Giant cell arteritis with spontaneous remission.

BACKGROUND: Clinical manifestations of giant cell arteritis (GCA) are variable. Whether signs and symptoms present in an explosive fashion or insidiously, once manifest the course is usually progressive unless treatment is initiated. METHODS: A retrospective review of patients with GCA seen in an outpatient neuro-ophthalmology clinic. RESULTS: We report four patients with biopsy-proven GCA who experienced spontaneous remission. Clinical manifestations consisted of headache and diplopia in two patients, constitutional symptoms in one patient and facial pain in another. CONCLUSIONS: Clinicians should be aware of this aspect of the disease in order to avoid a delay in diagnosis and treatment.

Étude de la fonction de GLUT8 sur un modèle de souris "knock-out"

Résumé GLUT8 est la première des nouvelles isoformes des GLUT récemment identifiés. Il est fortement exprimé dans les testicules et plus faiblement dans les blastocystes, le cerveau, particulièrement au niveau de l'hippocampe, et le coeur. En conditions basales, il est retenu dans un compartiment intracellulaire. Si on l'exprime en surface cellulaire, par la mutation du motif d'internalisation dileucine, il transporte le glucose avec une bonne affinité. Dans le but d'étudier sa fonction au niveau de l'organisme, nous avons créé un modèle de knock out conditionnel, en entourant le dernier exon du gène de GLUT8 par deux sites loxP. En croisant nos souris avec une souche de souris transgénique exprimant la cre-recombinase dans les cellules de la lignée germinale, nous avons généré un modèle de souris portant la délétion totale de GLUT8 de manière constitutionnelle. Les statistiques effectuées sur les premières naissances indiquent qu'une partie des souris knock out ne survit pas, suggérant un rôle de GLUT8 au niveau du développement embryonnaire. Les souris qui ont survécu ne présentent toutefois pas d'anomalies durant la croissance et sont fertiles. Elles ont des taux de glucose et d'insuline sanguins normaux. Au niveau cérébral, la structure de l'hippocampe n'est pas modifiée par la suppression de GLUT8, cependant, les souris GLUT8-/- présentent une prolifération cellulaire augmentée dans le gyrus denté. Cette augmentation de division cellulaire pourrait être la réponse adaptée à une éventuelle augmentation de la mort cellulaire au niveau de l'hippocampe. Elles ne semblent toutefois pas présenter de défauts cognitifs majeurs dans le bassin de Morris en conditions normales. Toutefois, en conditions de jeûne, elles tendent à une meilleure mémorisation à court terme. Les études morphologiques et histologiques au niveau cardiaque n'ont pas révélé de d'hypertrophie au niveau ventriculaire. La stimulation de la contraction à l'isoprotérénol n'a pas mis en évidence de défaut d'adaptation des coeurs GLUT8-/-. Cependant l'analyse fonctionnelle par électrocardiogramme, en conditions basales, a montré une augmentation de la durée de l'onde P, suggérant un défaut dans la dépolarisation des oreillettes. Nos résultats indiquent que GLUT8 ne joue pas un rôle prédominant dans la survie et la fonction basale des souris. Il pourrait jouer un rôle plus important dans des situations stressantes pour l'organisme, comme l'hypoglycémie ou les conditions d'ischémie qui induiraient son expression à la membrane plasmique et stimuleraient le captage du glucose. Abstract GLUT8 was the first of the recently identified isoform of the GLUT family proteins. It is strongly expressed in the testis. It is also found at a lower level in the blastocyst, in heart and in the brain. Under basal conditions, it is retained in the intracellular compartment, but when the internalization motif dileucine is mutated, GLUT8 translocates to the plasma membrane and transports glucose with a relatively high affinity. To study its function in vivo, we created a conditional knock out mouse model. To do so, we targeted the last exon of the GLUT8 gene with two loxP sites. We then crossed these mice with a transgenic model expressing the cre-recombinase in the gem' line to generate a constitutional total knock out mouse. The statistics made on the first breedings showed that some of the knock out mice do not survive, suggesting a role of GLUT8 in the embryonic development. Conversely mice who survive do not show developmental defects and they are fertile with normal glucose and insulin blood levels. In the brain, the general structure of the hippocampus is not modified by the deletion of GLUT8. However, GLUT8-/- mice show an increase in the cell proliferation in the dentate gyms. This cell proliferation could be due to an increase in the cell death in the hippocampus. When tested in the morris water maze, these mice do not show any cognitive defects in the basal conditions, but they have a tendency to learn better in fasted conditions. The morphological and histological studies made at the heart level did not show any cardiac hypertrophy in the ventricles. The stimulation with isoproterenol did not show any adaptation defects in the GLUT8-/- hearts. However, the functional analysis made in basal conditions with the electrocardiogram showed an increase in the P wave length, suggesting a defect in the atrial depolarization in the knock out mice. Overall, our results show that GLUT8 does not play an important role in the basal general functions in the mice, but might play a more important role during whole organism stress. Hypoglycaemia or ischemia, for example could stimulate the GLUT8 translocation to the plasma membrane to increase specifically glucose uptake. Résumé tout public Les différentes cellules de l'organisme possèdent des propriétés particulières, qui leur permettent de maintenir les fonctions de l'organe auquel elles appartiennent. La membrane plasmique qui les délimite sélectionne les substances qui vont pénétrer à l'intérieur de la cellule et permet ainsi de maintenir un environnement interne constant. Le glucose est une source d'énergie importante pour la cellule et doit pouvoir pénétrer à l'intérieur de la cellule. Il utilise pour cela des protéines de transport qui le feront passer de part et d'autre de la membrane. Les protéines de la famille des GLUT (pour GLUcose Transporter) possèdent cette capacité. GLUT8 est un membre de la famille des GLUT identifié récemment. Il possède la capacité de transporter le glucose quand il se présente à la surface de la cellule. Il est principalement exprimé dans les testicules, dans le coeur et le cerveau et durant le développement embryonnaire. Son rôle n'est toutefois pas encore défini. Ce travail consiste à étudier la fonction de GLUT8 au niveau de l'organisme entier. Nous avons créé un modèle de souris dans lesquelles l'expression de GLUT8 a été supprimée pour mettre en évidence son importance dans le maintien de l'intégrité des fonctions du corps. Les observations effectuées sur les souris qui n'expriment plus GLUT8 nous indiquent que leurs cellules prolifèrent plus vite au niveau de l'hippocampe. L'hippocampe est une structure située dans le cerveau qui est impliquée dans les phénomènes d'apprentissage. Les souris qui ont été testées dans des tâches d'apprentissage n'ont malgré cela pas montré une amélioration de la mémorisation. Dans le coeur, la suppression de GLUT8 semble présenter un défaut quand on mesure l'activité électrique du coeur par électrocardiogramme. Toutefois, ils fonctionnent normalement et ne présentent pas de défauts morphologiques en conditions normales. Les expériences effectuées sur les modèles de souris indiquent que GLUT8 ne jouerait pas un rôle prédominant dans le fonctionnement normal du corps. Il pourrait exercer sa fonction dans des situations plus particulières comme l'hypoglycémie, où il permettrait une meilleure capacité à transporter le glucose dans les cellules.

