Current State and Future Perspectives of the Use of Cold Plasma in Patients with Complicated Wounds.

We report our experience in patients who were treated with cold plasma wound therapy from 2016 to 2020. Thirty-six patients with a median age of 71 years (23 males, 13 females) were registered in a prospective database. The median follow up was six months. In 15 patients, their wounds were associated with peripheral arterial disease, and they received peripheral interventional or open revascularisation prior to cold plasma therapy. Seven patients had a chronic venous insufficiency and 3 diabetic patients had chronic wounds caused by polyneuropathy. One patient suffered from chronic lymphoid disease. The cause of the wound could not be identified in the remaining patients. Wound treatment was conducted in an outpatient setting, if possible. Four patients were lost during follow-up. Surgical debridement of the wound before cold plasma therapy began was necessary in 14 cases. Each patient received 1 to 3 cold plasma treatments a week; 2 patients were treated for 1 year and the remaining patients were treated for 4 to 11 weeks. There were no major amputations in the long-term follow-up. In 25 patients, the progress of the wound stopped and in 11 patients the wounds were closed at the end of the therapy. In conclusion, our results support the use of cold plasma in complex wounds. Causal therapy is mandatory. Further studies are necessary to evaluate the impact of supplemental modern wound treatment with cold plasma therapy.

Three-Dimensional Analysis of Component Stability of the Nellix Endovascular Aneurysm Sealing System After Treatment of Infrarenal Abdominal Aortic Aneurysms.

PURPOSE: To assess short-term stability and conformational changes of the Nellix EndoVascular Aneurysm Sealing (EVAS) System using 3-dimensional (3D) analysis. METHODS: Postoperative computed tomography (CT) scans obtained at 0, 3, and 12 months in 24 patients (mean age 75±7 years; 22 men) who underwent EVAS between December 2013 and December 2014 for intact abdominal aortic aneurysm (within the instructions for use) were evaluated for stent-graft deviation in multiple planes using dedicated 3D analysis software. In addition, 2D analysis using an anatomically fixed reference landmark was performed to assess craniocaudal migration. Clinical and follow-up data of the patients were recorded and matched with results of the imaging analysis. RESULTS: Overall stability of the Nellix endografts was promising. Relevant conformational changes in the majority of cases were limited to the iliac graft segment and were clinically benign in all cases. Conversely, the only deviation of the proximal stent-graft segment was found in a patient with type Ia endoleak. Additional 2D analysis found relevant (≥5 mm) caudal migration of the Nellix stent-graft in 6 patients, including the one with the type Ia endoleak. In 3 patients, 3D analysis demonstrated the absence of relevant conformational changes of the endografts despite caudal migration. CONCLUSION: Overall stability of the separate EVAS stent-grafts is promising in the short term. Relevant conformational changes (stent-graft deviation) in the majority of cases were benign and confined to the iliac segment.

Endovascular Repair of Paravisceral Aortic Aneurysms Combining Chimney Grafts and the Nellix Endovascular Aneurysm Sealing Technology (Four-Vessel ChEVAS).

Background We demonstrate our initial experience and first results of the endovascular aneurysm sealing (EVAS) technology with chimney grafts for the treatment of paravisceral aneurysms. Methods We present a consecutive series of seven patients with a mean age of 75 years who had been treated by four-vessel-chimney EVAS (ChEVAS) between May 2014 and May 2015. All patients were ASA grade ≥ III and were not eligible for fenestrated/branched endovascular aortic repair (fEVAR/brEVAR) due to urgency (n = 5) or anatomical constraints (n = 2). Results Total 28 renovisceral target vessels were treated by balloon-expandable covered stents and 14 Nellix devices were used to seal the paravisceral aorta. Overall, 16 Nellix (Endologix Inc., Irvine, California, United States) devices and 65 covered stents were implanted with a technical success of 100%. Perioperatively, one patient with ruptured aneurysm died due to respiratory failure following splenic laceration/splenectomy (mortality = 14%) and in one patient, laceration of an axillary access vessel occurred. At a median follow-up of 6 months, all six surviving patients were well and no reinterventions were necessary. One chimney was found occluded without clinical sequelae resulting in a patency rate of 96%. Conclusion Four-vessel ChEVAS may serve as alternative treatment option in highly selected cases of either acute paravisceral aortic pathology and/or situations, where the implantation of fEVAR/brEVAR is hampered by anatomical constraints. Further follow-up and a multicenter study are of course warranted to corroborate these initial results.

Inflammation is associated with a reduced number of pro-angiogenic Tie-2 monocytes and endothelial progenitor cells in patients with critical limb ischemia.

