Prostaglandin E Positively Modulates Endothelial Progenitor Cell Homeostasis: An Advanced Treatment Modality for Autologous Cell Therapy

Aims: The mobilization of endothelial progenitor cells (EPC) and their functioning in postnatal neovascularization are tightly regulated. To identify new modulators of EPC homeostasis, we screened biologically active prostaglandin E compounds for their effects on EPC production, trafficking and function. Methods and Results: We found that EPC are a rich source for prostaglandin E 2 (PGE 2), stimulating their number and function in an auto- and paracrine manner. In vivo blockade of PGE 2 production by selective cyclooxygenase-2 inhibition virtually abrogated ischemia-induced EPC mobilization demonstrating its crucial role in EPC homeostasis following tissue ischemia. Conversely, ex vivo treatment of isolated EPC with the clinically approved PGE 1 analogue alprostadil enhanced EPC number and function. These effects were mediated by increased expression of the chemokine receptor CXCR4 and were dependent on nitric oxide synthase activity. Most importantly, ex vivo PGE 1 pretreatment of isolated EPC significantly enhanced their neovascularization capacity in a murine model of hind limb ischemia as assessed by laser Doppler analysis, exercise stress test and immunohistochemistry. Conclusions: The conserved role for PGE in the regulation of EPC homeostasis suggests that ex vivo modulation of the prostaglandin pathway in isolated progenitor cells may represent a novel and safe strategy to facilitate cell-based therapies. Copyright (C) 2009 S. Karger AG, Base

Relevance of Type II Endoleak After Endovascular Repair of Ruptured Abdominal Aortic Aneurysms: A Retrospective Single-Center Cohort Study

Introduction: Endovascular aortic repair (EVAR) is widely used as an alternative to open repair in elective and even in emergent cases of ruptured abdominal aortic aneurysm (rAAA). One of the most frequent complications after EVAR is type II endoleak (T2EL). In elective therapy, evidence-based therapeutic recommendations for T2EL are limited. Completely unclear is the role of T2EL after EVAR for rAAA (rEVAR). This study aims to investigate the significance of T2ELs after rEVAR. Patients and methods: This is a retrospective single-center data analysis of all patients who underwent rEVAR between January 2010 and December 2020 with primary T2EL. The outcome criteria were overall and T2EL-related mortality and reintervention rate as well as development of aneurysm diameter over follow-up (FU). Results: During the study period between January 2010 and December 2020, 35 (25%) out of 138 patients with rEVAR presented a primary postoperative T2EL (age 74±11 years, 34 males). At rupture, mean aneurysm diameter was 73±12 mm. Follow-up was 26 (0–172) months. The reintervention-free survival was 69% (95% confidence interval [CI]: 55%–86%) at 30 days, 58% (95% CI: 43%–78%) at 1 year, and 52% (95% CI: 36%–75%) at 3 years. In 40% (n=14), T2ELs resolved spontaneously within a median time of 3.4 (0.03–85.6) months. The overall and T2EL reintervention rates were 43% (n=15) and 9% (n=3), respectively. Within 30 days, 11 patients (31%) required reintervention, of which 2 were T2EL related. Aneurysm sac growth by ≥5 mm was seen in 3 patients (9%), and aneurysm shrinkage rate was significantly higher in sealed T2EL group (86% vs 5%, p<0.0001). The overall survival was 85% (95% CI: 74%–98%) at 30 days, 75% (95% CI: 61%–92%) at 1 year, and 67% (95% CI: 51%–87%) at 3 years. Six deaths were aneurysm related, while 1 was T2EL related within the first 30 days due to persistent hemorrhage. During FU, one more patient died due to a T2EL-related secondary rupture (T2EL-related mortality, 5.7%, n=2). Multivariable analysis revealed that arterial hypertension was associated with an increased risk for reintervention (hazard ratio [HR]: 27.8, 95% CI: 1.48–521, p=0.026) and age was associated with an increased risk for mortality (HR 1.14, 95% CI: 1.04–1.26, p=0.005). Conclusion: T2ELs after rEVAR showed a benign course in most cases. In the short term, the possibility of persistent bleeding should be considered. In the mid term, a consequent FU protocol is required to detect known late complications after EVAR at an early stage and to prevent secondary rupture and death

Swiss Vascular Biobank: Evaluation of Optimal Extraction Method and Admission Solution for Preserving RNA from Human Vascular Tissue

Proper biobanking is essential for obtaining reliable data, particularly for next-generation sequencing approaches. Diseased vascular tissues, having extended atherosclerotic pathologies, represent a particular challenge due to low RNA quality. In order to address this issue, we isolated RNA from vascular samples collected in our Swiss Vascular Biobank (SVB); these included abdominal aortic aneurysm (AAA), peripheral arterial disease (PAD), healthy aorta (HA), and muscle samples. We used different methods, investigated various admission solutions, determined RNA integrity numbers (RINs), and performed expression analyses of housekeeping genes (ACTB, GAPDH), ribosomal genes (18S, 28S), and long non-coding RNAs (MALAT1, H19). Our results show that RINs from diseased vascular tissue are low (2-4). If the isolation of primary cells is intended, as in our SVB, a cryoprotective solution is a better option for tissue preservation than RNAlater. Because RNA degradation proceeds randomly, controls with similar RINs are recommended. Otherwise, the data might convey differences in RNA degradation rather than the expressions of the corresponding genes. Moreover, since the 18S and 28S genes in the diseased vascular samples were degraded and corresponded with the low RINs, we believe that DV200, which represents the total RNA's disintegration state, is a better decision-making aid in choosing samples for omics analyses