The legal and ethical framework governing Body Donation in Europe - A review of current practice and recommendations for good practice

Discussions at the inaugural meeting of a Trans-European Pedagogic Research Group for Anatomical Sciences highlighted the fact that there exist considerable variations in the legal and ethical frameworks throughout Europe concerning body bequests for anatomical examination. Such differences appear to reflect cultural and religious variations as well as different legal and constitutional frameworks. For example, there are different views concerning the "ownership" of cadavers and concerning the need (perceived by different societies and national politicians) for legislation specifically related to anatomical dissection. Furthermore, there are different views concerning the acceptability of using unclaimed bodies that have not given informed consent. Given that in Europe there have been a series of controversial anatomical exhibitions and also a public (televised) dissection/autopsy, and given that the commercial sale or transport of anatomical material across national boundaries is strongly debated, it would seem appropriate to "harmonise" the situation (at least in the European Union). This paper summarises the legal situation in a variety of European countries and suggests examples of good practice. In particular, it recommends that all countries should adopt clear legal frameworks to regulate the acceptance of donations for medical education and research. It stresses the need for informed consent, with donors being given clear information upon which to base their decision, intentions to bequest being made by the donor before death and encourages donors to discuss their wishes to bequeath with relatives prior to death. Departments are encouraged, where they feel it appropriate, to hold Services of Thanksgiving and Commemoration for those who have donated their bodies. Finally, there needs to be legislation to regulate transport of bodies or body parts across national borders and a discouragement of any moves towards commercialisation in relation to bequests.

