Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination

Blood-brain barrier (BBB) hyperpermeability in multiple sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in microvascular tight junctions (TJs). This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage. Frozen sections from plaque and normal-appearing white matter (NAWM) in 14 cases were studied together with white matter from six neurological and five normal controls. Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein zonula occludens-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to fibrinogen leakage. Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control white matter. These were frequent in oil-red O (ORO)+ active plaques, affecting 42% of vessel segments, but less frequent in ORO- inactive plaques (23%), NAWM (13%), and normal (3.7%) and neurological controls (8%). A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators. In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most fibrinogen leakage. This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage. It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage. TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process. In NAWM, it suggests either pre-lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy

Evaluation of extended training for general practice in Northern Ireland: qualitative study.

Objective To evaluate participants' perceptions of the impact on them of an additional six months' training beyond the standard 12 month general practice vocational training scheme. Design Qualitative study using focus groups. Setting General practice vocational training in Northern Ireland. Participants 13 general practitioner registrars, six of whom participated in the additional six months' training, and four trainers involved in the additional six months' training. Main outcome measures: Participants' views about their experiences in 18 month and 12 month courses. Results Participants reported that the 12 month course was generally positive but was too pressurised and focused on examinations, and also that it had a negative impact on self care. The nature of the learning and assessment was reported to have left participants feeling averse to further continuing education and lacking in confidence. In contrast, the extended six month component was reported to have restimulated learning by focusing more on patient care and promoting self directed learning. It developed confidence, promoted teamwork, and gave experience of two practice contexts, and was reported as valuable by both ex-registrars and trainers. However, both the 12 and 18 month courses left participants feeling underprepared for practice management and self care. Conclusions 12 months' training in general practice does not provide doctors with the necessary competencies and confidence to enter independent practice. The extended period was reported to promote greater professional development, critical evaluation skills, and orientation to lifelong learning but does not fill all the gaps.

Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms.

The murine VEGF gene is alternatively transcribed to yield the VEGF120, VEGF164, and VEGF188 isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to stimulate endothelial growth. Here, their role in retinal vascular development was studied in mice selectively expressing single isoforms. VEGF164/164 mice were normal, healthy, and had normal retinal angiogenesis. In contrast, VEGF120/120 mice exhibited severe defects in vascular outgrowth and patterning, whereas VEGF188/188 mice displayed normal venular outgrowth but impaired arterial development. It is noteworthy that neuropilin-1, a receptor for VEGF164, was predominantly expressed in retinal arterioles. These findings reveal distinct roles of the various VEGF isoforms in vascular patterning and arterial development in the retina.

La otra Ley de Foucault. Una lectura crítica

Few studies have addressed the relationship between law and power in the works of Michel Foucault. Some authors emphasize that law performs a completely secondary role in the diagram of power of modernity, while others argue that there is a close link between power relations and the law. Foucault's Law by Golden and Fitzpatrick aims to renew these discussions and reconstruct another law of Foucault. In this paper I make a critical reading of this work, highlighting the faulty presentation that the authors carried out of the works of Foucault.

Philosophy and Politics in the 20th in Argentina. Readings of Italian Idealism

The transition from a positivist matrix to an idealistic one in Argentinean academic philosophy can be read as a result of a gradual and problematic pollution. It was, also, heavily traversed by considerations that exceeded the theoretical aspects. Based on the willingness to explore this transit, the article pays attention to one of the episodes of this contamination: how the Revista de Filosofía reads Croce and Gentile’s philosophy. Observing there some possibility of dialogue between positivist assumptions, with which the journal takes a position, and the idealism the article analyze how this dialogue and its limits were given from a political consideration. If the idealism was condemned, it is centrally owed to its performance during the first years of the government of Mussolini. If, meanwhile, it was some to rescue of that philosophy, it was that it contributed to think the revolutionary change.