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ObjectiveLifestyle choices such as tobacco and e-cigarette use are a risk factor for peripheral arterial disease (PAD) and may influence therapeutic outcomes. The effect of chronic nicotine exposure on the angiogenic capacity of human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) was assessed in a murine model of PAD.MethodsMice were exposed to nicotine or phosphate-buffered saline (PBS) for 28 days, followed by induction of limb ischemia and iPSC-EC transplantation. Cells were injected into the ischemic limb immediately after induction of hindlimb ischemia and again 7 days later. Limb perfusion was assessed by laser Doppler spectroscopy, and transplant cell survival was monitored for 14 days afterward using bioluminescence imaging, followed by histological analysis of angiogenesis.ResultsTransplant cell retention progressively decreased over time after implantation based on bioluminescence imaging, and there were no significant differences in cell survival between mice with chronic exposure to nicotine or PBS. However, compared with mice without nicotine exposure, mice with prior nicotine exposure had had an impaired therapeutic response to iPSC-EC therapy based on decreased vascular perfusion recovery. Mice with nicotine exposure, followed by cell transplantation, had significantly lower mean perfusion ratio after 14 days (0.47 ± 0.07) compared with mice undergoing cell transplantation without prior nicotine exposure (0.79 ± 0.11). This finding was further supported by histological analysis of capillary density, in which animals with prior nicotine exposure had a lower capillary density (45.9 ± 4.7 per mm2) compared with mice without nicotine exposure (66.5 ± 8.1 per mm2). Importantly, the ischemic limbs mice exposed to nicotine without cell therapy also showed significant impairment in perfusion recovery after 14 days, compared with mice that received PBS + iPSC-EC treatment. This result sugge

The increase in survival rate under ECMO in many centres, the constant demands from governments and public opinion to increase support to reduce mortality in ICU have dramatically increased the number of ECMO centres and its application worldwide. Despite that, the basic scientific evidence of ECMO's superiority over other conventional or experimental treatments does not lie in classical evidence-based medicine and, furthermore, a number of issues in the daily management in several topics are unknown or neglected. The aim of this thesis was to elucidate clinical data and basic knowledge related to various challenges in ECMO practice in order to collect more solid data on current practice and guide future management strategies and interventional investigations. The topics considered in this PhD research were the anticoagulation management and best trigger for transfusions, the updated strategies to reduce the risk of limb ischemia during cardiac support, new biomolecular markers to monitor the clinical evolution of patients and the treatment of complications in a less-invasive way to improve survival All these considerations taken together may contribute to a more precise ECMO management, and a more efficient and sustainable allocation of this high-demanding health care resource, even more during the pandemic time.

The increase in survival rate under ECMO in many centres, the constant demands from governments and public opinion to increase support to reduce mortality in ICU have dramatically increased the number of ECMO centres and its application worldwide. Despite that, the basic scientific evidence of ECMO's superiority over other conventional or experimental treatments does not lie in classical evidence-based medicine and, furthermore, a number of issues in the daily management in several topics are unknown or neglected. The aim of this thesis was to elucidate clinical data and basic knowledge related to various challenges in ECMO practice in order to collect more solid data on current practice and guide future management strategies and interventional investigations. The topics considered in this PhD research were the anticoagulation management and best trigger for transfusions, the updated strategies to reduce the risk of limb ischemia during cardiac support, new biomolecular markers to monitor the clinical evolution of patients and the treatment of complications in a less-invasive way to improve survival All these considerations taken together may contribute to a more precise ECMO management, and a more efficient and sustainable allocation of this high-demanding health care resource, even more during the pandemic time.