BACKGROUND: Inflammation is the driving force in atherosclerosis. One central strategy in the treatment for PAD is the promotion of angiogenesis. Here, pro-angiogenic Tie-2-expressing monocytes (TEM) and endothelial progenitor cells (EPC) play a crucial role. Critical limb ischemia (CLI) is characterized by a severe, chronic inflammatory response; thus, progression of the disease might be related to the deleterious effects of inflammation on pro-angiogenic cells. METHODS: Forty-five patients with intermittent claudication (IC) [three groups: Rutherford (R)-1, -2, or -3; each n = 15], 20 patients with CLI [n = 20; Rutherford 4 (15 %), 5 (40 %), and 6 (45 %)], and 20 healthy controls were included in the study. Analysis of TEM and EPC was performed from whole blood by flow cytometry. Treatment for IC patients was conservative, and CLI patients underwent surgical revascularization. Follow-up was performed after mean of 7.1 months. RESULTS: In comparison with healthy controls, we found increased proportions of TEM and EPC in dependence of the severity of PAD, with the highest level in patients with severe claudication (R3) (p < 0.01). In contrast, for patients with CLI, we found a significantly reduced expression of both TEM and EPC in comparison with healthy controls (p < 0.05) or IC patients (R-1, R-2, and R-3) (all p < 0.001). At follow-up, TEM and EPC in CLI patients increased significantly (both p < 0.001). Serum levels of fibrinogen and CRP were significantly increased in CLI patients (all p < 0.001), but decreased at follow-up (all p < 0.05). TEM and EPC proportions correlated inversely with levels of fibrinogen [(TEM: r = −0.266; p < 0.01) (EPC: r = −0.297; p < 0.001)], CRP (TEM: r = −0.283; p < 0.01) (EPC: r = −0.260; p < 0.01). CONCLUSIONS: We found a strong association of diverse inflammatory markers with a reduced proportion of pro-angiogenic TEM or EPC in patients with CLI, giving rise to the speculation that a severe chronic inflammation might lead to deleterious effects on TEM and EPC, possibly interfering with angiogenesis, thus promoting an aggravation of the disease.

Leukocyte-platelet aggregates-a phenotypic characterization of different stages of peripheral arterial disease.

The formation of monocyte-platelet aggregates and neutrophil-platelet aggregates (MPA and NPA, respectively) is influenced by inflammation, but also might contribute to an exacerbation of inflammatory responses in atherosclerotic plaque. The purpose of this study was to analyze MPA and NPA proportions in regard to different stages of peripheral arterial disease (PAD). Forty-five patients with intermittent claudication (IC) (3 groups: Rutherford (R)-1, R-2, and R-3; each n = 15), 20 patients with critical limb ischemia (CLI) (Rutherford 5 (40%) and 6 (60%)), and 20 healthy controls were studied. Analyses of monocyte (Mon) subpopulations (CD14++CD16- (classical) Mon1, CD14++CD16+ (intermediate) Mon2, CD14+CD16++ (non-classical) Mon3), MPA, and NPA was performed from whole blood by flow cytometry. Controls showed an increased proportion of the Mon1 subpopulation (p < 0.001), whereas CLI patients showed a significant increase of the Mon2 subpopulation compared to controls, R-1, or R-2 patients (p < 0.0001). For the Mon3 subpopulation, CLI and R-3 patients showed an increased proportion (p < 0.05). MPA formation with the proinflammatory Mon2 and Mon3 subpopulations was increased in CLI patients (both p < 0.01). Similarly, NPA was significantly increased in CLI patients (p < 0.05). Serological markers of inflammation and procoagulation (fibrinogen [r = 0.459, p < 0.001], soluble triggering receptor expressed on myeloid cells (sTREM-1) [r = 0.237, p < 0.05] and P-Selectin [r = 0.225, p < 0.05]) correlated directly with MPA formation on the Mon2 subpopulation. We found an association of inflammatory and procoagulatory markers with increased formation of MPA on the Mon2 subpopulation. Since R-3 patients also had significantly increased MPA, one can speculate that the inflammatory burden might promote an aggravation of the disease.

Crural Bypass for Critical Lower Limb Ischemia with Omniflow II Prosthesis.

Background Reports about the use of the Omniflow II prosthesis (Bio Nova International, Victoria, Australia) in a crural position in patients with critical lower limb ischemia are rare. Methods All crural bypass operations were registered in a database. Primary end points of the study were amputation-free survival, limb salvage, and long-term patency. Results From January 2007 to December 2012, we implanted 27 Omniflow II prostheses in the crural position for critical lower limb ischemia. Of these, 12 crural bypasses were conducted with adjuvant distal arteriovenous fistula as a means to increase bypass flow in the presence of severely impaired intraoperative runoff or revision for early failure. Fifteen Omniflow II prosthesis bypasses were performed in the crural position without fistula. Overall, two patients died postoperatively. The limb salvage rate was 92% in the fistula group compared with 60% in the nonfistula group after a median observation time of 19 months in patients getting Omniflow prosthesis bypasses. Conclusion Omniflow II prosthesis in patients with critical lower limb ischemia and absence of sufficient autologous vein is durable. Moreover, the use of adjuvant distal arteriovenous fistula may increase the chance of limb salvage in this group of patients.

