuclear and mitochondrial encoded genes targeted by PGC-1α. A systematic upregulation of nuclear and mitochondrial encoded genes was not present in the early recovery period following acute HIT, but the expression of mitochondrial genes were coordinated at an individual level. Collectively, results from the current dissertation contribute to our understanding of the molecular mechanisms influencing skeletal muscle and whole-body adaptive responses to acute exercise and training in humans.

Review of head rotational measurements during biomechanical impact tests. Technical report.

Mode of access: Internet.

Environmental assessment using remotely sensed data : application of remote sensing data to environmental impact studies for transmission line routes /

Mode of access: Internet.