Lumbar incisional hernias are difficult to repair because one of the hernia margins is bone, namely, the iliac crest. Previous studies have described the use of orthopedic bone anchors that fix a mesh onto the iliac crest. We present a novel technique for open repair of large lumbar incisional hernias using a double-mesh technique in combination with suture-loaded bone anchors to reattach the abdominal wall musculature onto the iliac crest. The surgical technique involves creating a preperitoneal plane behind the transversus abdominus and above the iliac crest and iliacus, below the iliac crest, with application of a Prolene mesh in this layer. This is followed by the drilling of suture-loaded Christmas Tree bone anchorsTM along the rim of the iliac crest. The preloaded sutures are used to attach the myofascial component on the iliac crest, followed by the placement of a second Prolene mesh in an on-lay fashion. Drains are left in the preperitoneal and subcutaneous spaces. Unlike other reported techniques in the literature which only fix mesh onto the iliac crest, our technique with the use of Christmas Tree bone anchorsTM allows for complete reconstruction of the lumbar abdominal wall defect and its myofascial components.Copyright © 2019 Southeastern Surgical Congress. All rights reserved.

Therapeutic factors secreted by mesenchymal stem cells (MSCs) promote angiogenesis in vivo. However, delivery of MSCs in the absence of a cytoprotective environment offers limited efficacy due to low cell retention, poor graft survival, and the nonmaintenance of a physiologically relevant dose of growth factors at the injury site. The delivery of stem cells on an extracellular matrix (ECM)-based platform alters cell behavior, including migration, proliferation, and paracrine activity, which are essential for angiogenesis. We demonstrate the biophysical and biochemical effects of preconditioning human MSCs (hMSCs) for 96 h on a three-dimensional (3D) ECM-based microgel platform. By altering the macromolecular concentration surrounding cells in the microgels, the proangiogenic phenotype of hMSCs can be tuned in a controlled manner through cell-driven changes in extracellular stiffness and "outside-in" integrin signaling. The softest microgels were tested at a low cell dose (5 × 104 cells) in a preclinical hindlimb ischemia model showing accelerated formation of new blood vessels with a reduced inflammatory response impeding progression of tissue damage. Molecular analysis revealed that several key mediators of angiogenesis were up-regulated in the low-cell-dose microgel group, providing a mechanistic insight of pathways modulated in vivo. Our research adds to current knowledge in cell-encapsulation strategies by highlighting the importance of preconditioning or priming the capacity of biomaterials through cell-material interactions. Obtaining therapeutic efficacy at a low cell dose in the microgel platform is a promising clinical route that would aid faster tissue repair and reperfusion in "no-option" patients suffering from peripheral arterial diseases, such as critical limb ischemia (CLI).

Lumbar incisional hernias are difficult to repair because one of the hernia margins is bone, namely, the iliac crest. Previous studies have described the use of orthopedic bone anchors that fix a mesh onto the iliac crest. We present a novel technique for open repair of large lumbar incisional hernias using a double-mesh technique in combination with suture-loaded bone anchors to reattach the abdominal wall musculature onto the iliac crest. The surgical technique involves creating a preperitoneal plane behind the transversus abdominus and above the iliac crest and iliacus, below the iliac crest, with application of a Prolene mesh in this layer. This is followed by the drilling of suture-loaded Christmas Tree bone anchorsTM along the rim of the iliac crest. The preloaded sutures are used to attach the myofascial component on the iliac crest, followed by the placement of a second Prolene mesh in an on-lay fashion. Drains are left in the preperitoneal and subcutaneous spaces. Unlike other reported techniques in the literature which only fix mesh onto the iliac crest, our technique with the use of Christmas Tree bone anchorsTM allows for complete reconstruction of the lumbar abdominal wall defect and its myofascial components.Copyright © 2019 Southeastern Surgical Congress. All rights reserved.