Coexpression of receptor-tyrosine-kinases in gastric adenocarcinoma--a rationale for a molecular targeting strategy?

AIM: To define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) in human gastric adenocarcinoma. METHODS: The (co-)expression pattern of VEGFR1-3, PDGFR alpha/beta and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. RESULTS: The majority of samples revealed a VEGFR1 (98%), VEGFR2 (80%), VEGFR3 (67%), PDGFR alpha (82%) and PDGFR beta (82%) expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFR alpha revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additional nuclear staining for VEGFR3, EGFR1 was almost exclusively detected on the membrane of tumor cells. PDGFR beta was restricted to stromal pericytes, which also depicted a PDGFR alpha expression. CONCLUSION: Our results reveal a high rate of receptor-tyrosine-kinases coexpression in gastric adenocarcinoma and might therefore encourage an application of multiple-target RTK-inhibitors within a combination therapy.

Bcl-2 upregulation after 3-nitropropionic acid preconditioning in warm rat liver ischemia.

We aimed to determine whether 3-nitropropionic acid (3-NPA) preconditioning protects rat livers against warm ischemia/reperfusion injury. We hypothesized that 3-NPA mediates its protective effects by Bcl-2 upregulation. Brown-Norway rats (200 g) were injected with 3-NPA (10 mg/kg intraperitoneally) 24 h before 90 min of selective warm in situ ischemia. In additional experiments, 30-day survival was studied after 90 min of warm liver ischemia and resection of nonischemic liver tissue. We demonstrate increased mRNA and protein levels of Bcl-2 by real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis in 3-NPA-pretreated rats. All treated animals survived, whereas all untreated rats died within 3 days after selective ischemia and resection of the nonischemic tissue. This corresponded well with a significant decrease of caspases 3 and 9 activity at 1 h of reperfusion after preconditioning with 3-NPA as compared with untreated rats. The histological sections showed protection of liver tissue after 3-NPA by reduction of apoptotic and oncotic tissue damage. Lipid peroxidation in liver tissue was reduced after 3-NPA preconditioning. We show that subtoxic doses of the mitochondrial toxin 3-NPA induces tolerance to warm liver ischemia in rats associated by synthesis of Bcl-2. Bcl-2 upregulation might protect against the postischemic burst of reactive oxygen species and therefore reduces apoptotic- and oncotic-related cell death.

Alpha-lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway.

In liver resection and transplantation ischemia-reperfusion injury (IRI) is one of the main causes of organ dys- or nonfunction. The aim of the present study was to determine whether alpha-lipoic acid (LA) is able to attenuate IRI. Rat livers were perfused with Krebs-Henseleit buffer with or without LA (+/-wortmannin), followed by ischemia (1 h, 37 degrees C) and reperfusion (90 min). Efflux of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP) and hepatic ATP content were determined enzymatically. Activation of NF-kappaB and activating protein 1 (AP-1) was examined by EMSA, and protein phosphorylation was examined by Western blot. Caspase-3-like activity served as an indicator for apoptotic processes. Animals treated intravenously with 500 micromol LA were subjected to 90 min of partial no-flow ischemia followed by reperfusion for up to 7 days. Preconditioning with LA significantly reduced LDH and PNP efflux during reperfusion in isolated perfused rat livers. ATP content was significantly increased in LA-treated livers. Postischemic activation of NF-kappaB and AP-1 was significantly reduced in LA-pretreated organs. Preconditioning with LA significantly enhanced Akt phosphorylation. It showed neither effect on endothelial nitric oxide synthase nor on Bad phosphorylation. Importantly, simultaneous administration of wortmannin, an inhibitor of the phosphatidylinositol (PI)3-kinase/Akt pathway, blocked the protective effect of LA on IRI, demonstrating a causal relationship between Akt activation and hepatoprotection by LA. Interestingly, despite activation of Akt, LA did not reduce postischemic apoptotic cell death. The efficacy of LA treatment in vivo was shown by reduced GST plasma levels and improved liver histology of animals pretreated with LA. This study shows for the first time that the PI3-kinase/Akt pathway plays a central protective role in IRI of the rat liver and that LA administration attenuates IRI via this pathway.