The fusion approach – applications for understanding local government and European integration

The article explores the theoretical capabilities of the fusion approach as a conceptual ‘kit’ to explain the ‘bigger picture’ of European integration from a local government perspective. Fusion addresses the rationales and methods facilitating the transfer of policy-making competences to the European level. It understands European integration as a merging of public resources and policy instruments from multiple levels of government, whereby accountability and responsibilities for policy outcomes become blurred. The article argues that the fusion approach is useful to explain the systemic linkages between macro-trajectories and the corresponding change at the local level; the fusion dynamics of the local and European levels in a common policy-cycle; and the attitudes of local actors towards the EU. Although the article concludes that local government is rather modestly ‘fused’ into the EU, fusion approaches allow examining the extent to which the local level has become integrated into the European governance system

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee

Background To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies

Inhibitors of Trypanosoma brucei 6-phosphogluconate dehydrogenase

6-Phosphogluconate dehydrogenase (6PGDH) is the third enzyme of the pentose phosphate pathway. It converts 6- phosphogluconate to ribulose 5-phosphate and concomitantly provides NADPH required for many biosynthetic and detoxification reactions. Its presence has been shown to be essential for growth of bloodstream form Trypanosoma brucei, a parasite responsible for African trypanosomiasis and it may be considered a validated drug target in this protozoan. The structure of the enzyme is known from X-ray crystallographic studies. There appears to be relatively little difference between the active sites of the trypanosomal and human enzymes, although pharmacological analysis shows that selective inhibition of an extensive nature is possible. Work has been carried out on the design of several classes of inhibitors for the T. brucei enzyme that are selective over the same enzyme from mammalian liver. One class comprises sugar derivatives, which mimic the substrate of the catalysed reaction. A second class of more potent inhibitors mimic the transition-state and high-energy intermediates of the enzymatic reaction of 6PGDH. 4-Phospho-D-erythronohydroxamate with a Ki = 10 nM is the compound with the highest affinity for the T. brucei 6PGDH reported to date, and the selectivity of 254-fold over the sheep enzyme is also the highest found. A third class of inhibitors are triphenylmethane derivatives, examples of which also show very pronounced anti-trypanosomal activity