Therapeutic factors secreted by mesenchymal stem cells (MSCs) promote angiogenesis in vivo. However, delivery of MSCs in the absence of a cytoprotective environment offers limited efficacy due to low cell retention, poor graft survival, and the nonmaintenance of a physiologically relevant dose of growth factors at the injury site. The delivery of stem cells on an extracellular matrix (ECM)-based platform alters cell behavior, including migration, proliferation, and paracrine activity, which are essential for angiogenesis. We demonstrate the biophysical and biochemical effects of preconditioning human MSCs (hMSCs) for 96 h on a three-dimensional (3D) ECM-based microgel platform. By altering the macromolecular concentration surrounding cells in the microgels, the proangiogenic phenotype of hMSCs can be tuned in a controlled manner through cell-driven changes in extracellular stiffness and "outside-in" integrin signaling. The softest microgels were tested at a low cell dose (5 × 104 cells) in a preclinical hindlimb ischemia model showing accelerated formation of new blood vessels with a reduced inflammatory response impeding progression of tissue damage. Molecular analysis revealed that several key mediators of angiogenesis were up-regulated in the low-cell-dose microgel group, providing a mechanistic insight of pathways modulated in vivo. Our research adds to current knowledge in cell-encapsulation strategies by highlighting the importance of preconditioning or priming the capacity of biomaterials through cell-material interactions. Obtaining therapeutic efficacy at a low cell dose in the microgel platform is a promising clinical route that would aid faster tissue repair and reperfusion in "no-option" patients suffering from peripheral arterial diseases, such as critical limb ischemia (CLI).

Background: Owing to the aging population, the number of elderly patients with critical limb ischemia (CLI) has increased. The consequence of amputation is immense. However, at the moment, information about the mortality after amputation in the elderly vascular patients is unknown. For this reason, this study evaluated mortality rates and patient-related factors associated with mortality after a major amputation in elderly patients with CLI. Methods: From 2006 to 2013, we included patients aged >70 years who were treated for chronic CLI by primary or secondary major amputation within or after 3 months of initial therapy (revascularization or conservative management). Outcome measurements were mortality after major amputation and factors associated with mortality (age, comorbidity and timing of amputation). Results: In total, 168/651 patients (178 legs; 26%) underwent a major amputation. Patients were stratified by age: 70–80 years (n=86) and > 80 years (n=82). Overall mortality after major amputation was 44%, 66% and 85% after 1, 3 and 5 years, respectively. The 6-month and 1-year mortality in patients aged 80 years or older was, respectively, 59% or 63% after a secondary amputation <3 months versus 34% and 44% after a secondary amputation >3 months. Per year of age, the mortality rate increased by 4% (P=0.005). No significant difference in mortality after major amputation was found in the presence of comorbidity or according to Rutherford classification. Conclusion: Despite developments in the treatment of CLI by revascularization, amputation rates remain high and are associated with tremendous mortality rates. Secondary amputation after a failed attempt of revascularization causes a higher mortality. Further research concerning timing of amputation and patient-related outcome is needed to evaluate if selected patients might benefit from primary amputation.

We describe a 2.5 year-old child with toxic shock syndrome due to group A beta-hemolytic streptococcus (GABHS) who presented with purpura fulminans and limb ischemia treated with early microsurgical arteriolysis. The clinical picture of toxic shock syndrome (TSS) presenting with purpura fulminans and limb ischemia is an exceptionally uncommon finding in sepsis due to GABHS. This is the first case of purpura fulminans caused by GABHS reported in Europe and the third one described in the literature (Dhodapkar et al. 2000[1]; Renaud et a. 2011[2]). © 2013 Elsevier Inc., SCOPUS: ar.j, info:eu-repo/semantics/published

We describe a 2.5 year-old child with toxic shock syndrome due to group A beta-hemolytic streptococcus (GABHS) who presented with purpura fulminans and limb ischemia treated with early microsurgical arteriolysis. The clinical picture of toxic shock syndrome (TSS) presenting with purpura fulminans and limb ischemia is an exceptionally uncommon finding in sepsis due to GABHS. This is the first case of purpura fulminans caused by GABHS reported in Europe and the third one described in the literature (Dhodapkar et al. 2000[1]; Renaud et a. 2011[2]). © 2013 Elsevier Inc., SCOPUS: ar.j, info:eu-repo/semantics/published

