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.

The Tragedy of Darfur and the Limits of the Responsibility to Protect

The view that states which claim sovereign status must comply with the responsibility to protect their own citizens is gaining ground in international politics. When a state is unable or unwilling to meet this responsibility, the international community is justified in intervening militarily to end widespread human rights violations. This article argues that a diffuse responsibility to protect, as currently conceived, may have important negative consequences. By using the ongoing tragedy of Darfur as an example, the article argues that the responsibility to protect is reactive and focused on the short term, contributes to the outbreak of violence and perversely provides repressed groups with a further incentive to continue their armed struggle after war breaks out. The tragedy of Darfur shows that effective protection requires case-specific policies aimed at prevention, democratization and economic and political development.

The periodic variations of a white-light flare observed with ULTRACAM

High time resolution observations of a white-light flare on the active star EQ PegB show evidence of intensity variations with a period of ≈10 s. The period drifts to longer values during the decay phase of the flare. If the oscillation is interpreted as an impulsively-excited, standing-acoustic wave in a flare loop, the period implies a loop length of ≈3.4 Mm and ≈6.8 Mm for the case of the fundamental mode and the second harmonic, respectively. However, the small loop lengths imply a very high modulation depth making the acoustic interpretation unlikely. A more realistic interpretation may be that of a fast-MHD wave, with the modulation of the emission being due to the magnetic field. Alternatively, the variations could be due to a series of reconnection events. The periodic signature may then arise as a result of the lateral separation of individual flare loops or current sheets with oscillatory dynamics (i.e., periodic reconnection).

The WASP project in the era of robotic telescope networks

We present the current status of the WASP project, a pair of wide angle photometric telescopes, individually called SuperWASP. SuperWASP-I is located in La Palma, and SuperWASP-II at Sutherland in South Africa. SW-I began operations in April 2004. SW-II is expected to be operational in early 2006. Each SuperWASP instrument consists of up to 8 individual cameras using ultra-wide field lenses backed by high-quality passively cooled CCDs. Each camera covers 7.8 x 7.8 sq degrees of sky, for nearly 500 sq degrees of total sky coverage. One of the current aims of the WASP project is the search for extra-solar planet transits with a focus on brighter stars in the magnitude range similar to 8 to 13. Additionally, WASP will search for, optical transients, track Near-Earth Objects, and study many types of variable stars and extragalactic objects. The collaboration has developed a custom-built reduction pipeline that achieves better than I percent photometric precision. We discuss future goals, which include: nightly on-mountain reductions that could be used to automatically drive alerts via a small robotic telescope network, and possible roles of the WASP telescopes as providers in such a network. Additional technical details of the telescopes, data reduction, and consortium members and institutions can be found on the web site at: http://www.superwasp.org/. (c) 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.