Upon activation, neutrophils undergo histone citrullination by protein arginine deiminase (PAD)4, exocytosis of chromatin and enzymes as neutrophil extracellular traps (NETs), and death. In diabetes, neutrophils are primed to release NETs and die by NETosis. Although this process is a defense against infection, NETosis can damage tissue. Therefore, we examined the effect of NETosis on the healing of diabetic foot ulcers (DFUs). Using proteomics, we found that NET components were enriched in nonhealing human DFUs. In an independent validation cohort, a high concentration of neutrophil elastase in the wound was associated with infection and a subsequent worsening of the ulcer. NET components (elastase, histones, neutrophil gelatinase-associated lipocalin, and proteinase-3) were elevated in the blood of patients with DFUs. Circulating elastase and proteinase-3 were associated with infection, and serum elastase predicted delayed healing. Neutrophils isolated from the blood of DFU patients showed an increased spontaneous NETosis but an impaired inducible NETosis. In mice, skin PAD4 activity was increased by diabetes, and FACS detection of histone citrullination, together with intravital microscopy, showed that NETosis occurred in the bed of excisional wounds. PAD4 inhibition by Cl-amidine reduced NETting neutrophils and rescued wound healing in diabetic mice. Cumulatively, these data suggest that NETosis delays DFU healing.

The Advanced GAmma Tracking Array (AGATA) is a European project to develop and operate the next generation γ-ray spectrometer. AGATA is based on the technique of γ-ray energy tracking in electrically segmented high-purity germanium crystals. This technique requires the accurate determination of the energy, time and position of every interaction as a γ ray deposits its energy within the detector volume. Reconstruction of the full interaction path results in a detector with very high efficiency and excellent spectral response. The realisation of γ-ray tracking and AGATA is a result of many technical advances. These include the development of encapsulated highly segmented germanium detectors assembled in a triple cluster detector cryostat, an electronics system with fast digital sampling and a data acquisition system to process the data at a high rate. The full characterisation of the crystals was measured and compared with detector-response simulations. This enabled pulse-shape analysis algorithms, to extract energy, time and position, to be employed. In addition, tracking algorithms for event reconstruction were developed. The first phase of AGATA is now complete and operational in its first physics campaign. In the future AGATA will be moved between laboratories in Europe and operated in a series of campaigns to take advantage of the different beams and facilities available to maximise its science output. The paper reviews all the achievements made in the AGATA project including all the necessary infrastructure to operate and support the spectrometer

Although this meta-analysis highlights the need for more high-quality placebo-controlled trials, equipoise may no longer be guaranteed because autologous cell therapy has the potential to modify the natural history of intractable critical limb ischemia.

Methods and Results:We screened the English-language literature for longitudinal studies reporting the association between baseline CPC/EPC levels, future cardiovascular events, and death. We retrieved 28 studies, 21 of which contained poolable data and entered the meta-analysis, for a total of 4155 patients, mostly with a high baseline cardiovascular risk. Sixty percent of the studies met at least 11 of 16 items of quality assessment. Overall, reduced CPC/EPC levels were associated with a ≈2-fold increased risk of future cardiovascular events and cardiovascular death. The most predictive phenotype was CD34 + CD133 + : low versus high levels predicted cardiovascular events, restenosis after endovascular intervention, cardiovascular death, and all-cause mortality. Heterogeneity among studies and according to the CPC/EPC phenotype was generally high. Excluding studies for which the risk estimate had to be extrapolated or limiting the analyses to higher quality studies still indicated a significant risk for future cardiovascular events and death in patients with low versus high progenitor cell counts. Conclusions: This meta-analysis shows that a reduction in the levels

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