Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N-terminus of the polypeptide. Among those, the N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo. Here, we show that the N-terminal pE-formation depends on glutaminyl cyclase activity. The pE-residue increases stability against N-terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro. Genetic ablation of the glutaminyl cyclase iso-enzymes QC (QPCT) or isoQC (QPCTL) revealed a major role of isoQC for pE1-CCL2 formation and monocyte infiltration. Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration. The pharmacologic efficacy of QC/isoQC-inhibition was assessed in accelerated atherosclerosis in ApoE3*Leiden mice, showing attenuated atherosclerotic pathology following chronic oral treatment. Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers. The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

No abstract

Based on our experience, clinical long-term results are successful in certain patients with DAIIS. The aim for the near future should be a better patency rate to minimize the need for reoperations. In cases of extended limb necrosis/gangrene results were poor. In such patients primary closure of the access must be discussed.

Banding under blood flow control resulting in an approximately 50% reduction in the initial blood flow is an adequate therapeutic option in patients with brachial HA and type I-DASS. In type II-DASS, banding does not lead to satisfying results, more complex surgical options might be more successful. Diabetes is associated with poor HA outcome in case of DASS.

In addition to steal phenomenon (stage I), which can be treated conservatively, there are three stages of DASS following autogenuous HA that require surgical intervention (stage II, no acral lesions; stage III, small acral lesions; stage IV, extended acral lesions). HA banding leads to good results in stage II; in patients with stage III, interruption of the retrograde flow is indicated. However, in patients with extensive tissue loss (stage IV), closure of the HA should be considered.