[Results of the systematic literature search as basis for the "Evidence-based treatment recommendations for familial Mediterranean fever patients with insufficient response or intolerability to colchicine" of the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. / Ergebnisse der systematischen Literatursuche als Grundlage für die "evidenzbasierten Therapieempfehlungen für FMF-Patienten mit unzureichendem Ansprechen bzw. Unverträglichkeit auf Kolchizin" der Gesellschaft für Kinder- und Jugendrheumatologie und der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Familial Mediterranean fever (FMF) is a genetic disease of childhood and adulthood which is relatively rare in Germany. It is characterized by recurrent febrile attacks, peritonitis, pleuritis and arthritis. The established treatment with colchicine is effective and well-tolerated by most patients; however, some patients do not adequately respond or do not tolerate this treatment. Biologics can be considered for some of these patients. The Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Rheumatology (DGRh) have agreed to develop joint recommendations for this specific clinical situation. AIM: Implementation of a systematic literature search (SLR) on the basis of the EULAR recommendations published in 2016 as the foundation for the development of evidence-based treatment recommendations for FMF patients with insufficient response or intolerance to colchicine. METHODS: The SLR was performed using references from various databases as an update of the SLR carried out by EULAR up to 2014, whereby all articles must have been published between 1 January 2015 and 31 December 2017. The Rayyan abstract tool for the preselection and the classification of the Oxford Centre for Evidence Based Medicine 2009 were used for the preparation of the evidence tables. RESULTS: The search yielded 360 hits and after duplicate matching 263. A total of 88 publications were included (34%) and 102 excluded (39%), a review of the full publication was necessary for a further 73 (28%) and 43 were discussed more intensively. Finally, 64 publications (24%) remained. A total of 4 case-control studies, 31 cohort studies, 8 case series, 7 controlled studies (including 5 abstracts), 10 reviews, 4 meta-analyses and systematic reviews were accepted. DISCUSSION: The SLR was carried out in a scientifically accurate and transparent manner according to international standards. The SLR proved to be a good basis for a consensus on the 5 overarching principles and the 10 recommendations, so that the joint activity of the GKJR and DGRh was successfully and even promptly concluded. The recommendations are a solid basis for treating patients of all ages with FMF. The explanations on the problem of colchicine resistance play an important role here.

The Legionella pneumophila F-box protein Lpp2082 (AnkB) modulates ubiquitination of the host protein parvin B and promotes intracellular replication.

The environmental pathogen Legionella pneumophila encodes three proteins containing F-box domains and additional protein-protein interaction domains, reminiscent of eukaryotic SCF ubiquitin-protein ligases. Here we show that the F-box proteins of L. pneumophila strain Paris are Dot/Icm effectors involved in the accumulation of ubiquitinated proteins associated with the Legionella-containing vacuole. Single, double and triple mutants of the F-box protein encoding genes were impaired in infection of Acanthamoeba castellanii, THP-1 macrophages and human lung epithelial cells. Lpp2082/AnkB was essential for infection of the lungs of A/J mice in vivo, and bound Skp1, the interaction partner of the SCF complex in mammalian cells, similar to AnkB from strain AA100/130b. Using a yeast two-hybrid screen and co-immunoprecipitation analysis we identified ParvB a protein present in focal adhesions and in lamellipodia, as a target. Immunofluorescence analysis confirmed that ectopically expressed Lpp2082/AnkB colocalized with ParvB at the periphery of lamellipodia. Unexpectedly, ubiquitination tests revealed that Lpp2082/AnkB diminishes endogenous ubiquitination of ParvB. Based on these results we propose that L. pneumophila modulates ubiquitination of ParvB by competing with eukaryotic E3 ligases for the specific protein-protein interaction site of ParvB, thereby revealing a new mechanism by which L. pneumophila may employ translocated effector proteins to promote bacterial survival.

Tetrahydrofolate biosynthesis and distribution in higher plants.

One-carbon transfer reactions are mediated by H4F (tetrahydrofolate), a soluble coenzyme (vitamin B9) that is synthesized de novo by plants and microorganisms, and absorbed from the diet by animals. H4F synthesis in plants is quartered between the plastids, the cytosol and the mitochondria, a spatial distribution that is not observed in the other organisms and that suggests a complex intracellular traffic. Also, the activity of H4F synthesis fluctuates during plant growth, depending on the tissue and the developmental stage of the seedling, thus illustrating the flexibility of one-carbon metabolism in these organisms. This paper will focus on our recent knowledge about H4F synthesis in the plant cell and will briefly describe the activity of the pathway during the growth and development of the seedling.

Mechanistic and inhibition studies of chorismate-utilizing enzymes.

The shikimate biosynthetic pathway is utilized in algae, higher plants, bacteria, fungi and apicomplexan parasites; it involves seven enzymatic steps in which phosphoenolpyruvate and erythrose 4-phosphate are converted into chorismate. In Escherichia coli, five chorismate-utilizing enzymes catalyse the synthesis of aromatic compounds such as L-phenylalanine, L-tyrosine, L-tryptophan, folate, ubiquinone and siderophores such as yersiniabactin and enterobactin. As mammals do not possess such a biosynthetic system, the enzymes involved in the pathway have aroused considerable interest as potential targets for the development of antimicrobial drugs and herbicides. As an initiative to investigate the mechanism of some of these enzymes, we showed that the antimicrobial effect of (6S)-6-fluoroshikimate is the result of irreversible inhibition of 4-amino-4-deoxychorismate synthase by 2-fluorochorismate. Based on this study, a catalytic mechanism for this enzyme was proposed, in which the residue Lys-274 is involved in the formation of a covalent intermediate. In another study, Yersinia enterocolitica Irp9, which is involved in the biosynthesis of the siderophore yersiniabactin, was for the first time biochemically characterized and shown to catalyse the formation of salicylate from chorismate via isochorismate as a reaction intermediate. A three-dimensional model for this enzyme was constructed that will guide the search for potent inhibitors of salicylate formation, and hence of bacterial iron uptake.