The International Journal of Lower Extremity Wounds, 11(2), p.76; 2012

Considering the high frequency of bleeding complications following fibrinolytic treatment in neonates, peripheral nerve blockade (PNB) has been proposed alone or in association with lower doses of tissue plasminogen activator, as a possible new therapeutic approach in the management of neonatal limb ischemia (LI) secondary to vasospasm and/or thrombosis. The present article provides a review of the current knowledge about the topic, in order to evaluate the efficacy and safety of this therapeutic approach. According to the few case reports documented in literature and to our experience, PNB could be considered as valid procedure for the treatment of LI, especially during neonatal period, when the risk of serious bleeding associated with fibrinolytic or anticoagulant therapy is higher. Peripheral nerve blockade resulted in a safe and effective procedure for the treatment of neonatal vascular spasm and thrombosis.

type:text, Background: The purpose of this study was to determine the effect of a combination of bone marrow mononuclear cell (BM-MNC) implantation and sarpogrelate, a selective 5-HT2A antagonist, on endothelial function in patients with critical limb ischemia (CLI). Methods: We evaluated the leg blood flow (LBF) responses to acetylcholine (ACh) and sodium nitroprusside before and after BM-MNC implantation in 16 patients with CLI. We divided patients with CLI into 2 groups: those cotreated with sarpogrelate orally for 12 weeks (sarpogrelate group, n = 8) and those who remained on conventional therapy (control group, n = 8). LBF was measured by strain gauge plethysmography. Results: BM-MNC implantation improved ankle brachial pressure index, transcutaneous oxygen pressure, and pain-free walking time, There was no significant difference in these parameters between the 2 groups. Before BM-MNC implantation, LBF responses to ACh were similar in the sarpogrelate group and control group. Twelve weeks of BM-MNC implantation enhanced LBF responses to ACh in the sarpogrelate and control groups. After 12 weeks of BM-MNC implantation, LBF response to ACh was significantly greater in the sarpogrelate group than in the control group. BM-MNC implantation did not alter the LBF responses to sodium nitroprusside in either group. Conclusions: These findings suggest that BM-MNC implantation improved not only limb ischemic symptoms but also endothelium-dependent vasodilation in patients with CLI. A combination of BM-MNC implantation and sarpogrelate had a more beneficial effect on vascular function in these patients.

Background: The purpose of this study was to determine the effect of a combination of bone marrow mononuclear cell (BM-MNC) implantation and sarpogrelate, a selective 5-HT2A antagonist, on endothelial function in patients with critical limb ischemia (CLI). Methods: We evaluated the leg blood flow (LBF) responses to acetylcholine (ACh) and sodium nitroprusside before and after BM-MNC implantation in 16 patients with CLI. We divided patients with CLI into 2 groups: those cotreated with sarpogrelate orally for 12 weeks (sarpogrelate group, n = 8) and those who remained on conventional therapy (control group, n = 8). LBF was measured by strain gauge plethysmography. Results: BM-MNC implantation improved ankle brachial pressure index, transcutaneous oxygen pressure, and pain-free walking time, There was no significant difference in these parameters between the 2 groups. Before BM-MNC implantation, LBF responses to ACh were similar in the sarpogrelate group and control group. Twelve weeks of BM-MNC implantation enhanced LBF responses to ACh in the sarpogrelate and control groups. After 12 weeks of BM-MNC implantation, LBF response to ACh was significantly greater in the sarpogrelate group than in the control group. BM-MNC implantation did not alter the LBF responses to sodium nitroprusside in either group. Conclusions: These findings suggest that BM-MNC implantation improved not only limb ischemic symptoms but also endothelium-dependent vasodilation in patients with CLI. A combination of BM-MNC implantation and sarpogrelate had a more beneficial effect on vascular function in these patients.