Migrating concepts: Immigrant integration and the regulation of religious dress in France and Canada

Religion in general, and Islam in particular, has become one of the main focal points of policy-making and constitutional politics in many Western liberal states. This article proposes to examine the legal and political dynamics behind new regulations targeting individual religious practices of Muslims. Although one could presuppose that church-state relations or the understanding of secularism is the main factor accounting for either accommodation or prohibition of Muslim religious practices, I make the case that the policy frame used to conceptualize the integration of immigrants in each national context is a more significant influence on how a liberal state approaches the legal regulation of individual practices such as veiling. However, this influence must be assessed carefully since it may have different effects on the different institutional actors in charge of regulating religion, such as the Courts and the legislature. To assess these hypotheses I compare two countries, France and Canada, which are solid examples of two contrasting national policy frames for the integration of immigrants.

Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.

Using exome sequencing and a variant prioritization strategy that focuses on loss-of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division.

5-Azacytidine to Treat Acute Myeloid Leukemia In Elderly or Frail Patients: A Phase II Study (SAKK 30/07).

Background: Acute Myeloid Leukemia (AML) in the elderly is notoriously difficult to treat and has a low remission rate with very few long term survivors when using standard treatment approaches. Azacytidine, a hypomethylating agent, has been shown to induce remission and prolong survival in patients with myelodysplastic syndromes; studying this approach to patients with AML is therefore warranted. We present results of an ongoing phase II trial treating elderly or frail AML patients with Azacytidine. Methods: AML elderly or frail patients, and therefore unfit for an intensive chemotherapy regimens, with a WHO performance status 3 were considered for this trial. Trial therapy consisted of 100mg/m2 of Azacytidine injected subcutaneously on 5 consecutive days every 28 days up to 6 cycles, stopping at 6 months if no hematological improvement achieved, or earlier in the case of progression or complications. Treatment was continued beyond 6 months in responding patients. Trial therapy was considered uninteresting if the response rate (CR + PR) within 6 months of therapy initiation was 15% or less and promising if 34% or more. Using the exact single-stage phase II design by A'Hern with a 5% significance level and 90% power, 43 patients were required: If 10 or fewer achieved a response within 6 months the trial therapy should not be considered for further investigation in its current format for this indication and patient population. Results: Between September 2008 and January 2010, 45 evaluable patients across 10 Swiss centers were accrued with a median follow-up of 7 months (range: 0 - 13). 27 (60%) were male, median age was 74 (range: 55 - 86) years and 35 (78.8%) had performance status 0-1. Patients had been excluded from more intensive chemotherapy regimens because of age (n = 37) or due to comorbidities or patient refusal (n=8). Five patients had therapy related AML. Patients received a median of 3 (range: 1 - 10) cycles. Treatment was stopped for not achieving a response by the 6th cycle in 2 patients and earlier in 26 patients (for disease progression in 5, toxicity in 3, patient refusal in 2, recurrent infections in 1, and death in 8). Seventeen patients remain on therapy. The median time spent in the hospital was 12 days (1 - 30) in 24/38 patients hospitalized during the first treatment cycle and 13 days (2 - 28) in 15/31 patients hospitalized during subsequent cycles. Adverse events of grade III or higher most frequently reported were constitutional or hematologic, i.e. fatigue in 5, febrile neutropenia in 8, infections in 6, dyspnea in 6, anemia in 3, neutropenia in 12 and thrombocytopenia in 10, hemorrhage in 2 and retinal detachment in 5. Based on available data on 38 patients, CR/CRi or hematologic improvement or stable disease within 6 months of trial registration was observed in a proportion of patients. Final and mature data, determining whether the predefined proportion of responding patients has been reached or not, will be presented at the conference. Up to now there were a total of 26 deaths. Median overall survival time was 5.7 months (95% CI: 3.1, 8.7). Conclusions: The current results of this slightly modified Azacytidine schedule demonstrate a feasible new therapy option for elderly or frail AML patients in an outpatient setting with moderate, mainly hematologic toxicity.