Gigantism in unique biogenic magnetite at the Paleocene-Eocene Thermal Maximum

We report the discovery of exceptionally large biogenic magnetite crystals in clay-rich sediments spanning the Paleocene-Eocene Thermal Maximum (PETM) in a borehole at Ancora, New Jersey. Aside from previously-described abundant bacterial magnetofossils, electron microscopy reveals novel spearhead-like and spindle-like magnetite up to 4 μm long and hexaoctahedral prisms up to 1.4 μm long. Similar to magnetite produced by magnetotactic bacteria, these single-crystal particles exhibit chemical composition, lattice perfection, and oxygen isotopes consistent with an aquatic origin. Electron holography indicates single-domain magnetization despite their large crystal size. We suggest that the development of a thick suboxic zone with high iron bioavailability – a product of dramatic changes in weathering and sedimentation patterns driven by severe global warming – drove diversification of magnetite-forming organisms, likely including eukaryotes

The Use of Intact Fish Skin Grafts in the Treatment of Necrotizing Fasciitis of the Leg: Early Clinical Experience and Literature Review on Indications for Intact Fish Skin Grafts

Background: Necrotizing fasciitis (NF) is a serious infectious disease that can initially place the patient’s life in danger and, after successful surgical and antibiotic treatment, leaves extensive wounds with sometimes even exposed bones and tendons. Autologous skin grafts are not always possible or require adequate wound bed preparation. Novel intact fish skin grafts (iFSGs; Kerecis® Omega3 Wound, Kerecis hf, Isafjördur, Iceland) have already shown their potential to promote granulation in many other wound situations. Faster wound healing rates and better functional and cosmetic outcomes were observed due to their additionally postulated anti-inflammatory and analgesic properties. Therefore, iFSGs may also be essential in treating NF. We present our initial experience with iFSGs in treating leg wounds after NF and review the literature for the current spectrum of clinical use of iFSGs. Case Presentations: We present two male patients (aged 60 and 69 years) with chronic or acute postsurgical extensive leg ulcers six weeks and six days after necrotizing fasciitis, respectively. Both suffered from diabetes mellitus without vascular pathologies of the lower limbs. A single application of one pre-meshed (Kerecis® Graftguide) and one self-meshed 300 cm2 iFSG (Kerecis® Surgiclose) was performed in our operation room after extensive surgical debridement and single circles of negative wound pressure therapy. Application and handling were easy. An excellent wound granulation was observed, even in uncovered tibia bone and tendons, accompanied by pain relief in both patients. Neither complications nor allergic reactions occurred. The patients received autologous skin grafting with excellent functional and cosmetic outcomes. Conclusions: iFSGs have the potential to play a significant role in the future treatment of NF due to the fast promotion of wound granulation and pain relief. Our experience may encourage surgeons to use iFSGs in NF patients, although high-quality, large-sized studies are still required to confirm these results. The observed effects of iFSGs on wounds associated with NF may be transferred to other wound etiologies as well

oxLDL Downregulates the Dendritic Cell Homing Factors CCR7 and CCL21

Introduction. Dendritic cells (DCs) and oxLDL play an important role in the atherosclerotic process with DCs accumulating in the plaques during plaque progression. Our aim was to investigate the role of oxLDL in the modulation of the DC homing-receptor CCR7 and endothelial-ligand CCL21. Methods and Results. The expression of the DC homing-receptor CCR7 and its endothelial-ligand CCL21 was examined on atherosclerotic carotic plaques of 47 patients via qRT-PCR and immunofluorescence. In vitro, we studied the expression of CCR7 on DCs and CCL21 on human microvascular endothelial cells (HMECs) in response to oxLDL. CCL21- and CCR7-mRNA levels were significantly downregulated in atherosclerotic plaques versus non-atherosclerotic controls [90% for CCL21 and 81% for CCR7 (P < 0.01)]. In vitro, oxLDL reduced CCR7 mRNA levels on DCs by 30% and protein levels by 46%. Furthermore, mRNA expression of CCL21 was significantly reduced by 50% (P < 0.05) and protein expression by 24% in HMECs by oxLDL (P < 0.05). Conclusions. The accumulation of DCs in atherosclerotic plaques appears to be related to a downregulation of chemokines and their ligands, which are known to regulate DC migration. oxLDL induces an in vitro downregulation of CCR7 and CCL21, which may play a role in the reduction of DC migration from the plaques