Background: The purpose of this study was to determine the effect of a combination of bone marrow mononuclear cell (BM-MNC) implantation and sarpogrelate, a selective 5-HT2A antagonist, on endothelial function in patients with critical limb ischemia (CLI). Methods: We evaluated the leg blood flow (LBF) responses to acetylcholine (ACh) and sodium nitroprusside before and after BM-MNC implantation in 16 patients with CLI. We divided patients with CLI into 2 groups: those cotreated with sarpogrelate orally for 12 weeks (sarpogrelate group, n = 8) and those who remained on conventional therapy (control group, n = 8). LBF was measured by strain gauge plethysmography. Results: BM-MNC implantation improved ankle brachial pressure index, transcutaneous oxygen pressure, and pain-free walking time, There was no significant difference in these parameters between the 2 groups. Before BM-MNC implantation, LBF responses to ACh were similar in the sarpogrelate group and control group. Twelve weeks of BM-MNC implantation enhanced LBF responses to ACh in the sarpogrelate and control groups. After 12 weeks of BM-MNC implantation, LBF response to ACh was significantly greater in the sarpogrelate group than in the control group. BM-MNC implantation did not alter the LBF responses to sodium nitroprusside in either group. Conclusions: These findings suggest that BM-MNC implantation improved not only limb ischemic symptoms but also endothelium-dependent vasodilation in patients with CLI. A combination of BM-MNC implantation and sarpogrelate had a more beneficial effect on vascular function in these patients.

Umbilical cord-derived multipotent mesenchymal stromal cells (UC-MMSCs) are considered as a strong candidate for cell therapy of lower limb ischemia. Sustained calf muscle ischemia with aseptic inflammatory response was induced in Sprague-Dawley rats by excision of femoral and popliteal arteries. UC-MSCs were injected into the calf muscle on day 7 after surgery. The animals were sacrificed on days 3, 10, and 30 after transplantation. Animals responded to the transplantation by temporary improvement in their locomotor function as assessed by the rota-rod performance test. Measured size of the lesions was significantly smaller in the experimental group than in the control group at all time points throughout the observation. The transplantation stimulated angiogenic processes on day 10 after transplantation. Living transplanted cells were traced for up to 30 days after transplantation, during which time they migrated to the damaged area to be partially eliminated by host macrophages; none of them differentiated into endothelial or smooth muscle cells of blood vessels. Additionally, the transplantation led to the predominance of activated pro-angiogenic and anti-inflammatory M2 macrophages by inhibiting the CD68+ macrophage infiltration and stimulating the CD206+ macrophage activation at the site of injury. A single intramuscular injection of allogeneic umbilical cord-derived mesenchymal stromal cells reproducibly facilitated recovery of structural and functional properties of surgically ischemized calf muscles in a rat. No differentiation of the transplanted cells in vivo was observed. The transplantation negatively regulated inflammation and enhanced tissue repair chiefly by modulating local patterns of macrophage activation. © 2018 Human Stem Cell Institute. All rights reserved.

Background: The purpose of this study was to determine the effect of a combination of bone marrow mononuclear cell (BM-MNC) implantation and sarpogrelate, a selective 5-HT2A antagonist, on endothelial function in patients with critical limb ischemia (CLI). Methods: We evaluated the leg blood flow (LBF) responses to acetylcholine (ACh) and sodium nitroprusside before and after BM-MNC implantation in 16 patients with CLI. We divided patients with CLI into 2 groups: those cotreated with sarpogrelate orally for 12 weeks (sarpogrelate group, n = 8) and those who remained on conventional therapy (control group, n = 8). LBF was measured by strain gauge plethysmography. Results: BM-MNC implantation improved ankle brachial pressure index, transcutaneous oxygen pressure, and pain-free walking time, There was no significant difference in these parameters between the 2 groups. Before BM-MNC implantation, LBF responses to ACh were similar in the sarpogrelate group and control group. Twelve weeks of BM-MNC implantation enhanced LBF responses to ACh in the sarpogrelate and control groups. After 12 weeks of BM-MNC implantation, LBF response to ACh was significantly greater in the sarpogrelate group than in the control group. BM-MNC implantation did not alter the LBF responses to sodium nitroprusside in either group. Conclusions: These findings suggest that BM-MNC implantation improved not only limb ischemic symptoms but also endothelium-dependent vasodilation in patients with CLI. A combination of BM-MNC implantation and sarpogrelate had a more beneficial effect on vascular function in these patients.