Spatial planning to the test of property rights in Switzerland : an innovative land management approach to coordinate spatial planning goals with property rights interests

In Switzerland, the land management regime is characterized by a liberal attitude towards the institution of property rights, which is guaranteed by the Constitution. Under the present Swiss constitutional arrangement, authorities (municipalities) are required to take into account landowners' interests when implementing their spatial planning policy. In other words, the institution of property rights cannot be restricted easily in order to implement zoning plans and planning projects. This situation causes many problems. One of them is the gap between the way land is really used by the landowners and the way land should be used based on zoning plans. In fact, zoning plans only describe how landowners should use their property. There is no sufficient provision for handling cases where the use is not in accordance with zoning plans. In particular, landowners may not be expropriated for a non-conforming use of the land. This situation often leads to the opening of new building areas in greenfields and urban sprawl, which is in contradiction with the goals set into the Federal Law on Spatial Planning. In order to identify legal strategies of intervention to solve the problem, our paper is structured into three main parts. Firstly, we make a short description of the Swiss land management regime. Then, we focus on an innovative land management approach designed to implement zoning plans in accordance with property rights. Finally, we present a case study that shows the usefulness of the presented land management approach in practice. We develop three main results. Firstly, the land management approach brings a mechanism to involve landowners in planning projects. Coordination principle between spatial planning goals and landowners' interests is the cornerstone of all the process. Secondly, the land use is improved both in terms of space and time. Finally, the institution of property rights is not challenged, since there is no expropriation and the market stays free.

Citizen participation and the Lisbon Treaty : A legal perspective

How to "bring the [European] Union closer to its citizens" is a vexed and vital problem of European integration. Article 11 TEU on participatory democracy, recently introduced by the Lisbon Treaty, is meant to be part of the solution. The EU Economic and Social Committee has gone so far as to define this provision "a milestone on the road to a people's Europe that is real and feasible". This appears to be an overly optimistic assessment - partly because art. 11 relies heavily on the involvement of civil society organisations, which political science literature suggests is conceptually and/or practically irrelevant to citizen involvement; partly because it largely formalizes participatory practices that have been in existence for years without cognizable effects on citizen participation; and partly because even its most innovative element - the European citizens' initiative (ECI) - does not bring significant changes to the Union's constitutional arrangements in terms of redistributing decision-making power. In addition to that, secondary legislation places significant hurdles on the submission of ECIs and might prevent or delay their becoming a standard democratic practice. This is not to say that art. 11 TEU has no potential at all. Its insertion in the Treaty might provide impetus to rethink and develop past participatory practices, such as horizontal civil dialogue. Moreover, the effects of "popular input" in the form of ECIs on EU institutional dynamics is as yet unknown - and perhaps not negligible, to judge from the keen interest that the European Parliament and other bodies have demonstrated in "appropriating" it as a political asset. Finally, art. 11 raises the stakes of the Union's democratic challenge and might pressure EU institutions to make full use of its potential. Or, if eventually proved inadequate, art. 11 might constitute a constitutional experiment on the way to meaningful forms of direct democracy at EU level.

Enhancing centralized enforcement of EU law : Pandora's toolbox ?

State compliance with EU Law is crucial to the very existence of the Union. Traditionally, it has been secured through a combination of strong "private" and of weak "centralized" enforcement. However, this arrangement is no longer perceived to be sufficient. By endowing the Union with new tools vis-à-vis its Member States - penalties, conditionality, and the like - current reforms try to complement symbolic sanctioning with real "consequences". The goal is to reinforce the authority of EU Law. In this article, we question whether the new toolbox is fit for the purpose, or whether it risks to produce adverse effects which might even go as far as upsetting the Union's constitutional template.